SECTION 2.5 CLINICAL OVERVIEW

EMTRICITABINE/RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE FIXED-DOSE COMBINATION

Gilead Sciences International Limited

18 August 2010

CONFIDENTIAL AND PROPRIETARY INFORMATION

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.5 Clinical Overview Final

TABLE OF CONTENTS

SECTION 2.5 CLINICAL OVERVIEW ...... 1 TABLE OF CONTENTS ...... 2 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ...... 7 2.5. CLINICAL OVERVIEW...... 12 2.5.1. Product Development Rationale ...... 12 2.5.1.1. Introduction and Background...... 12 2.5.1.2. HIV-1 Infection and Current Approaches to Treatment...... 14 2.5.1.3. Rationale for Development of the FTC/RPV/TDF FDC Tablet...... 15 2.5.1.4. Overview of Clinical Development Program...... 16 2.5.2. Overview of Biopharmaceutics...... 18 2.5.2.1. Details of Formulation ...... 18 2.5.2.2. Results of Bioequivalence Study GS-US-264-0103...... 20 2.5.2.3. Effect of Food ...... 22 2.5.2.3.1. Emtriva ...... 22 2.5.2.3.2. Rilpivirine...... 23 2.5.2.3.3. Viread ...... 24 2.5.2.3.4. Truvada FDC tablet ...... 24 2.5.2.3.5. FTC/RPV/TDF FDC tablet...... 24 2.5.3. Overview of Clinical Pharmacology...... 25 2.5.3.1. Pharmacology/Virology ...... 25 2.5.3.1.1. Mechanism of Action ...... 25 2.5.3.2. Clinical Pharmacodynamics...... 27 2.5.3.3. Clinical Pharmacokinetics...... 28 2.5.3.3.1. Pharmacokinetic Profiles ...... 28 2.5.3.3.2. Demographic Effects ...... 32 2.5.3.3.3. Renal Impairment ...... 35 2.5.3.3.4. Hepatic Impairment ...... 36 2.5.3.4. Potential for Drug Interactions...... 37 2.5.3.4.1. Emtricitabine and Tenofovir DF...... 37 2.5.3.4.2. Rilpivirine...... 38 2.5.3.4.3. Clinically Important Drug Interactions...... 42 2.5.3.5. Summary of Clinical Pharmacology ...... 46 2.5.4. Overview of Efficacy...... 47 2.5.4.1. Efficacy of Emtricitabine ...... 48 2.5.4.2. Efficacy of Rilpivirine...... 48 2.5.4.3. Efficacy of Tenofovir DF...... 48 2.5.4.4. Efficacy of the Truvada FDC Tablet...... 48 2.5.4.4.1. Efficacy in Study GS-01-934...... 52 2.5.4.4.2. Efficacy in Study GS-99-903...... 55 2.5.4.4.3. Efficacy in Study M02-418...... 57 2.5.4.5. Efficacy of the FTC/RPV/TDF FDC Tablet ...... 58 2.5.4.5.1. Subanalysis of the Virologic Outcomes using Pooled Data for Subjects Receiving RPV or EFV in Combination with FTC/TDF ...... 62 2.5.4.5.2. Baseline Genotype and Phenotype Characteristics...... 63 2.5.4.5.3. Efficacy in Studies C209 and C215...... 65 2.5.4.6. Summary of Clinical Resistance Findings ...... 77 2.5.4.6.2. Clinical Resistance Findings for C209 and C215 ...... 81 2.5.4.7. Conclusions on Resistance Determination ...... 91

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2.5.4.7.1. Conclusions on Resistance Determination for Emtricitabine ...... 91 2.5.4.7.2. Conclusions on Resistance Determination for Rilpivirine...... 92 2.5.4.7.3. Conclusions on Resistance Determination for Tenofovir DF ...... 93 2.5.4.7.4. Conclusions on Resistance Determination for the FTC/RPV/TDF FDC Tablet...... 93 2.5.4.8. Efficacy Against HBV in HIV/HBV Coinfected Subjects...... 93 2.5.4.9. Efficacy Discussion and Conclusions ...... 94 2.5.5. Overview of Safety ...... 97 2.5.5.1. Introduction...... 97 2.5.5.2. Summary of Clinical Trial Safety Experience...... 99 2.5.5.2.1. Safety in Study GS-01-934...... 99 2.5.5.2.2. Safety in Study GS-99-903...... 101 2.5.5.2.3. Safety in Trials C209 and C215...... 103 2.5.5.2.4. AE Data to Support the FTC/RPV/TDF FDC Tablet ...... 121 2.5.5.3. Renal Adverse Events ...... 125 2.5.5.3.1. Renal Safety in Clinical Studies ...... 125 2.5.5.3.2. Experience in Postmarketing Surveillance ...... 128 2.5.5.3.3. Mechanisms of Renal Toxicity...... 129 2.5.5.3.4. Risk Factors ...... 130 2.5.5.3.5. Conclusions on Renal Safety ...... 131 2.5.5.4. Effects on the Skin ...... 132 2.5.5.4.1. Emtricitabine ...... 132 2.5.5.4.2. Rilpivirine...... 132 2.5.5.4.3. Tenofovir DF ...... 134 2.5.5.4.4. FTC/RPV/TDF FDC Tablet...... 134 2.5.5.5. Effects on the Bone ...... 134 2.5.5.5.1. Emtricitabine ...... 134 2.5.5.5.2. Rilpivirine...... 134 2.5.5.5.3. Tenofovir DF ...... 134 2.5.5.5.4. FTC/RPV/TDF FDC Tablet...... 136 2.5.5.6. Mitochondrial Toxicity and Metabolic Effects ...... 136 2.5.5.6.1. Emtricitabine ...... 137 2.5.5.6.2. Rilpivirine...... 137 2.5.5.6.3. Tenofovir DF ...... 138 2.5.5.6.4. FTC/RPV/TDF FDC Tablet...... 140 2.5.5.7. Neurologic Events...... 140 2.5.5.7.1. Emtricitabine ...... 140 2.5.5.7.2. Rilpivirine...... 140 2.5.5.7.3. Tenofovir DF ...... 142 2.5.5.7.4. FTC/RPV/TDF FDC Tablet...... 143 2.5.5.8. Psychiatric Events ...... 143 2.5.5.8.1. Emtricitabine ...... 143 2.5.5.8.2. Rilpivirine...... 143 2.5.5.8.3. Tenofovir DF ...... 144 2.5.5.8.4. FTC/RPV/TDF FDC Tablet...... 145 2.5.5.9. Hepatic Events ...... 145 2.5.5.9.1. Emtricitabine ...... 145 2.5.5.9.2. Rilpivirine...... 145 2.5.5.9.3. Tenofovir DF ...... 146 2.5.5.9.4. FTC/RPV/TDF FDC Tablet...... 146 2.5.5.9.5. Hepatitis B and/or C Coinfection...... 147 2.5.5.10. Events of Interest Potentially Related to QT Interval Prolongation...... 149

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2.5.5.10.1. Emtricitabine ...... 149 2.5.5.10.2. Rilpivirine...... 149 2.5.5.10.3. Tenofovir DF ...... 152 2.5.5.10.4. FTC/RPV/TDF FDC Tablet...... 152 2.5.5.11. Endocrine Events ...... 152 2.5.5.11.1. Emtricitabine ...... 152 2.5.5.11.2. Rilpivirine...... 152 2.5.5.11.3. Tenofovir DF ...... 153 2.5.5.11.4. FTC/RPV/TDF FDC Tablet...... 153 2.5.5.12. Safety in Special Populations...... 153 2.5.5.12.1. Safety in Pregnancy ...... 153 2.5.5.12.2. Safety in Elderly Patients...... 154 2.5.5.12.3. Safety in Children...... 155 2.5.5.12.4. Safety in Renal Impairment ...... 155 2.5.5.12.5. Safety in Hepatic Impairment and in Subjects with HIV and HBV and/or HCV Coinfection...... 156 2.5.5.13. Conclusions on Safety Experience ...... 157 2.5.6. Benefits and Risks Conclusions ...... 162 2.5.7. References...... 170 2.5.8. List of Gilead Nonclinical and Clinical Reports ...... 184

LIST OF IN-TEXT TABLES

Table 1. GS-US-264-0103: Statistical Comparisons of FTC, TFV, and RPV Pharmacokinetic Parameters for Test (Formulation 3) Versus Reference Treatment ...... 22 Table 2. Steady-State Pharmacokinetics of TMC278 After Administration of TMC278 25 mg Once Daily in Healthy Subjects (Trial C130 and C152) and in HIV-1 Infected Subjects (Trials C209 and C215, Pharmacokinetic Substudies) ...... 32 Table 3. Coadministration Recommendations Based on Drug-Drug Interaction Trials or Predicted Interaction (Rilpivirine)...... 44 Table 4. Principal Clinical Studies that Support Use of the Truvada Tablet – Design and Population Characteristics...... 50 Table 5. GS-01-934: Treatment Outcomes at Week 48 (TLOVR Analysis)...... 52 Table 6. GS-01-934: Treatment Outcomes at Week 144 (TLOVR Analysis, Week 144 Efficacy Analysis Set)...... 53 Table 7. GS-99-903: Summary of Response Rates of HIV-1 RNA 400 and 50 Copies/mL (ITT Population, Missing/Switch = Failure) ...... 55 Table 8. M02-418: Proportion of Subjects with HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96 ...... 58 Table 9. Principal Clinical Studies that Support Use of the FTC/RPV/TDF FDC Tablet – Design and Population Characteristics...... 60 Table 10. FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215: Virologic and Immunological Outcomes of Randomized Treatment at Week 48 (TLOVR Analysis)...... 62 Table 11. Rilpivirine Studies C209 and C215 (Pooled Data for Subjects Receiving RPV or EFV in Combination with FTC/TDF): Virologic Outcome of Randomized Treatment at Week 48 (Snapshot Analysis) ...... 63 Table 12. Phase 3 Trials C209, C215, and the Pooled Phase 3 Trials: Virologic Outcome (< 50 HIV-1 RNA Copies/mL, Snapshot) at Week 48 ...... 68 Table 13. Rilpivirine Studies C209 and C215 (Pooled Data): Proportion of Virologic Responders (< 50 HIV-1 RNA Copies/mL, TLOVR) at Week 48 by Subgroups ...... 72

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Table 14. GS-01-934: Cumulative Development of Resistance by Week 144 ...... 80 Table 15. Rilpivirine Studies C209 and C215 (Pooled Data): Virologic Failures - Number of Treatment-Emergent Reverse Transcriptase Mutations at Failure ...... 84 Table 16. Rilpivirine Studies C209 and C215 (Pooled Data): Virologic Failures: Individual Treatment-Emergent Resistance-Associated Mutations by Type at Failure in at Least 2 Subjects from the Pooled TMC278 or Control Group ...... 85 Table 17. FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215: Virologic Failures: Number of Treatment-Emergent Mutations - Failure ...... 87 Table 18. FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215: Virologic Failures: Emergent Extended NNRTI Mutations, IAS USA NNRTI Mutations and IAS-USA N(t)RTI Mutations - Failure ...... 88 Table 19. FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215: Virologic Failures: Phenotypic Resistance – Failure ...... 91 Table 20. Estimated Cumulative Postmarketing Exposure to the Individual Marketed Products ...... 98 Table 21. GS-01-934: Treatment-Emergent Adverse Events Reported in at Least 10% of Subjects in Either Treatment Group (Safety Analysis Set)...... 100 Table 22. Rilpivirine Studies C209 and C215: Summary of Adverse Events (Phase 3 Week 48 Analysis)...... 105 Table 23. Rilpivirine Studies C209 and C215: Lipid Values Reported in Subjects Receiving RPV or EFV in Combination with FTC/TDF ...... 117 Table 24. Rilpivirine Studies C209 and C215: Treatment-Emergent Abnormal Cortisol Response to ACTH Stimulation (Worst Case) (Phase 3 Week 48 Pooled Analysis) ...... 119 Table 25. Tabulated Summary of Adverse Reactions Associated with the Individual Components of the FTC/RPV/TDF FDC Tablet Based on Clinical Study and Postmarketing Experience ...... 122 Table 26. Summary of Gilead Clinical Studies that Assessed Renal Safety in HIV-1 Infected Subjects Receiving TDF ...... 126 Table 27. Rilpivirine Trials C209 and C215: Treatment-Related Rash (Grouped Term) Summary (Phase 3 Week 48 Pooled Analysis) ...... 133 Table 28. Rilpivirine Trials C209 and C215: Neurologic Events of Interest Summary (Phase 3 Week 48 Pooled Analysis) ...... 141 Table 29. Rilpivirine Trials C209 and C215: Neurologic Events of Interest in at Least 1.0% of Subjects in the TMC278 or Control Group, Regardless of Severity and Causality (Phase 3 Week 48 Pooled Analysis) ...... 142 Table 30. Rilpivirine Studies C209 and C215: Psychiatric Events of Interest in at Least 1.0% of Subjects in the TMC278 or Control Group, Regardless of Severity and Causality (Phase 3 Week 48 Pooled Analysis) ...... 144 Table 31. Gilead Nonclinical Reports ...... 185 Table 32. Gilead Clinical Reports ...... 221

LIST OF IN-TEXT FIGURES

Figure 1. GS-01-934: Mean (95% CI) Change from Baseline in HIV-1 RNA by Study Visit (AT Analysis Set)...... 54 Figure 2. GS-01-934: Mean (95% CI) Change From Baseline in CD4 Cell Count (AT Analysis Set)...... 54 Figure 3. GS-99-903: Mean (95% CI) Change from Baseline in Plasma HIV-1 RNA Levels (ITT Analysis Set)...... 56

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Figure 4. GS-99-903: Mean (95% CI) Change from Baseline in CD4 Cell Count (ITT Analysis Set)...... 56 Figure 5. Phase 3 Trials C209, C215, and the Pooled Phase 3 Trials: Proportion of Virologic Responders (< 50 HIV-1 RNA copies/mL, TLOVR) at Week 48 ...... 66 Figure 6. Rilpivirine Studies C209 and C215: Statistical Comparisons of Adverse Events Regardless of Relationship to Investigational Medication - Grouped terms (Phase 3 Week 48 Pooled Analysis)...... 107 Figure 7. Rilpivirine Studies C209 and C215: Statistical Comparisons of Adverse Events Regardless of Relationship to Investigational Medication – Most Frequent (> 10% overall) Individual Preferred Terms (Phase 3 Week 48 Pooled Analysis) ...... 108 Figure 8. Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from Baseline in Hemoglobin by Background Regimen: FTC/TDF (Top); AZT/3TC (Middle); ABC/3TC (Bottom) (Phase 3 Week 48 Pooled Analysis) ...... 111 Figure 9. Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from Baseline in Creatinine by Background Regimen: FTC/TDF (Top); AZT/3TC (Middle); ABC/3TC (Bottom) (Phase 3 Week 48 Pooled Analysis of C209 and C215) ...... 113 Figure 10. Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from Baseline in Total Cholesterol, HDL Cholesterol, Total Cholesterol/HDL Cholesterol Ratio, LDL Cholesterol and Triglycerides Over Time (Fasted) (Phase 3 Week 48 Pooled Analysis) ...... 115 Figure 11. Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from Baseline in QTcF interval Over Time: Overall (top) and Subanalysis by Gender (Phase 3 Week 48 Pooled Analysis)...... 150

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS

3TC lamivudine ABC abacavir ACTG AIDS Clinical Trials Group ACTH adrenocorticotropic hormone ADR adverse drug reactions AE adverse event AIDS acquired immunodeficiency syndrome ALT alanine aminotransferase ANCOVA analysis of covariance ART antiretroviral therapy ARV antiretroviral AST aspartate aminotransferase

AUC24h area under the plasma/serum concentration versus time curve from time 0 to 24 hours after dosing

AUCinf area under the concentration versus time curve extrapolated to infinite time, calculated as AUC0last + (Clast/Oz)

AUClast area under the concentration versus time curve from time zero to the last quantifiable concentration

AUCtau area under the concentration versus time curve over the dosing interval AVMR antiviral microbiology report AZT zidovudine; ZDV BCO biological cut-off BID twice daily BMD bone mineral density Caco-2 colon carcinoma-derived CBV Combivir (lamivudine/zidovudine) CCO clinical cut-off CDC Center for Disease Control and Prevention CHMP Committee for Medicinal Products for Human Use CI confidence interval

CLcr creatinine clearance CL/F apparent clearance

Cmax maximum observed concentration of drug in plasma

Cmin minimum observed concentration of drug in plasma (trough level) CPT Child-Pugh-Turcotte (classification system for hepatic impairment) CRR or CSR clinical research report or study report CV coefficient of variation CYP cytochrome P450 d4T stavudine

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) dATP deoxyadenosine triphosphate dCTP deoxycytidine triphosphate ddI didanosine DHEAS dehydroepiandrosterone sulphate DHHS Department of Human Health and Services DNA deoxyribonucleic acid DLV delavirdine DRV darunavir EACS European AIDS Clinical Society EC enteric coated

EC50 median 50% effective concentration ECG electrocardiogram EFV efavirenz (Sustiva“) eGFR estimated glomerular filtration rate eGFRcreat estimated glomerular filtration rate for creatinine as calculated by modification of diet in renal disease (MDRD) formula eGFRcyst estimated glomerular filtration rate for cystatin C EMA, EMEA European Medicines Agency EOI event of interest ESRD end-stage renal disease ETR etravirine EU European Union FC fold change FDA (US) Food and Drug Administration FDC fixed-dose combination FTC emtricitabine (Emtriva“) FTC/RPV/TDF emtricitabine/rilpivirine/tenofovir disoproxil fumarate (fixed-dose combination product) FTC/TDF emtricitabine/tenofovir disoproxil fumarate (Truvada“; fixed-dose combination product) FTC-TP emtricitabine triphosphate GAM generalized additive models GFR glomerular filtration rate GLS geometric least squares

H2 histamine-2 HAART highly active antiretroviral therapy HBV hepatitis B virus HCV hepatitis C virus

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)

HDL high-density lipoprotein HIV-1 (-2) human immunodeficiency virus type 1 (-2) hOAT (1, 3) human organic anion transporter (type 1, type 3) HOMA-IR homeostasis model assessment insulin resistance HPLC high-performance liquid chromatography IAS-USA International AIDS Society-United States of America ICH International Conference on Harmonization

IC50 50% inhibitory concentration IDV indinavir ITT intent-to-treat Ki inhibition constant LDL low-density lipoprotein LOCF last observation carried forward LPV lopinavir LPV/r lopinavir/ritonavir M = F missing = failure MAA (EU) Marketing Authorization Application MCS mental component summary MDCK Madin-Darby canine kidney MDRD modification of diet in renal disease MITT modified intent-to-treat MRP (2,4) multidrug resistance protein (type 2, type 4) mtDNA mitochondrial DNA NC = F noncompleter = failure NNRTI nonnucleoside reverse transcriptase inhibitor non-VF non-virologic failure NRTI nucleoside reverse transcriptase inhibitor NtRTI, N(t)RTI nucleotide reverse transcriptase inhibitor NVP nevirapine PBMC peripheral blood mononuclear cell PCS Physical Component Summary P-gp P-glycoprotein PI protease inhibitor PK pharmacokinetic PMPA 9-R-2-(phosphonomethoxy)propyl]adenine PP per protocol PNP purine nucleoside phosphorylase

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)

PSUR periodic safety update report QT interval representing the time for both ventricular depolarization and repolarization to occur QTc QT interval corrected for heart rate QTcF QT interval corrected by Fridericia’s formula /r ritonavir boosted RAM resistance-associated mutation RNA ribonucleic acid RPTEC renal proximal tubule cell RPV rilpivirine (27.5 mg rilpivirine hydrochloride is equivalent to 25 mg RPV) RT reverse transcriptase RTV ritonavir (Norvir“) rtv coadministered low-dose ritonavir SAE serious adverse event SAWP Scientific Advice Working Party SD standard deviation SF-36v2“ Short Form-36 version 2 SmPC Summary of Product Characteristics SNPs single-nucleotide polymorphisms SOC system organ class

T½, t1/2, term terminal elimination half-life TAM thymidine analogue-associated mutation Tenofovir DF, TDF tenofovir disoproxil fumarate (Viread“), (300 mg TDF is equivalent to 245 mg tenofovir disoproxil or 136 mg of tenofovir) TFV tenofovir TLOVR time to loss of virologic response TMC Tibotec Medicinal Compound tmax time (observed time point) of Cmax TQT thorough QT US, USA United States VF virologic failure ZDV zidovudine; AZT

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Rilpivirine Trial Naming Conventions

Throughout the development of TMC278, several different naming conventions were used for trials. The first part of the trial identifier was one of the following, depending on when the trial was conducted: x R278474-CDE- (used for the earlier trials) x R278474- x TMC278- x TMC278-TiDP6- (used for the most recent trials)

All trials were given a suffix of a unique 3-digit number preceded by the letter C (for “clinical”), e.g., C215 or C209. In this document, trials are referred to by only the final 4 characters of the trial identifier (e.g., C209, C215).

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2.5. CLINICAL OVERVIEW

2.5.1. Product Development Rationale

2.5.1.1. Introduction and Background

This dossier is being submitted in support of a marketing authorization application (MAA) for a fixed-dose combination (FDC) film-coated tablet that contains the active substances emtricitabine (FTC), rilpivirine (RPV, which is also referred to as TMC278 throughout this document), and tenofovir disoproxil fumarate (tenofovir DF, TDF). This FDC tablet is referred to as emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) throughout this document. Each FTC/RPV/TDF FDC tablet contains FTC, RPV, and TDF at the same dosages as recommended for the individual components in adults, i.e., 200 mg of FTC, 25 mg RPV (27.5 mg rilpivirine hydrochloride is equivalent to 25 mg RPV), and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil or 136 mg tenofovir [TFV]). Individual presentations of FTC (Emtriva“) and TDF (Viread“) are currently approved in the United States (US), the European Community, and other countries worldwide for use in adults. It is proposed that FTC/RPV/TDF FDC tablets be indicated for the treatment of HIV-1 infection in adults and taken orally once daily with a meal.

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and a synthetic analog of the naturally occurring pyrimidine nucleoside, 2ƍ-deoxycytidine. Intracellularly, FTC is phosphorylated by cellular enzymes to form emtricitabine triphosphate (FTC-TP), the active metabolite. Emtricitabine is the active ingredient in Emtriva hard capsules and oral solution. The Committee for Medicinal Products for Human Use (CHMP) approved Emtriva for the treatment of human immunodeficiency virus type 1 (HIV-1) infection on 24 October 2003 (EU/1/03/261/001-003).

Rilpivirine, which is developed by Tibotec BVBA, is an investigational agent of the nonnucleoside reverse transcriptase inhibitor (NNRTI) class that shows in vitro activity against wild-type HIV-1 and against HIV-1 strains harboring different mutations that result in resistance to the first-generation NNRTIs. Tibotec BVBA will submit their MAA in accordance with Article 8.3 of Directive 2001/83/EC.

Tenofovir DF, the oral prodrug of TFV, is a nucleotide reverse transcriptase inhibitor (NtRTI). After absorption, TDF is rapidly converted to TFV, which is metabolized intracellularly to the active metabolite, tenofovir diphosphate. Tenofovir disoproxil (as fumarate) is the active ingredient in Viread 300-mg film-coated tablets. The CHMP approved Viread for the treatment of HIV-1 infection on 05 February 2002, (EU/1/01/200/001-2).

Truvada“ film-coated tablets are an FDC containing 200 mg of FTC and 300 mg of TDF. The CHMP approved Truvada for the treatment of HIV-1 infection on 21 February 2005 (EU/1/04/305/001).

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Atripla“ film-coated tablets (EFV/FTC/TDF) are an FDC containing 600 mg of efavirenz (EFV), which is an NNRTI, 200 mg of FTC, and 300 mg of TDF. The CHMP approved Atripla for the treatment of HIV-1 infection on 13 December 2007 (EU/1/07/430/001-2).

In some regions, Emtriva and Viread are approved for use in adolescents; Emtriva, which is also available as an oral solution formulation, may be administered to children as young as 4 months of age.

A comprehensive program of clinical studies with FTC, TDF, and Truvada has previously been submitted in the original MAAs for Emtriva 200-mg hard capsules and Emtriva 10-mg/mL oral solution; Viread 300-mg film-coated tablets; and Truvada film-coated tablets. In addition, a variety of supplementary information from clinical studies with FTC, TDF, and Truvada has been submitted postauthorization, either via variations to the original marketing authorization or in accordance with specific obligations, follow-up measures, and periodic safety update reports for the above-mentioned products, as appropriate.

In accordance with the advice received from the European Medicines Agency (EMA) at the meeting held on 20 (see Module 1.2.5.14, meeting minutes) and in accordance with the Committee for Proprietary Medicinal Products Guideline on Fixed Combination Medicinal Products (CPMP/EWP/240/95 Rev. 1, 21 February 2008), the present application for a marketing authorization is being submitted in accordance with Article 8.3 of Directive 2001/83/EEC, as amended. The MAAs for RPV as a single agent tablet and for the FTC/RPV/TDF FDC tablet are being submitted in parallel by Tibotec BVBA and Gilead Sciences, respectively.

As the RPV component is a new chemical entity, this FDC MAA dossier contains full data on this new component while providing the key data on the Truvada (i.e., FTC, TDF, and FTC/TDF) components that support the efficacy and safety claims in the FTC/RPV/TDF FDC prescribing information. All Truvada studies considered to support the FDC are included to ensure that this is a “stand-alone dossier.” This is in agreement with the feedback received at the meeting with the EMA on 20 and with the meeting with on 20 (see Module 1.2.5.14, final minutes). To assist the reviewer, a listing of all the FTC, TDF, FTC/TDF, and EFV/FTC/TDF nonclinical and clinical reports is provided in Section 2.5.8. Clinical data for FTC, RPV, TDF, Truvada, and Atripla are provided in Module 2.7; clinical study reports (CSRs), periodic safety update reports (PSURs) and other relevant data for these products are provided in Module 5.

On 20 , Tibotec BVBA sought scientific advice for RPV and FDC tablets containing RPV (EMEA/CHMP/SAWP/670243/2009 corrigendum, see Module 1.2.5.14, Scientific Advice). The Scientific Advice Working Party (SAWP) confirmed that the demonstration of bioequivalence would be mandatory and should take into account the influence of food, but an additional specific clinical study to support the FTC/RPV/TDF FDC would not be needed, given the available clinical data on the combined use of the FDC components. The pharmacokinetic, efficacy, and safety data will characterize the benefits and risks of the component products in HIV-1 infected adult subjects; however, apart from bioequivalence studies conducted in the fed state, no clinical studies have been conducted

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with the FTC/RPV/TDF FDC. The 2 registrational trials for RPV, TMC278-TiDP6-C209 (C209, also known as ECHO) and TMC278-TiDP6-C215 (C215, also known as THRIVE), included Truvada as backbone antiretroviral therapy for approximately 80% of subjects in the pooled analysis.

This overview presents the clinical rationale for the development of the FTC/RPV/TDF FDC and reviews the information that is relevant to the assessment of the FTC/RPV/TDF FDC. This information includes the bioequivalence data and the clinical efficacy and safety data that support the positive benefit:risk profile for the use of the FTC/RPV/TDF FDC tablet for treatment of HIV-1 infection in adults. Justification is provided for specific recommendations for the use of the FTC/RPV/TDF tablet, as described in the proposed FTC/RPV/TDF prescribing information.

2.5.1.2. HIV-1 Infection and Current Approaches to Treatment

HIV-1 infection is a life-threatening and serious disease that is of major public health interest worldwide. There are now approximately 33 million people worldwide living with HIV-1 {12896}. The infection, if left untreated or suboptimally treated, is characterized by deterioration in immune function, the subsequent occurrence of opportunistic infections and malignancies, and death. Therapeutic strategies for the treatment of HIV-1 disease have been significantly advanced by the availability of highly active antiretroviral therapy (HAART), and the introduction of HAART was associated with a dramatic fall in acquired immunodeficiency syndrome (AIDS)-related mortality and morbidity in the US and Europe {2537}, {5125}, {8284}.

The goal of antiretroviral therapy for HIV-1 infection is to delay disease progression and increase the duration of survival by achieving maximal and prolonged suppression of HIV-1 replication. The standard of care for treatment involves the use of a combination of antiretroviral agents, typically a combination of at least 3 drugs, including a NNRTI or a protease inhibitor (PI) and 2 agents from the NRTI/NtRTI class.

NNRTIs play an important role and are widely used in the treatment of HIV-1 infection, most commonly in first line therapy. The currently approved NNRTIs in the US and/or Europe for use in treatment-naive adult patients are nevirapine (NVP; Viramune“) {15969}, delavirdine (DLV; Rescriptor“) {15967}, and EFV {15807}. These NNRTIs can be associated with safety and tolerability concerns (mainly hepatotoxicity, central nervous system symptoms, rash, and/or the risk of teratogenicity {15207}. Currently one novel NNRTI, etravirine (ETR, Intelence“), developed by Tibotec BVBA, is approved for use only in HIV-1 infected, treatment-experienced adult patients.

In recent years, new antiretroviral therapies have been approved with improved safety profiles and convenient dosing regimens. However, from results of controlled clinical trials, it is apparent that not all regimens are equivalent in terms of potency or toxicity. International treatment guidelines list FTC and TDF as a preferred NRTI/NtRTI backbone in an antiretroviral regimen for initial therapy {15207}, {12716}, {14065}.

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Although HAART has dramatically improved the prognosis of patients infected with HIV-1, eradication of the virus is not possible with therapies that are currently available. To achieve successful long-term treatment, maximizing viral suppression and prevention of drug resistance have become the primary goals. Adherence is known to be paramount in maintaining viral suppression, as missing doses can result in viral rebound and increased risk of resistance development. Among regimens of comparable efficacy, both physicians and HIV-1 infected patients receiving antiretroviral therapy rate total pill burden, dosing frequency, and safety concerns among the greatest obstacles to achieving adherence {4266}, {4256}.

Thus, there continues to be a need for new treatments that combine potent and sustained efficacy with acceptable tolerability and minimal long-term toxicity, as well as practical and convenient dosing.

2.5.1.3. Rationale for Development of the FTC/RPV/TDF FDC Tablet

The FTC/RPV/TDF fixed-dose combination tablet represents a new complete regimen for administration as a single tablet, to be taken once daily with a meal, for the treatment of adults with HIV-1 infection.

Current treatment guidelines recommend that initial therapy for HIV-1 infected subjects should consist of HAART: 2 NRTIs such as Truvada (FTC/TDF), plus either a NNRTI, usually EFV, or a ritonavir (RTV)-boosted protease inhibitor {12716}, {14065}, {15207}. While combination antiretroviral therapy has been largely successful in reducing the morbidity and mortality associated with HIV disease, a significant proportion of patients eventually experience loss of virologic, immunologic, or clinical benefit from their current regimens. Also, a significant proportion of patients experience side effects that can lead to poor/incomplete regimen adherence and missed doses that can result in loss of virologic, immunologic, or clinical benefit.

Incomplete adherence to antiretroviral regimens is a critical factor contributing to the development of viral resistance and treatment failure, and is thus a primary barrier to successful long-term treatment. Clinical studies have clearly demonstrated high levels of adherence and treatment satisfaction with simple, once-daily HAART regimens, resulting in persistent suppression of HIV viral load {7034}, {7035}, {7036}. Currently, Atripla represents the only simplified one tablet, once-daily product for the treatment of HIV-1.

Gilead Sciences has coformulated RPV, a potent NNRTI, with the standard-of-care NRTI backbone FTC/TDF into an FDC tablet to be administered once daily with a meal. This FDC represents a significant benefit to HIV-1 infected patients due to simplified dosing. The FDC of FTC/RPV/TDF has the potential to combine a next generation NNRTI, having an improved safety profile compared to EFV, with the standard-of-care, preferred-agent NRTIs FTC and TDF. This fixed-dose regimen would potentially be the second highly active, once daily FDC regimen, and will address limitations with the only other fixed-dose regimen (EFV/FTC/TDF). The combination tablet of FTC/RPV/TDF offers an attractive treatment option to a significant number of patients who wish to avoid using EFV due to

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concerns about tolerability (including central nervous system adverse reactions) and its potential for teratogenicity. Therefore, there remains a need for new combinations of potent agents exhibiting favorable tolerability, minimal short and long-term toxicity, and convenient dosing to maximize patient adherence.

2.5.1.4. Overview of Clinical Development Program

Emtricitabine and TDF underwent extensive development programs. The clinical trial programs of these agents were designed in accordance with regulatory guidance and clinical practice recommendations available at the time. The safety profiles of FTC, TDF, Truvada, and Atripla continue to be monitored through postmarketing surveillance and are reviewed in PSURs. Data from the clinical program on RPV are being submitted to the EMA both within this MAA and in the parallel submission for RPV.

The basis of the MAA for the FTC/RPV/TDF FDC tablet for the treatment of HIV-1 infection in adults is described in Section 2.5.1.1. The application is supported by data from Study GS-US-264-0103, which establishes bioequivalence between the FDC tablet and the concurrent administration of the individual agents. The data that support bioequivalence are described in Section 2.5.2.2. Additionally, data are reviewed from the comparative Phase 3 clinical studies C209 and C215 that provide efficacy and safety data most relevant to the use of the FTC/RPV/TDF FDC tablet. x Study C209 (also known as ECHO) is an ongoing double-blind, double-dummy active- controlled Phase 3 study to investigate the long-term efficacy, safety, and tolerability of TMC278 25 mg once daily compared with EFV 600 mg once daily (control), each in combination with a background regimen containing TDF and FTC. It is being conducted in USA, Canada, Europe, Australia, Asia, Africa, and Latin America. The key efficacy and safety data were obtained from the Week 48 primary analyses of this study. The analyses were performed when all subjects had completed at least 48 weeks of treatment or had discontinued earlier (i.e., up to the cut-off date of 01 February 2010) (see Module 5.3.5.1, TMC278-C209 clinical research report [CRR]).

x Study C215 (also known as THRIVE) is an ongoing double-blind, double-dummy active- controlled Phase 3 study to investigate the long-term efficacy, safety and tolerability of TMC278 25 mg once daily compared with EFV 600 mg once daily (control). Each of these nonnucleoside reverse transcriptase inhibitors (NNRTIs) was given in combination with a background regimen containing 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs). It is also being conducted in USA, Canada, Europe, Australia, Asia, Africa, and Latin America. The key efficacy and safety data were obtained from the Week 48 primary analyses of this study. The analyses were performed when all subjects had completed at least 48 weeks of treatment or had discontinued earlier (i.e., up to the cut-off date of 28 January 2010) (see Module 5.3.5.1, TMC278-C215 CRR).

The combination antiretroviral (ARV) treatment in the Phase 3 trials is in line with current treatment guidelines for HIV-1 infected, treatment-naive patients {15207}, {15965}. In C209, subjects received a fixed background regimen consisting of FTC/TDF. In C215, the

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background regimen contained 2 investigator-selected N(t)RTIs: either abacavir [ABC]/3TC, zidovudine [AZT]/3TC, or FTC/TDF. The background N(t)RTIs were to be fully active on screening resistance tests so as to maximize the potential for initial treatment response.

These 2 ongoing Phase 3 trials also form the basis of the TMC278 MAA.

Further comprehensive data from the 96-week efficacy and safety analysis of the dose-finding Phase 2b trial (TMC278-C204 [C204]) and long-term data up to 192 weeks of that same trial also support the FTC/RPV/TDF FDC MAA (see Modules 2.7.3 and 2.7.4 for Phase 2b data). In addition, a study with TMC278 was conducted in approximately 40 treatment-experienced HIV-1 infected subjects (Module 2.7.3.2.2.3.2 and Module 5.3.5.2, R27874-C202 CRR).

The use of the FTC/TDF tablet is primarily supported by efficacy and safety data from the following principal studies: x GS-01-934 is a completed, Phase 3, 288-week, open-label study, in which the once-daily regimen of FTC, TDF, and EFV (administered as the individual products [FTC + TDF + EFV] for the first 96 weeks and subsequently as the fixed-dose combination of FTC/TDF (Truvada) and EFV [FTC/TDF + EFV] through 144 weeks) is compared with the fixed-dose combination of Combivir (lamivudine/zidovudine, CBV) administered twice daily and efavirenz once daily (CBV + EFV). After completing 144 weeks of treatment, subjects from both treatment groups switched to a once-daily regimen of FTC, TDF, and EFV (as the Atripla tablet) in a 96-week extension period (144 weeks at sites in EU countries where Atripla was not launched) (see Module 5.3.5.1, GS-01-934 CSR). x GS-99-903 is an ongoing, Phase 3, 624-week study, in which the regimen of TDF + 3TC + EFV was compared with a regimen of stavudine (d4T) + 3TC + EFV in a double-blinded fashion for the first 144 weeks; from Week 144 to Week 480, patients at selected sites received open-label TDF + 3TC + EFV; from Weeks 480 to 624 the regimen of TDF + 3TC + EFV changed to open-label FTC/TDF (Truvada) + EFV. The experience with the TDF + 3TC + EFV regimen in this study is relevant to the efficacy of the Truvada tablet because (a) 3TC is a cytidine analog that is structurally closely related to FTC; (b) the resistance profiles of 3TC and FTC, characterized by M184V/I development, are similar; and (c) in Study FTC-303, FTC demonstrated equivalent antiviral efficacy and safety to 3TC when each was administered in a triple combination regimen to stable, treatment-experienced subjects (see Module 5.3.5.1, GS-01-903 CSR) . x M02-418 was a Phase 3, open-label, randomized, multicenter study in which antiretroviral-naive, HIV-1 infected subjects received FTC and TDF once daily in combination with a PI (800 mg/200 mg lopinavir/ritonavir (LPV/r) once daily or 400 mg/100 mg LPV/r twice daily) (see Module 5.3.5.1, M02-418 CSR).

No new supportive clinical efficacy and safety studies in subjects were considered warranted on the basis of available safety data and extensive clinical experience with the use of FTC

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and TDF, both alone and in combination, and with RPV for the treatment of HIV-1 infection in adults. The Scientific Advice Working Party confirmed that the demonstration of bioequivalence would be mandatory and should take into account the influence of food, but an additional specific clinical study to support the FTC/RPV/TDF FDC would not be needed, given the available clinical data on the combined use of the FDC components (see Module 1.2.5.14, Scientific Advice).

2.5.2. Overview of Biopharmaceutics

For detailed information on the biopharmaceutic data described in this section, refer to Module 2.7.1.

Information on bioavailability and the effect of food following oral administration of the individual agents is provided in the proposed FTC/RPV/TDF FDC tablet prescribing information.

This application for the FTC/RPV/TDF FDC tablet is supported by the bioequivalence study, GS-US-264-0103, which was conducted in healthy volunteers to evaluate the bioequivalence of 2 formulations of the FTC/RPV/TDF FDC tablet compared with a 200-mg capsule of FTC, a 25-mg tablet of RPV, and a 300-mg tablet of TDF taken concurrently under fed conditions (see Section 2.5.2.2).

In the bioequivalence study, the pharmacokinetic equivalence of the 2 treatment administrations (FTC/RPV/TDF FDC tablet [test] and concurrent administration of the individual dosage forms [reference]) was determined by measures of the rate and extent of absorption and systemic exposure (AUCinf, AUClast, and Cmax) for each agent. In accordance with the Committee for Proprietary Medicinal Products Note for Guidance on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1, 20 January 2010) and FDA Guidance for Industry (Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. March 2003), formulation bioequivalence was concluded if the 90% confidence interval (CI) for the ratio of geometric least squares (GLS) means (test/reference) fell within 80% to 125% for the 3 primary pharmacokinetic parameters (AUCinf, AUClast, and Cmax) for all analytes.

2.5.2.1. Details of Formulation

For the FTC/RPV/TDF FDC, a series of formulation experiments were performed to identify the appropriate composition that would allow the coformulation of the 3 active ingredients into a single tablet. Four formulations of the FDC tablets were tested in 2 Phase 1 studies. Formulations 1 and 2 FDC tablets were evaluated in Study GS-US-264-0101 (see Module 5.3.1.2, GS-US-264-0101 CSR) and Formulations 3 and 4 FDC tablets were evaluated in Study GS-US-264-0103 (see Module 5.3.1.2, GS-US-264-0103 CSR). In both studies, all treatments were administered in the fed state.

The initial approach involved developing a dry cogranulation of FTC, RPV, and TDF and compressing the blend into a single layer tablet (Formulation 1). Formulation 1 was manufactured by blending the 3 active ingredients together with excipients then granulating

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together in a dry granulation process consisting of roller compaction and milling. The granules were blended with extragranular excipients and compressed into tablet cores, which were then film-coated. This process allowed for high manufacturing throughput with an excellent yield.

The second approach consisted of 2 separate granulation processes in which RPV was wet granulated by a fluid bed granulation process and FTC and TDF were cogranulated in a high-shear wet granulation process. This formulation was designed to use the intragranular RPV formulation and fluid-bed granulation process from the 25-mg RPV Phase 3 tablet. The FTC/TDF powder blend was produced by the identical manufacturing process for Truvada tablets and was the identical intragranular composition of Truvada tablets. The 2 granulations were then blended together with lubricant, and compressed into a single layer tablet (Formulation 2).

Formulations 1 and 2 failed to demonstrate bioequivalence in Study GS-US-264-0101 for RPV, which had significantly higher area under the curve (AUC) and Cmax levels than those obtained with the 25-mg RPV Phase 3 clinical formulation (the proposed commercial formulation). These findings demonstrated the potential for physicochemical interactions between RPV and FTC/TDF compressed as a single layer tablet formulation. Emtricitabine and TFV AUC and Cmax levels from Formulations 1 and 2 were bioequivalent to the commercial formulations of Emtriva capsules and Viread tablets, respectively.

Bilayer formulations with one layer containing RPV and the other layer containing FTC and TDF were developed to minimize any potential physicochemical interactions between RPV with FTC and TDF. The bilayer formulation approach involved 2 separate granulation processes in which RPV was wet granulated by a fluid-bed granulation process, and FTC and TDF were cogranulated in a high-shear wet granulation process. The 2 granulations were physically separated by compressing the 2 blends into a bilayer tablet (Formulations 3 and 4). While Formulations 3 and 4 utilized the same manufacturing process, the formulation composition of the RPV granulation in each of the formulations differed in the relative proportion of the excipients used (see Module 2.7.1.4.2 for quantitative compositions).

Formulations 3 and 4 were evaluated in Study GS-US-264-0103. Results from this study demonstrated that exposure of FTC, RPV, and TDV, as assessed by AUCinf, AUClast, and Cmax, were bioequivalent between Formulation 3 (test) and the individual components (reference). Formulation 4 was found not to be bioequivalent with concurrent administration of the individual components (see Modules 2.7.1.3.5.2 and 3.2.P.2.2).

The proposed commercial formulation of the FTC/RPV/TDF FDC tablet, Formulation 3, is a purplish-pink, capsule-shaped, film-coated tablet, debossed with “GSI” on one side and plain-faced on the other side, and containing 200 mg of FTC, 25 mg of RPV, and 300 mg of TDF.

The FTC/RPV/TDF FDC tablet is a bilayer tablet with one layer containing RPV and the other layer containing FTC and TDF. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, povidone, polysorbate 20, magnesium stearate,

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pregelatinized starch, and microcrystalline cellulose. The quantitative composition of the FTC/RPV/TDF tablet is summarized in Module 2.7.1.4.1.

Dissolution Profile

The FTC/RPV/TDF FDC tablets are an immediate-release, solid oral-dosage form. The dissolution profiles for the proposed commercial tablet formulation (Lot BY1001B) showed that greater than 80% of FTC and TDF dissolved within 30 minutes, while greater than 80% of RPV dissolved in 60 minutes (see Module 2.7.1.1.2).

2.5.2.2. Results of Bioequivalence Study GS-US-264-0103

Study GS-US-264-0103 was an open-label, randomized, 3-way crossover, pharmacokinetic study in healthy subjects, designed to evaluate the bioequivalence of 2 distinct formulations of the FTC/RPV/TDF FDC tablets (Formulations 3 and 4) compared with FTC, RPV, and TDF taken concurrently under fed conditions. An earlier bioequivalence study, GS-US-264-0101, evaluated the bioequivalence of 2 FDC tablet formulations (Formulations 1 and 2). Although these formulations were not bioequivalent, the study report for GS-US-264-0101 is included in Module 5. These studies are described in detail in Modules 2.7.1.2.5.1 (GS-US-264-0103) and 2.7.1.2.5.2 (GS-US-264-0101).

The treatments used in Study GS-US-264-0103 were as follows:

FTC + RPV + TDF (reference): A single dose of FTC 1 u 200-mg strength capsule, RPV 1 u 25-mg strength tablet, and TDF 1 u 300-mg strength tablet administered together in the morning and within 5 minutes of consuming a standardized meal

FTC/RPV/TDF FDC Formulation 3 (test): A single dose of FDC tablet (FTC 200 mg, RPV 25 mg [as 27.5 mg of the hydrochloride salt], and TDF 300 mg) administered in the morning and within 5 minutes of consuming a standardized meal

FTC/RPV/TDF FDC Formulation 4 (test): A single dose of FDC tablet (FTC 200 mg, RPV 25 mg [as 27.5 mg of the hydrochloride salt], and TDF 300 mg) administered in the morning and within 5 minutes of consuming a standardized meal

The standardized meals contained approximately 400 calories (kcal) and approximately 13 g fat. On in-clinic confinement days when study drug was not being administered, breakfast meals contained 400 to 600 kcal. Afternoon and evening meals in the study facility were also standardized. Components of meals (e.g., margarine, jelly, bread) were given to subjects in individual portions (e.g., 1 tablespoon) per the approved meal schedule. The provision of meal components in bulk (e.g., a jar of jelly for subjects to share) was not practiced. All meals provided were approved by the sponsor. These meals were taken at approximately the same time each day (e.g., 07:30, 12:00, and 18:00).

Assessment of bioequivalence under fed conditions was considered to be scientifically and clinically appropriate in view of the following:

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x Emtricitabine is recommended to be taken with or without food in accordance with the Emtriva Summary of Product Characteristics (SmPC)

x Tenofovir DF is recommended to be taken with food in accordance with the Viread SmPC.

x Rilpivirine has been shown to exhibit a significant food-effect {14064} with exposures (Cmax, AUClast, and AUCinf) 40% lower when administered under fasted conditions compared to administration with either a standard or a high-fat breakfast. Additionally, the 25-mg dose of RPV was selected based on safety and efficacy (Phase 2b) and clinical pharmacology (thorough QT/QTc) studies as the dose providing appropriate drug exposures when administered with food. As such, subjects are instructed to take RPV with a meal in the ongoing Phase 2b (C204) and Phase 3 studies (C209 and C215); this method of administration will be recommended in the prescribing information for the FDC tablet. This recommendation will also be included in the prescribing information for the single agent RPV 25-mg tablets.

The assessment of pharmacokinetic equivalence of the 2 treatment administrations (FTC/RPV/TDF fixed-dose combination tablet relative to coadministration of the individual components) was determined by measures of the rate and extent of exposure (Cmax, AUClast and AUCinf) for each analyte.

Pharmacokinetic assessments are available for a total of 34 subjects who enrolled and completed the study. The mean (% coefficient of variation [CV]) primary pharmacokinetics parameters for FTC, RPV, and TFV and statistical analyses for the analytes within the Formulation 3 (test) compared to the individual components (reference) are summarized in Table 1. FTC/RPV/TDF FDC Formulation 4 did not achieve bioequivalence (see Module 2.7.1.3.5.2).

As observed for Formulation 3, the geometric mean ratios (test/reference) and the associated 90% confidence intervals were contained within the specified bounds of 80% to 125% for the pharmacokinetic parameters of FTC, RPV, and TFV. Therefore, the FDC tablet containing Formulation 3 (test) achieved bioequivalence as assessed by Cmax, AUClast, and AUCinf for all analytes.

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Table 1. GS-US-264-0103: Statistical Comparisons of FTC, TFV, and RPV Pharmacokinetic Parameters for Test (Formulation 3) Versus Reference Treatment

FTC/RPV/TDF FTC + RPV + TDF Geometric Least 90% Analyte Test Formulation Reference Squares Mean Confidence Parameter (N=34)a (N=34)a Ratio (%) Interval FTC

Cmax (ng/mL) 1753.9 (23.6) 1652.8 (21.9) 105.47 100.46, 110.74 Mean (%CV)

AUClast (ng˜h/mL) 9416.5 (14.3) 9417.5 (13.9) 99.94 97.77, 102.16 Mean (%CV)

AUCinf (ng˜h/mL) 9636.3 (14.1) 9644.5 (13.6) 99.86 97.67, 102.09 Mean (%CV) RPV

Cmax (ng/mL) 115.5 (29.6) 99.8 (30.5) 115.87 108.21, 124.06 Mean (%CV)

AUClast (ng˜h/mL) 3014.4 (34.5) 2597.2 (32.5) 115.71 109.13, 122.69 Mean (%CV)

AUCinf (ng˜h/mL) 3389.3 (39.4) 2923.3 (38.6) 115.64 108.71, 123.01 Mean (%CV) TFV

Cmax (ng/mL) 324.7 (26.0) 291.1 (26.4) 111.01 104.19, 118.28 Mean (%CV)

AUClast (ng˜h/mL) 3108.2 (21.1) 3040.3 (21.3) 102.14 99.00, 105.38 Mean (%CV)

AUCinf (ng˜h/mL) 3313.6 (19.7) 3246.8 (19.7) 101.99 99.06, 105.00 Mean (%CV) GLS = geometric least-squares FTC + RPV + TDF reference = a single dose of FTC 200-mg capsule, RPV 25-mg tablet, and TDF 300-mg tablet FTC/RPV/TDF FDC test formulation 3 = a single dose of FDC tablet (FTC 200 mg/RPV 25 mg/TDF 300 mg) a Subjects 3648-3008 and 3648-3026 did not have pharmacokinetic (PK) data for a treatment pair of interest and were excluded. Source: Module 5.3.1.2, GS-US-264-0103 CSR, Tables 10.1, 10.2, 10.3, 10.5, 10.6, 10.7

2.5.2.3. Effect of Food

The effect of food of FTC, RPV, TDF, Truvada, and the FTC/RPV/TDF FDC tablet is described in Module 2.7.1.3.6.

2.5.2.3.1. Emtriva

Emtriva capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (area under the plasma drug concentration-time curve >AUC@) was

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unaffected while Cmax decreased by 29% when Emtriva capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and Cmax were unaffected when 200 mg Emtriva oral solution was administered with either a high-fat or low-fat meal.

2.5.2.3.2. Rilpivirine

It is recommended that TMC278 be administered with a meal to ensure optimal absorption and exposure. In the Phase 2b trial and the Phase 3 trials, subjects were instructed to take the TMC278 tablet with a meal.

The effect of concomitant food intake on the oral bioavailability of TMC278, when administered as a tablet, was investigated in 2 Phase 1 trials in healthy subjects, trial C102 using the Phase 2b tablet, and trial C137 using the Phase 3 tablet.

In both trials, the effect of concomitant food intake was evaluated by administering TMC278 within 10 minutes after a standardized breakfast compared to administration under fasted conditions. In addition, trial C137 investigated the effect of a high-fat breakfast or just a protein-rich nutritional drink.

The exposure to TMC278 was notably higher when administered with a meal. This effect was comparable for the Phase 2b and the Phase 3 tablet. The exposure to TMC278 administered as the Phase 2b tablet (single 100-mg dose), was 1.7-fold (Cmax) and 1.5-fold (AUClast) higher after the standardized breakfast when compared to fasted conditions. Likewise, the mean exposure to TMC278 administered as the Phase 3 tablet (single 75-mg dose) was 1.9-fold (Cmax) and 1.8-fold (AUClast) higher after the standardized breakfast when compared to fasted conditions. It is anticipated that the food effect will be either similar or less for the TMC278 25 mg once daily dose.

In addition, it was shown that the mean exposure to TMC278 was similar when administered with a regular or a high-fat breakfast. However, the mean exposure to TMC278 was 50% lower when administered after a protein-rich nutritional drink as compared to the standardized breakfast. The mean exposure to TMC278 when administered after a protein- rich nutritional drink alone was comparable to that in the fasted state.

Increased bioavailability of poorly soluble drugs, such as TMC278, in the presence of food may be explained by improved solubilization due to increased levels of bile constituents and the presence of lipid digestion products within the intestinal lumen. Bile salts enhance absorption of lipophilic compounds by micellar solubilization. In addition, gastric residence time is prolonged in fed conditions, enabling longer dissolution and mixing of the drug.

It is not clear what may have caused the reduced absorption when TMC278 was administered after the nutritional drink. Potential factors that could have contributed to this result include the specific content of the nutritional drink, and the fact that a liquid meal was compared with a solid meal, involving a difference in gastric residence time and gastric emptying rate. Furthermore, there may be differences between the solid meal and the nutritional drink in terms of the potential for binding of TMC278 to (protein) components of the meal and a

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possible effect on gastric pH. Finally, multicomponent nutritional drinks can interfere with the disintegration and drug release from tablets in vitro and in vivo, e.g., by the formation of a film around the tablet.

Based upon the food effect data, it is recommended that TMC278 be administered with a meal to ensure optimal absorption and exposure. TMC278 should not be taken with a protein-rich nutritional drink alone. There is no relevant difference in the exposure of TMC278 when taken with a regular breakfast or a high-fat breakfast.

2.5.2.3.3. Viread

Administration of Viread following a high-fat meal (approximately 700 to 1000 kcal containing 40% to 50% fat) increases the oral bioavailability, with an increase in TFV AUC0-’ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of Viread with a light meal did not have a significant effect on the pharmacokinetics of TFV when compared to fasted administration of the drug. Food delays the time to TFV Cmax by approximately 1 hour. Cmax and AUC of TFV are 326 r 119 ng/mL and 3324 r 1370 ng·h/mL, respectively, following multiple doses of Viread 300 mg once daily in the fed state, when meal content was not controlled. In the EU it is recommended that Viread be taken with food.

2.5.2.3.4. Truvada FDC tablet

Compared with fasted administration, dosing of a fixed-dose combination of TDF and FTC with either a high-fat meal or a light meal increased the mean AUC and Cmax of TFV by 35% and 15%, respectively, with no effect on FTC exposure (Study GS-US-104-172). The lack of a food effect with FTC in this study is consistent with the results of the previous food effect study with the single agent (Study FTC-111), which indicates that FTC may be taken with or without food. The increased exposure to TFV when administered with food is consistent with findings from previous food effect studies of the single agent (Studies GS-00-914, GS-01-932 and GS-99-909). The applicant believes that TDF may be administered with or without food and that the increase in plasma exposure due to the effect of food on TDF is not of clinical relevance, as the active moiety, tenofovir diphosphate, acts intracellularly and exhibits a protracted half life. However the EU prescribing information recommends that Truvada be taken with food in order to optimize the absorption of tenofovir.

2.5.2.3.5. FTC/RPV/TDF FDC tablet

In accordance with the posology of the components, the FTC/RPV/TDF FDC tablet is recommended to be taken once daily, orally with a meal. The bioequivalence of the FTC/RPV/TDF FDC tablet with the individual agents was demonstrated under fed conditions and therefore supports the proposed posology.

To date, 2 bioequivalence studies (GS-US-264-0101 and GS-US-264-0103) have been conducted in which all tablet formulations, both as FDC and separate agents, were examined under fed conditions to determine if strict criteria for bioequivalence were met (see

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Section 2.5.2.2). Gilead Sciences is currently conducting a study (GS-US-264-0108) to evaluate the relative bioavailability of the FTC/RPV/TDF FDC tablet (Formulation 3) compared to a 200-mg capsule of FTC, a 25-mg tablet of RPV, and a 300-mg tablet of TDF taken concurrently under fasted conditions. Together, data from this study and Study GS-US-264-0103 are intended to allow descriptive analyses of the relative effect of food on the pharmacokinetics of the components of the fixed-dose combination tablet. The last subject observation in Study GS-US-264-0108 was 16 June 2010 and the clinical study report is due to be completed in October 2010.

2.5.3. Overview of Clinical Pharmacology

For detailed information on the clinical pharmacology data described in this section, refer to Module 2.7.2.

2.5.3.1. Pharmacology/Virology

A set of clinical pharmacology studies were conducted with the components of the FTC/RPV/TDF FDC tablet. Two studies addressed the antiviral activity in vitro of FTC, RPV, and TFV in 2- and 3-drug combinations (PC-264-2001, PC-264-2002). These studies showed additive to synergistic activity for the 2-drug combinations and synergy for the 3-drug combination. A study addressed the patterns of HIV-1 resistance mutations that emerged in vitro under selective pressure of FTC + RPV + TFV (PC-264-2003). This study showed that M184V/I and K65R emerged, and no RPV-associated mutations developed when the triple combination of drugs were used. The lack of cross-resistance to FTC and TFV was shown for a large panel for HIV-1 containing RPV-associated resistance mutations (PC-264-2004). Data for FTC, RPV and TDF are summarized in Module 2.7.2.

2.5.3.1.1. Mechanism of Action

2.5.3.1.1.1. Emtricitabine

Emtricitabine, an NRTI, is converted intracellularly through 3 phosphorylation reactions to its active phosphorylated anabolite FTC-TP {4527}, {4535}. FTC-TP inhibits viral polymerases by direct binding competition with the natural deoxyribonucleotide substrate (deoxycytidine triphosphate, dCTP), and after incorporation into deoxyribonucleic acid (DNA), by DNA chain termination {4249}. FTC-TP is a very weak inhibitor of mammalian DNA polymerases D, E, H, and mitochondrial DNA (mtDNA) polymerase J {4241}, (Report TEZZ/93/0007).

2.5.3.1.1.2. Rilpivirine

TMC278, a diarylpyrimidine derivative, is a potent NNRTI with in vitro activity against wild-type HIV-1 and NNRTI-resistant mutants, with a median 50% effective concentration (EC50) for HIV-1IIIB of 0.73 nM {15541}. Based on in vitro selection experiments, TMC278 has a higher genetic barrier to the development of HIV-1 resistance than EFV, DLV, or NVP (Report TMC278-IV1-AVMR).

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2.5.3.1.1.3. Tenofovir DF

Tenofovir DF, an NtRTI, is converted to TFV by serum esterases. Intracellularly, TFV is then converted through 2 phosphorylation reactions to its active phosphorylated anabolite, tenofovir diphosphate {1574}. Tenofovir diphosphate inhibits viral polymerases by direct binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine triphosphate, dATP), and after incorporation into DNA, by DNA chain termination {1131}. Tenofovir diphosphate is a very weak inhibitor of mammalian DNA polymerases D, E, į, İ, and mitochondrial DNA polymerase J {1131}, {2516}.

2.5.3.1.1.4. FTC/RPV/TDF FDC tablet

Tenofovir and FTC are analogs of 2 different nucleosides, adenosine and cytidine, respectively, and do not share a common intracellular metabolism pathway. In experiments where both drugs were incubated together at concentrations higher than achieved in the plasma (10 PM each), the intracellular activation of TFV to tenofovir diphosphate was not negatively influenced by the presence of FTC, and the activation of FTC to FTC-TP, was not negatively affected by the presence of TFV (Report PC-164-2002). As tenofovir diphosphate and FTC-TP are alternative substrates for different natural substrates, dATP and dCTP, respectively, there should be no competition for incorporation by HIV-1 RT and subsequent chain termination. Rilpivirine is a diarylpyrimidine derivative, a noncompetitive inhibitor of the HIV-1 reverse transcriptase. Rilpivirine binds tightly to the allosteric NNRTI-binding pocket on HIV-1 RT and so decreases the affinity of the enzyme for its substrate.

In Vitro Activity

In vitro studies have demonstrated potent antiviral activity of FTC, RPV, and TDF against laboratory and clinical strains of HIV-1, including virus with reduced sensitivity to other NRTIs and NNRTIs.

The EC50 of FTC against laboratory adapted strains of HIV-1 ranged from 0.0013 to 0.64 PM depending on cell type and virus strain used in the assay (Reports 462 v2 and 10498 v2), {4534}, {4541}, {4526}. With clinical isolates of HIV-1, EC50 values range from 0.002 to 0.028 PM (Report 462 v2), {4534}. Emtricitabine displays antiviral activity in vitro against HIV-1 subtypes A, B, C, D, E, F, and G with EC50 values ranging from 0.002 to 0.075 PM (Reports 10498 v2 and 11419 v2), and shows activity against HIV-2 (with an EC50 of 0.007 to 1.5 PM) {4534}, {4541}.

The median TMC278 (EC50) for HIV-1IIIB of 0.73 nM {15541}. Based on in vitro selection experiments, TMC278 has a higher genetic barrier to the development of HIV-1 resistance than EFV, DLV, or NVP. Although TMC278 demonstrated limited in vitro activity against HIV-2 with EC50 values ranging from 2510 to 5220 nM, treatment of HIV-2 infection with TMC278 is not recommended in the absence of clinical data.

The EC50 of TFV against wild-type HIV-1IIIB is 1 to 6 PM in T lymphoblastoid cell lines and 0.2 to 0.6 PM in peripheral blood mononuclear cells (PBMCs) {1574}, {39}. With clinical

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isolates of HIV-1, EC50 values range from 0.04 to 8.5 PM {625}. The mean EC50 values of TFV against HIV-1 subtypes A, C, D, E, F, G, and O in PBMCs were within 2-fold of subtype B (0.55 to 2.2 PM) {5044}. Tenofovir has an EC50 of 0.04 PM against HIV-1BaL in primary monocyte/macrophage cells and also is active against HIV-2 in vitro, with an EC50 of 1.6 to 5.5 PM ({39}, {625}, Reports PC-104-2003 and PC-104-2013).

The anti-HIV-1 activity of the 2-drug combinations of FTC, RPV, and TFV were found to be additive to synergistic in multiple in vitro assay systems, supporting the use of these agents in combination in HIV-1 infected patients (Report PC-164-2001, Report PC-164-2002, Report TMC278-IV1-AVMR, and Module 2.6.2.5). In addition, in vitro combination studies have shown that FTC, RPV, and TFV have additive to synergistic anti-HIV-1 activity with other approved NRTIs, NNRTIs, and PIs, as well as the integrase inhibitor elvitegravir (FTC and TFV) {1469}, (Report PC-183-2004, Report PC-264-2001, Report 470, Report 10804, and Report C1278-00005; see Modules 2.6.2.5 and 2.7.2.3.1.9.1).

The anti-HIV activity of the triple combination of FTC, RPV, and TFV in vitro demonstrates synergy for anti-HIV activity and no evidence of cytotoxicity (Report PC-264-2002).

In addition to anti-HIV activity, both FTC and TFV demonstrate potent and selective inhibition of hepatitis B virus (HBV) replication in vitro and in vivo. Tenofovir activity has been demonstrated against both wild-type and 3TC-resistant HBV {2368}, {3467}, {9266}. Clinical efficacy and safety experience in HIV-1 infected subjects coinfected with HBV is described in Sections 2.5.4.8 and 2.5.5.12.5, respectively. No activity of RPV was observed against HBV at concentrations up to 10 PM.

The principal findings of in vitro and in vivo studies that describe the resistance profiles of FTC, RPV, and TDF are summarized in the context of virologic response to treatment in Section 2.5.4.6 and Report PC-264-2005.

A variety of in vitro studies have been conducted to evaluate the ability of either FTC or TFV, alone or in combination, to exert mitochondrial toxicity. Results from these studies suggest that TFV and FTC have limited capability to inhibit human DNA polymerases or to mediate cytotoxicity or mitochondrial damage. Rilpivirine had no effects on DNA synthesis by human DNA polymerases. Based on these data and the clinical experience with FTC, RPV, and TDF, the potential for mitochondrial toxicity is considered to be low.

2.5.3.2. Clinical Pharmacodynamics

The antiviral effects of FTC, RPV, and TDF, and the relationship with dose were assessed in clinical Phase 1 studies that supported the dose selection for investigations in the respective Phase 2/3 clinical programs. The significant clinical efficacy demonstrated in pivotal Phase 3 studies with FTC 200 mg, RPV 25 mg, and TDF 300 mg, each administered once daily supports the antiviral efficacy of the FTC/RPV/TDF FDC tablet. The relevant clinical data for FTC, RPV, and TDF are detailed in Module 2.7.2.

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2.5.3.3. Clinical Pharmacokinetics

2.5.3.3.1. Pharmacokinetic Profiles

2.5.3.3.1.1. Emtricitabine and Tenofovir DF

Emtricitabine (see Module 2.7.2.3.1.1) and TDF (see Module 2.7.2.3.1.3) demonstrate similar pharmacokinetic profiles that are consistent across healthy volunteers and HIV-1 infected subjects (FTC Studies FTC-101, FTC-102, FTC-106, and FTC-303 [PK substudy]; TDF Studies GS-97-901, GS-99-907 [PK substudy], and GS-00-914). Following oral administration of FTC and TDF, both drugs are rapidly absorbed with maximum FTC and TFV concentrations observed within approximately 1 to 2 hours of dosing with or without food. After Cmax is achieved, plasma concentrations decline in a biexponential manner in both cases. The median plasma half-life of FTC following a single oral dose is approximately 10 hours, which is relatively long compared with other nucleoside analogs. The median terminal elimination half-life of TFV is approximately 17 hours, and steady-state is achieved in approximately 3 to 4 days. In vitro binding of FTC to human plasma proteins was 4% and independent of concentration over the range of 0.02 to 200 Pg/mL (Report TBZZ/93/0025). Tenofovir shows low protein binding in either human plasma (0.7%) or serum (7.2%) (Report P0504-00039).

Both FTC and TFV are eliminated primarily by renal excretion through a combination of glomerular filtration and active tubular secretion. Approximately 70% of an oral dose of FTC is recovered in urine as unchanged drug in subjects with normal renal function (Study FTC-106). After intravenous administration of TFV in subjects with normal renal function, approximately 70% to 80% of the dose is recovered in urine as unchanged TFV within 72 hours of dosing (Study GS-96-701). Despite the common route of elimination, the lack of effect on the pharmacokinetics of either drug when FTC and TDF are coadministered is supported by Study FTC-114. Metabolism is a minor elimination pathway for FTC. In a mass balance study with 14C-FTC in humans, approximately 13% of an oral dose was recovered as metabolites, 12.9% in the urine and 0.01% in feces (Study FTC-106). A 3'-sulfoxide diastereomer of FTC accounted for 8.7% of the dose and a 2'-O-glucuronide accounted for 4% of the dose.

2.5.3.3.1.2. Rilpivirine

2.5.3.3.1.2.1. Absorption of TMC278

The solubility of TMC278 drug substance is low and pH dependent. The highest solubility of TMC278 is obtained at pH 2.0 (0.003 g/100 mL) (see Module 2.7.2.3.1.2.1). At pH values above 2.0, drug dissolution decreases significantly (< 0.001 g/100 mL). Because an acceptable intravenous formulation suitable for use in humans is not available, the absolute bioavailability of TMC278 after oral administration has not been investigated.

TMC278 had intermediate permeability, and overall, TMC278 permeation is thought to occur predominantly via a passive transcellular diffusion mechanism.

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After oral administration as a tablet formulation, TMC278 is well absorbed, with the maximum plasma concentration attained approximately 4 hours after administration, both in healthy subjects and in HIV-infected subjects. The rate of TMC278 absorption is not influenced by the dose.

The impact of concomitant food intake (See Section 2.5.2.3.2) and the effect of drugs that increase intragastric pH (see Section 2.5.3.4.2.2) on the oral bioavailability of TMC278 have been investigated in specific clinical trials.

2.5.3.3.1.2.2. Distribution of TMC278

After a single oral dose of 150 mg 14C-TMC278 in healthy adults (Trial C119), the blood to plasma ratios of total 14C-radioactivity were time-independent, with values ranging between 0.65 and 0.75, indicating that TMC278 and its metabolites are predominantly distributed to plasma and not to blood cells (see Module 2.7.2.3.1.2.2).

The in vitro plasma protein binding of TMC278, determined by equilibrium dialysis, was on average 99.7%, irrespective of the TMC278 concentration (10 to 3000 ng/mL). TMC278 was extensively bound to human albumin and to a lesser extent to Į1-acid glycoprotein.

The distribution of TMC278 into compartments other than plasma (e.g., cerebrospinal fluid or genital tract secretions) has not been evaluated in humans.

2.5.3.3.1.2.3. Metabolism and Excretion of TMC278

In Vitro and In Vivo Metabolism

The in vitro metabolism of TMC278 was studied in human hepatocytes and liver subcellular fractions of humans and various animal species (see Module 2.7.2.3.1.2.3).

A major metabolic pathway of TMC278, representing the main in vitro biotransformation, was aromatic hydroxylation at the pyrimidinyl moiety, followed by glucuronidation. Another major metabolic pathway was aliphatic hydroxylation at one of the methyl groups of the cyanoethenyl-2,6-dimethylphenyl moiety (hydroxymethyl TMC278), followed by dehydration to form a tricyclic metabolite. Aliphatic hydroxylation in combination with glucuronidation was also observed.

The metabolism of 14C-TMC278 in human liver microsomes revealed that the primary TMC278 metabolism was mainly catalyzed by cytochrome P450 (CYP) 3A enzymes.

Clinical Trials

A mass-balance trial in healthy adults (Trial C119; Modules 2.7.2.3.1.2.3 and 2.7.2.2.2.2.1) showed that most of the administered 14C-TMC278-related radioactivity from a single 150-mg dose administered as an oral solution was excreted in feces. At 168 hours after dosing, a mean of 85.1% of the administered radioactivity was recovered in feces. Unchanged TMC278 accounted for a mean of 25.5% of the dose in feces. The excretion of

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radioactivity in urine was limited (mean 6.1% of the administered radioactive dose). Only trace amounts (d 0.03%) of unchanged TMC278 were detected in urine.

The metabolites of 14C-TMC278 in vivo were determined in feces, urine, and plasma collected from healthy adults after a single oral dose of 150 mg 14C-TMC278. TMC278 was extensively metabolized, with more than 15 metabolites detected. The most abundant metabolite originated from aromatic hydroxylation at the pyrimidinyl moiety, accounting for 16.1% of the TMC278-related radioactivity in feces. Three other metabolites in feces each accounted for 2.2% to 3.0% of the dose, including a carboxylic acid metabolite and hydroxymethyl TMC278.

In plasma, unchanged TMC278 represented the major fraction of the absorbed radioactivity. Several minor metabolites were detected in plasma, including a direct glucuronide of TMC278 the tricyclic metabolite and hydroxymethyl TMC278.

2.5.3.3.1.2.4. Pharmacokinetics of TMC278 after Single- and Multiple-Dose Administration in Healthy Subjects

Data on the single-dose and multiple-dose pharmacokinetics of TMC278 in healthy subjects are available from trials conducted with the oral solution that was used in the early Phase 1 and Phase 2a trials, with the Phase 2b tablet, and with the Phase 3 tablet (Modules 2.7.2.2.2.3 and 2.7.2.2.2.4).

After multiple-dose administration of TMC278 as the Phase 2b tablet (C103; Module 2.7.2.2.2.4.2), the exposure to TMC278 increased dose proportionally across a dose range of 25 to 150 mg once daily. The rate of TMC278 absorption was not influenced by the dose; the median tmax was 4 hours. The pharmacokinetic profile of TMC278 in plasma was generally similar after multiple-dose administration of different formulations (oral solution, Phase 2b tablet, or Phase 3 tablet).

The comparable range of t1/2, term values across doses and the comparable range of the mean apparent oral clearance (CL/F) after single and multiple dosing indicated that there was no time-dependent change in clearance of TMC278 following multiple oral dosing. The accumulation ratio of TMC278 between the first dose and steady-state was approximately 2 to 3, which concurred with the median t1/2, term of approximately 45 to 50 hours, across trials.

2.5.3.3.1.2.5. Pharmacokinetics of TMC278 in HIV-1 Infected Subjects

Pharmacokinetic data from intensive sampling in HIV-1 infected subjects are available from multiple-dose administration of TMC278 using the Phase 2b tablet in the Phase 2b trial and the Phase 3 tablet in the 2 Phase 3 trials (Module 2.7.2.2.2.6).

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In addition, population pharmacokinetic parameters are available from the Phase 2b trial, in which subjects were treated with Phase 2b tablet dose strengths of 25, 75, or 150 mg, and from the pooled Phase 3 trials, in which subjects were treated with the 25-mg Phase 3 tablet.

The rate of TMC278 absorption was not influenced by the dose level; the median tmax was 4 hours at all dose levels, in the different studies. Within each dose level, there was no difference in the mean exposure to TMC278 over time. There was a less than dose-proportional increase between the dose levels evaluated in Phase 2b, most pronounced between the 25 and 75 mg once daily dose levels. The range of exposures observed with the 25 mg once daily dose was comparable in the Phase 2b and the Phase 3 trials.

2.5.3.3.1.2.6. Comparison of Exposure to TMC278 Between Healthy Subjects and HIV-1 Infected Subjects

A comparison of the exposure to TMC278 between healthy subjects and HIV-1 infected subjects is based on across-trial comparisons of noncompartmental pharmacokinetic analyses of TMC278 plasma concentrations (intensive sampling), and from the population pharmacokinetic models for the Phase 2b and Phase 3 trials (Module 2.7.2.3.1.2.6).

After multiple-dose administration of TMC278 as the Phase 2b tablet at a dose of 25 mg once daily, the mean steady-state exposure (AUC24h) to TMC278 in HIV-1 infected subjects (Phase 2b trial C204, pharmacokinetic substudy) was in between that observed in healthy subjects in trial C103 and trial C151. At a dose of 150 mg once daily, the mean exposure to TMC278 was 22% to 50% lower in HIV-1 infected subjects in the pharmacokinetic substudy of trial C204 than in healthy subjects treated with the same dose of TMC278. In the population pharmacokinetic modeling of the Phase 2b trial, the exposure was estimated to be 20 to 30% lower in HIV-1 infected subjects compared to healthy subjects.

After multiple-dose administration of TMC278 as the Phase 3 tablet at a dose of 25 mg once daily, the mean exposure (AUC24h and Cmax) to TMC278 was more than 30% lower in HIV-1 infected subjects in the Phase 3 pharmacokinetic substudies compared to healthy subjects in trial C152. However, in another trial in healthy subjects (C130), the mean exposure to TMC278 with the Phase 3 tablet at a dose of 25 mg once daily was comparable with that in HIV-1 infected subjects in the Phase 3 pharmacokinetic substudies (Table 2). The median tmax of TMC278 at steady-state was comparable in healthy subjects and in HIV-1 infected subjects (5 hours and 4 hours, respectively).

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Table 2. Steady-State Pharmacokinetics of TMC278 After Administration of TMC278 25 mg Once Daily in Healthy Subjects (Trial C130 and C152) and in HIV-1 Infected Subjects (Trials C209 and C215, Pharmacokinetic Substudies)

Mean r SD; tmax: Median (Range) Healthy HIV-1 Infected Parameter C130 C152 C209 C215 Day 11 (Healthy) or any time point between Week 4 and 8 (HIV-1 Infected) N 16 57 12 32 tmax, h 5.0 (5.0 - 12.0) 5.0 (4.0 - 24.0) 4.01 (2.00 - 12.00) 4.00 (1.00 - 12.00)

Cmin, ng/mL 66.48 r 16.29 95.23 r 29.07 61.79 r 28.69 50.58 r 27.94

Cmax, ng/mL 145.5 r 31.97 246.8 r 74.36 138.6 r 66.73 132.5 r 74.79

AUC24h, ng.h/mL 2235 r 460.4 3324 r 884.0 2133 r 1016 1958 r 964.5 SD, standard deviation N = maximum number of subjects with data. Source: Module 2.7.2.3.1.2.6, Table 105

A lower exposure in HIV-1 infected subjects compared to healthy subjects was also observed in the population pharmacokinetic modeling of the Phase 3 trials. This was estimated to be approximately 40% lower in HIV-1 infected subjects in the Phase 3 trials. However, the magnitude of this difference in exposure between HIV-1 infected subjects and healthy subjects has to be interpreted with caution, as this was based on the comparison with a single trial in healthy subjects (C152). As discussed above, data from other recent trials in healthy subjects with the TMC278 Phase 3 tablet at a 25 mg once daily dose indicate that the exposures observed in trial C152 are at the high end of the exposure range observed in healthy subjects.

2.5.3.3.1.3. FTC/RPV/TDF FDC tablet

Single-dose administration of the FTC/RPV/TDF FDC tablet resulted in plasma concentration-time profiles of FTC, RPV, and TFV similar to those observed after the concurrent administration of the 3 separate formulations and consistent with their established pharmacokinetic profiles (Study GS-US-264-0103; see Section 2.5.2.2).

2.5.3.3.2. Demographic Effects

Pooled data from 108 healthy volunteers and 20 HIV-1 infected subjects were used to assess the influence of demographic variables on the pharmacokinetic profile of FTC (Studies FTC-101, FTC-103, FTC-104, FTC-106, FTC-107, FTC-108, FTC-109, FTC-110, FTC-111, and FTC-303).

In HIV-1 infected subjects, intrinsic factors that have been considered for their potential effect on the pharmacokinetics of TMC278 include age, gender, race, body weight, estimated

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glomerular filtration rate (eGFR), and hepatitis B and/or C virus coinfection status. The impact of these factors was evaluated in the subgroup analyses obtained in the individual and pooled Phase 3 trials (primary 48-week analysis) in HIV-1 infected subjects. In addition, the effect of these factors has also been explored using covariate analysis in the population pharmacokinetic analysis of TMC278 for the pooled data from the Phase 3 trials. Where investigated, information is also provided on the effect of intrinsic factors on the pharmacokinetics of TMC278 administered at doses of 25, 75, or 150 mg once daily to HIV-1 infected subjects in the Phase 2b trial.

For TDF, the relationship between demographic variables and the pharmacokinetics of TFV were evaluated based on a pooled dataset from HIV-1 infected subjects and healthy subjects (Studies GS-97-901, GS-99-907, and GS-00-914).

Clinically relevant differences in the pharmacokinetics of the FTC/RPV/TDF FDC tablet with respect to demographic variables are not anticipated based on data available for the individual agents. Pharmacokinetics by demographic variables are described in Module 2.7.2.3.1.5. The main findings of these analyses are described below.

2.5.3.3.2.1. Gender x The pharmacokinetics of FTC and TDF are similar in male and female subjects. x In the pooled analysis of the Phase 3 trials in HIV-1 infected subjects, a statistically significant effect of gender on the exposure to TMC278 was observed, with a somewhat higher exposure in females. This observed difference can be explained, at least in part, by the lower average body weight in females compared to males, as indicated by the absence of a significant effect of gender on the body weight-adjusted apparent oral clearance. Similar observations were made for HIV-1 infected subjects in the Phase 2b trial, at the different TMC278 dose levels. Also in the covariate analysis of the pooled Phase 3 pharmacokinetic data, a statistically significant effect of gender on the apparent oral clearance of TMC278 was observed, resulting in a slightly lower (13.6%) apparent oral clearance in females compared to males. However, this effect appeared to have no impact on the overall inter-individual variability and had only a minor effect on explaining the difference between the extremes of the covariate. This gender-related difference in apparent oral clearance is therefore considered not to be of clinical relevance.

2.5.3.3.2.2. Race x No pharmacokinetic differences due to race have been identified following the administration of FTC. x In the pooled analysis of the Phase 3 trials in HIV-1 infected subjects, a statistically significant effect of race on the exposure to TMC278 was observed, with a higher exposure in Asian subjects compared to the rest of the population. This observed difference was likely explained, at least in part, by the lower average body weight in Asian subjects, as indicated by the absence of a significant effect of race on the body

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weight-adjusted apparent oral clearance. A similar observation was made in the Phase 2b trial, where Asian subjects also had a somewhat higher exposure to TMC278. This difference was less pronounced but still significant for the body weight-adjusted apparent oral clearance, suggesting that race-related characteristics other than body weight influenced the pharmacokinetics of TMC278 by race across the different doses in the Phase 2b trial C204. Also in the covariate analysis of the pooled Phase 3 pharmacokinetic data, a statistically significant effect of race on the apparent oral clearance of TMC278 was observed, resulting in a slightly lower (17.2%) apparent oral clearance in Asian subjects compared to the rest of the population. The covariate effect of race appeared to have no impact on the overall inter individual variability and had only a minor effect on explaining the difference between the extremes of the covariate. This covariate induced difference in apparent oral clearance is therefore considered not to be of clinical relevance. x The numbers of subjects from racial and ethnic groups other than Caucasian were insufficient to adequately determine potential pharmacokinetic differences among these populations after administration of TDF.

2.5.3.3.2.3. Region

x In the pooled analysis of the Phase 3 trials, a statistically significant effect of region (region 1: United States, Canada, Europe, and Australia; region 2: Africa; region 3: Asia; and region 4: Latin America) on the exposure to TMC278 was observed in a univariate analysis. The TMC278 exposure was somewhat higher (approximately 10% to 16%) in HIV-1 infected subjects in Asia compared to other regions. However, in a multivariable analysis including also trial, gender, and race as factors in addition to region, region was no longer statistically significantly related to TMC278 exposure, while there was still a statistically significant effect of race. This indicates that, as to be expected, the factors race and region were likely related. A similar observation was made in the Phase 2b trial.

2.5.3.3.2.4. Age

x The pharmacokinetics of FTC or TFV have not been evaluated in subjects ! 65 years old.

x Age did not have a statistically significant effect on the exposure to TMC278 in HIV-1 infected subjects in the Phase 3 trials C209 and C215. This was confirmed in the covariate analysis of the pooled Phase 3 pharmacokinetic data, where age was not retained as a significant covariate affecting the apparent oral clearance of TMC278.

x The FTC/RPV/TDF FDC tablet should be administered with caution to elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this subpopulation (see Section 2.5.5.12.2).

x The FTC/RPV/TDF FDC tablet is not recommended for use in children and adolescents ( 18 years, see Section 2.5.5.12.3), however a Paediatric Investigation Plan has been

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agreed with the EMA Paediatric Development Committee (EMEA-000774-PIP01-09, the EMA Opinion is located in MAA Module 1.10). The pharmacokinetics, safety and efficacy of FTC have been investigated in HIV-1 infected children. In general, the pharmacokinetics of FTC in pediatric subjects are similar to those seen in adults. The pharmacokinetics, safety, and efficacy of RPV have not been investigated in HIV-1 infected children. Data on the use of TDF in subjects aged 12 to < 18 years (Study GS-US-104-0321) are currently under review by the CHMP. Only preliminary data are available on the pharmacokinetics of TFV in pediatric subjects < 12 years of age and its safety and effectiveness in this population has not been established.

2.5.3.3.3. Renal Impairment

Two studies in non-HIV-1 infected subjects determined the pharmacokinetics of FTC (Study FTC-107) and TFV (Study GS-01-919) in the presence of varying degrees of renal impairment, including end-stage renal disease (ESRD) requiring hemodialysis (see Modules 2.7.2.3.1.6.1 and 2.7.2.3.1.6.3).

In subjects with mild renal impairment, the pharmacokinetics of TFV and FTC are not substantially altered to warrant dose adjustment.

The mean (%CV) FTC drug exposure increased from 12 (25%) Pg·h/mL in subjects with normal renal function, to 20 (6%) Pg·h/mL, 25 (23%) Pg·h/mL, and 34 (6%) Pg·h/mL, in patients with mild, moderate and severe renal impairment, respectively.

The mean (%CV) TFV drug exposure increased from 2185 (12%) ng·h/mL in patients with normal renal function, to 3064 (30%) ng·h/mL, 6009 (42%) ng·h/mL, and 15,985 (45%) ng·h/mL, in patients with mild, moderate, and severe renal impairment, respectively.

In patients with end-stage renal disease (ESRD) requiring hemodialysis, between dialysis drug exposures substantially increased over 72 hours to 53 (19%) Pg·h/mL of FTC, and over 48 hours to 42,857 (29%) ng·h/mL of TFV.

In the pooled analysis of the Phase 3 trials in HIV-1 infected subjects, baseline eGFR did not have a statistically significant effect on the exposure to TMC278. This was confirmed in the covariate analysis of the pooled Phase 3 pharmacokinetic data, where eGFR was not retained as a significant covariate affecting the apparent oral clearance of TMC278. In view of the negligible renal excretion of TMC278 (< 1%), dose adjustment with RPV is unlikely to be needed (Module 2.7.2.3.1.6.2).

Limited pharmacokinetic data for HIV-1 infected subjects receiving FTC/TDF with renal impairment (Study GS-US-104-0235) suggest that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response. Furthermore, a subgroup of patients with creatinine clearance (CLcr) between 50 and 60 mL/min who received TDF in combination with FTC every 24 hours had a 2-4-fold higher exposure to TFV and worsening of renal function. Therefore, a careful benefit-risk assessment is needed

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when FTC/TDF is used in patients with CLcr < 60 mL/min, and renal function should be closely monitored. In addition, the clinical response to treatment should be closely monitored in patients receiving FTC/TDF at a prolonged dosing interval.

Limited data from clinical studies support once daily dosing of FTC/TDF in patients with mild renal impairment. In patients with moderate renal impairment (CLcr 30-49 mL/min) administration of FTC/TDF every 48 hours is recommended, based on modelling of single-dose pharmacokinetic data for FTC and TDF in non-HIV infected subjects with varying degrees of renal impairment. In patients with severe renal impairment (CLcr < 30 mL/min) and hemodialysis patients FTC/TDF is not recommended for patients with severe renal impairment (CLcr < 30 mL/min) and in patients who require hemodialysis because appropriate dose reductions cannot be achieved with the combination tablet (see Module 2.7.2.3.1.6.4).

In view of the experience above, patients with moderate to severe renal impairment (CLcr < 50 mL/min) require dosing interval adjustment that cannot be achieved with the FTC/RPV/TDF FDC tablet, and therefore use of the FDC tablet cannot be recommended (see Module 2.7.2.3.1.6.5).

2.5.3.3.4. Hepatic Impairment

Emtricitabine is not significantly metabolized by liver enzymes; therefore, the impact of liver impairment on the pharmacokinetics of FTC should be limited for this agent. The pharmacokinetics of FTC have not been studied in hepatically-impaired subjects. Metabolism is a minor pathway for the elimination of FTC ( 13% of oral dose, Study FTC-106). Therefore, in patients with various degrees of hepatic dysfunction, little change in FTC clearance is expected (see Module 2.7.2.3.1.7.1).

A specific trial (C130) was conducted to investigate the effects of mild and moderate hepatic impairment on the pharmacokinetics of TMC278 administered at a dose of 25 mg once daily in non-HIV-1 infected subjects. The steady-state exposure to TMC278 at a dose of 25 mg once daily was higher in subjects with mild hepatic impairment compared to matched healthy control subjects; the mean Cmax and AUC24h were 1.27- and 1.47-fold higher, respectively. The increase in TMC278 exposure is not expected to be of clinical relevance or cause safety concerns. In subjects with moderate hepatic impairment, the exposure to TMC278 after a single dose was lower compared to healthy subjects (Cmax: 30% lower; AUC24h: 24% lower). Based on the shape of the plasma concentration profiles, this appeared to be due to a difference in the absorption of TMC278. However, at steady-state, due to the longer t1/2, term in subjects with moderate hepatic impairment compared to matched healthy control subjects, the exposure to TMC278 was comparable in subjects with moderate hepatic impairment and healthy subjects. These data suggest that no dose adjustment of TMC278 is needed in subjects with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the exposure to TMC278 has not been studied (Module 2.7.2.3.1.7.2).

The pharmacokinetics of TFV after a 300-mg dose of TDF were studied in non-HIV-1 infected subjects with varying degrees of hepatic impairment, according to

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Child-Pugh-Turcotte (CPT) classification (Study GS-01-931 A/B). Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment compared with unimpaired subjects, suggesting that no dose adjustment of TDF is required in these subjects (see Module 2.7.2.3.1.7.3).

The pharmacokinetics of the FTC/TDF tablet or the FTC/RPV/TDF FDC tablet have not been studied in patients with hepatic impairment. However, based on minimal hepatic metabolism for FTC and the renal route of elimination for TFV and FTC, no dose adjustment would be required in patients with hepatic impairment (see Modules 2.7.2.3.1.7.4 and 2.7.2.3.1.7.5).

2.5.3.4. Potential for Drug Interactions

Based on the clinical pharmacology of the individual agents in the FTC/RPV/TDF FDC tablet, a targeted set of in vitro and clinical pharmacokinetic drug-drug interaction studies were conducted to evaluate the potential for interaction of each agent with other drugs. The potential for any drug interactions between the FTC/RPV/TDF FDC tablet and other medications frequently used by the HIV-infected population can be assessed from available drug interaction data and experience from clinical studies with use of concomitant medications during treatment with FTC, RPV, and TDF (see Module 2.7.2.3.1.9). The following sections provide an overview of the key drug interaction data and describe any recommendations for use of the FTC/RPV/TDF FDC tablet.

2.5.3.4.1. Emtricitabine and Tenofovir DF

Both FTC and TDF are considered to have a low potential for cytochrome P450-mediated interactions based on the results of in vitro experiments and the known renal elimination pathways of both agents (see Module 2.7.2.3.1.9.1 and Reports V990172-104, PDM-006, and PDM-007). Since both agents are primarily renally excreted, there is potential for interaction with other drugs that are similarly eliminated. Drugs that decrease renal function may also increase serum concentrations of these agents. Use of the FTC/RPV/TDF FDC tablet must be avoided with current or recent use of nephrotoxic agents.

Results of in vitro transport studies indicate that the active tubular secretion of TFV is mediated by human organic anion transporter (hOAT) type 1 (hOAT1) and multidrug resistance protein type 4 (MRP4) acting in series as the major uptake and efflux transporters in proximal tubules, respectively (Report PC-103-2001), {2520}, {7299}, {8418}, {9318}, {9863}, {10260}. The human organic anion transporter hOAT3 may play a secondary role in the tubular uptake of TFV {7299}. Neither multidrug resistance P-glycoprotein (P-gp) (Report AD-104-2002) nor multidrug resistance protein type 2 (MRP2, Report AD-104-2001) appear to be involved in the tubular efflux of TFV {9318}. As the primary transporter handling the tubular uptake of TFV, hOAT1 has been assessed for its potential role in drug interactions between TFV and other renally secreted therapeutics including antibiotics, anti-inflammatory agents, and other antivirals (including PIs). Under physiologically relevant conditions, none of the tested drugs affected hOAT1-mediated transport of TFV, indicating a low potential for renal interactions with TFV due to inhibition

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of this pathway (Reports PC-104-2010 and PC-104-2011). Similarly, PIsatazanavir, lopinavir, and ritonavirdid not exhibit any effect on the active cellular elimination of TFV mediated by MRP4 efflux pump {8418}, {9863}, {9864}. The results of in vitro drug interaction studies indicate that PIs are unlikely to exert any substantial effect on the accumulation of TFV in renal proximal tubules with consequential changes in the renal safety profile of TDF.

After the lack of interaction between P-gp and TFV was established, efforts continued to assess the potential transport of TDF by P-gp. Studies in human intestinal S9 fractions, the human colon carcinoma cell line Caco-2, and Madin-Darby canine kidney (MDCKII) cells stably transfected with the human gene that encodes P-gp, have suggested that the relative ability of PIs to inhibit esterase activity and inhibit or induce intestinal P-gp may account for the modest changes in plasma TFV levels when TDF is coadministered with some protease inhibitors (Report AD-104-2010) {11255}.

The findings of in vitro pharmacodynamic investigations suggest a low potential for intracellular drug antagonism between FTC or TFV and other antiretroviral compounds. The anti-HIV-1 activity of the 2-drug combinations of FTC, RPV, and TFV were found to be additive to synergistic in multiple in vitro assay systems, supporting the use of these agents in combination in HIV-1 infected patients (Report PC-164-2001, Report PC-164-2002, Report PC-264-2001; Report TMC278-IV1-AVMR, and Module 2.6.2.5). In addition, in vitro combination studies have shown that both TFV, RPV, and FTC have additive to synergistic anti-HIV-1 activity with other approved NRTIs, NNRTIs, and PIs, as well as the integrase inhibitor elvitegravir (FTC and TFV) {1469}, (Report PC-183-2004, Report PC-264-2001, Report 470, Report 10804, and Report C1278-00005; see Modules 2.6.2.5 and 2.7.2.3.1.9.1).

The in vitro anti-HIV activity of the triple combination of FTC, RPV, and TFV demonstrates moderate synergy for anti-HIV activity and no evidence of cytotoxicity (Report PC-264-2002).

2.5.3.4.2. Rilpivirine

Against the background of the in vitro findings and theoretical considerations for potential drug-drug interactions, 17 clinical trials have been conducted to evaluate the effects of coadministering TMC278 with other drugs (refer to Module 2.7.2 for more details on individual trials). TMC278 was coadministered with various classes of drugs, including other CYP3A substrates, CYP3A inducers or CYP3A inhibitors, a CYP2E1 substrate, and drugs that alter intragastric pH. The evaluated drugs are either other ARV drugs, non-ARV drugs that are frequently taken by HIV-1 infected subjects, or typical probe substrates.

2.5.3.4.2.1. Potential for TMC278 to Affect Other Drugs

Overall, TMC278 at the dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of coadministered drugs.

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Most of the clinical drug-drug interaction trials were performed with a TMC278 dose of 150 mg once daily, which was the highest dose studied in the Phase 2b dose-finding trial, to assess the maximal effect of TMC278 on other drugs within the dose range studied. With the TMC278 dose of 25 mg once daily, any observed effect on the pharmacokinetics of other drugs would either be similar or, more likely, lower than that observed with the TMC278 dose of 150 mg once daily because of the lower exposure to TMC278 (for more details, refer to Module 2.7.2.3.1.9.2).

CYP3A

In vitro, TMC278 was shown to be a moderate inducer of CYP3A4 and an inhibitor of CYP3A4 activity.

However, in vivo, there were no indications for inhibition of CYP3A activity by TMC278 at any of the doses tested, and indications of induction of CYP3A activity by TMC278 were apparent at the higher doses only (150 mg once daily and 300 mg once daily). With TMC278 150 mg once daily, modest induction of CYP3A activity was observed in a drug-drug interaction trial with atorvastatin, given an increase (1.3-fold) in the AUC24h ratio of 2-hydroxy-atorvastatin to atorvastatin by coadministration with TMC278. The CYP3A4-mediated metabolism of omeprazole on the other hand was not significantly affected by coadministration with TMC278 150 mg once daily in vivo, as shown by the absence of an effect on the AUC24h ratio of omeprazole sulfone to omeprazole. In a drug-drug interaction trial with oral contraceptives, the exposure to norethindrone was reduced by 41% in the presence of TMC278 at the dose of 150 mg once daily However, in a second drug-drug interaction trial with oral contraceptives, TMC278 at a dose of 25 mg once daily was shown not to affect the norethindrone exposure. In a drug-drug interaction trial with sildenafil, using a 75 mg once daily dose of TMC278, there was no effect on the exposure and metabolism of sildenafil, suggesting that there is also no effect of TMC278 on CYP3A4 activity at this TMC278 dose level. This is also further supported by the dose- related effect on the change in 6-ȕ-OH-cortisol/cortisol ratio in urine, a surrogate marker for CYP3A activity, when TMC278 was administered at doses of 75 and 300 mg once daily (trial C131). TMC278 at the proposed dose of 25 mg once daily does not inhibit or induce CYP3A.

P-glycoprotein

TMC278, although not a substrate for P-gp, inhibits the P-gp mediated transport of paclitaxel with an apparent 50% inhibitory concentration (IC50) of 9.2 PM (3.4 Pg/mL) in Caco-2 cells. An in vivo effect of TMC278 at the intestinal absorption level is unlikely, given the therapeutic dose of TMC278 (25 mg once daily) and the fact that the in vivo TMC278 total plasma concentrations at this dose are more than 10-fold lower compared to the high IC50 value.

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CYP2C19

In vitro studies with TMC278 indicated that TMC278 is a potent CYP2C19 inhibitor (IC50 <5 PM [1.8 Pg/mL]) and a moderate inducer of CYP2C19.

In vivo, after repeated administration of TMC278 150 mg once daily, the AUC24h ratio of 5-hydroxyomeprazole to omeprazole increased by 27%, suggesting a modest induction of CYP2C19-mediated metabolism by TMC278 at this high dose. This effect is probably even less relevant or absent at the 25 mg once daily dose of TMC278, and is therefore unlikely to result in clinically relevant interactions.

CYP2E1

In vivo, in a drug-drug interaction trial with the CYP2E1 probe substrate chlorzoxazone, TMC278 at a dose of 150 mg once daily was shown not to inhibit or induce CYP2E1 activity.

CYP2C8 and CYP2C9

In vitro, TMC278 inhibits CYP2C8 and CYP2C9 with an inhibition constant (Ki) of 10.0 PM (3.7 Pg/mL) and 1.7 PM (0.6 Pg/mL), respectively. Given the mean Cmax of approximately 0.13 Pg/mL in the pharmacokinetic substudy of the Phase 3 trials, the I/Ki value would be <0.1 for CYP2C8 and CYP2C9, and therefore inhibition of CYP2C8 or CYP2C9 by TMC278 25 mg once daily in vivo is unlikely. In vivo, there was also no relevant effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate ethinylestradiol by TMC278 at doses of 150 mg once daily and 25 mg once daily.

Furthermore, the in vitro IC50 for CYP2C8/9/10 (3.99 PM [1.5 Pg/mL]) inhibition by TMC278 was much higher than that for CYP2C19 (<0.06 PM [0.02 Pg/mL]), while in vivo, inhibition of CYP2C19 was not observed, even at the higher dose of 150 mg once daily.

Alcohol Dehydrogenase

An in vitro investigation of the effect of TMC278 on ABC metabolism (by alcohol dehydrogenase) in human liver cytosol indicated no inhibition potential by TMC278.

2.5.3.4.2.2. Potential for Other Drugs to Affect TMC278

In general, the exposure to TMC278 can be affected by modulators of CYP3A enzyme activity and by drugs that increase the gastric pH.

The primary metabolism of TMC278 is mainly catalyzed by CYP3A enzymes. Therefore, coadministration of TMC278 and drugs that induce CYP3A could decrease TMC278 plasma concentrations, which could potentially reduce the therapeutic effect of TMC278. This decrease in exposure was indeed shown in vivo by the results of drug-drug interaction trials with rifampin and rifabutin, which both significantly decreased the exposure to TMC278. Based on this, TMC278 should not be used in combination with inducers of CYP3A

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(e.g., rifampin, rifabutin, rifapentine, St John’s wort, systemic dexamethasone, carbamazepine, oxcarbazepine, phenobarbital, phenytoin).

Conversely, coadministration of TMC278 and drugs that inhibit CYP3A may increase TMC278 plasma concentrations, as evidenced in vivo by the results of drug-drug interaction trials with ketoconazole and ritonavir (rtv)-boosted PIs. The increase in TMC278 exposure (based on Cmax) compared to the exposure obtained with TMC278 25 mg once daily that can still be assumed to have no discernible effect on the QT interval (i.e., upper limit of the 90% confidence interval (CI) of the mean QTcF prolongation < 10 ms), was determined with simulations based on the pooled data of the thorough QT studies with TMC278 (25 to 300 mg once daily) in healthy volunteers (for more details, refer to Module 2.7.4.5.4 and Module 2.7.2.2.2.9). With these analyses, it was determined that there is a probability of 80% that the upper limit of the 2-sided 90% CI of the mean change in QTcF by TMC278 remains below 10 ms at an increase in exposure (based on Cmax) of 85% (i.e., 1.85-fold) compared to the observed Cmax at the 25 mg once daily dose in healthy volunteers. In none of the performed drug-drug interaction trials, including several with CYP3A inhibitors (ketoconazole, rtv-boosted darunavir, rtv-boosted lopinavir), did the Cmax of TMC278 increase by more than 85%. The observed interactions are thus not expected to be of clinical relevance or cause safety concerns, and therefore do not result in the need for dose adjustment.

As mentioned above, a number of the clinical drug-drug interaction trials were performed with a TMC278 dose of 150 mg once daily. TMC278 exhibits linear pharmacokinetics up to a dose of 150 mg once daily in healthy subjects, while in HIV-1 infected subjects, the increase in exposure across doses of 25 to 150 mg once daily was less than dose-proportional. This indicates that there is no saturation of the TMC278 metabolism up to the 150 mg once daily dose, as saturation would lead to a more than dose-proportional increase in TMC278 exposure. In the absence of metabolic pathway saturation, the effect of metabolic inhibitors such as ketoconazole on the pharmacokinetics of TMC278 at a dose of 25 mg once daily should not exceed the effect observed with TMC278 at a dose of 150 mg once daily Therefore, the dosing implications based on the results of the pharmacokinetic drug-drug interaction trials with TMC278 at a dose of 150 mg once daily can be extrapolated to a dose of TMC278 25 mg once daily.

The proposed prescribing information does not include the TMC278 dose used in the drug- drug interaction trials in the pharmacokinetic interaction table summarizing the outcome of these trials, unless required otherwise by health authorities. As a number of these trials are performed with a higher dose compared to the recommended dose of TMC278, the intent is to avoid any potential confusion towards dosing requirements for TMC278 in combination with these other comedications. Misinterpretation of the information provided in the prescribing information could lead to overdosing of TMC278.

The solubility of TMC278 is pH dependent (see Section 2.5.3.3.1.2.1). Drugs that alter intra-gastric pH may affect the solubility of TMC278 (i.e., reduced solubility at higher pH) in vivo and can therefore also indirectly affect the absorption of TMC278. This was shown in vivo in drug-drug interaction trials with omeprazole and famotidine, which both significantly

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decreased the exposure to TMC278 150 mg once daily when coadministered. Based on this, TMC278 should not be used in combination with proton pump inhibitors (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole) as coadministration may cause significant decreases in TMC278 plasma concentrations. This may result in loss of therapeutic effect of TMC278. For drugs with a short-lived effect on intragastric pH, such as the histamine-2 (H2)-antagonists and antacids, an effect on TMC278 exposure can be avoided by separating the intake of the drugs in time, as has been shown in the drug-drug interaction trial with famotidine. The combination of TMC278 and H2-receptor antagonists or antacids should be used with caution as coadministration may cause significant decreases in TMC278 plasma concentrations. H2-receptor antagonists should only be administered either 12 hours before or 4 hours after TMC278, and antacids should only be administered either 2 hours before or 4 hours after TMC278.

An additional trial (C154) is ongoing to investigate the interaction between omeprazole and TMC278 administered at doses of 25 and 50 mg once daily.

Details on trials studying the potential for drugs to affect TMC278 are presented in Module 2.7.2.3.1.9.2.

2.5.3.4.3. Clinically Important Drug Interactions

2.5.3.4.3.1. Emtricitabine

No clinically relevant drug interactions have been identified between FTC and the coadministered drugs investigated (i.e., TDF, d4T, indinavir (IDV), and zidovudine (ZDV) and famciclovir (Studies FTC-114, FTC-103, FTC-104, and FTC-115, and FTC-108).

2.5.3.4.3.2. Rilpivirine

When TMC278 was coadministered with didanosine (ddI) or TDF in healthy subjects, no clinically relevant changes occurred in the pharmacokinetic parameters for TMC278 or either coadministered drug (Trials C106 and C104). In addition, no treatment effect was shown for the urinary excretion of TFV in the presence of TMC278. TDF and ddI can be coadministered with TMC278 without dose adjustment for either drug. However, intakes of TMC278 and ddI need to be separated in time due to differences in meal requirements (ddI is recommended for administration on an empty stomach and TMC278 with a meal).

The effects of TMC278 on other NRTIs, and vice versa, have not been formally evaluated. Because TMC278 has negligible renal elimination (< 1%), no clinically relevant drug-drug interactions are expected between drugs that are primarily renally eliminated and TMC278. These drugs include NRTIs such as ABC, FTC, 3TC, d4T, and AZT. In the Phase 2b trial C204 the TMC278 dose level did not affect the pharmacokinetics of AZT and AZT-glucuronide. Also, the pharmacokinetics of TMC278 are not expected to be affected by these NRTIs. Therefore, TMC278 can be coadministered with NRTIs without dose adjustments.

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As mentioned above, TMC278 can be coadministered with lopinavir (LPV)/rtv (Trial C105) or with darunavir (DRV)/rtv (Trial C112) without dose adjustments. No drug-drug interaction trials have been performed with TMC278 and other PIs (either rtv-boosted or unboosted).

No clinically relevant drug-drug interaction is expected when TMC278 is coadministered with the integrase strand transfer inhibitor raltegravir or with the CCR5 antagonist maraviroc, given the facts that these drugs do not affect pH or CYP3A enzyme activity at the recommended dose in vivo, and TMC278 25 mg once daily is not expected to impact the metabolism of these drugs.

In conclusion, TMC278 has a well-characterized drug-drug interaction profile and can be used without dose modification or adjustment with all currently available N(t)RTIs, the boosted PIs DRV/rtv and LPV/rtv, and with raltegravir and maraviroc. Drugs that alter intra-gastric pH may affect the solubility of TMC278, therefore TMC278 should not be coadministered with proton pump inhibitors since coadministration may cause significant decreases in TMC278 plasma concentrations. For drugs with a short-lived effect on intra-gastric pH, such as the H2-antagonists and antacids, an effect on TMC278 exposure can be circumvented by separating the intake of the drugs in time. TMC278 should not be taken with CYP3A inducers as these could decrease TMC278 plasma concentrations, and potentially reduce the therapeutic effect of TMC278. TMC278 can be used with many other medications generally used in HIV-1 infected patients.

A summary of coadministration recommendations based on drug-drug interaction trials or predicted interaction for TMC278 is presented in Table 3.

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Table 3. Coadministration Recommendations Based on Drug-Drug Interaction Trials or Predicted Interaction (Rilpivirine)

Coadministration without Dose Coadministration with specific Coadministration Not Adjustment instructions Recommended x N(t)RTIs, other than ddI x ddI (which should be x inducers of CYP3A (e.g., TDF, ABC, FTC, 3TC, administered on an empty (e.g., rifampin, rifabutin, d4T, AZT) stomach) should be administered rifapentine, St John’s wort, x boosted PIs LPV/rtv and separated in time from TMC278 systemic dexamethasone, DRV/rtva (which should be administered carbamazepine, with a meal). oxcarbazepine, x raltegravir, maraviroc x when coadministering with phenobarbital, phenytoin). x ribavirin methadone, dose adjustment is x proton pump inhibitors x azole antifungal agents not needed when initiating (e.g., omeprazole, (including ketoconazole) treatment with TMC278 but lansoprazole, rabeprazole, x atorvastatin clinical monitoring for methadone pantoprazole, esomeprazole) withdrawal symptoms is x estrogen- and/or recommended. Methadone progesterone-based maintenance therapy may need to contraceptives be adjusted in some patients. x paracetamol x H2-antagonists (e.g., famotidine) or antacids, can be coadministered if separated in time. x clarithromycin, erythromycin, and troleandomycin may cause an increase in the plasma concentrations of TMC278. Where possible, alternatives such as azithromycin should be considered. a The combination of TMC278 with other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) or unboosted PIs (atazanavir, indinavir, nelfinavir) has not been studied; coadministration may cause an increase in the plasma concentrations of TMC278.

2.5.3.4.3.3. Tenofovir DF

No clinically relevant pharmacokinetic interactions between TDF and other antiretroviral drugs tested (i.e., abacavir, EFV, FTC, indinavir, 3TC, LPV/r, nelfinavir, or saquinavir/ritonavir) have been observed, with the exception of increased ddI exposure and decreased atazanavir (without ritonavir) described below. After multiple dosing to non-HIV infected subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state TFV pharmacokinetics were similar to those observed in previous studies, indicating a lack of clinically significant drug interactions between these agents and TDF.

Atazanavir/Ritonavir

In subjects failing antiretroviral therapy, addition of TDF to rtv-boosted atazanavir (300 mg) resulted in a trend towards reduction of both ritonavir and atazanavir pharmacokinetic parameters (PUZZLE 2 study) {6043}. The AUC and Cmin of atazanavir were decreased by

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approximately 25% and 23%, respectively, but were 1.2- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone in healthy volunteers. It is recommended that TDF should only be administered with boosted atazanavir (300 mg with 100 mg ritonavir).

Lopinavir/Ritonavir

Coadministration of TDF and LPV/r in Studies GS-00-909 and GS-01-943 resulted in an approximate 30% increase in Cmax and AUCtau of TFV relative to administration of TDF alone. This increase in TFV exposure is not considered clinically relevant with respect to an alteration in the clinical safety or efficacy profile of TDF and does not require a dose modification. Results of these 2 studies, when assessed alone or in a pooled analysis, established that TDF does not have a clinically significant effect on the pharmacokinetics of LPV/r and that a high lopinavir inhibitory quotient is maintained with their concomitant use. Although Study GS-00-909 showed that systemic exposures (AUCtau) of lopinavir and ritonavir were 15% and 24% lower when dosed with TDF versus when dosed alone, in Study GS-01-943 TDF did not affect the steady-state pharmacokinetics of lopinavir or ritonavir. The numerical differences observed between the 2 studies are likely due to a variety of factors that may include, but are not limited to, subject compliance to the study protocol, sampling variability, subject demographics, and meal types. Study M02-418 has demonstrated the efficacy and safety of TDF in PI regimens with once or twice daily LPV/r (see Section 2.5.4.4.3).

Coadministration with Didanosine (ddI)

“ In drug interaction studies of TDF and ddI (Videx ), the Cmax and AUC of ddI 400 mg, administered as either the buffered tablets or enteric-coated capsules, increased significantly (Studies GS-00-909 and GS-01-932). The likely mechanism of this interaction is inhibition of purine nucleoside phosphorylase (PNP) by TFV, which decreases PNP-mediated metabolic degradation of ddI and, hence, increases ddI drug levels {6054}. However, when a reduced dose of ddI (250-mg enteric-coated [EC] capsules) was administered in the fasted state 2 hours before TDF, systemic exposures to ddI were similar to those seen with the 400-mg enteric-coated capsules alone (Study GS-02-984). In a study sponsored by Bristol-Myers Squibb Company, 250 mg or 325 mg of ddI EC coadministered with 300 mg of TDF and food resulted in ddI exposures that were similar to 400 mg of ddI (EC) fasted {4620}.

A possible outcome of the increased AUC of ddI with concomitant administration of TDF would be an increased incidence of ddI-related adverse events (AEs), specifically pancreatitis, which is dose-related {6266}. Safety data from clinical studies of TDF did not indicate a higher risk of ddI-related AEs in subjects coadministered TDF and ddI. From individual case reports of suspected drug interactions received during postmarketing experience, it is difficult to determine whether TDF increased the risk of ddI-related adverse reactions. The proposed FTC/RPV/TDF prescribing information describes that rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported following coadministration of ddI and TDF.

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Preliminary analyses of several small studies in antiretroviral-naive subjects treated with a regimen of TDF, ddI (250 mg), and EFV {6923}, {7399}, {7325} indicated a higher than expected incidence of early virological failure and emergence of resistance. Suppression of CD4 cell counts has been observed in patients receiving TDF with ddI at a dose of 400 mg daily.

The EU prescribing information states that coadministration of TDF and ddI is not recommended.

2.5.3.4.3.4. The FTC/RPV/TDF FDC tablet

Based upon experience with the components, coadministration of FTC/RPV/TDF FDC tablet and ddI is not recommended, since the exposure of ddI is significantly increased following coadministration with TDF. In addition, coadministration of the FTC/RPV/TDF FDC tablet with proton pump inhibitors and inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, St John’s wort, systemic dexamethasone, carbamazepine, oxcarbazepine, phenobarbital, phenytoin) is not recommended.

The FTC/RPV/TDF FDC tablet should not be coadministered with related drugs that contain the same active components (i.e., FTC, RPV, or TDF), including Emtriva, RPV, Viread, Truvada, and Atripla. Because of similarities with FTC or with TDF, FTC/RPV/TDF FDC tablets should not be coadministered with other cytidine analogs, such as 3TC (including Combivir, Epivir“, Epivir-HBV“, Kivexa“ [Epzicom], and Trizivir), or with Hepsera (adefovir dipivoxil).

2.5.3.5. Summary of Clinical Pharmacology

Emtricitabine and TFV are potent and selective inhibitors of HIV-1. They are phosphorylated intracellularly through nonoverlapping pathways and in combination show no antagonism for the formation of their active metabolites. The anti-HIV-1 activity of the 2-drug combinations of FTC, RPV, and TFV were found to be additive to synergistic in multiple in vitro assay systems.

The pharmacokinetic profiles of the separate formulations of FTC, RPV, and TDF, including studies in HIV-1 infected subjects and certain special populations, have been well established. Clinically relevant differences in the pharmacokinetics of the FTC/RPV/TDF FDC with respect to demographic variables are not anticipated based on data available for FTC, RPV, and TDF.

Both FTC and TFV are primarily renally excreted intact. In subjects with mild renal impairment, the pharmacokinetics of TFV and FTC are not substantially altered to warrant dose adjustment. Dosing interval adjustment is required in patients with CLcr between 30 and 49 mL/min (one FTC/TDF tablet every 48 hours) and FTC/TDF tablets are not recommended for patients with CLcr < 30 mL/min and in patients who require hemodialysis. The proposed prescribing information for the FTC/RPV/TDF tablet states that patients with moderate to severe renal impairment (CLcr < 50 mL/min) require dosing interval adjustment that cannot

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be achieved with the FTC/RPV/TDF FDC tablet, and therefore use of the FDC tablet cannot be recommended (see Sections 2.5.5.12 and 2.5.6).

The FTC/RPV/TDF FDC tablet should not be administered concomitantly with other medicinal products containing any of the same components (including FTC, RPV, TDF, FTC/TDF, or EFV/FTC/TDF). Due to similarities with FTC, the FTC/RPV/TDF FDC tablet should not be administered concomitantly with other cytidine analogues, such as lamivudine. The FTC/RPV/TDF FDC tablet should not be administered concomitantly with adefovir dipivoxil.

Based upon the significant increase in exposure to ddI following coadministration with TDF, coadministration of the FTC/RPV/TDF FDC tablet with ddI is not recommended.

No clinically relevant drug interactions have been identified between FTC and the coadministered drugs investigated. Based on the drug-drug interaction profile of RPV (see Section 2.5.3.4.2), the FTC/RPV/TDF FDC tablet should not be coadministered with proton pump inhibitors since coadministration may cause significant decreases in TMC278 plasma concentrations. For drugs with a short-lived effect on intragastric pH, such as the H2-antagonists and antacids, an effect on RPV exposure can be circumvented by separating the intake of the drugs in time. The FTC/RPV/TDF FDC tablet should not be taken with CYP3A inducers as these could decrease TMC278 plasma concentrations, and potentially reduce the therapeutic effect of RPV. No clinically relevant pharmacokinetic interactions between TDF and other antiretroviral drugs tested. After multiple dosing to non-HIV infected subjects receiving chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state TFV pharmacokinetics indicated a lack of clinically significant drug interactions between these agents and TDF.

No drug interaction studies have been conducted with the FTC/RPV/TDF FDC tablet on the basis that available drug interaction data and clinical study experience with use of concomitant medications during treatment with the individual dosage forms are sufficient to allow assessment of the potential for any drug interactions between the FDC tablet and other medications frequently used by the HIV infected population. The proposed prescribing information for the FTC/RPV/TDF FDC tablet describes all relevant drug interactions.

2.5.4. Overview of Efficacy

More detailed information on the results of individual efficacy trials is provided in Module 2.7.3. The use of FTC/RPV/TDF FDC tablets indicated for the treatment of HIV-1 infection is supported by data from the individual components (FTC, RPV, and TDF), as well data from studies with FDCs of 2 of the components (FTC/TDF) and studies with all 3 of the components. In this overview of efficacy, data are presented for Truvada (see Section 2.5.4.4) and the FTC/RPV/TDF FDC tablet (see Section 2.5.4.5). See Module 2.7.3 for efficacy data for FTC, RPV, and TDF (cross references for results of individual studies are provided below).

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2.5.4.1. Efficacy of Emtricitabine

The following supportive studies for FTC are described in Module 2.7.3.2.1: x FTC-301A: Module 2.7.3.2.1.1.1 x FTC-302: Module 2.7.3.2.1.1.2 x FTC-303: Module 2.7.3.2.1.2.1

2.5.4.2. Efficacy of Rilpivirine

The 2 Phase 3 registrational studies, Trial C209 and Trial C215, are summarized in Section 2.5.4.5. The following supportive studies for RPV are described in Module 2.7.3.2.2: x TMC278-C204: Module 2.7.3.2.2.2 x R278474-C201: Module 2.7.3.2.2.3.1 x R278474-C202: Module 2.7.3.2.2.3.2

2.5.4.3. Efficacy of Tenofovir DF

The following supportive studies for TDF are described in Module 2.7.3.2.3: x GS-99-903: Module 2.7.3.2.3.1.1 x GS-98-902: Module 2.7.3.2.3.2.1 x GS-99-907: Module 2.7.3.2.3.2.2

2.5.4.4. Efficacy of the Truvada FDC Tablet

The use of the Truvada tablet is principally supported by data from Studies GS-01-934, GS-99-903, and M02-418, as follows: x GS-01-934 is a completed, Phase 3, 288-week, open-label study, in which the once-daily regimen of FTC, TDF, and EFV (administered as the individual products [FTC + TDF + EFV] for the first 96 weeks and subsequently as the fixed-dose combination of FTC/TDF (Truvada) and EFV [FTC/TDF + EFV] through 144 weeks) was compared with the fixed-dose combination of Combivir administered twice daily and EFV once daily (CBV + EFV). After completing 144 weeks of treatment, subjects from both treatment groups switched to a once-daily regimen of FTC, TDF, and EFV (as the Atripla tablet) in a 96-week extension period (144 weeks at sites in EU countries where Atripla was not launched at the time) (see Module 2.7.3.2.4.1).

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x GS-99-903 is an ongoing, Phase 3, 624-week study in which the regimen of TDF + 3TC + EFV was compared with a regimen of d4T + 3TC + EFV in a double-blinded fashion for the first 144 weeks; from Week 144 to Week 480, patients at selected sites received open label TDF + 3TC + EFV; from Weeks 480 to 624 the regimen of TDF + 3TC + EFV changed to open label FTC/TDF (Truvada) + EFV. Subjects who were randomized to TDF in the double-blind phase continued TDF treatment in the open-label phase. Subjects who were randomized to d4T in the double-blind phase were switched from d4T to TDF in the open-label phase. The experience with the TDF + 3TC + EFV regimen is relevant to the efficacy of the Truvada tablet because (a) 3TC is a cytidine analog that is structurally closely related to FTC; (b) the resistance profiles of 3TC and FTC, characterized by M184V/I development, are similar; and (c) in Study FTC-303, FTC demonstrated equivalent antiviral efficacy and safety to 3TC when each was administered in a triple combination regimen to stable treatment-experienced subjects (see Module 2.7.3.2.4.2). x M02-418 was a Phase 3, 96-week, open-label, randomized, multicenter study in which antiretroviral-naive, HIV infected subjects received FTC and TDF once daily in combination with a PI (800 mg/200 mg LPV/r once daily or 400 mg/100 mg LPV/r twice daily) (see Module 2.7.3.2.4.3).

Studies GS-01-934, GS-99-903, and M02-418 were of an adequate design and duration, as recommended in applicable regulatory guidance, to establish the efficacy and safety of the antiretroviral regimens under investigation for the treatment of HIV-1 infection. The main study design and population characteristics are summarized in Table 4.

Supportive evidence for the efficacy of Truvada is provided from studies in which antiretroviral-experienced subjects switched their NRTIs to Truvada (Studies GS-MC-164-0111, GS-US-164-0107, GS-DE-164-0106, and GS-ES-164-0154) and an open-label single group study in antiretroviral-naive subjects (Study GS-US-164-0115).

The following supportive studies are described in Module 2.7.3.2.5: x GS-MC-164-0111: Module 2.7.3.2.5.1 x GS-ES-164-0154: Module 2.7.3.2.5.2 x GS-US-164-0107: Module 2.7.3.2.5.3.1 x GS-DE-164-0106: Module 2.7.3.2.5.3.2 x GS-US-164-0115: Module 2.7.3.2.5.3.3

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Table 4. Principal Clinical Studies that Support Use of the Truvada Tablet – Design and Population Characteristics

Treatment No. of HIV-1 Characteristics at Study Design Population Regimens Subjectsa Duration Demographics Study Entry (Mean)

GS-01-934 Randomized (1:1), Treatment-naive EFVFTCTDF to 511 288 weeks Male (86%) HIV-1 RNA 5.01 log10 open-label, active- subjects (HIV-1 Week 96, then (completed) White (59%) copies/mL controlled, RNA ! 10,000 EFV+FTC/TDF Mean age 38 years 51% ! 100,000 copies/mL noninferiority study copies/mL) vs CD4 count 245 cells/mm3 EFVCombivir

From Week 144: Atripla for all subjects

GS-99-903 Randomized (1:1), Treatment-naive Up to Week 480 600 144 weeks Male (74%) HIV-1 RNA 4.9 log10 double-blind, active- subjects (HIV-1 TDF+3TC+EFV double-blind White (64%) copies/mL controlled study RNA ! 5000 vs phase, Mean age 36 years 43% ! 100,000 copies/mL. copies/mL) d4T+3TC+EFV followed by CD4 count 279 cells/mm3 Week 480 to Week 336-week 624 TDF+EFV vs open-label d4T+3TC+EFV phase at selected At selected centers centers after Week 144, (ongoing) TDF+3TC+EFV for all subjects

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Treatment No. of HIV-1 Characteristics at Study Design Population Regimens Subjectsa Duration Demographics Study Entry (Mean)

M02-418 Randomized (3:2), Treatment-naive FTC+TDF+LPV/r 190 96 weeks Male (78%) HIV-1 RNA 4.9 log10 open-label, active- subjects (HIV-1 (800 mg/200 mg (completed) White (54%) copies/mL in the once daily controlled, RNA ! 1000 once daily or Mean age 38 years group and 4.7 log10 noninferiority study copies/mL) 400 mg/100 mg copies/mL in the twice twice daily) daily group

CD4 count 266 cells/PL in the once daily group and 250 cells/PL in the twice daily group a Number of subjects randomized who received at least 1 dose of study medication.

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2.5.4.4.1. Efficacy in Study GS-01-934

In Study GS-01-934, both the FTC + TDF + EFV and CBV + EFV treatment groups demonstrated potent efficacy through 48 weeks of treatment (Table 32 has information regarding longer term data). The percentage of responders who achieved and maintained confirmed HIV-1 ribonucleic acid (RNA) 400 and 50 copies/mL (US FDA time-to-loss- of-virologic-response [TLOVR] algorithm analysis) was significantly higher in the FTC + TDF + EFV group compared with the CBV + EFV group for both the modified intent-to-treat (MITT) analysis set and the intent-to-treat (ITT) analysis set (Table 5). The MITT set excluded subjects who were antiretroviral treatment-experienced or had primary NNRTI resistance mutations at baseline. The ITT set included all subjects who were randomized into the study, received at least 1 dose of study medication, and had no major protocol eligibility violations, e.g., prior antiretroviral treatment.

Table 5. GS-01-934: Treatment Outcomes at Week 48 (TLOVR Analysis)

FTCTDFEFV CBVEFV Treatment Outcome at Week 48 n/N % n/N %

Responder (HIV-1 RNA 400 copies/mL), MITT 206/244 84% 177/243 73% p-valuea 0.002 Difference (95% CI)b 11% (4% to 19%)

Responder (HIV-1 RNA 400 copies/mL), ITT 207/255 81% 179/254 71% p-valuea 0.005 Difference (95% CI)b 11% (3% to 18%)

Responder (HIV-1 RNA 50 copies/mL), MITT 194/244 80% 171/243 70% p-valuea 0.021 Difference (95% CI)b 9% (2% to 17%)

Responder (HIV-1 RNA 50 copies/mL), ITT 195/255 77% 173/254 68% p-valuea 0.034 Difference (95% CI)b 9% (1% to 16%)

a The p-value was based on the Cochran-Mantel-Haenszel test stratified on baseline CD4 cell count. b The difference and 95% confidence interval were stratum weighted on baseline CD4 cell count using normal approximation. Source: Module 5.3.5.1, GS-01-934 48-Week CSR, Section 11.1, Tables 11, 12, 13, and 14

Noninferiority was predefined for the 48-week primary endpoint as a 95% CI of the treatment difference (FTC + TDF + EFV group minus CBV + EFV group) in the proportion of subjects with sustained viral suppression below 400 copies/mL with a lower bound greater than 0.13. Because the 95% CIs (MITT and ITT) for the treatment effect lie entirely above the limit of t 0.13 required for demonstration of noninferiority and, furthermore, lie entirely above zero, and because the p-values support rejection of the null hypothesis of no difference

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between the treatment groups, the FTC + TDF + EFV regimen was concluded to be superior to the CBV + EFV regimen.

The once-daily regimen of EFV + FTC + TDF demonstrated continued significant and potent antiretroviral efficacy through 144 weeks of treatment in Study GS-01-934. A significantly higher proportion of subjects in the FTC + TDF group (71%, 161/227) compared with the Combivir group (58%, 133/229) were Week 144 responders (HIV-1 RNA < 400 copies/mL; p = 0.004; 95% CI, 4% to 22%, Table 6). Similarly, the proportion of Week 144 responders (HIV-1 RNA < 50 copies/mL) was higher for the FTC + TDF group (64%, 146/227) compared with the Combivir group (56%, 130/231), although the difference was not statistically significant (p = 0.082).

Table 6. GS-01-934: Treatment Outcomes at Week 144 (TLOVR Analysis, Week 144 Efficacy Analysis Set)

EFV + FTC + TDF EFV + Combivir Treatment Outcome at Week 144 n/N % n/N %

Responder (HIV-1 RNA 400 copies/mL) 161/227 71% 133/229 58% p-valuea 0.004 Difference (95% CI)b 13% (4% to 22%)

Responder (HIV-1 RNA 50 copies/mL) 146/227 64% 130/231 56% p-valuea 0.082 Difference (95% CI)b 8% (1% to 17%) a The p-value was based on the Cochran-Mantel-Haenszel test stratified on baseline CD4 cell count. b The difference and 95% confidence interval were stratum weighted on baseline CD4 cell count using normal approximation. Source: Module 5.3.5.1, GS-01-934, 144-week CSR, Section 11.1, Table 14

Significantly greater proportions of subjects in the FTC + TDF group compared with the Combivir group achieved suppression of plasma HIV-1 RNA to 400 copies/mL and 50 copies/mL at Week 144 in both the ITT missing-or-switch-equals-failure and the ITT missing-equals-failure (M = F) analyses. The 144-week results also demonstrate high rates of virologic response to treatment with EFV +FTC + TDF in subjects with high baseline viral load (plasma HIV-1 RNA ! 100,000 copies/mL) and subjects with CD4 cell counts t 200 cells/mm3.

Changes in plasma HIV-1 RNA concentrations from baseline to Week 144 were similar between the 2 treatment groups in Study GS-01-934. Mean decreases of 3.32 log10 copies/mL for the FTC + TDF group and 3.30 log10 copies/mL for the Combivir group were observed (Figure 1).

CD4 cell counts increased over time for both treatment groups in Study GS-01-934 (Figure 2). At Week 144, mean increases of 312 cells/mm3 for the FTC + TDF group and 271 cells/mm3 for the Combivir group were observed.

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Figure 1. GS-01-934: Mean (95% CI) Change from Baseline in HIV-1 RNA by Study Visit (AT Analysis Set)

Source: Module 5.3.5.1, GS-01-934, 144-week CSR, Section 11.1, Figure 9

Figure 2. GS-01-934: Mean (95% CI) Change From Baseline in CD4 Cell Count (AT Analysis Set)

Source: Module 5.3.5.1, GS-01-934, 144-week CSR, Section 11.1, Figure 10

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2.5.4.4.2. Efficacy in Study GS-99-903

In Study GS-99-903, the regimens of TDF + 3TC + EFV and d4T + 3TC + EFV demonstrated potent and durable efficacy during 144 weeks of treatment. At Weeks 48, 96, and 144, the percentages of subjects with HIV-1 RNA levels 400 copies/mL and 50 copies/mL were similar between the treatment groups (Table 7).

Table 7. GS-99-903: Summary of Response Rates of HIV-1 RNA 400 and 50 Copies/mL (ITT Population, Missing/Switch = Failure)

TDF+3TC+EFV d4T+3TC+EFV Difference Response Rate (N=299) (N=301) (TDF-d4T) 95% CIa

400 copies/mL, n/N (%) Week 48 239/299 (80%) 253/301 (84%) 4% (10%, +2%) Week 96 226/299 (76%) 214/301 (71%) +4% (3%, +11%) Week 144 211/299 (71%) 193/301 (64%) +7% (1%, +14%) 50 copies/mL, n/N (%) Week 48 228/299 (76%) 240/301 (80%) 3% (10%, +3%) Week 96 217/299 (73%) 204/301 (68%) +5% (2%, +12%) Week 144 203/299 (68%) 188/301 (63%) +6% (2%, +13%) a Stratum weighted difference in percent and stratum weighted 95% confidence interval for difference in percent. Source: Module 5.3.5.1, GS-99-903 144-Week CSR; Section 15.3, Week 144 Tables 8.2 and 10.2

Following 144 weeks of double-blind treatment, there was a high proportion of subjects with HIV-1 RNA < 400 copies/mL and < 50 copies/mL: 71% and 68%, respectively, for the TDF + 3TC + EFV group compared with 64% and 63%, respectively, for the d4T + 3TC + EFV group. Subgroup analyses at Week 144 confirmed high rates of virologic response in subjects with baseline viral load ! 100,000 copies/mL and with CD4 cell count 200 cells/mm3 treated with the TDF + 3TC + EFV regimen.

Durable viral load suppression was demonstrated throughout this extended treatment period, and was accompanied by increasing CD4 cell counts from baseline levels (Figure 3 and Figure 4).

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Figure 3. GS-99-903: Mean (95% CI) Change from Baseline in Plasma HIV-1 RNA Levels (ITT Analysis Set)

0 0

-1 -1

-2 -2

-3 -3 Change in HIV-1 RNA HIV-1 in Change

-4 -4

-5 -5 BL8 1624324048566472808896 120 144 Weeks on Study TDF+3TC+EFV: 299 289 285 280 273 264 272 261 259 258 253 255 253 243 242 d4T+3TC+EFV: 301 288 284 283 271 268 273 269 260 262 257 256 253 242 237

Source: Module 5.3.5.1, GS-99-903 144-Week CSR; Section 15.3, Week 144 Figure 2.1

Figure 4. GS-99-903: Mean (95% CI) Change from Baseline in CD4 Cell Count (ITT Analysis Set)

500 500

400 400

300 300

200 200 Change in CD4

100 100

0 0 BL8 1624324048566472808896 120 144 Weeks on Study TDF+3TC+EFV: 299 274 282 275 269 246 264 257 257 257 249 252 252 242 239 d4T+3TC+EFV: 301 278 281 280 272 250 270 266 258 258 254 254 248 237 234 Source: Module 5.3.5.1, GS-99-903 144-Week CSR; Section 15.3, Week 144, Figure 3.1

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After 144 weeks of double-blind treatment, subjects at selected study sites were offered the option to continue into a 336-week, open-label, extension phase of Study GS-99-903 in which all subjects receive the regimen of TDF + 3TC + EFV. Table 32 has additional information regarding the longer-term data.

For the subset of subjects who continued on the TDF regimen (TDF/TDF group; n = 86) in the open-label phase, interim analyses demonstrate potent and durable efficacy through 240 weeks of treatment. The percentages of subjects in the TDF/TDF group with plasma HIV-1 RNA concentrations < 400 copies/mL and < 50 copies/mL at Week 240 (open-label Week 96) were 87% (75 of 86 subjects) and 83% (71 of 86), respectively (M = F analysis).

Virologic response was maintained in virologically-suppressed subjects who switched from the d4T regimen to the TDF regimen (d4T/TDF group; n = 85). Following 96-weeks of open-label treatment with TDF, the percentages of subjects with plasma HIV-1 RNA concentrations < 400 copies/mL and < 50 copies/mL were 95% (81 of 85 subjects) and 91% (77 of 85), respectively (M = F analysis).

The immunologic benefits of treatment as demonstrated by increasing CD4 cell count continued during long-term treatment. For the TDF/TDF group the mean increases from double-blind baseline at Weeks 144 and 240 were 273 and 421 cells/mm3, respectively. After the switch from d4T to open-label TDF, the mean increase from open-label baseline at open- label Week 96 for the d4T/TDF group was 118 cells/mm3.

2.5.4.4.3. Efficacy in Study M02-418

In Study M02-418, the regimens of FTC + TDF + LPV/r (once or twice daily) demonstrated potent and durable efficacy during 96 weeks of treatment. No statistically significant differences were observed between the once daily and twice daily groups for the proportions of subjects achieving plasma HIV-1 RNA < 50 copies/mL at Weeks 48 or 96. At Week 48, 70% of the subjects in the once daily group and 64% of subjects in the twice daily group achieved plasma HIV-1 RNA < 50 copies/mL using the ITT (noncompleter=failure [NC = F]) analysis (Table 8). At Week 96, 57% of the subjects in the once daily group and 53% of subjects in the twice daily group achieved plasma HIV-1 RNA < 50 copies/mL using the ITT (NC = F) analysis.

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Table 8. M02-418: Proportion of Subjects with HIV-1 RNA < 50 Copies/mL at Weeks 48 and 96

FTC + TDF + LPV/r FTC + TDF + LPV/r 95% Confidence 800/200 mg 400/100 mg Interval for Analysis Type Once Daily Twice Daily p-valuea Difference Week 48 ITT (NC = F) 81/115 (70%) 48/75 (64%) 0.353 –7.3%, 20.1% ITT (M = F) 80/115 (70%) 47/75 (63%) 0.324 –6.9%, 20.7% ITT (LOCF) 91/115 (79%) 54/75 (72%) 0.258 –5.5%, 19.7% Observed Data 80/89 (90%) 47/54 (87%) 0.600 –8.1%, 13.8% Week 96 ITT (NC = F) 66/115 (57%) 40/75 (53%) 0.582 –10.4%, 18.5% ITT (M = F) 66/115 (57%) 40/75 (53%) 0.582 –10.4%, 18.5% ITT (LOCF) 88/115 (77%) 53/75 (71%) 0.367 –7.0%, 18.8% Observed Data 66/74 (89%) 40/44 (91%) 0.765 –12.8%, 9.3%

LOCF, last observation carried forward a Comparing groups Source: Module 5.3.5.1, M02-418 CSR, Table 9

In both groups, statistically significant (p < 0.001) decreases in mean plasma HIV-1 RNA levels were seen as early as the first visit following the baseline evaluation and were maintained at all subsequent visits through Week 96. The mean decrease from baseline to Week 48 was 3.14 log10 copies/mL in the once daily group and 3.00 log10 copies/mL in the twice daily group. The mean decrease from baseline to Week 96 was 3.09 log10 copies/mL in the once daily group and 3.09 log10 copies/mL in the twice daily group.

Statistically significant (p < 0.001) increases in mean CD4 cell counts in both groups were observed at all visits. The mean change from baseline to Week 48 was 185 cells/PL in the once daily group and 196 cells/PL in the twice daily group. The mean change from baseline to Week 96 was 244 cells/PL in the once daily group and 264 cells/PL in the twice daily group. No statistically significant differences were observed between the once daily and twice daily groups in mean change from baseline in CD4 cell counts at any time point.

2.5.4.5. Efficacy of the FTC/RPV/TDF FDC Tablet

The use of the FTC/RPV/TDF FDC tablet is principally supported by data from the 2 Phase 3 Studies C209 and C215, as follows: x Week 48 efficacy data was pooled from the 2 ongoing registrational Phase 3 trials, C209 and C215. The pooled efficacy results from analyses performed when all subjects completed 48 weeks of treatment or discontinued earlier from these 2 Phase 3 trials (up to the cut-off date of 01 February 2010 for C209 and 28 January 2010 for C215) are

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presented in Section 2.5.4.5.1. The trials enrolled treatment-naive subjects. These pooled data provide the key efficacy results for TMC278 in this patient population. A pooling of the efficacy results of the 2 Phase 3 trials C209 and C215 was performed and a meta-analysis was performed in accordance with the ICH E9 guideline (Note for guidance on statistical principles for clinical trials. CHMP/ICH/363/96, 1996). Combining the efficacy results from the 2 trials was deemed appropriate based on the similarity in the trial designs. The main purposes of the pooled efficacy analysis were to determine a more precise overall treatment effect, to evaluate efficacy in prespecified relevant subgroups, to compile comprehensive data for the determination of the resistance profile of TMC278, and to gain a better understanding of any pharmacokinetic/pharmacodynamic relationship. Noninferiority of TMC278 versus control (EFV) was to be established in each of the 2 Phase 3 studies separately. Any clinically relevant differences between the trials are discussed. x A subanalysis of the virologic outcomes using pooled data for subjects receiving RPV or EFV in combination with FTC/TDF was performed and is presented in Section 2.5.4.5.1.

Trials C209 and C215 were of an adequate design and duration, as recommended in applicable regulatory guidance, to establish the efficacy and safety of the antiretroviral regimens under investigation for the treatment of HIV-1 infection. The main study design and population characteristics are summarized in Table 9.

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Table 9. Principal Clinical Studies that Support Use of the FTC/RPV/TDF FDC Tablet – Design and Population Characteristics

Treatment Regimens (Formulation F No. of HIV-1 Characteristics at Study Design Population Number)a Subjectsb Duration Demographics Study Entry (median) C209 Phase 3, randomized, HIV-1 infected, TMC278 690 96 weeksc Male 78.7% Viral Load: TMC278 Group (ECHO) double blind, treatment-naive 25 mg once daily Ongoing White 60.9 = 94,950 copies/mL; double-dummy, subjects (F006) (n = 346) Mean age 37years Control Group = 105,000 active-controlled Or copies/mL international trial EFV 600 mg once CD4 count: TMC278 Group daily = 240 cells/PL; Control (n = 344) Group = 257 cells/PL

Both groups receive a fixed background regimen of FTC/TDF

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Treatment Regimens (Formulation F No. of HIV-1 Characteristics at Study Design Population Number)a Subjectsb Duration Demographics Study Entry (median) C215 Phase 3, randomized, HIV-1 infected, TMC278 678 96 weeksc Male 72.9% Viral Load: TMC278 Group (THRIVE) double blind, treatment-naive 25 mg once daily Ongoing White 60.7 = 83,950 copies/mL; double-dummy, subjects (F006) (n = 340) Median age Control Group = 102,500 active-controlled Or 36 years copies/mL international trial EFV 600 mg once CD4 count: TMC278 Group daily = 263 cells/PL; Control (n = 338) Group = 263 cell/PL

Both groups receive a background regimen of 2 investigator- selected N(t)RTIs (ABC/3TC; AZT/3TC or FTC/TDF) a Oral film-coated tablets b Subjects randomized and treated c This Clinical Overview includes data up to and including the Week 48 primary analysis time point

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2.5.4.5.1. Subanalysis of the Virologic Outcomes using Pooled Data for Subjects Receiving RPV or EFV in Combination with FTC/TDF

In the Phase 3 RPV trials, the investigational ARV treatment (TMC278 or EFV as control) had to be administered in combination with a background regimen consisting of 2 N(t)RTIs. As defined in the protocol, all subjects in trial C209 took FTC/TDF as their background regimen. In trial C215 the background regimen consisted of 2 investigator-selected N(t)RTIs: the majority of subjects took FTC/TDF (approximately 60%), whereas the remaining subjects in this trial took AZT/3TC (approximately 30%) or ABC/3TC (approximately 10%). As a result, most subjects in the pooled Phase 3 analysis (approximately 80%) took FTC/TDF as their background regimen, in both treatment groups. A subanalysis of the virologic outcomes using pooled data for subjects receiving RPV or EFV in combination with FTC/TDF was performed.

Treatment outcomes through 48 weeks for subjects who received FTC/TDF (N = 1096) in C209 and C215, are presented in Table 10 (TLOVR analysis) and Table 11 (Snapshot analysis). The TLOVR and Snapshot algorithms are described in Module 2.7.3.2.6. Virologic response parameters for the subanalysis using pooled data for subjects receiving RPV or EFV in combination with FTC/TDF were consistent with results from the overall pooled analysis for C209 and C215.

In the pooled ITT population for the FTC/TDF subset, the difference in virologic response (viral load < 50 copies/mL, TLOVR; Table 10) between the TMC278 + FTC/TDF and control groups was 1.0 (95% CI, í3; 6). The lower limit of the 95% CI of the difference between the treatment groups was well above í12% and í10%, therefore, noninferiority of TMC278 versus control was established at the 12% and 10% noninferiority margins.

Table 10. FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215: Virologic and Immunological Outcomes of Randomized Treatment at Week 48 (TLOVR Analysis)

RPV + FTC/TDF EFV + FTC/TDF N = 550 N = 546 HIV-1 RNA < 50 copies/mL (TLOVRa)b 83.5% (459/550) 82.4% (450/546) Mean Change from Baseline in CD4 Cell +193 +182 Count (cells/mm3)

N = total number of subjects per treatment group a TLOVR = time to loss of virologic response (ITT population) b The difference of response rate is í3% to 6% (95% CI) using normal approximation Source: 2.7.3, Table 60 and Table 68

Eighty-three percent of the subjects in the RPV + FTC/TDF arm and 81% of the subjects in the EFV + FTC/TDF arm achieved plasma HIV-1 RNA < 50 copies/mL by Week 48 (Snapshot analysis; Table 11). The difference of response rate was í3% to 6% (95% CI). Therefore, RPV in combination with FTC/TDF has been shown to be noninferior in

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achieving HIV-1 RNA < 50 copies/mL when compared to EFV in combination with FTC/TDF.

Table 11. Rilpivirine Studies C209 and C215 (Pooled Data for Subjects Receiving RPV or EFV in Combination with FTC/TDF): Virologic Outcome of Randomized Treatment at Week 48 (Snapshot Analysis)

RPV+ FTC/TDF EFV + FTC/TDF Virologic Outcomea N = 550 N = 546 Virologic success HIV-1 RNA < 50 copies/mL 83% 81% Virologic failureb 13% 8% No virologic data at Week 48 window

Reasons Discontinued study due to adverse event or deathc 2% 7% Discontinued study for other reasonsd 2% 4% Missing data during window but on study < 1% < 1% a The snapshot analysis was based on the last observed viral load data within the Week 48 window (Week 4454) b Includes subjects who had t 50 copies/mL in the Week 48 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of t 50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol. c Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 48 window. d Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. Source: Module 2.7.3, Appendix 2.7.3.6.6

2.5.4.5.2. Baseline Genotype and Phenotype Characteristics Both at screening and baseline, the genotypic sensitivity to the NNRTIs and N(t)RTIs was determined by the virco“TYPE HIV-1 test.

For simplicity, ‘baseline’ genotype refers to the determinations at ‘baseline and/or screening’, unless indicated otherwise.

Subjects with 1 or more NNRTI resistance-associated mutations (RAMs), from the list defined in the protocol exclusion criteria, on their screening (or historical) genotype were not eligible for participation in the Phase 3 trials. The data on screen failures are presented in Module 2.7.3.3.3.4.1.1, Table 28. The genotype data obtained at screening confirmed that the subjects enrolled into the trials had no NNRTI RAMs according to the protocol exclusion list with 2 exceptions who were categorized as protocol violators. In addition, at screening, 2 subjects had mutation E138A, which was added to the protocol exclusion list only after these subjects were enrolled and started treatment.

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2.5.4.5.2.1. Genotypic and Phenotypic Sensitivity to NNRTIs at Baseline

Since not all known NNRTI RAMs were covered by the protocol exclusion criteria list, 13.5% of all randomized and treated subjects had 1 or 2 NNRTI RAMs at baseline according to the Extended NNRTI RAMs list. The distribution was well balanced between the 2 treatment groups and did not seem to affect phenotypic susceptibility to the regimen NNRTI.

No relevant differences were noted between the treatment groups or between the trials either for the total number of NNRTI RAMs or for the presence of specific NNRTI mutations.

Based on phenotypic sensitivity analyses to ARV treatments using Antivirogram“, the median TMC278 fold change (FC) in the TMC278 group at baseline was 1.10 (range 0.2-6.1) and 1.20 (range 0.2–5.5) in the control group. The median FC values at baseline for the other NNRTIs (EFV, ETR, and NVP) were all below the respective biological cut-offs (BCOs).

Nearly all subjects were sensitive to TMC278 (99.3%) and to EFV (99.3%). For the TMC278 group, 99.4% of subjects were sensitive to TMC278 and 99.4% to EFV. Comparable results were observed for the control group (99.3%, 99.2%, respectively).

2.5.4.5.2.2. Genotypic and Phenotypic Sensitivity to N(t)RTIs at Baseline

The number of subjects with at least 1 N(t)RTI RAM from the International AIDS Society-United States of America (IAS-USA) list {13428} at baseline was 26 (3.8%) in the TMC278 group and 15 (2.2%) in the control group. At the individual trial level, more subjects had N(t)RTI RAMs in the TMC278 group (6.2%) than in the control group (2.1%) in C215, whereas the proportion of subjects with N(t)RTI RAMs was comparable in the TMC278 group (1.4%) and the control group (2.3%) in C209. The most prevalent N(t)RTI RAMs from this list at baseline in the pooled analysis were M41L and A62V (each in 15 subjects [1.1%]) with no apparent difference between the treatment groups.

The median FC values for each N(t)RTI observed at baseline were below their respective BCOs or clinical cut-offs (CCOs) (for N(t)RTI BCOs and CCOs, refer to Module 2.7.3.3.6.1.3, Table 73).

For the TMC278 group in the pooled analysis, the phenotypic sensitivity to ARV treatments determined using Antivirogram“ at baseline indicated that most subjects (93.7%) were sensitive to the 7 N(t)RTIs assessed. Comparable results were observed for the control group in the pooled analysis (94.5%, respectively).

At baseline, phenotypic sensitivity indicated that a large proportion of subjects (95.5%) was sensitive to both background N(t)RTIs selected by the investigator based on the screening virco“TYPE report, with no differences between the treatment groups. No differences in sensitivity to N(t)RTIs (for the allowed background N(t)RTIs in each trial) were observed between the treatment groups.

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It is important to note that nearly all randomized and treated subjects (99.9%) were sensitive to both their background N(t)RTIs (according to the virco“TYPE HIV-1) at screening since this was a selection criterion and only one subject did not comply with this requirement and was classified as a protocol violator. The difference between screening and baseline is small and mostly due to the differences in the way FC values were calculated by these assays (virco“TYPE HIV-1 at screening for inclusion into the trial, and Antivirogram“ at baseline for the analysis) (Report TMC278-C204-C215-C904-W48-AVMR).

No subjects were resistant to ABC or to FTC at baseline. For 3TC, 2 subjects (0.3%) in the TMC278 group and none in the control group were resistant at baseline. For AZT, 5 subjects (0.8%) in the TMC278 group and 2 (0.3%) in the control group were resistant at baseline, and for TDF, resistance was observed in 32 subjects (4.8%) in the TMC278 group and 33 (5.0%) in the control group. In all the cases where resistance was detected, the FC values observed were marginally above the BCO/CCO.

2.5.4.5.3. Efficacy in Studies C209 and C215

This section provides an overview of the 48-week primary analysis of the efficacy results for the Phase 3 trials C209 and C215 with focus on the pooled analysis, highlighting any clinically relevant differences between the studies.

The efficacy results of the Week 48 primary analyses were generally consistent across both Phase 3 trials. In the individual trials, the difference in virologic response rates between the TMC278 and the control groups was similar. Both trials individually and independently demonstrated noninferiority of TMC278 versus control at the 12% and 10% noninferiority margins.

For details, refer to Module 2.7.3.2.6. Full results for the individual trials are available in the individual CRRs (Module 5.3.5.1, TMC278-C209-CRR and Module 5.3.5.1, TMC278-C215-CRR).

For resistance determination data from the pooled Phase 3 analysis, see Section 2.5.4.6.2.

Pharmacokinetic/pharmacodynamic relationships based on observed data in the Phase 3 trials were evaluated for the relationship between pharmacokinetic parameters and efficacy; an overview is presented in Section 2.5.3.3.1.2.

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2.5.4.5.3.1. Primary and Secondary Efficacy Parameters

2.5.4.5.3.1.1. Virologic Response

The primary efficacy parameter was the proportion of subjects with plasma viral load < 50 copies/mL at Week 48 according to the TLOVR imputation algorithm (FDA Guidance for industry, antiretroviral drugs using plasma HIV RNA Measurements - Clinical considerations for accelerated and traditional approval, prepared by the Division of Antiviral Drug Products: Office of Drug Evaluation IV in the Center for Drug Evaluation and Research (CDER), Appendix B; October 2002).

Figure 5 presents the proportion of subjects demonstrating virologic response (< 50 copies/mL, TLOVR) for the ITT population.

Figure 5. Phase 3 Trials C209, C215, and the Pooled Phase 3 Trials: Proportion of Virologic Responders (< 50 HIV-1 RNA copies/mL, TLOVR) at Week 48

Source: Module 2.7.3.3.6.1.1, Figure 21

The proportion of subjects that achieved a viral load < 50 copies/mL according to the TLOVR algorithm at Week 48 was similar between the TMC278 group (84.3%) and the control group (82.3%).

Statistical comparison using a logistic regression model showed a predicted difference [95% CI] in virologic response (viral load < 50 copies/mL, TLOVR) at Week 48 between the pooled TMC278 and control treatment groups of 1.6 [-2.2; 5.3] (p-value < 0.0001), demonstrating noninferiority at both the 12% (primary endpoint) and 10% (secondary endpoint) margins. Superiority of TMC278 compared to control was not established.

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In both trials C209 and C215 individually, there was no notable difference in response rate (< 50 copies/mL, TLOVR, ITT population) between the TMC278 group and the control group (82.9% vs 82.8% in C209, and 85.6% vs 81.7% in C215, see Figure 5) and the primary endpoint of noninferiority at the 12% margin was met in each trial independently. Based on the ITT and per protocol (PP) population, noninferiority was also demonstrated at the 10% margin in both trials.

The proportion of virologic responders seen in the control group in the Phase 3 trials was greater than or comparable to that seen for the same EFV-based combination antiretroviral therapies (ARTs) in previous trials. In light of this and the noninferiority of TMC278 to control established in the Phase 3 trials, the efficacy of TMC278 in respect of the proportion of virologic responders can be considered comparable to previously published data for EFV {15040}, {15966}, {15968}, {12654}.

The proportions of virologic responders between the TMC278 and control groups was similar when virologic response was defined as < 200 copies/mL or < 400 copies/mL (TLOVR).

The proportion of virologic responders at Week 48 with viral load < 50 copies/mL according to the snapshot analysis, together with reasons for nonresponse, is presented in Table 12 for the ITT population. The snapshot analysis was in line with the TLOVR pooled analysis data, with virologic response rates of 82.5% in the TMC278 group and 80.1% in the control group, confirming that noninferiority of TMC278 compared with control was demonstrated with maximum allowable differences of 12% and 10% (predicted difference [95% CI] in virologic response of 2.0 [-2.1; 6.1]) (both with p < 0.0001, logistic regression model).

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Table 12. Phase 3 Trials C209, C215, and the Pooled Phase 3 Trials: Virologic Outcome (< 50 HIV-1 RNA Copies/mL, Snapshot) at Week 48

C209 C215 Pooled

Snapshot Outcome at Week 48, TMC278 Control TMC278 Control TMC278 Control n (%) N = 346 N = 344 N = 340 N = 338 N = 686 N = 682 Virologic Response HIV RNA 285 (82.4) 281 (81.7) 281 265 566 (82.5) 546 (80.1) < 50 copies/mL (82.6) (78.4) Nonresponders 61 (17.6) 63 (18.3) 59 (17.4) 73 (21.6) 120 (17.5) 136 (19.9) Virologic Failurea 47 (13.6) 24 (7.0) 41 (12.1) 38 (11.2) 88 (12.8) 62 (9.1) Ongoing and HIV RNA 17 (4.9) 13 (3.8) 17 (5.0) 15 (4.4) 34 (5.0) 28 (4.1) t 50 copies/mL Virologic failure leading to 20 (5.8) 4 (1.2) 12 (3.5) 8 (2.4) 32 (4.7) 12 (1.8) discontinuation Discontinued due to other reason 10 (2.9) 7 (2.0) 8 (2.4) 9 (2.7) 18 (2.6) 16 (2.3) and last available HIV RNA t 50 copies/mLb Switch in background N(t)RTIs not 0 0 4 (1.2) 6 (1.8) 4 (0.6) 6 (0.9) permitted by protocol No Viral Load Data in Week 48 14 (4.0) 39 (11.3) 18 (5.3) 35 (10.4) 32 (4.7) 74 (10.9) Window Discontinued due to AE/deathc 6 (1.7) 25 (7.3) 9 (2.6) 24 (7.1) 15 (2.2) 49 (7.2) Discontinued due to other reason 5 (1.4) 12 (3.5) 8 (2.4) 11 (3.3) 13 (1.9) 23 (3.4) and last available HIV RNA < 50 copies/mL (or missing)b Missing data during window but 3 (0.9) 2 (0.6) 1 (0.3) 0 4 (0.6) 2 (0.3) on study N = number of subjects per treatment group; n = number of observations a Includes subjects who had t 50 copies/mL in the Week 48 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than AE, death or lack or loss of efficacy and at the time of discontinuation had a viral load value of t 50 copies/mL (or missing), and subjects who had a switch in background regimen that was not permitted by the protocol. b Includes subjects who discontinued for reasons other than AE, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. c Includes subjects who discontinued due to AE or death if this resulted in no on-treatment virologic data in the Week 48 window. No subjects died in trial C209 and 1 subject in the TMC278 group and 3 subjects in the control group died in trial C215. Note: The snapshot analysis was based on the last observed viral load data within the Week 48 window (Week 44 - 54). Source: Module 2.7.3.3.6.1.1, Table 64

A tabulation of virologic outcome for the viral load < 50 copies/mL using the TLOVR analysis is provided in Module 2.7.3.3.6.1.1, Table 63.

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Table 12 also presents the categorization by reason of nonresponse according to the snapshot analysis for the ITT population. In the TMC278 group, 12.8% of subjects were virologic failures versus 9.1% of subjects in the control group. Among these, a greater proportion of subjects discontinued due to virologic failure in the TMC278 than in the control group (4.7% versus 1.8%, respectively) according to the snapshot analysis. For the other categories of virologic failure, the proportions were similar between treatment groups. The proportions of treatment failures with missing viral load data in the Week 48 window were similar per treatment group across the individual Phase 3 trials; in both trials, there were a smaller proportion of subjects in the TMC278 group than in the control group. Of the subjects who were treatment failures due to missing viral load data in the Week 48 window, the most frequent reason for discontinuation was due to AE/death in both trials, with smaller proportions of subjects discontinuing for this reason in the TMC278 group than in the control group.

In the pooled analysis, the results of different sensitivity analyses confirmed that the primary analysis results for virologic response defined as the proportion of subjects with confirmed < 50 copies/mL were robust and consistent across different populations. For all analyses, the lower limit of the 95% CI of the difference between the treatment groups was consistently and considerably above -12% demonstrating noninferiority of TMC278 versus control. Sensitivity analyses also showed noninferiority of TMC278 versus control at the 10% margin.

When comparing with the virologic response at Week 48 in the Phase 2b trial, it can be concluded that the virologic response rates in the Phase 2b and the Phase 3 trials are highly consistent. Overall, the virologic response rates (< 50 copies/mL TLOVR) at Week 48 in the Phase 3 pooled analysis (84.3% and 82.3% in the TMC278 and control groups, respectively) were similar to those in the Phase 2b trial at Week 48 (80.6% and 80.9% with TMC278 and control, respectively).

2.5.4.5.3.1.2. Virologic Response over Time

In the Phase 3 pooled analysis, the proportion of responders (viral load < 50 copies/mL, TLOVR) over time in the TMC278 and control groups were similar up to Week 48 with overlapping curves.

2.5.4.5.3.1.3. Time to Response and Time to Treatment Failure

No clear difference between the 2 treatment groups was noticed from the Kaplan-Meier curves for time to response (< 50 copies/mL, TLOVR) in the pooled analysis. Some separation between the curves for the 2 treatment groups was seen from Week 18 onwards when around 75% cumulative proportion of responders was reached, but this difference disappeared from approximately Week 36 onwards. By the latter time points, the cumulative proportions of responders were similar between the treatment groups in the pooled analysis. These findings indicate that subjects took somewhat longer in the TMC278 group to reach virologic suppression.

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A Cox proportional hazards model for time to response (< 50 copies/mL, TLOVR) comparing treatments adjusted for baseline viral load showed significant effects of baseline viral load and treatment in the pooled analysis (p < 0.0001 and p = 0.0001, respectively). Subjects in the TMC278 group took longer to reach virologic response than those in the control group and subjects with a higher baseline viral load took longer to respond in both treatment groups.

Subgroup analysis of time to virologic response by baseline viral load category indicated that the median time to response was approximately 12 weeks for the low baseline viral load category (” 100,000 copies/mL), approximately 16 weeks for the > 100,000 to ” 500,000 copies/mL category, and to between 18 and 24 weeks for the highest viral load category (> 500,000 copies/mL). The median time to response was similar for both treatment groups in the low and intermediate baseline viral load categories, while in the highest viral load category the median time to response was longer in the TMC278 group than in the control group. These results should be interpreted with caution, however, due to the small numbers of subjects in the highest viral load subgroup.

Although more subjects in the control group were never suppressed, the rate of treatment failures between treatment groups was similar. Kaplan-Meier curves and Cox proportional hazards models (TLOVR and TLOVR nonvirologic failure [non-VF] censored analyses) indicated that treatment group had no effect on time to treatment failure in the pooled analysis, i.e., subjects were experiencing treatment failure at similar rates between the treatment groups. A statistically significant effect of baseline viral load was seen in both treatment groups (p < 0.0001), i.e., for subjects with lower baseline viral load, it took longer to reach treatment failure.

Subgroup analyses of time to treatment failure indicated that greater proportions of virologic failures were seen with increasing baseline viral load category, and this was seen in both treatment groups in the pooled analysis.

2.5.4.5.3.1.4. Immunology

Both treatment groups showed a reconstitution of absolute and relative (%) CD4+ cell count at Week 48. The mean change from baseline in imputed absolute CD4+ cell count at Week 48 was 192.1 cells/PL; 95% CI [181.30; 202.94] in the TMC278 group and 176.2 cells/PL; 95% CI [164.63; 187.76] in the control group. Although in the pooled analysis, this difference in favor of TMC278 was statistically significant (p = 0.0263, analysis of covariance [ANCOVA]). The difference between the treatment groups in increase from baseline in CD4+ cell count did not reach statistical significance in the individual trials.

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2.5.4.5.3.2. Subgroup Analysis of Factors Influencing Efficacy

Subgroup analyses of factors influencing efficacy presented in this section showed some differences in virologic response. Limitations of these univariate subgroup analyses should, however, be acknowledged when interpreting the data and differences. In particular, data need to be interpreted with caution for subgroups that are small in sample size.

A more robust multivariate analysis using generalized additive models (GAM) to evaluate the impact of various potential predictive factors on efficacy parameters is presented in Section 2.5.4.5.3.4.

2.5.4.5.3.2.1. Virologic Response

Virologic response (viral load < 50 copies/mL, TLOVR) by subgroups is displayed in Table 13 for the Phase 3 pooled analysis.

Virologic response was also analyzed by patient-reported adherence for the treatment NNRTI for the overall treatment period (refer to Module 2.7.3.3.6.1.3, Table 70).

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Table 13. Rilpivirine Studies C209 and C215 (Pooled Data): Proportion of Virologic Responders (< 50 HIV-1 RNA Copies/mL, TLOVR) at Week 48 by Subgroups

TMC278 Control Parameter, n(%) N n (%) N n (%) Gender Male 518 438 (84.6) 519 425 (81.9) Female 168 140 (83.3) 163 136 (83.4) Race White 420 359 (85.5) 410 340 (82.9) Black/African American 165 124 (75.2) 156 116 (74.4) Asian 78 74 (94.9) 97 90 (92.8) Other 14 13 (92.9) 12 11 (91.7) Region Region 1: USA, Canada, Europe, Australia 379 309 (81.5) 347 271 (78.1) Region 2: Africa 51 42 (82.4) 69 55 (79.7) Region 3: Asia 106 96 (90.6) 112 103 (92.0) Region 4: Latin America 150 131 (87.3) 154 132 (85.7) Clade B 485 405 (83.5) 462 376 (81.4) C 76 65 (85.5) 89 70 (78.7) CRF01_AE 76 69 (90.8) 70 64 (91.4) Other 49 39 (79.6) 61 51 (83.6) Baseline Viral Load Category, copies/mL ” 100,000 368 332 (90.2) 330 276 (83.6) > 100,000 - ” 500,000 249 198 (79.5) 270 223 (82.6) > 500,000 69 48 (69.6) 82 62 (75.6) Baseline CD4+ Count Category, cells/PL < 50 34 20 (58.8) 36 29 (80.6) t 50 - < 200 194 156 (80.4) 175 143 (81.7) t 200 - < 350 313 272 (86.9) 307 253 (82.4) t 350 144 130 (90.3) 164 136 (82.9) Background Regimen FTC/TDF 550 459 (83.5) 546 450 (82.4) AZT/3TC 101 88 (87.1) 103 83 (80.6) ABC/3TC 35 31 (88.6) 33 28 (84.8) N = number of subjects per subgroup category; n = number of subjects with virologic response < 50 copies/mL. Source: Module 2.7.3.3.6.1.3, Table 69

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A trend for greater proportions of virologic responders with lower baseline viral load was seen in both treatment groups. In the ” 100,000 copies/mL baseline viral load category, 90.2% and 83.6% of subjects in the TMC278 and control groups, respectively, had virologic response, whereas 69.6% and 75.6% of subjects respectively had virologic response in the > 500,000 copies/mL category. Similar trends for the influence of high baseline viral load on virologic response have been reported with other ARV treatments {15873}, {12554}, {14246}, {15869}, {15864}. This pattern was also seen in both individual trials C209 and C215, although to a much lesser extent in the control group in trial C209. In trial C209, a smaller proportion of responders was seen in the TMC278 group than the control group in the > 500,000 copies/mL category (61.8% versus 80.9%), whereas this was not seen in trial C215 (77.1% versus 68.6%).

The proportion of virologic responders in the TMC278 group in the pooled analysis increased with increasing baseline CD4+ cell count category, ranging from 58.8% in subjects with baseline CD4+ cell count < 50 cells/PL to 90.3% in subjects with baseline CD4+ cell count > 350 cells/PL. There was little variation in the proportion of virologic responders in the control group with increasing baseline CD4+ cell count. The proportion of virologic responders in the TMC278 group was greater than control in the t 350 cells/PL (90.3% versus 82.9%) and the t 200 to < 350 cells/PL categories (86.9 versus 82.4%). Virologic response was similar in the 2 treatment groups in the t 50 to < 200 cells/PL category (80.4% versus 81.7%) and lower in the TMC278 group than control (58.8% versus 80.6%) for the < 50 cells/PL category.

While acknowledging the low numbers of subjects (n = 14 and n = 15 in the TMC278 and control groups, respectively), the response rates in subjects with very high baseline viral load (> 500,000 copies/mL) and low baseline CD4+ cell count (< 50 cells/PL) were 71.4% in the TMC278 group and 73.3% in the control group (see Module 2.7.3.3.6.1.3).

Background regimen did not appear to have an effect on virologic response as the proportions of virologic responders were similar for the different background regimens. The greatest proportions of virologic responders were seen for the ABC/3TC background regimen in both treatment groups, but only a small number of subjects were receiving this background regimen (approximately 5% of the total population in the pooled analysis). The proportions of subjects with virologic response taking FTC/TDF (the largest subgroup) were similar across the individual Phase 3 trials.

Male and female subjects responded equally well to the NNRTI treatments in the pooled analysis. A difference between the trials was seen for gender, with lower proportions of responders in the TMC278 group for female subjects in the C209 trial, which was not observed in the C215 trial. In the control group in trial C209, the proportion of responders was higher in males, while in trial C215 it was higher in females.

Virologic response rates were approximately 75% in Black/African American subjects in both treatment groups, compared to > 80% in the other races. The highest response rate was seen in Asian subjects in both treatment groups.

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The proportions of virologic responders per region were lower in Region 1 (USA, Canada, Europe and Australia) and 2 (Africa) than in Region 3 (Asia) and 4 (Latin America) in both treatment groups in the pooled analysis. There were a greater proportion of subjects with virologic response in the TMC278 group in the C215 trial in Region 2 (Africa) (94.7%) compared to the other regions; however, this was not observed in the C209 trial, where Region 2 (Africa) (75.0%) had the lowest proportion of virologic responders compared with the other regions. It should be noted that the number of subjects per treatment group in trial C215 was not balanced in this region.

For clade B, the most prominent clade in the Phase 3 trials, no difference in virologic response between treatment groups was observed. Greater proportions of virologic responders (TLOVR) were seen in the CRF01_AE clade category compared to the other clades, for both TMC278 and control. However, since the number of subjects in the non-B clade subgroups was small, results should be interpreted with caution.

In the TMC278 group for the pooled analysis, the proportion of responders in subjects who did not have hepatitis B/C coinfection at baseline was 85.0%, whereas the proportion of responders who did have hepatitis B/C coinfection was 73.5%. In the control group, 82.6% of subjects without hepatitis B/C infection at baseline were responders, and 79.4% of subjects with infection were responders (Module 5.3.5.3, TMC278-C904-Anal-Eff-Viral/Display EFF.26).

Analysis of virologic response by adherence, as measured by responses in the patient- reported questionnaire Short Form-36 version 2 (SF-36v2“), showed that the proportion of virologic responders was similar between the TMC278 and control group by adherence rate for the NNRTI, assessed for the overall treatment period. Of those subjects who were at least 95% adherent, the virologic response rates were high and similar between the TMC278 and control groups (87.6% and 88.4%). Virologic response rates were lower among subjects who were less than 95% adherent (66.3% on TMC278 and 68.4% on control).

An analysis using generalized additive models (GAM), which evaluated the impact of various potential predictive factors on efficacy parameters, also demonstrated an important role of adherence in determining virologic response (see Section 2.5.4.5.3.4).

2.5.4.5.3.3. Patient-Reported Outcomes

Patient-reported outcomes were evaluated based on the SF-36v2“ questionnaire. At baseline, the subjects in the TMC278 and control group had mean physical component summary (PCS) and mental component summary (MCS) scores similar to those found in the general population. Changes in scores from baseline to Week 48 demonstrated improvements over time in almost all subscales (except for the role physical scale in the control group of study C215), summary component scores, and SF-6D (a preference based utility index). The repeated measures analysis indicated no statistically significant difference between the TMC278 and control group on PCS, MCS, or SF-6D from baseline through Week 48.

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Full details of the results from the SF-36v2“ questionnaire are provided in the technical report (Module 5.3.5.3, TMC278-C904-Report-SF-36).

2.5.4.5.3.4. Pharmacokinetic/Pharmacodynamic Relationships

All analyses exploring the relationship of TMC278 exposure and efficacy parameters at Week 48 were done using the TLOVR non-VF censored analysis.

The results described below focus on AUC24h as a measure of TMC278 exposure and plasma viral load < 50 copies/mL as efficacy parameter. Results are similar for Ctrough, and for plasma viral load < 400 copies/mL.

Overall, the response rates were high in all the AUC quartiles, ranging from 78.3% to 95.7%. A lower response rate was observed in the lower quartiles of exposure compared to the higher quartiles.

Factors potentially associated with virologic response were evaluated in a logistic regression model including the effects of log10 baseline plasma viral load, exposure (log10-transformed AUC24h), and background regimen. Both baseline viral load and exposure were significantly associated (p < 0.001) with a viral load < 50 copies/mL at Week 48 (TLOVR non-VF censored analysis), while it was independent of the background regimen (p = 0.4774).

Several candidate drug-related factors (i.e., TMC278 AUC24h or C0h, FC for TMC278 at baseline, having undetectable TMC278 plasma levels at any time during the trial), treatment-related factors (i.e., background regimen, PSS), disease-related factors (i.e., baseline viral load, baseline CD4+ cell count), as well as subject-related factors (i.e., age, weight, gender, race, treatment adherence, and hepatitis B and/or C coinfection) that may impact the clinical efficacy of TMC278 were assessed using GAM analyses based on pooled data from the Phase 3 trials (TLOVR non-VF censored). The advantage of GAM compared to conventional logistic regression is that it is not necessary to make prior assumptions about the way the candidate factors are included in the model (data-driven rather than model-driven analysis).

Factors found to be the most predictive for higher virologic response (< 50 copies/mL) in subjects on TMC278 and a background regimen were in order of importance: 1) higher adherence, 2) higher TMC278 exposure (C0h), 3) lower baseline viral load, 4) lower phenotypic FC for TMC278 at baseline, and 5) higher baseline CD4 count. The other retained prognostic factors (having an undetectable TMC278 plasma concentration at any time during treatment, and trial) were considered to be less important in explaining the likelihood of virologic response.

Further details on the GAM analysis results are presented in Module 2.7.2.3.2.4.2.

2.5.4.5.3.5. Conclusions on Efficacy of the Phase 3 Trial Data

The pooled Phase 3 trials were well-balanced with regards to the demographic and baseline disease characteristics. Trial C209 had a fixed background regimen of FTC/TDF, and in trial

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C215, the majority of subjects took FTC/TDF as their background regimen; subjects taking AZT/3TC and ABC/3TC constituted approximately 15% and 5% of subjects, respectively, in the pooled Phase 3 trials.

Virologic response (< 50 copies/mL, TLOVR) rates were high and consistent between the individual Phase 3 trials. The proportions of subjects with virologic response in the Phase 3 pooled analysis ITT population were 84.3% and 82.3% in the TMC278 and control groups, respectively. TMC278 was clearly noninferior to control, well above both the 12% and 10% margins. Superiority for TMC278 was not demonstrated.

The snapshot analysis confirmed the results of the TLOVR analysis: 82.5% and 80.1% of subjects in the TMC278 and control groups, respectively, were responders at Week 48.

The different sensitivity analyses on the pooled Phase 3 data confirmed noninferiority of TMC278 versus control at the 12% level demonstrating robustness of the results.

In both Phase 3 trials, more subjects on TMC278 failed virologically (particularly in C209) compared to control (both according to snapshot and TLOVR outcome). In contrast, more subjects on control discontinued from the trial for safety reasons (AE/death) than on TMC278.

In the Phase 3 pooled analysis (< 50 copies/mL, TLOVR), response rates over time were similar for the treatment groups and there were no notable differences in response rates over time between the individual Phase 3 trials. Virologic response parameters for the subanalysis using pooled data for subjects receiving RPV or EFV in combination with FTC/TDF were consistent with results from the overall pooled analysis for C209 and C215.

Time to virologic response was slightly longer with TMC278 than with control in the Phase 3 pooled analysis and the individual trials. There were no differences between treatments for the time to treatment failure in the pooled analysis or either trial.

The mean increase from baseline in imputed absolute CD4+ cell count was 192.1 cells/PL in the TMC278 group and 176.2 cells/PL in the control group in the pooled analysis. Although no statistically significant differences were seen in the individual trials for mean change from baseline in imputed absolute CD4+ cell count, the difference between the TMC278 and control groups was statistically significant in the pooled analysis.

Response rates were high and comparable to control, irrespective of background regimen and baseline characteristics such as gender, race, hepatitis coinfection status, or HIV clade. Background regimen did not have an effect on virologic response for both treatment groups. Baseline viral load affected the virologic response in both treatment groups, with decreased response with higher baseline viral load, in line with virologic response to many other ARV treatments {15873}, {12554}, {14246}, {15869}, {15864}. This effect was more apparent in the TMC278 subjects, particularly in trial C209. Time to response was similarly affected in both treatment groups by baseline viral load as was time to (virologic) failure. Baseline CD4+ cell count affected virologic response in the TMC278 group, where a higher virologic

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response was observed with higher CD4+ cell count, whereas a minor influence of the baseline CD4+ cell count on virologic response was observed in the control group. While acknowledging the low number of subjects (14 and 15 in the TMC278 and control groups, respectively), subjects with the lowest baseline CD4+ cell count and the highest baseline viral load had comparable virologic response rates in the 2 treatment groups.

Adherence (as measured by a patient-reported questionnaire) had an effect on response in both treatment groups to the same extent, i.e., lower response in subjects who were less adherent to their regimen.

Performed for TMC278 only, the pharmacokinetic/pharmacodynamic analyses found a statistically significant effect of baseline viral load and TMC278 exposure on virologic response. In an analysis using GAM to evaluate the impact of various possible predictive factors on the efficacy parameters, adherence was found to be the most important predictor of virologic response (< 50 copies/mL, TLOVR non-VF censored), followed by exposure of TMC278 and baseline viral load. Also, the predicted virologic response was higher for subjects with a lower phenotypic FC for TMC278 and a higher CD4+ count at baseline.

There were no notable differences between treatment groups in the patient-reported outcomes measured by the SF-36v2“ questionnaire, at Week 48.

2.5.4.6. Summary of Clinical Resistance Findings

HIV-1 isolates with reduced susceptibility to each of the individual agents of the FTC/RPV/TDF FDC tablet have been selected in vitro and identified in clinical isolates from subjects with virological failure.

Between FTC, RPV, and TFV, no substantial cross-resistance to RPV or TFV has been demonstrated with the FTC-selected M184V/I mutation. In vitro cross-resistance to FTC has been shown with the TFV-selected K65R mutation, but there was no cross-resistance to RPV (TMC278-IV2-AVMR and PC-264-2004). The much higher levels of resistance afforded by the M184V/I mutation and its greater ease of selection relative to K65R suggest that the M184V/I mutation will dominate the resistance profile for the combined use of FTC and TDF in vivo. The selection of the M184V/I mutation prior to selection of the K65R mutation has been demonstrated in vitro with the combination of FTC and TFV (Report PC-164-2005). The more common development of the M184V mutation relative to K65R is also observed in clinical data in subjects treated with TDF and either FTC (GS-01-934) or 3TC (GS-99-903). NNRTI mutations emerging in HIV-1 under selective pressure of RPV included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L, where E138R represented a newly identified NNRTI mutation. A panel of 139 HIV-1 with NNRTI mutations showed full susceptibility to TFV, and showed full susceptibility to FTC for the subset of those lacking M184V/I in vitro (Report PC-264-2004). In a pooled analysis for subjects receiving FTC/RPV/TDF in clinical trials C209 and C215, there were 62 virologic failure subjects, with resistance information available for 54 of those subjects. The amino acid substitutions associated with NNRTI resistance that developed most commonly in these

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subjects were: V90I, K101E, E138K/Q, Y181C, V189I, and H221Y. However, the presence of the substitutions V90I and V189I at baseline did not affect the viral response. The amino acid substitutions associated with NRTI resistance that developed in 3 or more subjects during the treatment period were: K65R, K70E, M184V/I, and K219E.

A summary of the principal resistance data relevant to the use of the Truvada and FTC/RPV/TDF FDC tablets is provided in this section. Resistance data from Studies GS-01-934, GS-99-903, M02-418, C209, and C215 are presented. Pertinent results are reflected in the proposed FTC/RPV/TDF prescribing information.

Resistance data for the following supportive studies are described in Module 2.7.3.3.5.3:

x FTC-301A: Module 2.7.3.3.5.3.1

x GS-98-902: Module 2.7.3.3.5.3.2

x GS-99-907: Module 2.7.3.3.5.3.3

Resistance data for the RPV supportive study TMC278-C204 (Phase 2b) is described in Module 2.7.3.2.2.2.

2.5.4.6.1.1. Established Resistance Profiles

Emtricitabine-resistant isolates of HIV-1 have been selected in vitro {1794}. Reduced susceptibility is associated with the M184V/I mutation of the RT gene which also confers cross-resistance to 3TC, zalcitabine (ddC), and to abacavir (ABC) when present with K65R or L74V/I. Emtricitabine remains active in vitro against laboratory and clinical strains of HIV-1 with mutations associated with reduced susceptibility to thymidine analogs, ddI (L74V), and NNRTIs (Report 11148 and TMC278-IV1-AVMR and TMC278-IV2-AVMR). Emtricitabine-resistant isolates of HIV-1 with the M184V/I mutation were recovered from some subjects treated with FTC in combination with other antiretroviral agents in clinical studies (FTC-301A, FTC-302, FTC-303). These viruses were shown to be phenotypically resistant to inhibition by FTC and 3TC but remained sensitive to inhibition by ddI, ZDV, d4T, TFV, and abacavir ( 3-fold change in EC50).

In vitro selection experiments performed at high multiplicity of infection (MOI) showed that TMC278 was capable of inhibiting viral replication at concentrations where first-generation NNRTIs fail to do so. The rate of in vitro selection of TMC278-resistant strains at low MOI was comparable among HIV-1 group M subtypes. The NNRTI mutations emerging in HIV-1 under selective pressure of TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L, where E138R represented a newly identified NNRTI mutation.

In vitro, TFV selected strains of HIV-1 with mutations at K65R that showed reduced susceptibility to TFV {2078}. The K65R mutation also showed reduced susceptibility to abacavir, ddI, FTC, 3TC, and ddC in vitro {2141}, {1003}, {1004}, {1793}. Tenofovir shows reduced activity in vitro and in vivo against strains of HIV-1 with certain patterns of multiple

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thymidine analog mutations {5010}, {5482}. Tenofovir shows slightly increased anti-HIV-1 activity against the M184V mutation selected by abacavir, FTC, and 3TC {2078}, {1649} and full activity against NNRTI-resistant clinical isolates expressing K103N, Y181C or other NNRTI mutations (Report P4331-00035, TMC278-IV1-AVMR, TMC278-IV2-AVMR, and PC-264-2004). In clinical experience, development of K65R has occurred infrequently in subjects treated with TDF alone or in combination with additional antiretroviral agents from other drug classes. No subject developed the K65R mutation or any other detectable sequence changes in RT during up to 4 weeks of monotherapy with TDF (Study GS-97-901). In treatment-experienced subjects, 3% developed the K65R mutation (Studies GS-98-902 and GS-99-907) after 12 to 96 weeks of combination therapy {4343}. At failure, K65R in the pooled phase III studies of FTC/RPV/TDF (C209 and C215) in 3 subjects in the RPV group and 2 subjects in the efavirenz group.

2.5.4.6.1.2. Resistance Findings in Study GS-01-934

Reverse transcriptase and protease genotypic and phenotypic resistance analyses were performed at Weeks 48, 96, and 144 for all subjects who had confirmed plasma HIV-1 RNA ! 400 copies/mL at the respective time points while on study drug or after treatment switch. Through Week 144, 19 subjects from the FTC + TDF group and 31 subjects from the Combivir group met resistance analysis criteria (Table 14). Genotypic and phenotypic data were obtained for all 19 subjects in the FTC + TDF group and 29 of the 31 subjects in the Combivir group. For the remaining 2 subjects in the Combivir group, resistance analyses failed for technical reasons. For both treatment groups, the most common form of resistance to develop was resistance to EFV, predominantly the K103N mutation (5% [13/244] in the FTC + TDF group and 9% [21/243] in the Combivir group). The M184V/I mutation, selected by FTC or 3TC, developed significantly less frequently in the FTC + TDF group (1%, 2/244) compared with the Combivir group (4%, 10/243, p = 0.021). Two subjects in the Combivir group developed thymidine analog mutations, specifically, D67N or K70R mutations in RT. Through Week 144, no subject developed the K65R mutation that can be selected by TFV.

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Table 14. GS-01-934: Cumulative Development of Resistance by Week 144

EFV + FTC + TDF, (N = 244) EFV + Combivir, (N = 243) Subject Outcomes n (% Total, % With Genotype) n (% Total, % With Genotype) p-valuea Subjects Analyzed 19 (8%) 31 (13%) 0.075 Subjects with Datab 19 (8%) 29 (12%) 0.13 Any Resistance 13 (5%, 68%) 22 (9%, 76%) 0.12 EFV-Resistancec 13 (5%, 68%) 21 (9%, 72%) 0.16 K103N 8 (3%, 42%) 18 (7%, 62%) 0.046 K101E 3 (1%, 16%) 3 (1%, 10%) 1.0 G190A/S 2 (1%, 10.5%) 4 (2%, 14%) 0.45 Y188C/H 1 (0.4%, 5%) 2 (1%, 7%) 0.63 V108I 1 (0.4%, 5%) 1 (0.4%, 3%) 1.0 P225H 0 2 (1%, 7%) 0.25 M184V/I 2 (1%, 10.5%) 10 (4%, 34.5%) 0.021 TAMsd 0 2 (1%, 7%) 0.25 K65R 0 0 NA Wild-type 6 (NAe, 32%) 7 (NAe, 24%) NA a The p-values are based on the Fisher exact test and the percentage of total. b Genotypic analysis for 2 subjects in the Combivir group failed for technical reasons. c Other EFV resistance mutations included A98G (n = 1), K103E (n = 1), V179D (n = 1), and M230L (n = 1). d Thymidine analog mutations included D67N (n = 1) and K70R (n = 1) e Not applicable (NA) as wild type HIV sequence was not confirmed from subjects with HIV RNA < 400 copies/mL. Source: Module 5.3.5.1, GS-01-934 CSR, Appendix 14, Virology Listings 1 and 2

2.5.4.6.1.3. Resistance Findings in Study GS-99-903

During the 144-week treatment period in Study GS-99-903, a similar proportion of subjects in each of the 2 treatment groups met the failure criteria for resistance analysis: 47 of 299 subjects (16%) in the TDF  3TC  EFV group and 49 of 301 subjects (16%) in the d4T  3TC  EFV group. Mutations conferring resistance to the NNRTI class (and specifically the K103N mutation associated with EFV resistance) were most commonly observed. Among NRTI-associated resistance mutations, the most common mutation was the M184V/I associated with 3TC resistance. There were no differences between the treatment groups in the incidences of these mutations. The majority of virologic failures occurred within the first 48 weeks of treatment.

During 144 weeks of therapy, the K65R mutation developed in 8 subjects taking the TDF regimen (7 subjects before Week 48, 1 subject from Weeks 48 to 96, and none after Week 96) and in 2 subjects taking the d4T regimen (2.7% versus 0.7%: p 0.06). K65R was always accompanied by resistance to EFV or EFV plus 3TC. Among the 8 subjects who developed K65R in the TDF  3TC  EFV group, successful virologic outcomes were

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achieved upon initiation of second line therapy, with 5 of 8 subjects maintaining 50 copies/mL of HIV-1 RNA through a median of 155 weeks of follow up.

Consistent with the 144-week double-blind period, virologic failure was uncommon during the open-label phase, and was limited to 2 subjects who continued TDF treatment and no subjects who switched from d4T to TDF. The K65R mutation was not detected in subjects who discontinued TDF due to virologic failure.

2.5.4.6.1.4. Resistance Findings in Study M02-418

In Study M02-418, a total of 17 subjects in the once daily group (15%) and 11 subjects in the twice daily group (15%) had samples eligible for testing. Resistance testing was successful in 15 subjects in the once daily group and 8 subjects in the twice daily

Three subjects in the once daily group and 1 subject in the twice daily group demonstrated an M184V/I mutation in reverse transcriptase, indicating the development of FTC resistance. No reverse transcriptase mutations at positions 41, 44, 62, 65, 67, 69, 70, 74, 115, 118, 210, 215, or 219, suggestive of selection of NRTI resistance, emerged in any subject.

Six (4 once daily, 2 twice daily) of 23 subjects demonstrated an amino acid substitution in protease in a postbaseline sample at a position with wild-type amino acid at baseline. Most of the new amino acid substitutions observed in these 6 subjects were at positions that are commonly polymorphic. Overall, the evidence suggests that these genotypic changes in protease were not the direct result of selective pressure of the ARV regimen. No clinically relevant changes in phenotypic resistance to lopinavir or other PIs were observed, compared to baseline values, and none of these 6 subjects developed the M184V/I mutation in reverse transcriptase.

2.5.4.6.2. Clinical Resistance Findings for C209 and C215

This section describes resistance data for subjects experiencing virologic failure in the Phase 3 trials.

The resistance determination analysis includes data from any subject experiencing virologic failure as defined in Module 2.7.3.2.6; this definition of virologic failure is different from that used for the efficacy outcome analysis to capture as much resistance data as possible.

The results at the failure time point are the most clinically relevant because this is the time at which the subject should withdraw from treatment, therefore these results are used for determination of the resistance profile. Failure and end of treatment data were comparable because the time points were very close to one another.

Emergent RT mutations are those present at failure that are not present at baseline (and/or screening).

At baseline, given the exclusion criteria applied in the Phase 3 trials (subjects were not to have NNRTI RAMs from the predefined list of RAMs as per protocol), the vast majority of

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subjects had were susceptible to all NNRTIs. It should be noted that the Extended NNRTI RAMs list used in the analyses presented in this section contains more mutations (see Module 5.3.5.4, TMC278-C209-C215-C904-W48-AVMR) as compared to the list used in the exclusion criteria of the protocols.

2.5.4.6.2.1. Resistance Determination in the Phase 3 Trials C209 and C215

The focus of the resistance analysis presented in this section is on the pooled data set for the combined Phase 3 trials with any NRTI backbone (All Subjects) and on the pooled FTC/TDF subset for the combined Phase 3 trials. It should be noted that the Extended NNRTI RAMs list used in the analysis presented in this section contains 48 mutations (see Module 5.3.5.4, TMC278-C209-C215-C904-W48-AVMR) as opposed to the list used in the exclusion criteria, which contained 39 mutations.

Resistance Determination: Pooled Analysis: All Subjects

In total in the pooled analysis, 72 (10.5%) subjects in the TMC278 and 39 (5.7%) subjects in the control group in the ITT population met the definition of virologic failure. Of these, 62 (86.1%) of the TMC278 virologic failures and 28 (71.8%) of the control virologic failures had postdose resistance data at time of failure and were included in the resistance determination analysis at failure. This resistance analysis focused on these 90 virologic failures.

The median time to virologic failure was 113.5 days for the TMC278 virologic failures which was shorter than the 188.0 days for the control virologic failures.

Resistance Determination: FTC/TDF Pooled Subset Analysis

For the pooled FTC/TDF subset analysis, 62 (11.3%) subjects in the TMC278 and 27 (4.9%) in the control group met the definition of virologic failure. Note that the definitions for these resistance analyses differ from those used for the efficacy determination. Of the 62 TMC278 virologic failures and 27 control virologic failures, 54 and 20 respectively had postdose resistance data at the time of failure and were included in the resistance determination analysis at failure.

2.5.4.6.2.1.1. Impact of Genotypic and Phenotypic Baseline Characteristics on Virologic Failure

The baseline characteristics of the virologic failure population were compared to those of the ITT (VF Excluded) population, i.e., the ITT population from which any subjects complying with at least one of the 3 virologic criteria (presented in Module 5.3.5.4, TMC278-C209-C215-C904-W48-AVMR) were excluded.

Evaluation for any over- or under-representation of subjects in the pooled virologic failure population versus the pooled ITT population (from which virologic failures were excluded [VF Excluded]) for both treatment groups was conducted according to a number of demographic and baseline characteristics. Characteristics for which comparable results were

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observed for subjects in the virologic failure and the ITT (VF Excluded) populations in the pooled analysis, at the individual trial level, and for both treatment groups, included TMC278 FC, N(t)RTI background regimen, number of sensitive NNRTIs, most prevalent Extended NNRTI RAMs, HIV-1 clades, and coinfection with hepatitis B/C.

Characteristics for which differences between the 2 populations were observed included baseline viral load, baseline CD4+ cell count, and race. The differences observed for these characteristics between the virologic failure and ITT (VF Excluded) populations were observed in both the TMC278 and control groups. The only difference between treatment groups was a higher proportion of subjects in the > 100,000 - ” 500,000 copies/mL baseline viral load category in the TMC278 virologic failure population compared to the ITT (VF Excluded) population which was not observed in the control group virologic failure population.

2.5.4.6.2.1.2. Emergence of Mutations and Phenotypic Analysis

Emergence of Mutations: Pooled Analysis, All Subjects

The number of virologic failures with treatment-emergent resistance by type and number of mutations at failure are presented in Table 15 and discussed below. For details, refer to Module 2.7.3.3.6.1.3, Table 77.

At failure, proportions of virologic failures with any treatment-emergent RT mutation were comparable in the TMC278 and control groups: 53 (85.5%) versus 25 (89.3%). This also applies to the Extended NNRTI RAMs: 39 (62.9%) versus 15 (53.6%), respectively, albeit with a higher proportion of virologic failures with 2 or more treatment-emergent NNRTI RAMs (Extended list) for the TMC278 than for the control group.

The proportion of virologic failures with at least 1 treatment-emergent IAS-USA N(t)RT RAM was higher in the TMC278 group (42 subjects, 67.7%) than in the control group (9 subjects, 32.1%).

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Table 15. Rilpivirine Studies C209 and C215 (Pooled Data): Virologic Failures - Number of Treatment-Emergent Reverse Transcriptase Mutations at Failure

VFs with Postdose Resistance Data at Failure Analysis, n (%) TMC278 Control Number of mutations N’ = 62 N’ = 28 VFs with any treatment- 53 (85.5) 25 (89.3) emergent RT mutation VFs with any treatment- emergent Extended NNRTI 39 (62.9) 15 (53.6) RAM 1 18 (29.0) 10 (35.7) 2 12 (19.4) 3 (10.7) 3 8 (12.9) 1 (3.6) 4 1 (1.6) 0 5 0 1 (3.6) VFs with any treatment- emergent IAS-USA N(t)RTI 42 (67.7) 9 (32.1) RAM 1 35 (56.5) 9 (32.1) 2 5 (8.1) 0 3 2 (3.2) 0 N’ = number of virologic failures with postdose resistance data per treatment group; n = number of subjects with mutations; VF = virologic failure Note: both baseline and failure are needed to determine treatment-emergent mutations. Source: Module 2.7.3.3.6.1.3, Table 77

Table 16 lists all individual treatment-emergent RT RAMs from the Extended list of NNRTI RAMs and the IAS-USA list of N(t)RTI RAMs present in at least 2 virologic failures from the same pooled treatment group at failure. For details, refer to Module 2.7.3.3.6.1.3, Table 78.

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Table 16. Rilpivirine Studies C209 and C215 (Pooled Data): Virologic Failures: Individual Treatment-Emergent Resistance-Associated Mutations by Type at Failure in at Least 2 Subjects from the Pooled TMC278 or Control Group

VFs with Postdose Resistance Data at Failure, n (%) TMC278 Control Individual Mutations N’ = 62 N’ = 28 Treatment-emergent Extended NNRTI 39 (62.9) 15 (53.6) RAMs E138K 28 (45.2) 0 K101E 8 (12.9) 1 (3.6) H221Y 6 (9.7) 0 V90I 5 (8.1) 0 Y181C 5 (8.1) 0 V189I 5 (8.1) 0 E138Q 2 (3.2) 0 F227C 2 (3.2) 0 L100I 2 (3.2) 1 (3.6) V179I 2 (3.2) 0 K103N 0 11 (39.3) V106M 0 3 (10.7) Y188C 0 2 (7.1) Treatment-emergent IAS-USA NRTI 42 (67.7) 9 (32.1) RAMs M184I 29 (46.8) 2 (7.1) M184V 14 (22.6) 6 (21.4) K65R 3 (4.8) 2 (7.1) K219E 3 (4.8) 0 A62V 2 (3.2) 0 Y115F 2 (3.2) 0

N’ = number of virologic failures with postdose resistance data per treatment group; n = number of subjects with mutations; VF = virologic failure Note: both baseline and failure are needed to determine treatment-emergent mutations. Source: Module 2.7.3.3.6.1.3, Table 78

The most prevalent treatment-emergent NNRTI and N(t)RTI RAMs at failure in TMC278 virologic failures were E138K (45.2%) and M184I (46.8%), respectively, and these mutations were usually not found in the control virologic failures, except for 2 subjects with M184I. Among the control virologic failures, the most frequently emerging NNRTI and

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N(t)RTI RAMs were K103N (39.3%), which was not found in the TMC278 virologic failures, and M184V (21.4%). M184V was found in a similar proportion of TMC278 virologic failures (22.6%).

Emergence of Mutations: FTC/TDF Pooled Subset Analysis

A subanalysis of the proportion and number of virologic failures with emergent NNRTI and NRTI mutations per treatment group was performed using pooled data for subjects receiving RPV (n = 550) or EFV (control; n = 546) in combination with FTC/TDF.

For the pooled FTC/TDF subset analysis, 62 (11.3%) subjects in the TMC278 and 27 (4.9%) in the control group met the definition of virologic failure. Note that the definitions for these resistance analyses differ from those used for the efficacy determination. Of the 62 TMC278 virologic failures and 27 control virologic failures, 54 and 20 respectively had postdose resistance data at the time of failure and were included in the resistance determination analysis at failure. This resistance analysis of the pooled FTC/TDF subgroup focuses on these 74 virologic failures.

The FTC/TDF pooled data, at failure are presented in Table 17 and Table 18. The comparison of the data obtained at failure shows differences in the proportion and number of virologic failures developing each mutation in the 54 virologic failures in the TMC278 group and the 20 in the control group.

At failure, the proportions of virologic failures with any treatment-emergent RT mutation were comparable in the TMC278 and control groups: 46 (85.2%) versus 18 (90%). This also applies to the Extended NNRTI RAMs: 34 (63%) versus 10 (50%), respectively, albeit with a higher proportion of virologic failures with 2 or more treatment-emergent Extended NNRTI RAMs for the TMC278 group than for the control group.

The proportion of virologic failures with at least 1 treatment-emergent IAS-USA NRTI RAM was higher in the TMC278 group (37 subjects, 68.5%) than in the control group (6 subjects, 30%).

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Table 17. FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215: Virologic Failures: Number of Treatment-Emergent Mutations - Failure

Pooled FTC/TDF Subset Failure VFs with Postdose Resistance Data at TMC278 Control Failure, n (%) N = 54 N = 20 VFs with Any Treatment-Emergent RT 46 (85.2) 18 (90.0) Mutation VFs with Any Treatment-Emergent 34 (63.0) 11 (55.0) Extended NNRTI RAMs -- Any 1 14 (25.9) 7 (35.0) 2 12 (22.2) 2 (10.0) 3 7 (13.0) 1 (5.0) 4 1 (1.9) 0 5 0 1 (5.0) VFs with Any Treatment-Emergent IAS- 18 (33.3) 10 (50.0) USA NNRTI RAMs -- Any 1 14 (25.9) 6 (30.0) 2 4 (7.4) 2 (10.0) 3 0 2 (10.0) VFs with Any Treatment-Emergent IAS- 37 (68.5) 6 (30.0) USA NRTI RAMs -- Anya 1 31 (57.4) 6 (30.0) 2 4 (7.4) 0 3 2 (3.7) 0

N = number of subjects per group; n = number of observations; VF = virologic failure Note: both baseline and failures are needed to determine treatment-emergent mutations. a The RT mutation K65N is not included in the IAS-USA listing of NRTI mutations and was not included in this table. However, 2 subjects in the TMC278 group developed K65N: one at virologic failure and one at end of treatment; both showed phenotypic resistance to TFV. No subjects in the control group developed K65N. Source: Report PC-264-2005 and Module 2.7.3.3.6.1.3, Table 79

Table 18 lists all individual treatment-emergent RT RAMs by type, which were present in at least 2 virologic failures from the pooled data for all subjects in the TMC278 or control group at failure.

In the pooled FTC/TDF subset, the amino acid substitutions associated with NNRTI resistance that developed most commonly in the FTC/TDF subset at virologic failure were: V90I, K101E, E138K/Q, Y181C, V189I, and H221Y. However, in trials C209 and C215, the presence of the substitutions V90I and V189I at baseline did not affect the viral response.

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The amino acid substitutions associated with NRTI resistance that developed in 3 or more patients were: K65R, K70E, M184V/I, and K219E. The M184V/I mutation occurred more frequently in the TMC278 group compared to the control group (63% in the TMC278 group versus 20% in the control group) at the failure time point.

Table 18. FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215: Virologic Failures: Emergent Extended NNRTI Mutations, IAS USA NNRTI Mutations and IAS-USA N(t)RTI Mutations - Failure

Pooled FTC/TDF Subset VFs with Postdose Resistance Data at Failure TMC278 Failure Control Failure, n (%) N = 54 N = 20 VFs with Any Emergent RT Mutation 46 (85.2) 18 (90.0) Treatment-Emergent Extended NNRTI 34 (63.0) 11 (55.0) RAMs -- Any E138K 25 (46.3) 0 K101E 7 (13.0) 0 H221Y 6 (11.1) 0 V90I 5 (9.3) 0 Y181C 5 (9.3) 0 V189I 4 (7.4) 0 E138Q 2 (3.7) 0 F227C 2 (3.7) 0 L100I 1 (1.9) 1 (5.0) V179I 2 (3.7) 0 K103N 0 7 (35.0) V106M 0 3 (15.0) Y188C 0 2 (10.0) Treatment-Emergent IAS-USA NNRTI 18 (33.3) 10 (50.0) RAMs -- Any K101E 7 (13.0) 0 V90I 5 (9.3) 0 Y181C 5 (9.3) 0 L100I 1 (1.9) 1 (5.0) K103N 0 7 (35.0) V106M 0 3 (15.0) Y188C 0 2 (10.0)

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Pooled FTC/TDF Subset VFs with Postdose Resistance Data at Failure TMC278 Failure Control Failure, n (%) N = 54 N = 20 Treatment-Emergent IAS-USA NRTI 37 (68.5) 6 (30.0) RAMs -- Anya M184I and/or V 34 (63.0) 4 (20.0) M184I only 23 (42.6) 1 (5.0) M184V only 6 (11.1) 2 (10.0) M184V/I mixtures 5 (9.3) 1 (5.0) K65Rb 3 (5.6) 2 (10.0) K219Ec 3 (5.6) 0 K70Ed 1 (1.9) 0

N = number of subjects per group; n = number of observations; VF = virologic failure Virologic failures with missing data at failure are included in the analysis done for end of treatment as long as the genotypic and phenotypic data at end of treatment were available. Only the NNRTI mutations found in at least 2 virologic failures of the same group according to the pooled all subjects analysis are presented. a The list of NRTI mutations has been expanded from that of the all subjects analysis to highlight potential FTC/TDF resistance. The RT mutation K65N is not included in the IAS-USA listing of NRTI mutations and was not included in this table. However, 2 subjects in the TMC278 group developed K65N: one at virologic failure and one at end of treatment; both showed phenotypic resistance to TFV. Y115 developed in 2 subjects in the TMC278 group at virologic failure. D67N developed in 2 subjects in the TMC278 group: one at virologic failure and one at end of treatment. No subjects in the control group developed K65N, D67N, or Y115F. b Two additional subjects in the TMC278 group developed K65R at the end of treatment time point c Two additional subjects in the TMC278 group developed K219E at the end of treatment time point d Two additional subjects in the TMC278 group developed K70E at the end of treatment time point Source: Report PC-264-2005 and Module 2.7.3.3.6.1.3, Table 80

Phenotypic Analysis

Phenotypic Analysis: Pooled Analysis – All Subjects

Twenty–five treatment-emergent RT RAMs were found in the virologic failures with a TMC278 FC > BCO (of 3.7): x 16 NNRTI RAMs: V90I, L100I, K101E, K101P, K101T, V106A, V108I, E138K, E138Q, Y181C, Y181I, V189I, H221Y, F227C, F227L, and M230L, and; x 9 N(t)RTI RAMs: A62V, K65R, D67N, K70E, V75I, Y115F, M184I, M184V, and K219E.

Some of these mutations were observed in only one TMC278 virologic failure.

Of the 31 virologic failures in the TMC278 group with a TMC278 FC > BCO, 30 (96.8%) had a combination of at least one NNRTI RAM and one N(t)RTI RAM. Conversely, of the

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31 TMC278 virologic failures with a TMC278 FC ” BCO, 7 (22.5%) had a combination of at least one NNRTI RAM plus one N(t)RTI RAM and 18 (58.1%) had no detectable NNRTI or N(t)RTI RAMs. Of note, the 2 virologic failures who had treatment-emergent NNRTI RAMs only, had TMC278 FC ” BCO (these NNRTI RAMs were V179I and V189I/V, which are both recognized as polymorphisms).

In 37 of 53 TMC278 virologic failures with treatment-emergent RT RAMs at failure, NNRTI and N(t)RTI RAMs were present in combination.

The most common combination, E138K + M184I, was observed in 21 (39.6%) of the 53 TMC278 virologic failures.

x A large proportion of the virologic failures with this combination of RT RAMs (17 subjects, 81.0%) had a TMC278 FC > BCO.

x The combination E138K + M184I (free of mixtures) was also seen in the absence of any other NNRTI and/or N(t)RTI RAMs in 6 virologic failures (median TMC278 FC of 6.5 [ranging from 1.6 to 8.8]). Of these, 5 were above the TMC278 BCO.

The combination E138K + M184V (free of mixtures) and in the absence of any other NNRTI and/or N(t)RTI RAMs) was observed in 3 TMC278 virologic failures (median TMC278 FC of 2.6 [ranging from 1.8 to 6.5]). Of these, 2 were below the TMC278 BCO.

Of the 62 TMC278 virologic failures with resistance data, 31 (50.0%) had phenotypic resistance to TMC278 at failure. Among these 31 TMC278 virologic failures resistant to TMC278, 87.1% were cross-resistant to EFV, 90.3% to ETR, and 45.2% to NVP.

Of the 28 control virologic failures with resistance data, 12 (42.9%) had phenotypic resistance to EFV at failure. Among the 12 control virologic failures resistant to EFV at failure, none were cross-resistant to ETR or TMC278 whereas all 12 demonstrated cross-resistance to NVP.

Resistance to FTC and 3TC was observed in the majority of TMC278 virologic failures (67.7% and 67.2%, respectively), and to a lesser degree in the control virologic failures (25.0% and 28.6%, respectively). More than 90.0% of the TMC278 and control virologic failures retained susceptibility to TDF, ABC, and AZT at failure.

FTC/TDF Pooled Subset Analysis

Table 19 lists all virologic failures from the pooled FTC/TDF subset for TMC278 and control groups at failure.

Of the 54 subjects with virologic failure and available phenotypic resistance data at virologic failure, 37 lost susceptibility to FTC, 29 lost susceptibility to RPV, and 2 lost susceptibility to TDF. Among these subjects, 37 were resistant to lamivudine, 28 were resistant to etravirine, 26 to efavirenz, and 12 to nevirapine. Reduced susceptibility was observed to abacavir and/or ddI in some cases.

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Table 19. FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215: Virologic Failures: Phenotypic Resistance – Failure

Pooled FTC/TDF Subset Failure

Virologic Failures with Postdose TMC278 Control Resistance Data at Failure, n (%) N = 54 N = 20 Resistance to NNRTIs 31 (57.4) 9 (45.0) TMC278 29 (53.7) 0 EFV 26 (48.1) 7 (35.0) ETR 28 (51.9) 0 NVP 12 (22.2) 9 (45.0) Resistance to NRTIs 39 (72.2) 7 (35.0) TDF 2 (3.7)a 1 (5.0)a FTC 37 (68.5) 4 (20.0) 3TC 37 (68.5)b 5 (25.0) ABC 6 (11.1) 0 ddI 7 (13.0) 0 d4T 3 (5.6) 0 ZDV 2 (3.7) 1 (5.0)

N = number of subjects per group; n = number of observations a One additional subject in the TMC278 group and 2 additional subjects in the control group developed phenotypic resistance to TDF at the end of treatment time point. b Subject 2150515 had available resistance data at Week 12 and Week 16. The genotype showed K101E/K, V118I/V, E138E/K, M184I/M/V, E204E/K, and H221H/Y at both time points. The phenotypic assay showed resistance to FTC and had no data reported for 3TC at Week 12. The Week 16 sample was resistant to both FTC and 3TC. For the purposes of this analysis, at Week 12 this subject’s 3TC phenotypic data was imputed as “resistant” due to the presence of M184V/I. Source: PC-264-2005 and Module 2.7.3.3.6.1.3, Table 81

2.5.4.7. Conclusions on Resistance Determination

2.5.4.7.1. Conclusions on Resistance Determination for Emtricitabine

Emtricitabine-resistant isolates of HIV-1 have been selected in vitro {1794}. Reduced susceptibility is associated with the M184V/I mutation of the RT gene which also confers cross-resistance to lamivudine and zalcitabine (ddC). Emtricitabine remains active in vitro against laboratory and clinical strains of HIV-1 with mutations associated with reduced susceptibility to thymidine analogs, ddI (L74V), and NNRTIs (Report 11148). Emtricitabine-resistant isolates of HIV-1 with the M184V/I mutation were recovered from some subjects treated with FTC in combination with other antiretroviral agents in clinical studies (FTC-301A, FTC-302, FTC-303). These viruses were shown to be phenotypically

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resistant to inhibition by FTC and lamivudine but remained sensitive to inhibition by ddI, zidovudine, d4T, TDF, and abacavir (< 3-fold change in EC50).

2.5.4.7.2. Conclusions on Resistance Determination for Rilpivirine

The ARV treatment-naive population included in the C209 and C215 trials was characterized by the near absence of NNRTI RAMs (based on population sequencing) with the exception of a limited proportion of patients carrying mutations 90I, 106I, 179I and/or 189I (which were not excluded based on the protocol list). These 4 mutations had no effect on treatment response to TMC278 or EFV. At baseline, the vast majority of subjects in each treatment group were susceptible to their treatment NNRTI and N(t)RTIs.

In total, 72 subjects (10.5%) in the TMC278 group and 39 subjects (5.7%) in the control group met the definition of virologic failure (VF) adopted for the resistance analysis. The median time to virologic failure in the TMC278 group was shorter than in the control group (113.5 days versus 188 days, respectively).

The emergence of at least one NNRTI RAM from the Extended NNRTI list was equally frequent in the TMC278 and control virologic failures, however, more TMC278 virologic failures had 2 or more emerging NNRTI RAMs compared to the control group virologic failures. The most frequent NNRTI RAM emerging in the TMC278 virologic failures was E138K which was also the most common emerging mutation in the Phase 2b trial C204, confirming this observation made in the earlier trial. Other NNRTI RAMs emerging in 3 or more TMC278 virologic failures were K101E, H221Y, and Y181C. In the control group, the most frequent emerging NNRTI RAM was K103N which was not observed in the TMC278 virologic failures.

The proportion of TMC278 virologic failures with emerging N(t)RTI RAMs was approximately double that of the virologic failures in the control group in the pooled analysis. Among TMC278 virologic failures, M184I was the most frequent N(t)RTI RAM emerging in trial C209, but comparable numbers of virologic failures with emerging M184I and M184V were observed in trial C215. In the control group virologic failures, M184V was the most common emerging N(t)RTI RAM.

Fifty percent and 42.9% of TMC278 and control group virologic failures, respectively, developed phenotypic resistance to their treatment NNRTI. In subjects with TMC278 virologic failure, phenotypic resistance to TMC278 was almost always associated with the presence of emerging NNRTI and N(t)RTI RAMs. Conversely, only 22.5% of TMC278 virologic failures who remained phenotypically susceptible to TMC278 had a combination of at least one NNRTI and one N(t)RTI RAM.

In the TMC278 virologic failures, E138K and M184I usually emerged together and were associated with phenotypic resistance to TMC278 in most cases.

The majority of TMC278 virologic failures with phenotypic resistance to TMC278 were also resistant to ETR and EFV, while those with phenotypic susceptibility to TMC278 generally retained susceptibility to both these NNRTIs.

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The resistance findings in C209 and C215 confirmed the resistance observations made in the Phase 2b trial, from the Week 96 and Week 192 analyses, with the exception of the higher frequency of the mutation M184I in subjects failing TMC278 which was not previously noted in Phase 2b.

2.5.4.7.3. Conclusions on Resistance Determination for Tenofovir DF

In vitro, TFV selected strains of HIV-1 with mutations at K65R that showed reduced susceptibility to TFV {2078}. The K65R mutation also showed reduced susceptibility to abacavir, ddI, FTC, lamivudine, and zalcitabine in vitro {2141}, {1003}, {1004}, {1793}. Tenofovir shows reduced activity in vitro and in vivo against strains of HIV-1 with certain patterns of multiple thymidine analog mutations {5010}, {5482}. Tenofovir shows slightly increased anti-HIV-1 activity against the M184V mutation selected by abacavir, FTC, and lamivudine {2078}, {1649} and full activity against NNRTI-resistant clinical isolates expressing K103N, Y181C and other RPV-resistant HIV-1 (Reports P4331-00035 and PC-264-2004). In clinical experience, development of K65R has occurred infrequently in subjects treated with TDF alone or in combination with additional antiretroviral agents from other drug classes. No subject developed the K65R mutation or any other detectable sequence changes in RT during up to 4 weeks of monotherapy with TDF (Study GS-97-901). In treatment-experienced subjects, < 3% developed the K65R mutation (Studies GS-98-902 and GS-99-907) after 12 to 96 weeks of combination therapy {4343}. At failure, K65R in the pooled Phase 3 studies of FTC/RPV/TDF (C209 and C215) in 3 subjects in the RPV group and 2 subjects in the efavirenz group.

2.5.4.7.4. Conclusions on Resistance Determination for the FTC/RPV/TDF FDC Tablet

In a pooled analysis for subjects receiving FTC/RPV/TDF in clinical trials C209 and C215, there were 62 virologic failure subjects, with resistance information available for 54 of those subjects. The amino acid substitutions associated with NNRTI resistance that developed most commonly in these subjects were: V90I, K101E, E138K/Q, Y181C, V189I, and H221Y. However, the presence of the substitutions V90I and V189I at baseline did not affect the viral response. The amino acid substitutions associated with NRTI resistance that developed in 3 or more subjects during the treatment period were: K65R, K70E, M184V/I, and K219E.

Of the 54 subjects with virologic failure and available phenotypic resistance data, 37 lost susceptibility to FTC, 29 lost susceptibility to RPV, and 2 lost susceptibility to TDF. Among these subjects, 37 were resistant to lamivudine, 28 were resistant to etravirine, 26 to efavirenz, and 12 to nevirapine. Reduced susceptibility was observed to abacavir and/or ddI in some cases.

2.5.4.8. Efficacy Against HBV in HIV/HBV Coinfected Subjects

In addition to anti-HIV activity, both FTC and TFV demonstrate potent and selective inhibition of HBV replication in vitro and in vivo. No activity of RPV was observed against HBV at concentrations up to 10 PM. Coinfection with HIV-1 increases the risk of HBV

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related progressive disease {6181}, {6180}, {5024}. Antiretroviral medications with dual activity against both HIV-1 and HBV, such as TDF and FTC, may represent a therapeutic advantage in terms of controlling the replication of both viruses.

Data supporting the anti-HBV activity of TDF 300 mg once daily in subjects with HIV/HBV coinfection are available from a variety of sources including a controlled study conducted by the AIDS Clinical Trials Group (ACTG A5127), retrospective analyses of data from Gilead-sponsored controlled studies, and published data from uncontrolled studies conducted by independent investigators.

In ACTG A5127, the mean decrease in serum HBV DNA from baseline was greater in HIV/HBV coinfected subjects treated with TDF 300 mg than with adefovir dipivoxil 10 mg {7469}. In substudies of coinfected subjects who participated in the pivotal Phase 3 HIV clinical trials of TDF (Studies GS-99-907 and GS-99-903), similar significant decreases in HBV DNA levels were observed in subjects treated with TDF {6586}. Genotyping revealed that TDF treatment was not associated with the development of the 3TC-resistance YMDD mutation. Moreover, the anti-HBV efficacy of TDF was unaffected by the presence of the YMDD mutation. Several external investigator studies provide further support for the efficacy of TDF in HIV/HBV coinfected subjects {4376}, {6379}, {6837}, {3940}, {4630}, {6849}. Based on this experience, current clinical practice guidelines recommend TDF as the treatment of choice for patients with HBV and HIV confection who require antiviral therapy, particularly those with 3TC-resistant infection {6389}.

Tenofovir DF (300 mg once daily) is approved for treatment of HBV monoinfection in the US, Europe, and other countries. Significant decreases in HBV DNA levels with FTC 200 mg once daily were demonstrated in 2 Phase 2 dose-response studies (FTCB-101 and FTCB-102) and in 1 Phase 3 study (FTCB-301) of subjects with chronic hepatitis B (without HIV-1). The efficacy and safety of Truvada is being evaluated in this population.

In pivotal Phase 3 studies of FTC for the treatment of HIV-1 infection, the magnitude of HBV DNA suppression in HIV/HBV coinfected subjects was similar to that observed in subjects with HBV monoinfection given FTC 200 mg once daily in FTCB-102.

HBV DNA levels were similarly suppressed for a small number of subjects with HBV coinfection who received FTC and TDF in Study GS-01-934.

2.5.4.9. Efficacy Discussion and Conclusions

Emtricitabine, RPV, and TDF are potent and selective HIV-1 reverse transcriptase inhibitors; each individual agent demonstrates potent and durable efficacy in the treatment of HIV-1 infection in combination with other antiretroviral agents.

In antiretroviral-naive subjects in Study GS-01-934, the antiviral efficacy of the once-daily regimen of FTC  TDF  EFV, administered without regard to food, was superior to that of the CBV (twice daily)  EFV (once daily), as demonstrated by the proportion of subjects who achieved and maintained confirmed HIV-1 RNA 400 copies/mL at Week 48. The

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once-daily regimen of EFV + FTC + TDF demonstrated continued significant and potent antiretroviral efficacy through 144 weeks of treatment in Study GS-01-934. Genotypic resistance to EFV (predominantly the K103N mutation) was most commonly observed. Resistance to FTC (M184V/I mutation) developed infrequently, and no resistance to TDF (K65R mutation) developed.

Potent and durable efficacy in treatment-naive subjects was similarly demonstrated with the regimen of TDF + 3TC + EFV in comparison with the regimen of d4T + 3TC + EFV during 144 weeks of treatment in Study GS-99-903. The effectiveness of the TDF regimen was comparable to that of the d4T regimen for primary and secondary analyses of proportion of subjects with plasma HIV-1 RNA concentrations 400 copies/mL and 50 copies/mL, change from baseline in plasma HIV-1 RNA, and change from baseline in CD4 cell count. The most common resistance mutations in virologic failures were associated with resistance to EFV (K103N) and 3TC (M184V/I). The K65R mutation occurred in 3% of subjects treated with TDF during the 144-week double-blind treatment period. In subjects continuing in the extension phase, efficacy was maintained through 240 weeks of treatment, with no further reports of K65R development.

Study M02-418 demonstrated potent and durable efficacy in treatment-naive subjects receiving FTC and TDF with a protease inhibitor (LPV/r once or twice daily). The effectiveness of regimens was similar for primary and secondary analyses of proportion of subjects with plasma HIV-1 RNA concentrations 50 copies/mL, change from baseline in plasma HIV-1 RNA, and change from baseline in CD4 cell count. Resistance to FTC (M184V/I mutation) developed infrequently, and no resistance to TDF (K65R mutation) developed.

The efficacy of TMC278 and FTC/RPV/TDF FDC tablets for the treatment of HIV-1 infection in adult patients is based on efficacy data of the Week 48 analysis from 2 Phase 3 registrational trials. The efficacy of TMC278 is further supported by the long-term efficacy data (up to 192 weeks) from a Phase 2b trial (C204) in HIV-1 infected, treatment-naive adult subjects (see Module 2.7.3.2.2.2). In the Phase 2 and Phase 3 trials, a total of 779 subjects have been treated with the recommended dose of TMC278 25 mg once daily. The results seen in subjects given FTC + RPV + TDF in the 2 studies are similar to those seen in the 2 studies overall since 80% of the subjects received FTC/TDF as their NRTI regimen. Thus, FTC + RPV + TDF had noninferior efficacy with a higher rate of virologic failure and lower rates of adverse effects (particularly dizziness, rash, and elevation in total cholesterol) compared to FTC + EFV + TDF.

In the Week 96 analysis of the Phase 2b dose-finding trial, all TMC278 doses tested were highly active and demonstrated substantial and durable efficacy across the TMC278 dose groups.

The efficacy results of the Phase 3 trials demonstrated that in ARV treatment-naive adult patients, TMC278 dosed at 25 mg once daily with a background regimen consisting of 2 N(t)RTIs demonstrated substantial and sustained efficacy that was noninferior to EFV 600 mg once daily with the same background regimen, a recommended first-line treatment

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for HIV disease. The primary noninferiority endpoint of 48 weeks of treatment in the Phase 3 clinical trials was met and the results of the PP population confirmed the results of the ITT population. The snapshot analysis confirmed the results of the TLOVR analysis. Different sensitivity analyses on the pooled Phase 3 data established noninferiority of TMC278 versus control at the 12% level, demonstrating robustness of the results.

Response rates with TMC278 were high and comparable to control, irrespective of background regimen and of baseline characteristics such as gender, race, hepatitis coinfection status, or HIV clade. There was a trend for lower response rates in the TMC278 treatment group for subjects with high baseline viral loads, which was less evident in the control group. For both treatment groups, baseline viral load was a statistically significant factor in relation to time to virologic response, time to treatment failure, and time to virologic failure.

Baseline CD4+ cell count affected virologic response in the TMC278 group, where the virologic response was higher with higher CD4+ cell count, whereas a minor influence of the baseline CD4+ cell count on virologic response was observed in the control group.

At Week 48, the TMC278 group showed reconstitution of absolute and relative (%) CD4+ cell count, comparable to that in the control group.

Investigations of potential factors influencing virologic response in the TMC278 group have identified adherence as the most important predictor of response, followed by exposure to TMC278, baseline viral load, and CD4+ cell count at baseline. Virologic response analyzed by adherence measured both by using a patient-completed questionnaire and pill count showed that greater proportions of virologic responders were seen for subjects who were adherent than those who were not adherent, and this was observed in both treatment groups.

The number of virologic failures in the Phase 3 trials was limited in both treatment groups, with comparable proportions of failures with NNRTI RAMs. The proportion of TMC278 virologic failures with emerging N(t)RTI RAMs was approximately double that of the virologic failures in the control group in the pooled analysis. Among the TMC278 virologic failures, 50% lost susceptibility to TMC278. TMC278 failures who were resistant to TMC278 developed phenotypic cross-resistance against EFV and ETR. The control virologic failures resistant to EFV retained sensitivity to ETR and TMC278 but were cross-resistant to NVP.

Subjects receiving TMC278 tolerated treatment better and had fewer discontinuations due to AEs than subjects on control.

The durable antiviral effect of ARV regimens containing TMC278 was also seen in the results of the long-term Week 192 efficacy analyses of the Phase 2b trial, which demonstrated a persistent long-term decrease from baseline in viral load and an immunological benefit. The vast majority of subjects with undetectable viral load (< 50 copies/mL) at Week 96 maintained this level of virologic suppression to at least 192 weeks of treatment.

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Overall, TMC278 combined with an active background regimen has demonstrated significant efficacy, which is sustained with long-term follow-up, in a population of HIV-1 infected ARV treatment-naive adult patients.

With respect to treatment-experienced patients, the clinical data and resistance profiles for the individual agents provide adequate assurance that the FTC/RPV/TDF FDC tablet will effectively maintain control of plasma HIV-1 RNA levels. Studies GS-MC-164-0111, GS-ES-164-0154, GS-US-164-0106, and GS-DE-164-0106 demonstrate the maintenance of virologic suppression for subjects who switch their NRTIs to FTC/TDF. Efficacy and safety of FTC, RPV, TDF, and FTC/TDF in treatment-experienced subjects have been demonstrated in the following studies: x Emtricitabine: Study FTC-303 (see Modules 2.7.3.2.1.2.1) x Rilpivirine: Trial C202 (see Module 2.7.3.2.2.3.2)

x Tenofovir DF: Studies GS-98-902 and GS-99-907 (see Module 2.7.3.2.3.2.1)

x FTC/TDF: GS-MC-164-0111 (SWEET) (see Module 2.7.3.2.5.1)

In conclusion, the potent efficacy and low level of adverse events that has been demonstrated with the regimens containing FTC + RPV + TDF support the clinical effectiveness of the FTC/RPV/TDF FDC tablet.

2.5.5. Overview of Safety

More detailed information on the safety results of individual trials is provided in Module 2.7.4.

2.5.5.1. Introduction

The safety profiles of the individual agents in adult HIV-1 infected subjects were primarily established from pivotal Phase 3 clinical studies in treatment-naive and treatment-experienced subjects as follows:

x Emtricitabine: Studies FTC-301A and FTC-303

x Rilpivirine: Trials C209 and C215 (treatment-naive only)

x Tenofovir DF: Study GS-99-907

Safety and efficacy for Truvada was primarily established in Studies GS-01-934 and GS-99-903.

No new supportive clinical efficacy and safety studies for FTC/RPV/TDF FDC tablets were considered warranted on the basis of available safety data and extensive clinical experience with the use of FTC and TDF, both alone and in combination, and RPV for the treatment of

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HIV-1 infection in adults. Safety data from Tibotec’s Phase 1 and Phase 2 clinical studies conducted with RPV are appended to Module 2.7.4 (Appendix 2.7.4.7.3).

The safety profiles of FTC, TDF, and Truvada continue to be monitored through postmarketing surveillance and are reviewed in PSURs. The cumulative patient exposure for each product through the last PSUR is presented in Table 20.

Table 20. Estimated Cumulative Postmarketing Exposure to the Individual Marketed Products

Cumulative Postmarketing Product Period Exposure (patient-years) Emtriva (FTC) Cumulative to 30 June 2010 109,883 Viread (TDF) Cumulative to 30 June 2010 1,546,629 Truvada (FTC/TDF) Cumulative to 30 June 2010 1,363,365

Given that there is little overlap in the toxicities of FTC, RPV, and TDF, no additional or exacerbated toxicities would be expected with use of the FTC/RPV/TDF FDC tablet. Clinical experience is consistent with this conclusion.

The main safety findings from Studies GS-01-934 and GS-99-903 and Trials C209 and C215 are provided in Section 2.5.5.2 and Module 2.7.4. Safety data from Study M02-418 are not described in this clinical overview since all subjects received a regimen containing FTC and TDF, and the designated study drugs were LPV/r (see Module 2.7.4).

This safety overview also includes discussion of the clinical trial experience, as well as several safety topics that require specific consideration for the use of the FTC/RPV/TDF FDC tablet. Pertinent data, including nonclinical information, clinical trial and postmarketing experience, are reviewed for the following:

Renal safety (Section 2.5.5.3): due to preclinical findings and case reports of renal events during postmarketing experience with TDF.

Skin effects (Section 2.5.5.4): due to the occurrence of skin hyperpigmentation in patients treated with FTC. Certain skin events are side effects commonly observed with drugs of the NNRTI class and are therefore closely monitored in all clinical trials with TMC278.

Bone toxicity (Section 2.5.5.5): due to preclinical findings and case reports of osteomalacia associated with proximal tubulopathy during postmarketing experience with TDF.

Mitochondrial toxicity and metabolic effects (Section 2.5.5.6): due to the association of this toxicity with nucleoside analog therapy.

Neurologic events (Section 2.5.5.7): Certain neurologic events are reported to be associated with the use of drugs of the NNRTI class and are therefore closely monitored in all trials with TMC278.

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Psychiatric Events (Section 2.5.5.8): Certain psychiatric events are reported to be associated with the use of drugs of the NNRTI class and are therefore closely monitored in all TMC278 clinical trials.

Hepatic Events (Section 2.5.5.9): Hepatic AEs were of special interest as in certain cases ARV treatments have been associated with hepatotoxicity and there is a potential risk of hepatitis flare in patients with underlying HBV infection following discontinuation of these agents.

Events related to QT interval prolongation (Section 2.5.5.10): In a thorough QT (TQT) trial, a QT interval prolongation effect of TMC278 was observed in healthy volunteers at doses that are multiples (3 to 12 times higher) of the 25 mg once daily dose selected for further development.

Endocrine events (Section 2.5.5.11): Endocrine monitoring, including gonadal, adrenal and thyroid, was included as a way of assessing adrenal and thyroid function, because effects on the adrenal gland were observed in rats, dogs and cynomolgus monkeys with TMC278

Special populations (Section 2.5.5.12): patients coinfected with HIV-1 and HBV or hepatitis C virus (HCV), pregnancy, elderly patients, pediatric patients, and patients with renal or hepatic impairment are specifically considered.

2.5.5.2. Summary of Clinical Trial Safety Experience

2.5.5.2.1. Safety in Study GS-01-934

The once-daily regimen of EFV + FTC + TDF was well tolerated through 144 weeks of treatment in Study GS-01-934, and demonstrated a preferential safety profile compared with the EFV + Combivir regimen.

Through Week 144, at least 1 treatment-emergent AE was reported for 95% of subjects (245/257) in the FTC + TDF group and 97% of subjects (246/254) in the Combivir group (Table 21). The most frequently reported treatment-emergent AEs (for at least 20% of either treatment group) were diarrhea (28%, 73/257), dizziness (28%, 71/257) nausea (26%, 66/257), and headache (20%, 51/257) in the FTC + TDF group and nausea (33%, 83/254), dizziness (29%, 74/254), and diarrhea (20%, 50/254) in the Combivir group.

Five deaths (2 in the FTC + TDF group and 3 in the Combivir group) were reported through Week 144, all of which were considered unrelated to treatment. Treatment-emergent serious adverse events (SAEs) were reported for 11% of subjects (29/257) in the FTC + TDF group and 14% of subjects (35/254) in the Combivir group. AEs leading to study drug discontinuation occurred in a significantly smaller percentage of subjects in the FTC + TDF group compared with the Combivir group (5% [13 subjects] vs 11% [29 subjects], p = 0.010).

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Table 21. GS-01-934: Treatment-Emergent Adverse Events Reported in at Least 10% of Subjects in Either Treatment Group (Safety Analysis Set)

EFV + FTC + TDF EFV + Combivir (N 257) (N 254) a AEs by System Organ Class and Preferred Term n % n % Any AE 245 95% 246 97% Gastrointestinal Disorders Diarrhoea 73 28% 50 20% Nausea 66 26% 83 33% Vomiting 20 8% 33 13% General Disorders and Administrative Site Conditions Fatigue 46 18% 46 18% Infections and Infestations Nasopharyngitis 45 18% 33 13% Upper Respiratory Tract Infection 48 19% 27 11% Sinusitis 33 13% 17 7% Musculoskeletal and Connective Tissue Disorders Back Pain 26 10% 20 8% Nervous System Disorders Headache 51 20% 43 17% Dizziness 71 28% 74 29% Psychiatric Disorders Depression 38 15% 33 13% Insomnia 44 17% 45 18% Abnormal Dreams 45 18% 34 13% Respiratory, Thoracic, and Mediastinal Disorders Cough 31 12% 31 12% Pharyngolaryngeal Pain 14 5% 28 11% Skin and Subcutaneous Tissue Disorders Rash 39 15% 33 13% a All adverse events reported in t 10% of subjects in either treatment group are included, regardless of severity grade or relationship to treatment. Each subject is counted only once per treatment and preferred term. Source: Module 5.3.5.1, GS-01-934, 144-week CSR, Section 11.1, Table 33

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No changes in the safety profile of EFV, FTC or TDF were observed with 48 weeks of coadministration compared to previous experience with the use of the individual agents in other combination regimens. Through Week 144 in Study GS-01-934, treatment-emergent AEs considered by the investigator as possibly or probably related to the complete study regimen (EFV + FTC + TDF or CBV + EFV) were reported for 69% of subjects (177/257) in the FTC + TDF group and 76% of subjects (193/254) in the Combivir group. The most frequently reported treatment-emergent AEs (for at least 10% of either treatment group) related to study regimen were dizziness (25%, 63/257), nausea (18%, 46/257), and abnormal dreams (17%, 44/257) in the FTC + TDF group and nausea (27%, 69/254), dizziness (26%, 66/254), abnormal dreams (13%, 34/254), and fatigue (10%, 25/254) in the Combivir group.

There was no evidence of a TDF effect on renal function as determined by the evaluation of serum creatinine and serum phosphorus concentrations and the lack of occurrence of clinically significant renal-related AEs (see Section 2.5.5.3). Similarly, there was no evidence of bone toxicity associated with TDF, as indicated by the similar incidence of bone fractures between the treatment groups; all fractures were considered by the investigator as not related to any of the study drugs, and no change in study regimen dosing was made as a result of any fracture. Few subjects reported skin hyperpigmentation: 15 subjects in the EFV + FTC + TDF group and 9 subjects in the CBV + EFV group. Hyperpigmentation was Grade 2 in severity for 2 subjects (one in each treatment group) and Grade 1 for all other subjects.

Treatment effects on lipid metabolism favored the EFV + FTC + TDF regimen (see Section 2.5.5.6 and Module 2.7.4.3.4).

In summary, the once-daily regimen of FTC + TDF + EFV has demonstrated an acceptable safety profile in treatment-naive HIV-1 infected subjects through long-term treatment. The FTC + TDF + EFV regimen was better tolerated than the CBV + EFV regimen, as evidenced by the significantly lower rate of study drug discontinuation due to an AE. There was no effect on renal function or evidence of bone toxicity, and few reports of hyperpigmentation.

2.5.5.2.2. Safety in Study GS-99-903

The once-daily regimen of TDF + 3TC + EFV was well tolerated through 144 weeks of treatment in Study GS-99-903, and demonstrated a preferential safety profile compared with the d4T + 3TC + EFV regimen.

Through 144 weeks of double-blind treatment, the most common AEs in both treatment groups were headache, viral infection and diarrhea, each of which occurred with similar incidences between treatment groups. Most AEs were of mild or moderate severity. Only 10 subjects (3%) in the TDF + 3TC + EFV group compared with 21 subjects (7%) in the d4T + 3TC + EFV group had Grade 3/4 AEs that were considered to be possibly or probably related to study treatment (i.e., TDF or d4T).

Eleven deaths (5 in the TDF + 3TC + EFV group and 6 in the d4T + 3TC + EFV group) occurred during the 144-week study period and were due to largely complications of

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advanced HIV disease; none were considered by the investigator to be related to study medication. The incidence of SAEs was similar between the 2 treatment groups. SAEs were generally of a type that would be expected in a study population of HIV-1 infected subjects requiring antiretroviral therapy. Few SAEs were considered possibly or probably related to study treatment. There was a higher incidence of discontinuations due to AEs in the d4T + 3TC + EFV group (13%) compared with the TDF + 3TC + EFV group (6%), mainly attributed to the higher rate of occurrence of lipodystrophy with the d4T regimen. During the study, 47 subjects substituted nevirapine for EFV (7% of subjects in the TDF group and 9% of subjects in the d4T group). The most common reason for substitution was EFV-associated central nervous system toxicity (6% in each group; other reasons included rash, pregnancy, and protocol exception).

The incidences of serum creatinine elevations and hypophosphatemia were similar between the 2 treatment groups and there were no clinically significant drug-related renal AEs (see also Section 2.5.5.3). There was no increased risk of bone fractures or evidence for clinically relevant bone abnormalities with the TDF regimen over the 144-week treatment period (see also Section 2.5.5.5).

The results of the assessment of metabolic effects and potential mitochondrial toxicities through 144 weeks indicated a more favorable safety profile with the TDF regimen compared with the d4T regimen as demonstrated by the overall incidence of events related to potential mitochondrial toxicity, changes in body weight and limb fat, and changes in serum lipid profiles (see Section 2.5.5.6 and Module 2.7.4.4.5.1) {7013}. The incidence of Grade 3 and Grade 4 laboratory abnormalities was similar in both treatment groups, except for serum cholesterol and triglyceride elevations that were more common in the d4T + 3TC + EFV group (15% and 14%, respectively) compared with the TDF + 3TC + EFV group (5% and 3%, respectively).

During the open-label extension phase, TDF was well tolerated both in the subset of subjects who continued TDF (mean of 248 weeks of TDF treatment) and those who switched from d4T to TDF (mean of 99 weeks of TDF treatment). Most AEs were mild to moderate in severity and did not result in treatment discontinuation. Only 1 subject discontinued TDF treatment due to an AE (asymptomatic serum amylase and lipase increased). There was no evidence of any clinically significant toxicity related to the use of TDF. The renal safety profile remained stable in the TDF/TDF group through the extended treatment period. The small changes in bone mineral density (BMD) that were seen in the first 48 weeks of double-blind treatment were nonprogressive for the remainder of TDF treatment. In subjects who switched from d4T to TDF in the open-label phase, there was a significant improvement in the lipid profile and a marked increase in limb fat.

In summary, during long-term treatment in Study GS-99-903, TDF administered in combination with 3TC and EFV was well tolerated in antiretroviral-naive HIV-1 infected subjects. The results of several key measures used to assess safety and tolerability, including discontinuations due to AEs and the serum lipid profile, indicate that the TDF regimen has a more favorable safety profile than the d4T regimen.

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2.5.5.2.3. Safety in Trials C209 and C215

2.5.5.2.3.1. Analysis of Safety Data and Extent of Exposure

The integrated overview of the safety and tolerability profile of the recommended dose TMC278 25 mg once daily in HIV-1 infected subjects is based on the primary 48-week safety analysis of the pooled Phase 3 trials. In the Phase 3 trials, 686 subjects started treatment with TMC278 25 mg once daily (taken with a meal), while the pooled control group consisted of 682 subjects receiving EFV (taken without food). Subjects received TMC278 or EFV plus a background regimen containing 2 investigator-selected N(t)RTIs: in C209, the fixed background regimen was FTC/TDF, and in C215, the background regimen was either ABC/3TC, AZT/3TC, or FTC/TDF

The median treatment duration was approximately 55 weeks in both treatment groups. A total of 611 subjects (89.1%) were exposed to TMC278 for at least 48 weeks.

The double-blind, double-dummy controlled design and the similarity of the background regimen in the Phase 3 trials allows for a relevant safety assessment and ensured a comparative evaluation of safety between TMC278 and EFV as control.

Further details on safety in the Phase 3 trials are provided in the TMC278-C209 CRR and the TMC278-C215 CRR (Module 5.3.5.1).

2.5.5.2.3.2. Overall Safety Profile of TMC278 in Pooled Phase 3 Trials

2.5.5.2.3.2.1. Overall Incidence of AEs in Pooled Phase 3 Trials of TMC278 (C209 and C215)

This section provides an overall summary of AEs in the Phase 3 pooled analysis.

An overview of AEs, including AEs of special interest, reported in the Phase 3 trials is provided in Table 22.

The incidence of any AE was similar in both treatment groups (89.8% in the TMC278 group and 92.2% in the control group).

Most AEs were Grade 1 or 2 in severity. Grade 3 or 4 AEs were reported by 13.3% of subjects in the TMC278 group and by 18.0% of subjects in the control group.

A lower proportion of subjects in the TMC278 group (46.4%) than in the control group (64.1%) had at least 1 AE that was assessed by the investigator to be treatment-related.

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The proportion of subjects experiencing AEs leading to permanent discontinuation was smaller in the TMC278 group (3.4%) than in the control group (7.6%). The most common AEs leading to permanent discontinuation on TMC278 belonged to the system organ class (SOC) psychiatric disorders (1.5% versus 2.2% on control). In the control group, subjects mostly discontinued due to AEs in the SOCs of skin and subcutaneous tissue disorders (0.3% on TMC278 versus 1.8% on control), mostly driven by the individual preferred term rash, infections and infestations (0.3% on TMC278 versus 1.3% on control), and psychiatric disorders (1.5% on TMC278 versus 2.2% on control).

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Table 22. Rilpivirine Studies C209 and C215: Summary of Adverse Events (Phase 3 Week 48 Analysis)

TMC278 Control AE Summary, n (%) N = 686 N = 682 Treatment duration (weeks) 55.7 55.6 Median (range) (0 - 87) (0 - 88) Subject-years of exposurea 740.1 714.4 Any AE 616 (89.8) 629 (92.2) Any Grade 1 or 2 AEa 607 (88.5) 618 (90.6) Grade 1 561 (81.8) 565 (82.8) Grade 2 333 (48.5) 366 (53.7) Any Grade 3 or 4 AE 91 (13.3) 123 (18.0) Grade 3 79 (11.5) 114 (16.7) Grade 4 23 (3.4) 23 (3.4) Any treatment-relatedb AE 318 (46.4) 437 (64.1) Any treatment-relatedb AE and at 109 (15.9) 212 (31.1) least Grade 2 Death 1 (0.1) 4 (0.6) Any SAEc 45 (6.6) 55 (8.1) AE leading to discontinuation 23 (3.4) 52 (7.6) AE leading to temporary 28 (4.1) 44 (6.5) discontinuation Any skin event of interestd,e 96 (14.0) 177 (26.0) Rash (grouped term) 51 (7.4) 150 (22.0) Any neuropsychiatric event of 276 (40.2) 388 (56.9) interestd,f Any neurologic event of interest 184 (26.8) 308 (45.2) Any psychiatric event 164 (23.9) 198 (29.0) Any hepatic event of interestd,g 38 (5.5) 45 (6.6) Any event of interest potentially 3 (0.4) 8 (1.2) related to QT interval prolongationd,g Any endocrine event of interestd,g 34 (5.0) 26 (3.8) N = number of subjects per treatment group; n = number of observations. a Post hoc analyses were performed to determine the number of subjects with Grade 1 or 2 AEs. b Defined as possibly, probably, or very likely related to treatment in the opinion of the investigator. c Includes SAEs with an outcome of death. d AEs of interest were not identified from single relevant SOCs, but were based on selected AE preferred terms from a number of relevant SOCs. e Presented overall for event of interest category (defined in Appendix 2.7.4.7.3, Section 1.3.2.4.1) and by grouped term. f Presented overall for neuropsychiatric events of interest and by neurologic/psychiatric event of interest categories g Presented overall for event of interest category Source: Module 2.7.4.2.1.1.2, Table 23

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The most commonly reported AEs in the TMC278 group (in at least 10.0% of subjects) were headache (13.8%), nausea (13.4%), diarrhea (11.4%) and nasopharyngitis (10.1%). These events were reported at a similar incidence in the control group. The most clear differences in common AEs between treatment groups were in favor of TMC278 and were seen for rash (individual preferred term) (5.2% with TMC278 versus 13.2% with control) and dizziness (9.9% with TMC278 % versus 28.4% with control) (see Module 2.7.4.2.1.1.2, Table 25).

When considering treatment-related AEs, dizziness (TMC278: 8.0%; control: 26.2%), somnolence (TMC278: 3.6%; control: 7.2%), rash (individual preferred term) (TMC278: 2.5%; control: 8.9%), disturbance in attention (TMC278: 0.7%; control: 2.5%), and vertigo (TMC278: 0.3%; control: 2.3%) were reported by lower proportions of subjects on TMC278 than on control.

Statistical comparisons for the Phase 3 pooled analysis were performed as predefined in the statistical analysis plan, using the TMC278/control odds ratio (with associated 95% CIs) and Fisher exact test for the parameters shown in Figure 6 and Figure 7. For any single preferred terms (or the planned psychiatric event of interest grouped term, “abnormal dreams/nightmare”) comparisons were made when the incidence was more than 10% overall, regardless of relationship to study medication.

Statistical testing comparing the TMC278 and control groups in the incidence of AEs reported in more than 10% of subjects (by preferred term, using the Fisher exact test), revealed statistically significant differences in favor of TMC278 for dizziness (p < 0.0001), abnormal dreams/nightmare (p = 0.0093) and for the individual preferred term of rash (p < 0.0001). No statistically significant differences were found in favor of control for the AEs tested.

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Figure 6. Rilpivirine Studies C209 and C215: Statistical Comparisons of Adverse Events Regardless of Relationship to Investigational Medication - Grouped terms (Phase 3 Week 48 Pooled Analysis)

P-values from Fisher exact test EOI, event of interest Source: Module 5.3.5.3, TMC278-C904-Anal-Saf-AE, Display SAF.19

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Figure 7. Rilpivirine Studies C209 and C215: Statistical Comparisons of Adverse Events Regardless of Relationship to Investigational Medication – Most Frequent (> 10% overall) Individual Preferred Terms (Phase 3 Week 48 Pooled Analysis)

P-values from Fisher exact test Source: Module 5.3.5.3, TMC278-C904-Anal-Saf-AE, Display SAF.19

For details, refer to Section 2.5.5.4.2 on rash, Section 2.5.5.7.2 on neurologic events of interest and Section 2.5.5.8.2 on psychiatric event of interest.

2.5.5.2.3.2.2. Mortality in Pooled Phase 3 Trials of TMC278

In the 35 RPV clinical trials with safety data included in this submission, a total of 9 subjects died; 4 subjects in the Phase 2b trial (see Module 2.7.4, Appendix 2.7.4.7.3), and 5 subjects in the Phase 3 trials. None of these deaths was considered related to study medication.

In the 2 Phase 3 trials, 5 subjects had died at the time of the primary Week 48 analysis. One subject (0.1%) in the TMC278 group due to bronchopneumonia and 4 subjects (0.6%) in the control group due to Burkitt’s Lymphoma, cerebral toxoplasmosis and respirator failure (in 1 subject), dysentery, and cerebrovascular accident.

Further details on AEs leading to death in the Phase 3 trials are provided in Module 2.7.4.2.1.2.2. Details on AEs leading to death in the Phase 2b trial (C204) are

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provided in Module 2.7.4, Appendix 2.7.4.7.3, Section 4.3.1.3 (Week 96 analysis) and Module 2.7.4, Appendix 2.7.4.7.3, Section 4.4.1.3 (Week 192 analysis).

2.5.5.2.3.2.3. SAEs and Other Significant AEs in Pooled Phase 3 Trials of TMC278

SAEs were reported during the treatment period in the 2 Phase 3 trials at similar rates in the 2 treatment groups, by 45 subjects (6.6%) in the TMC278 group and 55 subjects (8.1%) in the control group.

The reported SAEs were from a variety of SOCs, and many occur commonly in HIV-infected patients. For each treatment group, the highest incidence of SAEs was observed in the SOC of infections and infestations (2.6% in the TMC278 group and 2.5% in the control group). The only notable difference in incidence of SAEs between TMC278 and control was seen in the SOC of hepatobiliary disorders (0.9% on TMC278 versus 0.1% on control).

The incidence of treatment-related SAEs was 1.0% (7 subjects) in the TMC278 group and 0.9% (6 subjects) in the control group. The only SOCs in which more than 1 subject had a treatment-related SAE was the SOC of psychiatric disorders (3 subjects [0.4%] on TMC278 versus 2 subjects [0.3%] on control) and the SOC of investigations (1 subject [0.1%] on TMC278 versus 2 subjects [0.3%] on control).

In the control group, more subjects discontinued due to AEs and generally did so earlier than subjects in the TMC278 group, and the difference was sustained throughout the treatment period. The proportion of subjects who experienced an AE leading to permanent discontinuation was 3.4% in the TMC278 group and 7.6% in the control group. The difference between the TMC278 and control groups was mainly driven by the SOC of skin and subcutaneous tissue disorders (0.3% versus 1.8%), infections and infestations (0.3% versus 1.3%) and psychiatric disorders (1.5% versus 2.2%).

2.5.5.2.3.2.4. Clinical Laboratory Evaluations in Pooled Phase 3 Trials of TMC278

In the TMC278 group, changes over time in the selected laboratory parameters, if any, were generally modest in either treatment group of the pooled Phase 3 trials and considered not clinically relevant.

TMC278 was not found to have any clinically relevant effect on hepatic parameters, pancreatic parameters amylase and lipase, glucose and insulin or lipids. In general, changes over time for these parameters were not substantially different between the 2 treatment groups.

Initial decreases in hemoglobin, mainly observed in the AZT/3TC subgroup, were consistent with the known effect of AZT.

Small mean increases from baseline for creatinine were observed in the TMC278 group, accompanied by decreases in estimated glomerular filtration rate for creatinine as calculated by modification of diet in renal disease (MDRD) formula (eGFRcreat) below baseline levels,

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but the likely effect of TMC278 on tubular secretion of creatinine is not considered of clinical relevance.

In addition, there has been no trend or signal of adrenal dysfunction. Thyroid monitoring was not done in Phase 3 trials as close monitoring of thyroid hormone levels in the Phase 2b trial did not identify any clinically relevant effects of TMC278 on thyroid function.

The most frequently reported treatment-emergent graded laboratory abnormalities in any treatment group were elevated total and LDL cholesterol levels, which were reported at a lower frequency in the TMC278 group compared to the control group.

Clinical laboratory evaluations over time are presented by background N(t)RTI subgroup for parameters that are known to be affected by background N(t)RTI regimen. Since the number of subjects in the ABC/3TC subgroup was small (5.0% of subjects overall), data for this subgroup are not discussed as comparisons with this subgroup are not considered meaningful.

The incidence of treatment-emergent Grade 3 or 4 laboratory abnormalities was lower in the TMC278 group (10.9%) than in the control group (17.6%).

The most common Grade 3 and 4 laboratory abnormalities in the TMC278 group were increased pancreatic amylase (2.9% in the TMC278 group and 4.0% in the control group), increased aspartate aminotransferase (AST) (2.0% in the TMC278 group and 2.8% in the control group), and increased alanine aminotransferase (ALT) (1.5% in the TMC278 group and 3.4% in the control group). No Grade 4 laboratory abnormalities were reported in more than 2 subjects (0.3%) in the TMC278 group, with the exception of ALT (5 subjects, 0.7%) and AST (3 subjects, 0.4%), and Grade 4 laboratory abnormalities were reported in no more than 1.3% of subjects in the control group.

Further details on laboratory safety in Phase 3 trials are provided in Module 2.7.4.3.1.2.

Hemoglobin

In the overall pooled Phase 3 TMC278 population, mean hemoglobin values remained close to baseline levels early on in the trial and showed a similar pattern in both treatment groups. At Week 48, mean hemoglobin values increases above baseline to values of 5.3 g/L on TMC278 and 4.9 g/L on control.

In the Phase 2b trial C204, decreases in hemoglobin levels (and events of anemia) occurred predominantly in the subgroup of patients using AZT/3TC as the N(t)RTI backbone (see Module 2.7.4, Appendix 2.7.4.7.3, Section 4.3.2.2). Review of the mean changes in hemoglobin over time by background regimen in the pooled Phase 3 analysis indicates that initial hemoglobin decreases only occurred in the AZT/3TC subgroup (Figure 8), consistent with the known hematotoxic effects of AZT {2226}.

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Figure 8. Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from Baseline in Hemoglobin by Background Regimen: FTC/TDF (Top); AZT/3TC (Middle); ABC/3TC (Bottom) (Phase 3 Week 48 Pooled Analysis) FTC/TDF

AZT/3TC

ABC/3TC

Source: Module 2.7.4.3.6.1.1, Figure 20

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In the AZT/3TC subgroup, maximum mean decreases from baseline were seen at Week 8, after which hemoglobin gradually returned to baseline levels by Week 48. No notable mean decreases in hemoglobin were seen in the TMC278 group for the other background regimen subgroups. Hepatic Parameters The laboratory evaluation of hepatic parameters in the TMC278 group showed mean decreases from baseline for AST and ALT that stabilized over time. These changes were not different from the control group and considered not clinically relevant. Most individual AST and ALT abnormalities in TMC278 treated subjects were Grade 1 or 2 (i.e., mild or moderate) in severity; their incidence was not higher than in the control group. Incidences of Grade 3 and 4 ALT and AST abnormalities were 2.0% in the TMC278 group and 2.8% in the control group for increased AST and 1.5% in the TMC278 group and 3.4% in the control group for increased ALT. Grade 2 or 3 hyperbilirubinemia was reported at a higher incidence in the TMC278 group (3.1%) than in the control group (0.4%). Pancreatic Parameters Small mean increases from baseline in pancreatic amylase and lipase were initially observed in the TMC278 group followed by small mean decreases from baseline. A similar pattern was seen in the control group and the changes in pancreatic amylase and lipase in both treatment groups were considered not clinically relevant. Renal Parameters Serum creatinine changes over time were observed in the Phase 2b trial of TMC278. Based on investigations in trial C131, there appeared to be no effect on estimated glomerular filtration rate for cystatin C (eGFRcyst), suggesting that creatinine changes appeared to be related to NNRTI effects on the disposition of creatinine rather than to renal toxicity. There is also a known potential tubulotoxicity with TDF, and an effect of decreasing eGFR. For these reasons, creatinine and eGFRcreat changes were analyzed in the Phase 3 trials and blood cystatin C (eGFRcyst) was analyzed in trial C215, overall and by background regimen. In the overall pooled Phase 3 TMC278 population, small mean increases in serum creatinine were observed for the TMC278-treated subjects, from the first on-treatment assessment onwards and remained stable over the treatment period, ranging from 0.06 mg/dL at the first on-treatment assessment to 0.09 mg/dL at Week 48. For control-treated subjects, serum creatinine fluctuated around the baseline level over the treatment period. The mean change from baseline in serum creatinine over time in the pooled Phase 3 analysis is presented for the subgroups of subjects receiving FTC/TDF, AZT/3TC and ABC/3TC in Figure 9. Mean serum creatinine increases were observed for TMC278-treated subjects in each background regimen subgroup, but these were greater in the FTC/TDF subgroups compared to the AZT/3TC subgroup. In the control group, mean decreases in serum creatinine from baseline were observed for the AZT/3TC subgroup consistently from Week 2 up to Week 48, whereas no notable difference from baseline was observed for subjects in the control group treated with FTC/TDF.

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Figure 9. Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from Baseline in Creatinine by Background Regimen: FTC/TDF (Top); AZT/3TC (Middle); ABC/3TC (Bottom) (Phase 3 Week 48 Pooled Analysis of C209 and C215) FTC/TDF

AZT/3TC

ABC/3TC

Source: Module 2.7.4.3.3.1, Figure 8

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Consistent with observations of creatinine increases, a decrease in eGFRcreat was observed, which remained stable over the 48 weeks with values of 7 to 10 mL/min/1.73m2 from Week 2 to Week 48. The mean decreases observed for TMC278-treated subjects were greater in the FTC/TDF subgroup than in the AZT/3TC subgroup. A decrease in eGFRcreat is a known effect of TDF.

Conversely, in the control group, mean eGFRcreat did not change significantly from baseline during treatment.

The mean decreases observed for TMC278-treated subjects were greater in the FTC/TDF subgroup than in the AZT/3TC subgroup.

In the control group, mean increases from baseline were observed in eGFRcreat throughout the trial for each of the background regimen subgroups but this was least pronounced for the FTC/TDF subgroup. A decrease in eGFRcreat is a known effect of TDF.

There were no treatment discontinuations due to renal impairment or elevated serum creatinine.

Exploratory analyses performed in the Phase 1 trial C131 (refer to Module 2.7.4, Appendix 2.7.4.7.3, Section 6.1.4.1.1) to investigate the effects of TMC278 on the markers of renal function, i.e., markers of glomerular filtration and proximal tubular function, demonstrated that TMC278 does not affect the eGFRcyst, nor does it affect proximal tubular function {11576}. In order to further evaluate whether the effect of TMC278 on serum creatinine reflected a true change in GFR or could have an alternative explanation, such as an interaction with the tubular secretion of creatinine, cystatin C was measured in subjects in the C215 trial at baseline, Week 2 and Week 24. One of the reasons why cystatin C is accepted to be a better marker of glomerular filtration rate (GFR) than creatinine is because it is freely filtered by the glomeruli without proximal tubular secretion {15884}, {15851}. The results of this analysis show a small mean increase in eGFRcyst in the TMC278 group at Week 2 (+2.6 mL/min with TMC278 and 5.3 mL/min with control) and at Week 24 (+21.7 mL/min with TMC278 and +31.4 mL/min with control). The increase in eGFRcyst was seen in all subgroups by background regimen, at Week 2 and at Week 24, with TMC278 and with control. These data indicate that there is no TMC278-induced nephrotoxicity.

The results of the analysis of cystatin C performed in trial C215 are described in an addendum to the CRR (Module 5.3.5.1, TMC278-C215-W48-CRR-Add).

Lipids

Mean changes from baseline in total cholesterol, high density lipoprotein (HDL) cholesterol, total cholesterol/HDL cholesterol ratio, low density lipoprotein (LDL) cholesterol and triglycerides are presented graphically in Figure 10. Fasted values are presented for all lipid parameters.

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Figure 10. Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from Baseline in Total Cholesterol, HDL Cholesterol, Total Cholesterol/HDL Cholesterol Ratio, LDL Cholesterol and Triglycerides Over Time (Fasted) (Phase 3 Week 48 Pooled Analysis) Total Cholesterol HDL Cholesterol

Total Cholesterol/HDL Cholesterol Ratio LDL Cholesterol

Triglycerides

Source: Module 2.7.4.3.4.1, Figures 13–17

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Changes over time in laboratory lipid parameters were less pronounced in the TMC278 group than in the control group, with statistically significant differences between the 2 treatment groups for total, HDL, LDL cholesterol, and triglycerides (all p < 0.001).

Mean total and LDL cholesterol values over time remained close to baseline in the TMC278 group, while mean values for these lipids increased significantly in the control group (p < 0.001). The increase in HDL cholesterol over time was less pronounced with TMC278 than with control subjects, and there was no difference between treatment groups at Week 48 in decrease from baseline of the total cholesterol/HDL ratio. Mean triglyceride values remained close to baseline throughout the trial in both treatment groups, showing a small decrease with TMC278 and a small increase with control.

The most frequently reported treatment-emergent graded laboratory abnormalities in any treatment group were elevated LDL cholesterol levels, in the 2 treatment groups, reported at a higher frequency in the control group compared to the TMC278 group. Grade 2 or 3 abnormalities in total cholesterol were reported in a total of 5.0% of subjects in the TMC278 group compared to 18.4% in the control group, and Grade 2 to 3 abnormalities in LDL cholesterol were reported in a total of 5.5% of subjects in the TMC278 group compared to 15.3% in the control group. Four subjects had Grade 4 abnormalities in triglycerides; all were in the control group. The use of lipid lowering drugs was low in this patient population (2.2% and 4.0% of subjects in the TMC278 and control groups, respectively).

Grade 3 or 4 laboratory abnormalities in lipids were more common on control than on TMC278. The differences between the treatment groups in the incidence of Grade 3 or 4 increases were statistically significant in favor of TMC278 for total cholesterol, LDL cholesterol and triglycerides (p ” 0.001) (post hoc analyses).

Lipid data in support of the FTC/RPV/TDF Tablet

Changes from baseline in total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides in subjects receiving RPV plus FTC/TDF in Studies C209 and C215 are presented in Table 23. The mean changes from baseline were smaller in the RPV + FTC/TDF arm versus the EFV + FTC/TDF arm (see Module 2.7.4.3.4.1).

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Table 23. Rilpivirine Studies C209 and C215: Lipid Values Reported in Subjects Receiving RPV or EFV in Combination with FTC/TDF

RPV + FTC/TDF EFV + FTC/TDF N = 550 N = 546 Baseline Week 48 Baseline Week 48 Mean Changea Mean Changea Mean (mg/dL) (mg/dL) Mean (mg/dL) (mg/dL) Total cholesterol (fasted) 162 -0.4 161 26 HDL cholesterol (fasted) 41 3 40 10 LDL cholesterol (fasted) 97 -2 96 13 Triglycerides (fasted) 124 -12 132 12 a The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values. Source: Module 2.7.4.3.4.1, Table 93

Glucose, Insulin, and Homeostasis Model Assessment Insulin Resistance

No clinically relevant changes in mean fasted serum glucose or insulin levels were noted throughout the treatment period in the TMC278 group and the control group. Minor changes in Homeostasis Model Assessment Insulin Resistance (HOMA-IR) in the TMC278 group and the control group were also not considered clinically relevant.

2.5.5.2.3.2.5. Electrocardiogram (ECG) and Vital Signs in Pooled Phase 3 Trials of TMC278

No effect of TMC278 on vital sign parameters was seen. There were no consistent or clinically relevant changes over time in vital signs and there were also no clinically relevant differences in the incidence of treatment-emergent vital sign abnormalities between the treatment groups. Vital signs abnormalities reported as AEs were reported at low incidence in both treatment groups.

QTc interval results for the Phase 3 pooled analysis are discussed in Section 2.5.5.10, together with the analysis of potential events of interest for QT interval prolongation.

For other ECG parameters (Heart Rate, PR interval and QRS interval), small fluctuations were observed over the 48-week treatment period and there were no consistent or clinically relevant changes over time in these parameters.

There were also no clinically relevant differences between the TMC278 and control groups in the incidence of treatment-emergent ECG abnormalities. The incidence of ECG abnormalities reported as AEs was low and similar in both treatment groups. The most commonly reported ECG-related AEs were bundle branch block right (1.3% subjects with TMC278 group and 1.5% with control group), and palpitations (1.7% with TMC278 group

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and 1.0% with control). There was no difference between the TMC278 group and the control group with respect to the incidence of treatment-emergent ECG abnormalities in any of the background N(t)RTI regimen subgroups.

2.5.5.2.3.2.6. Adrenal Safety in Pooled Phase 3 Trials of TMC278

To determine whether there was an effect of TMC278 or control on the biosynthesis of adrenal and gonadal hormones in humans, basal cortisol, 17-OH progesterone, aldosterone, androstenedione, dehydroepiandrosterone sulphate (DHEAS), progesterone and testosterone were assessed at specified time points, before and during double-blind treatment in the Phase 3 trials. Adrenocorticotropic hormone (ACTH) stimulation tests were routinely done at baseline and at Week 48, and additionally, based on basal cortisol results or an abnormal ACTH test.

There were no clinically relevant changes in basal cortisol, 17-OH progesterone, or aldosterone over time and no consistent or clinically relevant changes for the other endocrine parameters (androstenedione, DHEAS, luteinizing hormone [LH], and testosterone) in either treatment group.

The mean increase from baseline at Week 48 for maximum change in cortisol after ACTH stimulation observed in the TMC278 group (16.5 nmol/L) was lower than the increase observed in the control group (58.1 nmol/L). Neither treatment affected the mean increases from baseline for maximum change in 17-OH progesterone and aldosterone after ACTH stimulation at Week 48.

The incidence of abnormal cortisol responses after ACTH stimulation is presented in Table 24.

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Table 24. Rilpivirine Studies C209 and C215: Treatment-Emergent Abnormal Cortisol Response to ACTH Stimulation (Worst Case) (Phase 3 Week 48 Pooled Analysis)

Parameter TMC278 Control Abnormality, n (%) N = 686 N = 682 ACTH stimulation test at Week 48 N' 593 558 Any abnormal ACTH test 23 (3.9) 8 (1.4) 450, 500 nmol/L 13 (2.2) 4 (0.7) < 450 nmol/L 10 (1.7) 4 (0.7) ACTH stimulation tests in the course of the 48-week treatment period, including Week 48 N' 643 605 Any abnormal ACTH test 38 (5.9) 13 (2.1) 450, 500 nmol/L 18 (2.8) 7 (1.2) < 450 nmol/L 20 (3.1) 6 (1.0) At least 2 consecutive abnormal 11 (1.7) 0 ACTH test N = overall number of subjects, N' = number of subjects per test and treatment group; n = number of observations. A test result was defined as abnormal when none of the cortisol values at T0, T30, or T60 was t 500 nmol/L. Percentages are calculated relative to the number of subjects with data. Source: Module 2.7.4.4.3.2, Table 116

The incidence of a treatment-emergent abnormal cortisol response to ACTH stimulation at Week 48 was slightly higher in the TMC278 group than in the control group, both at Week 48 (3.9% with TMC278 compared to 1.4% with control) as during the entire treatment period (5.9% with TMC278 versus 2.1% with control). The incidence of at least 2 consecutive abnormal cortisol responses (< 500 nmol/L) to ACTH stimulation was 1.7% in the TMC278 group compared to none in the control group.

No subjects discontinued the trial due to an AE of blood cortisol decreased (nor for any other endocrine event of interest). There were no clinical signs or symptoms of adrenal insufficiency in either treatment group.

All data related to adrenal safety from preclinical and clinical trials were thoroughly assessed by an independent endocrinologist in order to determine the effect of TMC278 on steroidogenesis within the adrenal gland and the gonads. From the clinical data it was concluded that TMC278 25 mg once daily does not have a clinically relevant effect on adrenal function in HIV-infected adult subjects. A White Paper on the endocrine safety evaluation of TMC278 is presented in Module 5.4, TMC278 20100630 Expert Endocrinology.

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In conclusion, none of these changes, investigated and described in considerable detail, are considered to be clinically relevant. There were no clinical signs or symptoms suggestive of an adrenal or gonadal dysfunction.

Endocrine events of interest, including events related to adrenal insufficiency, are discussed in Section 2.5.5.11.2.

2.5.5.2.3.2.7. Adverse Drug Reaction Analysis in Pooled Phase 3 Trials of TMC278

Adverse Drug Reactions (ADRs) are AEs that are considered at least possibly related to the use of a drug substance. Adverse drug reactions, rather than treatment-emergent AEs, are identified to facilitate communication of possible drug-associated risks within prescribing information.

In order to identify AEs as ADRs, data from the 35 trials included in the Summary of Safety were analyzed and reviewed in accordance with company methodology, as detailed in Module 2.7.4, Appendix 2.7.4.7.3, Appendix 12.10.1.

A complete list of AEs identified as ADRs is presented in Module 5.3.5.3, TMC278-C904-Anal-ADD, Display ADD.5. An overview of AEs not considered to be ADRs is presented in Module 5.3.5.3, TMC278-C904-Anal-ADD, Display ADD.8.

A tabulation of all ADRs, regardless of grade, reported during 48-week treatment with TMC278 or control is provided in Module 2.7.4, Appendix 2.7.4.7.3, Section 9.1.2, Table 113. ADRs related to laboratory abnormalities are excluded from this table and are described in detail in Module 2.7.4, Appendix 2.7.4.7.3, Section 9.1.3.

In general, the proportion of subjects experiencing at least one ADR in the Phase 3 trials was lower in the TMC278 group (51.6%) compared with the control group (67.9%). The majority of ADRs reported were Grade 1 or 2 in severity. Grade 3 or 4 ADRs occurred in 3.1% and 5.6% of TMC278- and control-treated subjects, respectively. Serious ADRs were infrequently reported, with very low incidences in the 2 treatment groups (4 subjects [0.6%] with TMC278 and 8 subjects [1.2%] with control). There were no serious ADRs with an outcome of death. The proportion of subjects experiencing ADRs leading to permanent discontinuation of study medication was 1.6% in the TMC278 group and 4.0% in the control group.

Adverse drug reactions of at least Grade 2 did not occur frequently with TMC278. The most common ADRs (in at least 2.0% of subjects) with at least Grade 2 severity reported with TMC278 treatment were depression (3.5% on TMC278 versus 2.2% on control), insomnia (2.9% versus 3.2%), headache (2.6% versus 3.4%) and rash (2.2% versus 9.4%). The greatest differences between the treatment groups in the incidence of ADRs of at least Grade 2 were seen for rash (2.2% on TMC278 versus 9.4% on control) and dizziness (0.7% versus 6.6%).

Individual Grade 3 and/or 4 ADRs were reported in at most 2 subjects in the TMC278 group.

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Overall, the percentage of subjects reported with an ADR leading to discontinuation was low in both treatment groups. A slightly smaller proportion of subjects in the TMC278 group (1.2%) experienced at least 1 ADR leading to discontinuation when compared to the control group (3.2%). In the TMC278 group, all ADR grouped terms leading to permanent discontinuation had an incidence below 0.5%. By grouped term, the most common ADRs leading to discontinuation in the control group were rash (1.5%), depression (0.6%) and abnormal dreams (0.6%).

There were no additional preferred terms identified as ADRs from the Phase 1, Phase 2a and Phase 2b trials that were not already listed from the pooled Phase 3 ADR analysis.

No clinically important differences were revealed in the comparison of the incidence of AEs (regardless of causality), in the AEs considered at least possibly related in the opinion of the investigator, and in ADRs. It can be concluded that the presentation of ADRs in the full prescribing information of TMC278 represents a complete and accurate safety and tolerability profile of the product based on the cumulative available safety data.

2.5.5.2.4. AE Data to Support the FTC/RPV/TDF FDC Tablet

The adverse reactions considered at least possibly related to treatment with the components of the FTC/RPV/TDF FDC tablet from clinical trial data (as detailed above for FTC, RPV, and TDF) and postmarketing experience (for FTC and TDF) are listed in Table 25, below, by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (t 1/10), common (t 1/100 to < 1/10), uncommon (t 1/1,000 to < 1/100) or rare (t 1/10,000 to < 1/1,000).

The safety assessment of RPV is based on pooled data from 686 patients who received RPV 25 mg once daily in the Phase 3 trials C209 and C215 (see Section 2.5.5.2.3.2.7). Clinical ADRs of at least moderate intensity (t Grade 2) and selected treatment-emergent clinical laboratory abnormalities, considered as ADRs for RPV, are summarized in Table 25.

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Table 25. Tabulated Summary of Adverse Reactions Associated with the Individual Components of the FTC/RPV/TDF FDC Tablet Based on Clinical Study and Postmarketing Experience

Frequency FTC RPVa TDF Blood and lymphatic system disorders: Common: neutropenia decreased white blood cell count — decreased hemoglobin, decreased platelet — Uncommon anaemiab : count Immune system disorders: Common: allergic reaction — — Metabolism and nutrition disorders: Very common: — — Hypophosphataemiac Common: hyperglycemia, hypertriglyceridemia decreased appetite — increased total cholesterol (fasted), Uncommon: — increased LDL cholesterol (fasted), Hypokalaemiac increased triglycerides (fasted) Rare: — — lactic acidosis Psychiatric disorders: depression, insomnia, abnormal dreams, Common: insomnia, abnormal dreams — sleep disorders Uncommon — depressed mood Nervous system disorders: Very common: headache — dizziness Common: dizziness headache headache

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Frequency FTC RPVa TDF Uncommon — dizziness, somnolence — Gastrointestinal disorders: Very common: diarrhoea, nausea — diarrhoea, vomiting, nausea elevated amylase including elevated increased pancreatic amylase, abdominal abdominal pain, abdominal distension, Common: pancreatic amylase, elevated serum lipase, pain, nausea flatulence vomiting, abdominal pain, dyspepsia increased lipase, vomiting, abdominal pancreatitis Uncommon: — discomfort Hepatobiliary disorders: elevated serum aspartate aminotransferase increased transaminases (AST and/or ALT) (AST) and/or elevated serum alanine Common: increased transaminases aminotransferase (ALT), hyperbilirubinemia Uncommon — increased bilirubin — Rare: — — hepatic steatosis, hepatitis Skin and subcutaneous disorders: Very common: — — rash vesiculobullous rash, rash Common: pustular rash, maculopapular rash, rash, — pruritus, urticaria, skin discoloration (increased pigmentation)b Uncommon: angioedemad — angioedema Musculoskeletal and connective tissue disorders: Very common: elevated creatine kinase — —

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Frequency FTC RPVa TDF Uncommon: — — Rhabdomyolysisc, muscular weaknessc osteomalacia (manifested as bone pain and Rare: — — infrequently contributing to fractures)c,d, myopathyc Renal and urinary disorders: Uncommon: — — increased creatinine, proteinuria renal failure (acute and chronic), acute tubular necrosis, proximal renal tubulopathy Rare: — — including Fanconi syndrome, nephritis (including acute interstitial nephritis)d, nephrogenic diabetes insipidus General disorders and administration site conditions: Very common: — — asthenia Common: pain, asthenia fatigue — a Only adverse reactions of moderate intensity (Grade 2 to 4 for adverse reactions and Grade 3 to 4 for laboratory abnormalities) are included for RPV. b Anaemia was common and skin discoloration (increased pigmentation) was very common when FTC was administered to pediatric patients. c This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with TDF in the absence of this condition. d This adverse reaction was identified through postmarketing surveillance but not observed in randomized, controlled clinical trials in adults or pediatric HIV clinical trails for FTC or in randomized controlled clinical trials or the TDF expanded access program for TDF. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to FTC in randomized controlled clinical trials (n = 1,563) or TDF in randomized controlled clinical trials and the expanded access program (n = 7319). Source: RPV: Module 2.7.4, Appendix 2.7.4.7.3, Section 9.1.2, Table 114 and Module 2.7.4, Appendix 2.7.4.7.3, Section 12.5, Table 120; FTC and TDF: SmPC for Truvada (EPAR-Product Information, last updated 16/2/2010)

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2.5.5.3. Renal Adverse Events

Renal adverse events are described in Module 2.7.4.2.1.5.2. Creatinine and eGFRcreat changes were analyzed in the Phase 3 trials, and eGFRcyst was analyzed in trial C215, overall and by background regimen (see Section 2.5.5.2.3.2.4). The results of the analysis of cystatin C performed in trial C215 are also described in an addendum to the CRR (Module 5.3.5.1, TMC278-C215-W48-CRR-Add).

Renal excretion by a combination of glomerular filtration and tubular secretion is also the primary route of elimination of FTC. Preclinical testing of FTC did not detect evidence of kidney toxicity even at very high doses.

No data are currently available for TMC278 in patients with renal impairment. Since the renal clearance of TMC278 is negligible (< 1% of total), a decrease in total body clearance is not expected in patients with renal impairment. No dose adjustment is required for renally impaired subjects.

The primary route of elimination of TFV is renal excretion by a combination of glomerular filtration and tubular secretion. Nonclinical studies of TFV at exposures similar to or 2- to 20-fold higher than that achieved in humans after a 300-mg daily dose detected some evidence of mild nephrotoxicity in the dog, rat, and monkey. In addition, nephrotoxicity is the dose-limiting toxicity associated with the clinical use of other nucleotide compounds in this class, i.e., cidofovir and high doses of adefovir dipivoxil (60 mg and 120 mg) evaluated for HIV disease. Long-term safety data from clinical trials of TDF do not demonstrate a causal association between renal events and TDF therapy. However, postmarketing safety data indicate that TDF therapy may cause renal adverse reactions, including renal failure, Fanconi syndrome and other proximal tubulopathies.

The following sections summarize the principal renal safety data from clinical studies of TDF, the renal toxicity profile during postmarketing experience, potential mechanisms of renal toxicity and risk factors for renal dysfunction.

2.5.5.3.1. Renal Safety in Clinical Studies

In long-term clinical studies of TDF in HIV-1 infected subjects, renal safety was determined based on clinical AEs and laboratory measures of renal function, specifically changes in serum creatinine and phosphorus, and calculated CLcr (Cockcroft-Gault equation). Subjects participating in these studies had to have adequate renal function at baseline (typically CLcr t 60 mL/min, or t 50 mL/min in Study GS-01-934), and could not receive drugs that are nephrotoxic, have nephrotoxic potential, or compete for active renal elimination. The principal Gilead clinical studies of TDF and the main findings related to renal safety are summarized in Table 26.

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Table 26. Summary of Gilead Clinical Studies that Assessed Renal Safety in HIV-1 Infected Subjects Receiving TDF

Principal Clinical Dataset Study Study Design Regimen Evaluated Main Renal Outcome GS-99- Randomized, double TDF + 3TC + 144 weeks Acute renal failure occurred in 903 blind, active- EFV (n = 299) 2 subjects (one each in 2 groups), controlled, d4T + 3TC + both unrelated to drugs, and led to equivalence study in EFV (n = 301) discontinuation of 1 subject in the antiretroviral-naive d4T group; graded serum creatinine subjects, 144-week elevation: TDF = 13 subjects (4%, 0 double-blind period Grade 3); d4T = 9 subjects (3%, 2 and 336-week open- Grade 3); graded hypophosphatemia: label ext. TDF = 22 subjects (7%, 1 Grade 3); d4T = 19 subjects (6%, 2 Grade 3). GS-01- Randomized, 144- TDF + FTC + 144 weeks Nephrolithiasis, unrelated to study 934 week, open-label, EFV (n = 257) drugs, occurred in 4 subjects in the active-controlled, Combivir + TDF group, and 2 subjects in the study in treatment- EFV Combivir group. Acute renal failure naive subjects, (n = 254) for 1 subject in the Combivir group, followed by 96-week unrelated to study drugs. Mild renal single-treatment impairment for 1 subject in the TDF phase group, related to study drugs. Confirmed (on 2 consecutive visits) graded serum creatinine elevation: TDF = 1 subject (Grade 1); Combivir = 2 subjects (Grade 2); confirmed graded hypophosphatemia: TDF = 1 subject (Grade 2), Combivir = 2 subjects (Grade 2) GS-98- Randomized (2:2:2:1) HAART + 24 and Through 48 weeks, 2 subjects (1%) 902 placebo-controlled TDF 75 mg 48 weeks in TDF group had a renal AE t study in treatment- (n = 54), Grade 3 (1 subject nephrolithiasis, experienced subjects, 150 mg 1 subject pyelonephritis, both in blinded through (n = 51), initial 24 weeks), versus none in the Week 48 300 mg placebo group. Graded serum (n = 56), or creatinine: TDF = 2 subjects (4%), placebo placebo = 1 subject (1%) (all (n = 28) Grade 1); graded hypophosphatemia through 24 weeks: TDF = 24 subjects (15%, 1 Grade 3); placebo = 1 subject (4% Grade 2)

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Principal Clinical Dataset Study Study Design Regimen Evaluated Main Renal Outcome GS-99- Randomized (2:1), HAART + 24 and Through the blinded 24-week period, 907 placebo-controlled TDF 300 mg 48 weeks 2 subjects in TDF group had a renal study in treatment- (n = 368) AE t Grade 3 (nephrolithiasis). experienced subjects, or Through 48 weeks, a total of 4 cases 24-week double-blind placebo of nephrolithiasis occurred versus period and 24-week (n = 182) none in placebo group. Graded serum open-label extension creatinine: TDF = 6 (2%); placebo = 2 (1%), all Grade 1; graded hypophosphatemia: TDF = 55 subjects (15%, 1 Grade 4); placebo = 15 subjects (8%, 1 Grade 3) GS-99- Rollover protocol HAART + 2.3 years 2 subjects discontinued due to renal 910 from GS-98-902 TDF 300 mg (mean events, 1 subject with renal (n = 102), (n = 573) dosing insufficiency, 1 subject with Fanconi GS-99-907 period) syndrome; graded serum creatinine: (n = 465), 45 subjects (8%, all Grade 1); graded and GS-97-901 hypophosphatemia: 131 subjects (n = 6) (23%, 6 subjects Grade 3, 1 subject Grade 4), most transient & resolved without phosphate supplementation

There was no evidence of renal toxicity during 2 long-term, controlled studies in antiretroviral-naive subjects that compared NNRTI-based regimens containing TDF with control regimens (144 weeks of follow-up in Studies GS-99-903 and GS-01-934). Overall, few graded serum creatinine or serum phosphorus abnormalities were observed in the TDF or control groups in either study. There was no evidence that continued dosing of TDF led to progression from Grade 1 renal abnormalities to more severe grades. During 144 weeks of treatment in Study GS-99-903, 2 subjects in the TDF group and 1 subject in the d4T group had an episode of renal failure or renal insufficiency that was reported as an SAE. Neither of the TDF cases was considered related to treatment. In Study GS-01-934, there was a small but statistically significant decrease from baseline to Week 144 in estimated glomerular filtration rate for the FTC + TDF group; the significance of this change is unknown. No cases of Fanconi syndrome were reported, and no subjects in the TDF groups permanently discontinued study medication due to a renal abnormality. Further long-term data available from up to 240 weeks in Study GS-99-903 continue to support a lack of effect of TDF on renal function.

The safety and efficacy profile of TDF in HIV-1 infected subjects with mild renal impairment has been characterized based on a pooled subset of subjects (n = 28) who participated in Studies GS-99-903 and GS-01-934 and whose baseline calculated CLcr was t 50 mL/min to < 80 mL/min. The results demonstrated a similar safety and efficacy profile in subjects with mild renal impairment compared with subjects with normal renal function in Studies GS-99-903 and GS-01-934.

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Through 144 weeks in Studies GS-99-903 and GS-01-934, no clinically relevant changes in renal function were seen in black subjects, subjects t 50 years old, subjects with mild renal impairment, or in subjects taking antihypertensive or antidiabetic medications {12702}.

These findings support the use of TDF 300 mg once daily, in combination with other antiretroviral regimens in HIV-1 infected subjects with a calculated CLcr t 50 mL/min.

Similarly, in antiretroviral-experienced subjects, renal toxicity was not identified during the placebo-controlled studies, GS-98-902 and GS-99-907, and during the rollover, long-term, extension study, GS-99-910, with a median duration of follow-up of 2.3 years. The 24-week placebo-controlled pooled data analysis of Studies GS-98-902 and GS-99-907 demonstrated that the incidence of elevations in serum creatinine was similar for the placebo and TDF groups (1% in both groups). The incidence of hypophosphatemia in the TDF group was slightly higher than in the placebo group (13% versus 8% of subjects). With long-term follow-up in the extension study, the rate of occurrence of hypophosphatemia in subjects treated with TDF did not increase over time. In most cases, hypophosphatemia (< 2.0 mg/dL) was transient and resolved with continued TDF dosing without need for phosphate supplementation {6137}.

The renal safety of TDF when administered in combination with PIs has been reported from 2 controlled studies, Abbott Study M02-418 in antiretroviral-naive subjects and Bristol-Myers Squibb Study AI424045 in antiretroviral-experienced subjects. In these studies, HIV-1 infected subjects received TDF in PI-based regimens that included LPV/r or atazanavir, respectively. When coadministered with TDF, LPV/r and atazanavir increase the systemic exposure to TFV by 32% and 24%, respectively (also see Section 2.5.3.4.3). Therefore, AE experience with these regimens is of particular importance for the assessment of renal safety. During 96 weeks of follow-up, the renal safety profile was consistent with the Gilead-sponsored studies {7974}, {6134}, {7358}, {7374}.

In summary, results from long-term, controlled efficacy and safety studies of TDF in HIV-1 infected subjects have not demonstrated an increased risk of renal events in subjects on TDF therapy.

2.5.5.3.2. Experience in Postmarketing Surveillance

Although clinical trial safety data do not indicate a causal association between TDF therapy and renal events, postmarketing drug safety surveillance data have indicated that TDF may cause renal adverse reactions (see Module 2.7.4.6). These reactions include acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, and polyuria. The incidence and severity of these renal events are expected to be dose-related, based on the current understanding of the mechanism of renal toxicity, as well as experience with cidofovir and adefovir dipivoxil.

The following adverse reactions may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to

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fractures), hypokalemia, muscular weakness, myopathy, and hypophosphatemia. These events are not considered to be causally associated with TDF therapy in the absence of proximal renal tubulopathy.

2.5.5.3.3. Mechanisms of Renal Toxicity

A range of in vitro studies have been conducted to characterize the potential of TFV for renal toxicity.

As a part of these studies, the effects of TFV on the growth and viability of normal human renal proximal tubule cells (RPTECs) were evaluated and compared with those of 2 related acyclic nucleotide analogs, cidofovir and adefovir {2520}. Tenofovir demonstrated markedly less cytotoxicity in RPTECs compared with adefovir and cidofovir, a finding consistent with the relative potential of the 3 nucleotide analogs to cause renal tubular dysfunction in vivo.

Evidence of mitochondrial damage on electron microscopy (EM) in renal tubules has been observed from limited data in patients experiencing TDF-associated renal dysfunction and in animals treated with TDF, although no conclusions can be drawn on whether the observed EM findings of morphologic mitochondrial damage are a cause or effect of TDF-associated renal dysfunction {9005}, {10960}, {12007}, {13786}, {14196} . In contrast with other NRTIs (ddI, d4T, or zalcitabine), TFV does not affect the replication of mitochondrial DNA in human RPTECs in vitro (Report P1278-00042 and {3320}, {9864}). This observation is consistent with the weak inhibition of DNA polymerase J by tenofovir diphosphate and indicates that TFV-associated renal dysfunction is unlikely to be a direct consequence of mitochondrial toxicity due to the inhibition of DNA polymerase J {3320}, {9864}.

As described in Section 2.5.3.4.1, results of in vitro transport studies indicate that the active tubular secretion of TFV is principally mediated by hOAT1 and MRP4 acting in series as the major uptake and efflux transporters, respectively, in the proximal tubule. Data from extensive in vitro drug interaction studies using the identified transporters indicate a low potential of PIs to affect TFV renal secretion and/or its accumulation in the proximal tubule, with consequential changes in the renal safety profile of TDF. (Gilead Report Nos. PC-104-2010, PC-104-2011 and PC-104-2018 and PC-104-2019) {8418}, {9863}, {9864}. The results of these studies do not provide evidence to support an interaction between HIV protease inhibitors and TFV during the active tubular secretion of TFV.

Recent data indicate that intestinal drug-drug interactions between TDF and some frequently used PIs may occur during the process of TDF intestinal absorption {8904}, {11255}, {10610}, {10611}.

In contrast to the lack of involvement of MRP2 in the renal tubular efflux of TFV concluded from in vitro studies, the findings of a published study (in MRP2 deficient rats and in rats treated with probenecid) {8646}, and pharmacogenomics studies {10259}, {14978} propose a potential modulatory effect of MRP2 on TFV exposure and excretion. The results from these small exploratory studies are not considered as conclusive evidence for the association between any specific transporter genotype and TFV-related renal adverse events.

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Furthermore, the studies come to conflicting conclusions about the importance of various single-nucleotide polymorphisms (SNPs) in MRP2 {14978}, {10259}. A further study found a SNP in MRP4 that they believed correlated with changes in TFV pharmacokinetics (renal clearance and intracellular tenofovir diphosphate concentrations) but did not find a correlation with either of the MRP2 SNPs {12344}, {12230}.

The authors from one in vitro study suggested that MRP7 may also play a role in the elimination of TFV from renal tubular cells {15430}. However, the physiological relevance of these preliminary findings is unclear including the assessment of the role of MRP7 relative to MRP4 in the renal efflux of TFV.

Although the molecular mechanism of TFV associated renal dysfunction is not fully understood at the present time, it is plausible that this adverse effect might be a consequence of disrupted transport equilibrium between the tubular uptake and efflux of TFV due to genetic polymorphism in renal transporters.

2.5.5.3.4. Risk Factors

Based on the renal excretion of TFV, the main risk factors with respect to the development of renal dysfunction are pre-existing renal disease and concurrent administration of nephrotoxic agents. The potential for investigating risk factors for renal toxicity from the clinical trial database is limited due to the small number of cases of renal AEs and entry criteria necessitating adequate renal function at baseline and excluding concomitant nephrotoxic medications. In a published analysis, a subset of subjects in Study GS-99-903 were identified as taking concomitant antihypertensive and/or diabetes drugs during the study (68 subjects, 28 of whom received TDF). Analysis of the glomerular filtration rate (Cockcroft-Gault equation) for this subgroup showed no significant changes from baseline to Week 144 {8414}.

Large observational cohort studies with long periods of follow-up have utility for further assessing the postmarketing experience on a population basis and are particularly suitable for the assessment of potential risk factors for TDF-associated renal toxicity. A number of analyses of cohort databases (including Johns Hopkins HIV clinic cohort, the Chelsea and Westminster HIV cohort, and the CHORUS study) and expanded access programs have reported the effect of TDF on renal function and associated risk factors {7672}, {7987}, {6772}, {8056}, {7625}, {8344}, {7725}, {7987}, {8715}, {9023}, {9161}, {9334}, {10394}. These studies indicate that the incidence of renal dysfunction in patients receiving antiretroviral regimens that include TDF is low and similar to that in regimens without TDF. The most frequently identified predictors for development of renal events were pre-existing renal disease, concurrent administration of nephrotoxic agents, and advanced HIV disease with low CD4 cell counts. Serious comorbid conditions such as severe intercurrent illness, severe hypertension, and diabetes mellitus were not consistently identified as predictors for TDF-associated renal dysfunction. In several studies, use of PIs or LPV/r was not associated with an increased risk of renal dysfunction. In the EuroSIDA cohort study, a large prospective nonrandomized cohort study, older age, hypertension, hepatitis C coinfection,

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lower baseline eGFR and CD4 count were independently associated with increased risk of chronic kidney disease in patients who started TDF {15280}.

Additionally, in TDF expanded access programs, data indicate that risk factors for increased serum creatinine included low CD4 cell count, older age, low baseline body weight, higher baseline serum creatinine concentration, and concomitant nephrotoxic medications; however, coadministration of LPV/r was not a risk factor {7725}, {10921}.

Patients who have previously experienced renal events while receiving other nucleotide analogues, such as adefovir dipivoxil, may be at an increased risk of developing renal toxicity on TDF given the similar structure of these drugs and renal toxicity profiles.

2.5.5.3.5. Conclusions on Renal Safety

Long-term safety data from clinical trials do not demonstrate a causal association between renal events and TDF therapy. Postmarketing safety data indicate that TDF therapy may cause renal adverse reactions. These reactions include acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, and polyuria. The following adverse reactions may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalemia, muscular weakness, myopathy and hypophosphatemia. These events are not considered to be causally associated with TDF therapy in the absence of proximal renal tubulopathy. Renal safety data for TDF remain under close monitoring.

In order to further evaluate whether the effect of TMC278 on serum creatinine cystatin C was measured in subjects in the C215 trial at baseline, Week 2 and Week 24 (see Section 2.5.5.2.3.2.4). The results of this analysis show a small mean increase in eGFRcyst in the TMC278 group at Week 2 and at Week 24. The increase in eGFRcyst was seen in all subgroups by background regimen, at Week 2 and at Week 24, with TMC278 and with control. These data indicate that there is no TMC278-induced nephrotoxicity.

The proposed FTC/RPV/TDF FDC tablet prescribing information contains guidance in relation to the management of the risk of renal toxicity. Specifically, the guidance details the renal safety profile of TDF and the recommendations for monitoring of renal function, particularly in at-risk populations and states that the use of the FDC tablet cannot be recommended in patients with moderate to severe renal impairment (CLcr < 50 mL/min) as they require dosing interval adjustment that cannot be achieved with the FTC/RPV/TDF FDC tablet.

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2.5.5.4. Effects on the Skin

Skin adverse events are described in Module 2.7.4.2.1.5.3.

2.5.5.4.1. Emtricitabine

Skin discoloration, reported as hyperpigmentation and usually affecting either the palms of the hands or the soles of the feet, or both, has been reported in HIV-1 infected patients treated with FTC. Most of the hyperpigmentation events were asymptomatic, and nearly all of the events were assessed by the investigator as being mild in severity. The skin discoloration was very common when FTC was administered to pediatric patients. The mechanism and clinical significance of the hyperpigmentation associated with FTC are unknown. Events of hyperpigmentation continue to be monitored during postmarketing surveillance.

2.5.5.4.2. Rilpivirine

Certain skin events are side effects commonly observed with drugs of the NNRTI class and are therefore closely monitored in all clinical trials with TMC278.

For the Phase 3 pooled analysis and the Phase 2b analysis, based on the list of preferred terms occurring across all trials, a list of events to be considered as skin events of interest was created and an “alternative grouping” was used (refer to Module 2.7.4, Appendix 2.7.4.7.3, Section 1.3.2.4.1 for details).

The most common skin event of interest was rash (a grouped term including any type of rash) in both the TMC278 and control groups. The incidence of other skin events of interest was low without substantial difference between the treatment groups. Dermatitis/eczema (grouped term) was reported at a somewhat higher incidence on TMC278 than on control (4.7% versus 2.3%, respectively).

Rash (grouped term, regardless of causality) was reported with a significantly lower incidence in the TMC278 group compared to the control group (7.4% vs 22.0%) (p < 0.0001, Fisher exact test). The majority of rashes were Grade 1 or 2 in severity and there were no Grade 4 rashes. Grade 3 rashes were reported by 2 subjects (0.3%) in the TMC278 group versus 5 subjects (0.7%) in the control group.

The incidence of any rash was highest in the first 4 weeks, consistent with other drug-related rashes, with a much lower incidence in the TMC278 group than the control group. Few new rash events occurred thereafter, and with comparable incidence in the TMC278 and control groups. More rashes led to permanent discontinuation in the control group (11 subjects [1.6%] than in the TMC278 group (1 subject [0.1%]). Rashes not leading to disconintuation mostly resolved.

Treatment-related rash (grouped term) is summarized in Table 27.

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Table 27. Rilpivirine Trials C209 and C215: Treatment-Related Rash (Grouped Term) Summary (Phase 3 Week 48 Pooled Analysis)

TMC278 Control AE Summary N = 686 N = 682 Any, n (%) 21 (3.1) 93 (13.6) Grade 1 17 (2.5) 42 (6.2) Grade 2 6 (0.9) 52 (7.6) Grade 3 1 (0.1) 5 (0.7) Time of first onset (days) Number of eventsa 14 55 Median 10.5 11.0 (1 - 407) (1 - 280) (range) Duration (days), n Number of eventsa 17 57 Median 17.0 10.0 (3 - 96) (1 - 470) (range) Leading to permanent stop, n 1 (0.1) 11 (1.6) (%) Leading to temporary stop, n 1 (0.1) 15 (2.2) (%) N = number of subjects per treatment group; n = number of observations. a For ‘Time to onset’, only the first treatment-emergent event is counted. For ‘Duration’, all treatment-emergent events are counted (i.e., a subject can be counted twice) Treatment related defined as possibly, probably, or very likely related to treatment in the opinion of the investigator. Source: Module 2.7.4.2.1.5.3, Table 58

Treatment-related rash (grouped term) was reported at a lower incidence in the TMC278 group (3.1%) than in the control group (13.6%). The difference in incidence was statistically significant in favor of TMC278 (p < 0.0001; Fisher exact test). The median time to onset of treatment-related rash was similar in the TMC278 group and control group (10.5 and 11.0 days, respectively), while the median duration of treatment-related rash was longer on TMC278 (18 days) than on control (10 days).

In the TMC278 group, 2 subjects had Grade 3 rashes during treatment with TMC278, of which one was very likely related to TMC278 and led to permanent discontinuation. In the control group, 5 subjects had Grade 3 rashes. All 5 AEs were judged by the investigator to be very likely related to study medication and led to discontinuation.

Overall, 1 subject (0.1%) discontinued the trial due to treatment-related rash in the TMC278 group, compared to 11 subjects (1.6%) in the control group.

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2.5.5.4.3. Tenofovir DF

Rash has been identified as an adverse drug reaction to TDF in postmarketing experience. However, skin effects are not considered to be an important safety concern for TDF.

2.5.5.4.4. FTC/RPV/TDF FDC Tablet

The proposed FTC/RPV/TDF prescribing information includes the term “rash” as a very common adverse reaction. The following are included as “common adverse reactions”: x Rash, vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, and skin discoloration (increased pigmentation)

2.5.5.5. Effects on the Bone

Bone adverse events are described in Module 2.7.4.2.1.5.1.

2.5.5.5.1. Emtricitabine

FTC is not considered to have any effects on bone safety. In preclinical studies of FTC, no effects on bone were observed.

2.5.5.5.2. Rilpivirine

RPV is not considered to have any affects on bone safety.

2.5.5.5.3. Tenofovir DF

In preclinical toxicology studies of TDF, bone abnormalities were reported in the juvenile macaque/simian immunodeficiency virus model at subcutaneous doses of 30 mg/kg/day (i.e., systemic exposure approximately 25-fold higher than human exposure). The abnormalities included reduced BMD, joint swellings, and bone fractures. Elevated alkaline phosphatase activity, decreased serum phosphorus concentration, glucosuria, and proteinuria were also observed in the macaques with bone lesions; serum calcium values were normal. Discontinuation of treatment or reduction of the dose to 10 mg/kg/day or less was associated with resolution of the bone abnormalities and biochemical changes. Preclinical studies that investigated potential mechanisms for direct or indirect effects of TFV on bone provided no evidence of in vitro and in vivo cytotoxicity to bone. The mechanism underlying this bone toxicity is unknown. An assessment of the clinical data related to bone toxicity in adult HIV-1 infected subjects is presented below.

The 144-week safety database of Study GS-99-903 provides the largest, prospective, centrally analyzed evaluation of bone-related parameters in previously untreated HIV-1 infected subjects. No increased risk of bone factures was observed during the 144-week double-blind treatment period. At Week 144, there were small decreases from baseline in BMD of the lumbar spine and hip in both treatment groups. There was a greater mean percentage decrease from baseline in BMD at the lumbar spine with the TDF regimen

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compared with the d4T regimen (2.2% TDF versus 1.0% d4T, p 0.001). Changes in BMD at the hip were similar between the 2 treatment groups (2.8% TDF versus 2.4% d4T, p = 0.064). The majority of the changes in BMD occurred in the first 24 weeks of the study for the spine and in the first 48 weeks of the study for the hip. There was little or no progression in loss of BMD for the remainder of the study. Since there is no evidence of an increased risk in bone fractures during 144 weeks of treatment, these small nonprogressive reductions in BMD are not considered to be clinically relevant.

Through Week 144, markers of both bone formation (serum osteocalcin and bone-specific alkaline phosphatase) and bone resorption (urinary N-telopeptide and serum C-telopeptide) demonstrated greater and significant changes in the TDF group compared with the d4T group. The mean changes from baseline appeared to peak at Week 48 and then were lower at Week 96 through Week 144, consistent with the nonprogressive changes seen on bone densitometry after Week 48. Overall, there appeared to be a transitory increase in bone remodeling in the TDF subjects; however, a new equilibrium was reached without evidence of imbalance between bone formation and bone resorption.

The incidence of osteopenia and osteoporosis in the spine were evaluated at baseline and at Week 144 in Study GS-99-903 using the World Health Organization criteria (T-score 2.5 to 1.0 for osteopenia and T-score 2.5 for osteoporosis) {8115}. A relatively high proportion of this study population (approximately 25% to 30%) had spine osteopenia and osteoporosis at baseline compared with an expected value of 16% in a normal population, confirming other literature reports that bone loss may be a consequence of HIV-1 infection itself. There were no significant differences in the incidences of osteopenia and osteoporosis in the spine between the TDF and d4T groups either at baseline or at Week 144. Neither were there any significant differences between the treatment groups in terms of progression to osteopenia or osteoporosis.

For the subset of subjects who continued TDF during the extension phase of Study GS-99-903, interim data following 96-weeks of open-label treatment confirm that the majority of the change occurred in the first 24 to 48 weeks of the study with little or no progression in loss of BMD for the remainder of treatment through Week 240. A small percentage decrease (0.7%) in spine BMD was observed in the subset of subjects who switched from d4T to TDF (the d4T/TDF group) at open-label Week 96, the magnitude of which is consistent with the decline expected in a normal aging population (0.5% to 1% per year after age 35) {9115}, {9116}. In the d4T/TDF group, the mean decrease in hip BMD at Week 96 (2.8%) was slightly higher than for spine BMD. These BMD changes are unlikely to be of clinical significance, as no subject receiving TDF experienced pathologic fractures during the 5-year study.

In the antiretroviral-naive population of Study GS-01-934, the evaluation of bone safety based on the incidence and type of bone fractures was consistent with the experience in Study GS-99-903, with no clinically significant bone abnormalities observed.

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The incidence rates of bone fractures in clinical studies of treatment-experienced subjects have been low and do not indicate any increased risk of bone fractures with TDF therapy even with long-term exposure.

In summary, long-term clinical trial data in antiretroviral-naive and experienced HIV-1 infected subjects do not indicate that TDF is associated with an increased risk of bone fractures.

During postmarketing experience, a number of cases of bone AEs have been received; alternative causes of the bone events have been present in most cases. However, there is evidence to suggest that osteomalacia (manifested as bone pain and infrequently contributing to fractures) may occur as a result of TDF–associated proximal tubulopathy in some reports. Osteomalacia occurring in the absence of proximal renal tubulopathy is not considered to be related to TDF.

HIV-1 infection itself is known to be associated with bone disease {6133} and may also be considered as an alternative cause of bone events in some spontaneous reports.

The assessment of clinical trial data demonstrates minimal risk of bone toxicity with prolonged administration of TDF. The clinical relevance of the changes in surrogate bone biomarkers and BMD in antiretroviral-naive subjects has yet to be determined. Osteomalacia, occurring as a result of TDF–associated proximal tubulopathy, was identified as an adverse reaction during postmarketing surveillance.

2.5.5.5.4. FTC/RPV/TDF FDC Tablet

The proposed FTC/RPV/TDF prescribing information describes the following in the “Special warnings and precautions for use” section: x In a 144-week controlled clinical study that compared TDF with d4T in combination with lamivudine and efavirenz in antiretroviral-naive patients, small decreases in bone mineral density of the hip and spine were observed in both treatment groups. Decreases in bone mineral density of spine and changes in bone biomarkers from baseline were significantly greater in the TDF treatment group at 144 weeks. Decreases in bone mineral density of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.

Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy. If bone abnormalities are suspected then appropriate consultation should be obtained.

2.5.5.6. Mitochondrial Toxicity and Metabolic Effects

Mitochondrial toxicity adverse events are described in Module 2.7.4.2.1.5.4.

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The major adverse effects of many NRTIs have been linked to mitochondrial toxicity. These AEs include lactic acidosis, pancreatitis, peripheral neuropathy, lipodystrophy, metabolic abnormalities, and myopathy. The mechanism of toxicity of NRTIs is thought to result from inhibition of mtDNA polymerase J, leading to depletion of mtDNA and impaired synthesis of respiratory chain enzymes. The respiratory chain functions in many metabolic pathways including adenosine triphosphate synthesis, fatty acid oxidation, and synthesis of pyrimidine nucleotides {2522}. Therefore, disruption of the respiratory chain may lead to a wide variety of metabolic and organ system disorders. Mitochondrial toxicity due to NRTIs is characterized by the following: toxicity is concentration-dependent, the onset of toxicity requires prolonged exposure and is typically not observed in the first few months of treatment, and combination therapy with NRTIs may result in additive or synergistic toxicity {8920}.

NRTIs differ markedly in their propensity to cause mitochondrial toxicity depending on their ability to interact with mtDNA polymerase J. The results of in vitro studies suggest that tenofovir diphosphate and FTC-TP have limited capacity to inhibit human DNA polymerases or to mediate cytotoxicity (see Section 2.5.3.1). US HIV treatment guidelines identify d4T, ddI, and zidovudine as more strongly associated with severe mitochondrial toxicities than other NRTIs. As a result, HIV treatment guidelines now recommend using the NRTIs with less propensity for mitochondrial toxicities, like TDF, FTC, 3TC, and abacavir, when initiating HAART and as alternate NRTIs for patients who develop mitochondrial toxicities {15207}. As described below, results from long-term clinical studies of Truvada, FTC, and TDF confirm a low risk of mitochondrial toxicity with these antiretroviral agents.

2.5.5.6.1. Emtricitabine

The incidences of AEs of symptomatic hyperlactatemia (including lactic acidosis), pancreatitis, peripheral neuropathy, and lipodystrophy were assessed across 3 controlled Phase 3 studies of FTC. The incidences of symptomatic hyperlactatemia and pancreatitis were uniformly low in the FTC groups of all 3 studies (overall d 1% for the combined FTC group). In antiretroviral-naive subjects, the incidence of peripheral neuropathy was similar between FTC- and 3TC-treated subjects (Study FTC-302) and significantly lower than in d4T-treated subjects (Study FTC-301A). Similarly, the incidence of lipodystrophy in these studies was 1% in FTC and 3TC groups compared with 6% for d4T. There was a higher rate of lipodystrophy in antiretroviral-experienced subjects receiving FTC or 3TC in Study FTC-303, which may have been due to concomitant use of PIs by 80% of subjects and the longer cumulative duration of antiretroviral therapy (mean duration of prior treatment: 35 months). The overall assessment of these mitochondrial-related AEs in clinical studies confirms a low risk of mitochondrial toxicity associated with FTC.

2.5.5.6.2. Rilpivirine

In an in vitro study with RPV, there were no inhibitory effects on human polymerases, Į, ȕ, or Ȗ (see Module 2.6.2.2.6.2), suggesting a low potential for mitochondrial toxicity. As mitochondrial toxicity is generally less relevant for NNRTIs than NRTIs, and as RPV is not

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anticipated to significantly increase the exposure of FTC or TFV, the potential for exacerbating mitochondrial toxicity is low.

2.5.5.6.3. Tenofovir DF

The assessment of potential mitochondrial toxicities through 144 weeks in the antiretroviral-naive population of Study GS-99-903 indicates a preferential safety profile with a TDF regimen compared to a d4T regimen. Through 144 weeks, the combined incidence of lipodystrophy, lactic acidosis, and peripheral neuritis/neuropathy was significantly lower in the TDF group than in the d4T group (6% versus 28%; p d 0.001 in all cases). There were no reports of lactic acidosis in the TDF group versus 3 cases in the d4T group.

The radiological findings from whole-body, dual-energy x-ray absorptiometry scans were further indicative of higher rates of lipodystrophy in the d4T group. The mean body composition in limb fat at Week 144 was significantly greater in the TDF group compared with the d4T group (8.6 kg vs 4.5 kg, respectively; p 0.001). A similar trend was seen with respect to abdominal fat, left thigh fat, and trunk fat. During the open-label phase, limb fat increased slightly in the subset of subjects who continued on TDF (TDF/TDF group) and increased markedly in the subset of subjects who switched from d4T to TDF (d4T/TDF group) (from a mean limb fat of 4.6 kg at the start of the open-label phase to 5.5 kg at open-label Week 96).

Tenofovir DF was associated with smaller mean increases from baseline in fasting lipid parameters, specifically triglycerides, total cholesterol, and low density lipoprotein cholesterol, and a greater increase in high density lipoprotein cholesterol compared with the d4T treatment group following 144 weeks of treatment in Study GS-99-903. In addition, significantly more subjects commenced first use of a lipid-lowering drug (fibrate acid derivative and/or statin) in the d4T group than in the TDF group (p 0.001). Data from the open-label extension phase continue to support the preferential lipid profile of TDF. In the TDF/TDF group, lipid parameters remained essentially unchanged through Week 240. In the d4T/TDF group, significant decreases in triglycerides and total cholesterol were observed from open-label baseline to open-label Week 96.

These findings for subjects receiving TDF and 3TC in combination are considered reflective of the anticipated profile of the Truvada tablet, given the similarity between 3TC and FTC.

When TDF and FTC were administered in combination in Study GS-01-934, a similar favorable metabolic profile was observed. The mean increases in fasting serum triglyceride concentrations and fasting total serum cholesterol concentrations from baseline to Week 144 were significantly smaller for the FTC + TDF + EFV group relative to the CBV + EFV group (p = 0.047 and p < 0.001, respectively). Additionally, there was a significant increase in mean body composition in limb fat in the FTC + TDF + EFV group (+1.13 kg change from Week 48 to Week 144, p < 0.001) compared with a significant decrease in the CBV + EFV group (1.09 kg change from Week 48 to Week 144, p < 0.001).

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In antiretroviral-experienced subjects, the incidences of pancreatitis, hyperamylasemia, increased lipase, peripheral neuropathy, and lactic acidosis were similar between subjects who added TDF or placebo to their standard regimens (Studies GS-98-902 and GS-99-907). In the few cases of mitochondrial-related AEs that were considered to be possibly related to TDF (i.e., pancreatitis and lactic acidosis), other risk factors were present, including concomitant exposure to ddI and/or d4T. During long-term exposure to TDF in antiretroviral-experienced subjects (Study GS-99-910: mean treatment duration of 2.3 years), isolated events potentially linked to mitochondrial toxicity occurred in subjects on multidrug regimens, but there was no evidence that these events were directly linked to TDF.

A number of clinical studies, including GS-MC-164-0111 and GS-DE-164-0106, demonstrate improvements in metabolic profiles and lipodystrophy in treatment-experienced subjects switched to TDF-based regimens. Data from the RECOVER study indicate that switching to TDF improves dyslipidemia and lipoatrophy associated with d4T-based regimens, while maintaining viral suppression {6074}, {7760}, {7932}. In Study GS-02-1008, subjects with moderate to severe lipoatrophy who substituted TDF for a thymidine analog rather than abacavir showed greater improvement in median changes in metabolic parameters.

Postmarketing Experience

During postmarketing surveillance, AEs potentially associated with mitochondrial dysfunction are closely reviewed on an ongoing basis for FTC, TDF, and Truvada.

Lactic acidosis, hepatic steatosis and lipodystrophy are important identified risks for both FTC and TDF, while pancreatitis is an important identified risk for TDF. The exact role of FTC and TDF in causing these events in humans is unclear due to the presence of concurrent medications which are also associated with these adverse reactions.

During postmarketing experience, spontaneous cases of lactic acidosis and pancreatitis have typically involved patients receiving other NRTIs known to be associated with mitochondrial-related AEs, in particular ddI. Concurrent use of TDF and ddI may increase ddI-related toxicity because TFV increases systemic exposure to ddI. Pancreatitis and lactic acidosis are some of the more serious, and potentially fatal, dose-related adverse reactions to ddI. The EU prescribing information states that coadministration of TDF and ddI is not recommended.

Evidence of mitochondrial damage on electron microscopy (EM) in renal tubules has been observed from limited data in patients experiencing TDF-associated renal dysfunction and in animals treated with TDF, although no conclusions can be drawn on whether the observed EM findings of morphologic mitochondrial damage are a cause or effect of TDF-associated renal dysfunction {9005}, {10960}, {12007}, {13786}, {14196}. Tenofovir DF has been assessed for its potential to cause mitochondrial toxicity in in vivo and in vitro studies. In vitro studies consistently demonstrated that TDF has a limited capacity to inhibit human DNA polymerases or to mediate cytotoxicity via inhibition of mitochondrial DNA synthesis. The mechanism of renal effects remains undefined.

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In summary, the assessment of clinical trial safety data and postmarketing experience to date demonstrates a low risk of mitochondrial toxicity and metabolic effects with FTC and TDF. Nonetheless, warning and precaution statements regarding metabolic effects are included in the proposed prescribing information for the FTC/RPV/TDF FDC tablet as well as the inclusion of pancreatitis, lactic acidosis, and hepatic steatosis in the Undesirable Effects section. On the basis of nonclinical and clinical data, FTC and TDF are considered to be less likely than other NRTIs to cause mitochondrial toxicity, a conclusion supported by current US HIV treatment guidelines {15207}.

2.5.5.6.4. FTC/RPV/TDF FDC Tablet

The proposed FTC/RPV/TDF prescribing information describes the following in the “Special warnings and precautions for use” section: x Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse reactions reported are hematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behavior). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

2.5.5.7. Neurologic Events

2.5.5.7.1. Emtricitabine

Headache and dizziness have been identified as adverse drug reactions to FTC in clinical trials. However, neurological effects are not considered to be an important safety concern for FTC.

2.5.5.7.2. Rilpivirine

Certain neurologic events are reported to be associated with the use of drugs of the NNRTI class, especially EFV {15207}, and are therefore closely monitored in all trials with TMC278. Based on the list of preferred terms occurring across all trials, a list of events to be considered as neurologic events of interest was created from the SOCs nervous system disorders, eye disorders, ear and labyrinth disorders, or general disorders and administration site conditions. The list of preferred terms considered as neurologic events of interest is presented in Module 2.7.4, Appendix 2.7.4.7.3, Section 1.3.2.4.1.

Neurologic events of interest in the pooled Phase 3 analysis are summarized Table 28.

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Table 28. Rilpivirine Trials C209 and C215: Neurologic Events of Interest Summary (Phase 3 Week 48 Pooled Analysis)

TMC278 Control AE Summary N = 686 N = 682 Any, n (%) 184 (26.8) 308 (45.2) Grade 1 165 (24.1) 246 (36.1) Grade 2 26 (3.8) 81 (11.9) Grade 3 2 (0.3) 8 (1.2) Grade 4 1 (0.1) 1 (0.1) Time of first onset (days) Number of eventsa 211 402 Median (range) 5.0 (1 - 400) 2.0 (1 - 457) Duration (days) Number of eventsa 220 424 Median (range) 12.5 (1 - 519) 15.0 (1 - 581) Treatment-related AEb, n (%) 117 (17.1) 258 (37.8) Any SAE, n (%) 2 (0.3) 1 (0.1) Leading to permanent stop, n (%) 1 (0.1) 5 (0.7) Leading to temporary stop, n (%) 2 (0.3) 5 (0.7) N = number of subjects per treatment group; n = number of observations. a For ‘Time to onset’, only the first treatment-emergent event is counted. For ‘Duration’, all treatment-emergent events are counted (i.e., a subject can be counted twice). b Defined as possibly, probably, or very likely related to treatment in the opinion of the investigator. Source: Module 2.7.4.2.1.5.5, Table 65

Neurologic events of interest were reported at a lower incidence in the TMC278 group (26.8%) than in the control group (45.2%) and were reported as treatment-related by the investigator for a smaller proportion of subjects on TMC278 (17.1%) compared with subjects on control (37.8%). The difference in incidence was statistically significant in favor of TMC278, both for any neurologic event of interest and for treatment-related events only (p<0.0001; Fisher exact test).

The median time to onset for neurologic events of interest was 5 days in the TMC278 group and 2 days in the control group. The median duration was comparable in each group (12.5 versus 15.0 days, respectively).

The majority of the neurologic events of interest in TMC278 subjects were Grade 1 or 2 in severity. Three subjects had Grade 3 or 4 neurologic events of interest during treatment with TMC278, of which one was probably related to study medication. In the control group, 8 subjects had Grade 3 neurologic events of interest, of which one event worsened to Grade 4. All these events were considered at least possibly related to treatment.

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The most commonly reported neurologic events of interest were headache (13.8% in the TMC278 group versus 13.5% in the control group), dizziness, reported at a significantly lower incidence in the TMC278 group (9.9% in the TMC278 group versus 28.4% in the control group, p < 0.0001; Fisher exact test) and somnolence (4.1% in the TMC278 group versus 7.5% in the control group) (Table 29). All other neurologic events of interest were reported in fewer than 3% of subjects in either group.

Table 29. Rilpivirine Trials C209 and C215: Neurologic Events of Interest in at Least 1.0% of Subjects in the TMC278 or Control Group, Regardless of Severity and Causality (Phase 3 Week 48 Pooled Analysis)

System Organ Class TMC278 Control Preferred Term, n (%) N = 686 N = 682 Nervous system disorders 175 (25.5) 291 (42.7) Headache 95 (13.8) 92 (13.5) Dizziness 68 (9.9) 194 (28.4) Somnolence 28 (4.1) 51 (7.5) Disturbance in attention 7 (1.0) 17 (2.5) General disorders and administration site 10 (1.5) 12 (1.8) conditions Irritability 10 (1.5) 11 (1.6) Ear and labyrinth disorders 5 (0.7) 20 (2.9) Vertigo 5 (0.7) 20 (2.9) Eye disorders 3 (0.4) 7 (1.0) Vision blurred 3 (0.4) 7 (1.0) N = number of subjects per treatment group; n = number of observations. Source: Module 2.7.4.2.1.5.5, Table 66

Neurologic events of interest were reported at a slightly greater incidence in subjects with a history of neurologic or psychiatric illness than in subjects with no history, both for TMC278 (34.5% vs 23.1%) and control (49.1% vs 43.4%).

In conclusion, TMC278 appeared to have limited potential for inducing neurologic events, and this was at a significantly lower rate than in the control group.

2.5.5.7.3. Tenofovir DF

Dizziness and headache have been identified as adverse drug reactions to TDF in clinical trials in HIV infected subjects. However, neurological effects are not considered to be an important safety concern for TDF.

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2.5.5.7.4. FTC/RPV/TDF FDC Tablet

The proposed FTC/RPV/TDF prescribing information includes headache, dizziness and somnolence as adverse reactions.

2.5.5.8. Psychiatric Events

2.5.5.8.1. Emtricitabine

Insomnia and abnormal dreams have been identified as adverse drug reactions to FTC in clinical trials. However, psychiatric effects are not considered to be an important safety concern for FTC.

2.5.5.8.2. Rilpivirine

Certain psychiatric events are reported to be associated with the use of drugs of the NNRTI class and are therefore closely monitored in all TMC278 clinical trials. All preferred terms from the SOC psychiatric disorders were considered psychiatric events of interest.

Incidences of psychiatric events of interest, mainly Grade 1 or 2 in severity, were slightly but significantly lower in the TMC278 group (23.9%) than in the control group (29.0%), and were reported to be treatment-related by the investigator for a significantly smaller proportion of subjects on TMC278 (14.9%) than on control (22.7%) (p = 0.0321 and p = 0.0002, respectively; Fisher exact test).

The median time of onset of psychiatric events of interest was longer in the TMC278 group (29 days) than in the control group (6 days). The median duration of these events was longer on TMC278 than on control (76 days versus 53.5 days).

Grade 4 psychiatric events of interest were reported by 3 subjects in the TMC278 group: suicide attempt (SAE reported as possibly related to study medication by the investigator); auditory and visual hallucinations (considered doubtfully related to study medication by the investigator), and alcoholism and major depression (nonrelated SAEs). In the control group, one subject had Grade 4 bipolar disorder (nonrelated SAE). Grade 3 psychiatric events of interest were reported for 1.2% and 1.9% of subjects in the TMC278 and control groups, respectively.

In total, 1.5% and 2.2% subjects in the TMC278 and control groups, respectively, discontinued due to psychiatric events of interest.

The incidence of psychiatric events of interest in the Phase 3 pooled analysis is summarized in Table 30.

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Table 30. Rilpivirine Studies C209 and C215: Psychiatric Events of Interest in at Least 1.0% of Subjects in the TMC278 or Control Group, Regardless of Severity and Causality (Phase 3 Week 48 Pooled Analysis)

System Organ Class TMC278 Control Preferred Term, n (%) N = 686 N = 682 Psychiatric disorders 164 (23.9) 198 (29.0) Insomnia 54 (7.9) 52 (7.6) Abnormal dreams 46 (6.7) 66 (9.7) Depression 40 (5.8) 32 (4.7) Anxiety 16 (2.3) 35 (5.1) Nightmare 16 (2.3) 26 (3.8) Sleep disorder 11 (1.6) 24 (3.5) Depressed mood 7 (1.0) 5 (0.7)

N = number of subjects per treatment group; n = number of observations. Source: Module 2.7.4.2.1.5.6, Table 68

The most commonly reported psychiatric events of interest on TMC278 were insomnia (7.9% versus 7.6% on control), abnormal dreams (6.7% versus 9.7% on control) and depression (5.8% versus 4.7% on control).

Abnormal dreams/nightmare (a planned psychiatric event of interest grouped term, “abnormal dreams/nightmare”, see Section 2.5.5.2.3.2.1) were reported at a statistically significantly lower incidence in the TMC278 group (8.7%) than in the control group (13.2%) (p = 0.0093; Fisher exact test). Although abnormal dreams/nightmares were also seen at a lower incidence for the TMC278 group in each of the individual trials, the difference between treatment groups was not statistically significant for the trials individually. Anxiety was also seen at a lower incidence on TMC278 than on control (2.3% versus 5.1%).

Psychiatric events of interest were reported in a greater proportion of subjects with a history of psychiatric illness than in subjects without a history of psychiatric illness, both for TMC278 (34.5% versus 21.1%) and control (41.0% versus 26.0%).

In conclusion, TMC278 appeared to have limited potential for inducing psychiatric events, and this was numerically lower than in the control group.

2.5.5.8.3. Tenofovir DF

Psychiatric effects are not considered to be a safety concern for TDF.

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2.5.5.8.4. FTC/RPV/TDF FDC Tablet

The proposed FTC/RPV/TDF prescribing information describes the following adverse reactions as “common”: x Depression, insomnia, abnormal dreams, sleep disorders

And as “uncommon”: x Depressed mood

2.5.5.9. Hepatic Events

2.5.5.9.1. Emtricitabine

Hyperbilirubinemia and transaminase elevations (AST and/or ALT) have been identified as adverse reactions to FTC in clinical trials. Hepatic effects are not considered to be an important safety concern for FTC other than risks of posttreatment hepatic flares in HIV/HBV coinfected patients (Section 2.5.5.12.5).

2.5.5.9.2. Rilpivirine

Hepatic AEs were of special interest because in certain cases ARV treatments have been associated with hepatotoxicity. Safety and toxicity assessments in the clinical trials with TMC278 included detailed monitoring and management guidelines for hepatic events. For the Phase 3 pooled analysis and the Phase 2b analysis, based on the list of preferred terms occurring across all trials, a list of events to be considered as hepatic events of interest was created including selected preferred terms from 3 SOCs: hepatobiliary disorders, investigations,and infections and infestations. The list of preferred terms considered as hepatic events of interest is presented in Module 2.7.4, Appendix 2.7.4.7.3, Section 1.3.2.4.1.

In the pooled Phase 3 analysis, the incidence of hepatic events of interest was low and similar in the TMC278 group (5.5%) and in the control group (6.6%).

There were few reports of Grade 4 hepatic events of interest: 3 subjects had a Grade 4 event during treatment with TMC278 (nonserious ALT and AST increases, and hepatitis C infection), versus 6 subjects in the control group. Grade 3 hepatic events of interest were reported for 1.7% and 3.5% of subjects in the TMC278 and control groups, respectively.

In addition to the above mentioned Grade 3 and 4 events, 3 additional hepatic events were reported as SAEs (Grade 1 or 2 cholelithiasis in the TMC278 group and Grade 2 AST increase in the control group).

There were no relevant differences between treatment groups with regard to hepatic SAEs, whereas there tended to be less hepatic AEs leading to permanent discontinuation with TMC278 (3 subjects [0.4%] versus 9 subjects [1.3%] in the control group).

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In conclusion, the clinical data have not demonstrated a relevant effect of TMC278 on hepatic parameters.

Hepatic Impairment

TMC278 is primarily metabolized and eliminated by the liver. A trial to evaluate the potential impact of mild to moderate hepatic impairment (Child-Pugh class A or B) on the clinical pharmacokinetics and short-term safety and tolerability of TMC278 has been conducted in non-HIV infected subjects (C130). Hepatic impairment did not affect the safety and tolerability profile of TMC278. It was concluded that no dose adjustment is required in patients with mild to moderate hepatic impairment. The pharmacokinetics of TMC278 have not been studied in patients with severe hepatic impairment (Child-Pugh class C).

2.5.5.9.3. Tenofovir DF

Hepatic steatosis, hepatitis and increased liver enzymes (most commonly AST, ALT, gamma GT) have been identified as adverse drug reactions to TDF from postmarketing experience. However, hepatic effects are not considered to be an important safety concern for TDF other than risks of posttreatment hepatic flares in HIV/HBV coinfected patients (Section 2.5.5.12.5) and hepatic steatosis (mitochondrial toxicity; Section 2.5.5.6).

2.5.5.9.4. FTC/RPV/TDF FDC Tablet

The proposed FTC/RPV/TDF prescribing information describes the following in the “Special warnings and precautions for use” section:

x Hepatic impairment: Patients with mild to moderate liver disease (Child Pugh Turcotte (CPT), Grade A and B) may be treated with the normal recommended dose of FTC/RPV/TDF FDC tablets. As FTC/RPV/TDF has not been studied in patients with severe hepatic impairment (CPT Grade C), no dosing recommendation can be made for patients in this subgroup x The safety and efficacy of FTC/RPV/TDF have not been established in patients with significant underlying liver disorders. The pharmacokinetics of FTC have not been studied in patients with hepatic impairment. Emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. No dose adjustment is required for RPV in patients with mild or moderate hepatic impairment (CPT Grade A or B). Rilpivirine has not been studied in patients with severe hepatic impairment (CPT Grade C). The pharmacokinetics of TFV have been studied in patients with hepatic impairment and no dose adjustment is required in these patients. It is unlikely that a dose adjustment would be required for FTC/RPV/TDF in patients with mild to moderate hepatic impairment. x Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of

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worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

In addition, in the “Pharmacokinetic properties” section of the prescribing information, the following pharmacokinetic information is provided: x Hepatic impairment: The pharmacokinetics of FTC/RPV/TDF FDC have not been studied in patients with hepatic impairment. It is unlikely that a dose adjustment would be required for FTC/RPV/TDF in patients with mild to moderate hepatic impairment.

x The pharmacokinetics of FTC have not been studied in non-HBV infected subjects with varying degrees of hepatic insufficiency. In general, FTC pharmacokinetics in HBV-infected subjects were similar to those in healthy subjects and in HIV-infected subjects.

x Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 patients with mild hepatic impairment (CPT Grade A) to 8 matched controls and 8 patients with moderate hepatic impairment (CPT Grade B) to 8 matched controls, the multiple dose exposure of RPV was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. Rilpivirine has not been studied in patients with severe hepatic impairment (CPT Grade C).

x A single 245-mg dose of TDF was administered to non-HIV infected patients with varying degrees of hepatic impairment defined according to the CPT classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) TFV Cmax and AUC0-’ values were 223 (34.8%) ng/mL and 2,050 (50.8%) ng•h/mL, respectively, in normal subjects compared with 289 (46.0%) ng/mL and 2,310 (43.5%) ng•h/ml in subjects with moderate hepatic impairment, and 305 (24.8%) ng/mL and 2,740 (44.0%) ng•h/ml in subjects with severe hepatic impairment.

In the “Undesirable Effects” section of the SmPC the following hepatobiliary events are included as “common”:

x Increased transaminases, hyperbilirubinemia

And as “uncommon”:

x Increased bilirubin

2.5.5.9.5. Hepatitis B and/or C Coinfection

Safety in hepatic impairment and in subjects with HIV and HBV and/or HCV coinfection, including hepatitis flare following discontinuation of FTC and TDF, is described in Section 2.5.5.12.5.

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2.5.5.9.5.1. Rilpivirine

In order to collect safety data in HIV-1 infected subjects coinfected with hepatitis B and/or C virus, it was decided to allow recruitment of these subjects in the Phase 2b trial and Phase 3 trials.

In the pooled Phase 3 analysis, approximately 9% of subjects were reported to be coinfected with hepatitis B and/or C. A similar proportion of subjects were coinfected in each treatment group. Comparisons between the subgroups must be treated with caution due to the small number of subjects with hepatitis B and/or C coinfection relative to the number of subjects without coinfection.

The incidence of hepatic events of interest was similar between treatment groups irrespective of coinfection status. A higher proportion of TMC278-treated subjects with hepatitis B and/or C coinfection experienced hepatic events of interest (27.8%) than subjects without coinfection (3.6%). These events were mostly abnormalities in AST and ALT reported in the SOC of investigations. Similar results were observed in the control group. The higher rate of hepatic related events in the hepatitis B/C population is to be expected given their underlying liver pathology.

Differences in graded laboratory abnormalities between coinfected and not coinfected subjects were consistent with the underlying chronic hepatitis coinfection. Review of Grade 2 to 4 hepatic laboratory abnormalities for TMC278-treated subjects indicates that Grade 2 to 4 increases in AST and ALT are seen at higher incidence in subjects with hepatitis B and/or C coinfection (20.4% and 33.3%, respectively) than in subjects who are not coinfected (3.5% and 2.7%, respectively). On control, AST and ALT increases were seen for 18.2% and 28.8% of coinfected subjects and for 8.0% and 7.8% of non coinfected subjects.

2.5.5.9.5.2. FTC/RPV/TDF FDC Tablet

The proposed FTC/RPV/TDF prescribing information describes the following in the “Special warnings and precautions for use” section: x Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients coinfected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant prescribing information for these medicinal products. The safety and efficacy of FTC/RPV/TDF FDC tablets have not been established for the treatment of chronic HBV infection. Emtricitabine and TFV individually and in combination have shown activity against HBV in pharmacodynamic studies. Limited clinical experience suggests that FTC and TDF have anti-HBV activity when used in antiretroviral combination therapy to control HIV infection. x Discontinuation of FTC/RPV/TDF FDC tablets therapy in patients coinfected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients

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coinfected with HIV and HBV who discontinue FTC/RPV/TDF FDC tablets should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since posttreatment exacerbation of hepatitis may lead to hepatic decompensation.

In the “Undesirable effects” section of the prescribing information, the following text is included: x HIV/HBV or HCV coinfected patients: The adverse reaction profile of FTC, RPV, and TDF in patients coinfected with HIV/HBV or HIV/HCV was similar to that observed in patients infected with HIV without coinfection. However, as would be expected in this patient population, elevations in AST and ALT occurred more frequently than in the general HIV-infected population.

2.5.5.10. Events of Interest Potentially Related to QT Interval Prolongation

2.5.5.10.1. Emtricitabine

QT effects are not considered to be a safety concern for FTC.

2.5.5.10.2. Rilpivirine

In a TQT trial, a QT interval prolongation effect of TMC278 was observed in healthy volunteers at doses that are multiples (3 to 12 times higher) of the 25 mg once daily dose selected for further development (see Module 2.7.4, Appendix 2.7.4.7.3, Section 6.1.5.3.1). Therefore, AEs that could be related to cardiac conduction abnormalities or to rate and rhythm disturbances were closely monitored in the Phase 3 and Phase 2b trials with TMC278. A list of events that could potentially be related to QT interval prolongation and that originates from a “Standardised MedDRA Query” named “Torsade de Pointes/QT prolongation” was used to identify such events (refer to Module 2.7.4, Appendix 2.7.4.7.3, Section 1.3.2.4.1 for details).

An independent cardiologist made an integrated assessment of the QT parameters of the nonclinical and clinical trials to investigate the potential of TMC278 to influence cardiac repolarization. From the overall review, including data from thorough QT trials, pharmacokinetic/pharmacodynamic modeling and data from 3 Phase 2/3 trials, it was concluded that TMC278 at a daily dose of 25 mg is not associated with QTcF interval prolongation or any proarrhythmic potential. This assessment is included as a “White Paper” in Module 5.4, TMC278-20100613-Expert-TQT.

The analysis of events of interest potentially related to QTc interval prolongation in the Phase 3 trials showed that such events were reported at a very low incidence in the pooled TMC278 group (0.4% of subjects) and in the control group (1.2%). Also, events of interest potentially related to QTc interval prolongation did not occur more notably at any particular time period throughout the treatment period in the Week 48 analysis.

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2.5.5.10.2.1. QTc Interval Over Time

Results of ECG monitoring in the pooled Phase 3 analysis, showed that there was a gradual increase over time in QTcF interval, which was somewhat higher in the control group (Figure 11).

Overall, no difference in increase in mean QTcF interval over time was observed in the subanalysis by gender (Figure 11).

Figure 11. Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from Baseline in QTcF interval Over Time: Overall (top) and Subanalysis by Gender (Phase 3 Week 48 Pooled Analysis)

Women Men

Source: Module 2.7.4.4.2.1.1, Figure 26 and Figure 27

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Subanalysis by background regimen showed that in each of the background regimen subgroups, the QTcF interval increase over time was similar in the 2 treatment groups. The increase in QTcF interval was more pronounced in subjects treated with AZT/3TC compared with those treated with FTC/TDF, regardless of treatment group (TMC278 or control). The ABC/3TC subgroup (5.0% of the overall population) was too small to make any meaningful comparisons between this and the other subgroups.

There were no clinically relevant differences between the TMC278 and control groups in the incidence of treatment-emergent QTcF abnormalities. During treatment, 0.3% of subjects in the TMC278 group and 0.2% of subjects in the control group had a prolonged QTcF interval (> 480 ms) at least once. There were no incidences of a QTcF interval > 500 ms, a typical proarrhythmic threshold, in either treatment group.

Looking at the incidence of QTc abnormalities over time, abnormalities mostly occurred at 1 or 2 time points in the course of the treatment period, and returned to normal with continued treatment.

Analysis by concomitant medication with potential impact on the QT interval indicated that in both treatment groups the mean maximum change from baseline was similar in the subjects taking CYP3A4 inhibitors and in the subgroup of subjects without QTc interval-prolonging comedication. The number of subjects taking a potassium-depleting diuretic or another drug with known QT-prolonging effect was too small to draw valid conclusions.

2.5.5.10.2.2. Individual QTcF abnormalities

Abnormal increases from baseline between 30 and 60 ms in QTcF interval were reported in 18.6% of subjects in the TMC278 group and in 19.9% of subjects in the control group. An increase in QTcF interval greater than 60 ms was recorded in 1.2% of subjects in the TMC278 group and in 0.9% of subjects in the control group. The abnormal QTcF interval changes (t 30 ms) resulted in a QTcF interval > 450 ms in 0.9% of subjects in the TMC278 group and in 1.7% of subjects in the control group.

The incidence of ECG abnormalities was similar in the subanalyses by gender, by race, and in the subanalysis of race by gender. The incidence of an abnormal QTcF interval (> 480 ms) and the incidence of abnormal changes in QTcF interval were similar for men and women, both on TMC278 and on control.

The incidence of QTcF interval abnormalities and abnormal changes from baseline was higher in the subgroup taking AZT/3TC than in the TDF-FTC subgroup, both in the TMC278 group and in the control group.

In conclusion, there were no signs or abnormalities related to QT interval prolongation to suggest safety issues with the use of TMC278 25 mg once daily in combination with FTC/TDF, AZT/3TC, or ABC/3TC.

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2.5.5.10.3. Tenofovir DF

QT effects are not considered to be a safety concern for TDF.

2.5.5.10.4. FTC/RPV/TDF FDC Tablet

The proposed FTC/RPV/TDF prescribing information describes the following in the interaction section:

x FTC/RPV/TDF FDC should be used with caution when coadministered with a medicinal product with a known risk of Torsade de Pointes. There is limited information available on the potential for a pharmacodynamic interaction between RPV and medicinal products that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of RPV (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram.

2.5.5.11. Endocrine Events

2.5.5.11.1. Emtricitabine

Endocrine effects are not considered to be a safety concern for FTC.

2.5.5.11.2. Rilpivirine

Endocrine monitoring, including gonadal, adrenal and thyroid, was included as a way of assessing adrenal and thyroid function, because effects on the adrenal gland were observed in rats, dogs and cynomolgus monkeys with TMC278 (see Module 2.4). Thyroid monitoring was not done in Phase 3 trials as close monitoring of thyroid hormone levels in the Phase 2b trial did not identify any clinically relevant effects of TMC278 on thyroid function.

Additional safety assessments of adrenal function in clinical trials comprised ACTH stimulation testing, with measurements of basal and stimulated cortisol, 17-OH progesterone, and aldosterone (the latter only in Phase 3 trials). Basal DHEAS, progesterone, androstenedione, testosterone and LH were measured in Phase 3 and 2b studies. For the Phase 3 pooled analysis and the Phase 2b analysis, a list was created of events to be considered as endocrine events of interest that could be related to adrenal insufficiency (21-hydroxylase inhibition) and decreased androgen production (17-hydroxylase inhibition). Preferred terms were selected in the SOCs endocrine disorders, investigations, reproductive system and breast disorders, cardiac disorders (only preferred term ‘postural orthostatic tachycardia syndrome’), and skin and subcutaneous tissue disorders.

The incidence of endocrine events of interest in the Phase 3 trials was low in both treatment groups (5.0% in the TMC278 group and 3.8% in the control group). The incidence of endocrine events of interest was highest in the first 4 weeks of the study in both treatment groups.

Adrenal safety is discussed in Section 2.5.5.2.3.2.6.

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The clinical data show that the endocrine effects seen in preclinical studies are not of clinical relevance and it can be concluded that TMC278 has no clinically relevant effect on endocrine function in humans.

2.5.5.11.3. Tenofovir DF

Endocrine effects are not considered to be a safety concern for TDF.

2.5.5.11.4. FTC/RPV/TDF FDC Tablet

Endocrine effects are not considered to be a safety concern for the FTC/RPV/TDF FDC tablet.

2.5.5.12. Safety in Special Populations

2.5.5.12.1. Safety in Pregnancy

Safety in pregnancy and lactation is described in Module 2.7.4.5.5.

2.5.5.12.1.1. Emtricitabine and Tenofovir DF

Animal reproduction studies of both FTC and TDF did not indicate harmful effects of either agent with respect to fertility, pregnancy, fetal development, parturition, or postnatal development. Postmarketing reports of pregnancy involving exposure to FTC or TDF are reported to the Antiretroviral Pregnancy Registry. No new safety issues relating to use in pregnancy have been identified to date; however, the available data are insufficient to conclude that these drugs are safe to use during pregnancy. Clinical trial and spontaneous AE data are also being monitored for evidence of mitochondrial disease in children exposed in utero. Additionally, a cross-sectional study of HIV negative children exposed in utero or perinatally to NRTIs or NtRTIs is being conducted by the Collaborative Committee for Mitochondrial Toxicity in Children (MITOC; established by Bristol-Myers Squibb, Gilead, and GlaxoSmithKline after discussion with the European Medicines Agency [EMEA] and the Committee for Medicinal Products for Human Use [CHMP]). The primary objective of the study will be to determine the prevalence of neurological clinical symptoms of severe cognitive deficiency or motor delay (with or without seizures), suggestive of mitochondrial dysfunction. Emtricitabine and TDF should be used during pregnancy only when the potential benefit outweighs the potential risk to the fetus.

2.5.5.12.1.2. Rilpivirine

Data from nonclinical trials have shown that fertility, early embryonic development, pre- and postnatal development were not affected by TMC278. Phase 1 drug-drug interaction trials showed there is no pharmacokinetic interaction between TMC278 and ethinylestradiol/norethindrone-based oral contraceptives. The gender subgroup analysis of the Phase 3 safety data indicated that there were no gender-specific safety signals for women.

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TMC278 may therefore represent a good therapeutic option for women of childbearing potential.

Studies in animals have shown no evidence of embryonic or foetal toxicity or an effect on reproductive function. The exposures in the rat and rabbit studies that did not show teratogenicity or effects or embryonic development are respectively 63 times and 97 times higher than the exposure in patients treated with TMC278 at the recommended human dose of 25 mg/day. Since there are no adequate and well-controlled or pharmacokinetic studies with TMC278 in pregnant women, the targeted product information will recommend that TMC278 should be used during pregnancy only if the potential benefit justifies the potential risk and that mothers should be instructed not to breastfeed if they are receiving TMC278.

In the 2 Phase 3 trials C209 and C215, 3 pregnancies were reported during treatment with TMC278 after drug exposure ranging from 59 days to approximately 10 months. All 3 subjects subsequently discontinued the trial. Two of the 3 pregnancies were ongoing at the time of reporting. One subject gave birth prematurely by caesarean section as there were no contractions. The baby was born healthy, with no reported anomalies.

2.5.5.12.1.3. FTC/RPV/TDF FDC Tablet

No adequate and well-controlled studies of the Truvada tablet or the FTC/RPV/TDF FDC tablet have been conducted in pregnant women. Applicable warnings are included in the proposed FTC/RPV/TDF FDC prescribing information with regard to women of child bearing potential and pregnancy (see Section 2.5.6).

2.5.5.12.2. Safety in Elderly Patients

Safety in elderly patients is described in Module 2.7.4.5.1.1.

Clinical studies of FTC or TDF did not include sufficient numbers of elderly subjects (i.e., aged t 65 years) to allow evaluation of efficacy and safety in this population. Similarly, the pharmacokinetics of FTC and TDF have not been evaluated in patients t 65 years.

There are limited data from clinical trials on safety and tolerability in adults above 65 years old. No conclusions can be drawn in the elderly population (i.e., those aged 65 years or over) since only 2 elderly subjects were treated with TMC278 in the Phase 3 trials. Data are available from 30 subjects aged 55 years or over who were treated with TMC278 in the pooled Phase 3 trials. For both the TMC278 and control groups, the type and incidence of AEs were generally similar in subjects aged t 55 years, compared with subjects aged < 55 years.

Since elderly patients are more likely to have decreased renal function, the FTC/RPV/TDF FDC tablet should be used with caution when treating patients over the age of 65 years.

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2.5.5.12.3. Safety in Children

Safety in children is described in Module 2.7.4.5.1.1.

Dosing recommendations for FTC in the pediatric setting are provided in the Emtriva SmPC. The efficacy and safety of TDF as a single drug product in HIV-1 infected children is under investigation.

The safety profile of TMC278 in children and adolescents is under investigation. TMC278 25 mg once daily will be administered in HIV-1 infected ARV treatment-naive adolescents aged 12-18 years old in planned pediatric trial C213. A trial in HIV-infected treatment-naive children < 12 years of age is also planned.

The FTC/RPV/TDF FDC tablet is not recommended for use in children or adolescents (< 18 years) due to insufficient efficacy and safety data in this population, and the inability to adjust dose or dose interval, however a Paediatric Investigation Plan has been agreed with the EMA Paediatric Development Committee (EMEA-000774-PIP01-09, the EMA Opinion is located in MAA Module 1.10).

2.5.5.12.4. Safety in Renal Impairment

Safety in renal impairment patients is described in Module 2.7.4.5.1.2.

Data pertinent to renal safety are reviewed in Section 2.5.5.3.

No data are currently available for TMC278 in patients with renal impairment. Since the renal clearance of TMC278 is negligible (< 1% of total), a decrease in total body clearance is not expected in patients with renal impairment. For TMC278, no dose adjustment is required for renally impaired subjects.

Long-term safety data from controlled clinical trials do not demonstrate a causal association between renal events and TDF therapy. However, postmarketing safety data indicate that TDF therapy may cause renal adverse reactions. The risk of such events may be increased in patients with underlying renal impairment. Therefore, the proposed FTC/RPV/TDF FDC prescribing information is as follows:

Because TFV and FTC are excreted via the kidneys, and exposure is increased in patients with renal impairment (see Section 2.5.3.3.3), FTC/RPV/TDF FDC tablets are not recommended for patients with moderate or severe renal impairment (creatine clearance < 50 mL/min). Patients with moderate or severe renal impairment require dose interval adjustment of FTC and TDF that cannot be achieved with the combination tablet. Use of FTC/RPV/TDF FDC tablets should be avoided with concurrent or recent use of a nephrotoxic medicine. If concomitant use of the FTC/RPV/TDF FDC tablet and nephrotoxic agents is unavoidable, renal function must be monitored weekly.

Renal failure, renal impairment, elevated creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of TDF in

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clinical practice. It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with FTC/RPV/TDF FDC tablets and renal function (creatinine clearance and serum phosphate) is also monitored every 4 weeks during the first year and then every 3 months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.

If serum phosphate is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance is decreased to < 50 mL/min in any patient receiving FTC/RPV/TDF FDC tablets, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations. Since FTC/RPV/TDF FDC tablet is a combination product and the dosing interval of the individual components cannot be altered, treatment with FTC/RPV/TDF FDC tablets must be interrupted in patients with confirmed creatinine clearance decreased to < 50 mL/min or decreases in serum phosphate to < 1.0 mg/dL (0.32 mmol/L). Where discontinuation of therapy with one of the components of FTC/RPV/TDF FDC tablets is indicated or where dose modification is necessary, separate preparations of FTC, RPV, and TDF are available.

In the “Undesirable effects” section of the prescribing information the following information is given: x In patients receiving TDF, rare events of renal impairment, renal failure and proximal renal tubulopathy (including Fanconi Syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving FTC/RPV/TDF FDC tablets (see Section 2.5.6).

2.5.5.12.5. Safety in Hepatic Impairment and in Subjects with HIV and HBV and/or HCV Coinfection

Safety in hepatic impairment is described in Module 2.7.4.5.1.3.

The pharmacokinetics of TDF were not significantly altered in subjects with hepatic impairment (see Section 2.5.3.3.4). The pharmacokinetics of FTC have not been established in patients with hepatic impairment. Emtricitabine is not significantly metabolized by liver enzymes, and so the impact of liver impairment should be limited for this agent.

Through 144 weeks of treatment in Study GS-01-934, elevations of aspartate aminotransferase and alanine aminotransferase to > 5 times the upper limit of the normal range were reported in 3% and 2% of subjects in the FTC + TDF group and 3% and 3% of subjects in the Combivir group, respectively.

The safety and tolerability profile of TMC278 were not altered in HIV-negative subjects with mild or moderate hepatic impairment compared to matched healthy control subjects. The changes in pharmacokinetic parameters in subjects with mild or moderate hepatic impairment are not considered to be of clinical relevance or cause safety concerns. The prescribing information for FTC/RPV/TDF FDC tablets for patients with liver disease is as follows:

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The safety and efficacy of FTC/RPV/TDF FDC tablets have not been established in patients with significant underlying liver disorders. The pharmacokinetics of FTC have not been studied in patients with hepatic impairment. Emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. No dose adjustment is required for RPV in patients with mild or moderate hepatic impairment (CPT Grade A or B). RPV has not been studied in patients with severe hepatic impairment (CPT Grade C). The pharmacokinetics of TFV has been studied in patients with hepatic impairment and no dose adjustment is required in these patients. It is unlikely that a dose adjustment would be required for FTC/RPV/TDF FDC tablets in patients with mild to moderate hepatic impairment.

Consistent with the underlying chronic hepatitis coinfection, hepatic events of interest and elevated hepatic parameters were observed at a higher incidence in subjects who were coinfected with hepatitis B and/or C than in subjects who were not coinfected, and this was seen in both treatment groups (see Section 2.5.5.9.2). The incidence of hepatic events of interest in coinfected subjects was comparable in both the TMC278 and control groups. In the TMC278 group, Grade 2-4 increases in AST and ALT are seen at a higher incidence in subjects with hepatitis B and/or C coinfection (20.4% and 33.4%, respectively) than in subjects who are not coinfected (3.5% and 2.7%, respectively).

FTC/TDF tablets are not indicated for the treatment of chronic HBV infection, and safety and efficacy have not been established in patients coinfected with HBV and HIV-1. A limited number of HIV-1 infected subjects in clinical trials of TDF and FTC were also coinfected with HBV, HCV, or both.

Since TDF and FTC demonstrate anti-HBV activity, there is a potential risk of hepatitis flare following discontinuation of these agents, not unlike that observed with other agents with anti-HBV activity (e.g., adefovir dipivoxil and 3TC). Although the postmarketing data are limited, hepatitis flares, or possible signs and symptoms of hepatitis flares, have been observed following withdrawal of treatment with FTC/TDF in subjects coinfected with HIV-1 and HBV. Warnings and guidance in relation to use of the FTC/RPV/TDF FDC tablet this population are as follows:

Discontinuation of FTC/RPV/TDF FDC therapy in patients coinfected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients coinfected with HIV and HBV who discontinue FTC/RPV/TDF FDC tablet should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, discontinuation of anti-HBV therapy is not recommended since posttreatment exacerbation of hepatitis may lead to hepatic decompensation.

2.5.5.13. Conclusions on Safety Experience

Emtricitabine and TDF were each evaluated for safety in substantial populations of clinical study subjects treated with the individual agents in various combinations with other licensed antiretroviral agents. Data from controlled clinical studies of combination regimens including

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FTC + TDF demonstrated acceptable tolerability and safety profiles to support use in the adult HIV-1 infected population.

The safety and tolerability profile of TMC278 for the treatment of HIV-1 infection in ARV treatment-naive adult patients is supported by a safety database derived from 35 trials, which is robust in terms of numbers of subjects receiving the recommended dose and formulation and the length of treatment.

In the Phase 3 trials, the most common AEs (> 10% of subjects) with TMC278 were headache (13.8%), nausea (13.4%), diarrhea (11.4%) and nasopharyngitis (10.1%), reported at a similar incidence in the control group. Dizziness (28.4%) and rash (13.2%) were common in the control group, and reported at a significantly higher rate than with TMC278. In the TMC278 group, the most frequently reported AEs (> 5% of subjects) that were reported to be at least possibly related to treatment by the investigator were nausea (10.1% versus 11.3% on control), dizziness (8.0% versus 26.2% on control), abnormal dreams (6.3% versus 9.4% on control) and headache (6.1% versus 6.2% on control).

The incidence of any treatment-related Grade 2 to 4 AEs was lower in the TMC278 group (15.9%) than in the control group (31.1%). Incidences of treatment-related rash (individual preferred term) and dizziness with a severity grade of at least 2 were significantly less frequent with TMC278 (0.6% each) than with control (5.3% and 6.3%, respectively).

The incidence of any Grade 3 or 4 AE, regardless of relationship to study medication, was also lower in the TMC278 group (13.3%) than in the control group (18.0%). The most common Grade 3 or 4 AEs were related to laboratory abnormalities in the SOC of investigations.

Serious AEs were reported in 6.6% and 8.1% of subjects in the TMC278 and control group, respectively. There was no consistent pattern of SAEs in either treatment group. There was 1 death in the TMC278 group and 4 deaths in the control group; none was considered to be related to the study medication.

AEs leading to permanent treatment discontinuation occurred less frequently in the TMC278 group (3.4%) than in the control group (7.6%). TMC278-treated subjects who discontinued due to AEs did so later than subjects in the control group and this difference was sustained throughout the treatment period. The incidence of any individual AE leading to discontinuation was below 0.5% in the TMC278 group.

Special attention was given to the following AEs of interest: skin events, neurologic events, psychiatric events, hepatic events, endocrine events, and events potentially related to QT interval prolongation.

Rash (grouped term) was the most common skin event of interest and was reported significantly less frequently in the TMC278 group (7.4%) than in the control group (22.0%) (p < 0.001). The incidence of other skin events of interest was low. Consistent with rashes related to other drugs, most rash events emerged during the first 4 weeks of treatment and were usually mild to moderate. There were no Grade 4 rashes. Treatment-related Grade 3

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rash was reported in 0.1% of subjects in the TMC278 group and in 0.7% of subjects in the control group. Treatment-related rash (grouped term) led to permanent treatment discontinuation of 0.1% of TMC278-treated subjects and of 1.6% subjects in the control group. The incidence of rash showed no gender difference.

The incidence of neurologic events of interest (mostly Grade 1 or 2) was lower on TMC278 (26.8%) than on control (45.2%). The most commonly reported neurologic events of interest were headache (13.8% with TMC278, 13.5% with control), dizziness (9.9% versus 28.4%) and somnolence (4.1% versus 7.5%). Psychiatric events of interest (mostly Grade 1 or 2) were reported for 23.9% subjects in the TMC278 group compared with 29.0% subjects in the control group. A significant difference in favor of TMC278 was seen for combined individual preferred terms abnormal dreams/nightmare.

In the other categories of AEs of interest, i.e., hepatic events, endocrine events, and events potentially related to QT interval prolongation, the incidence and severity of events was low and similar in both treatment groups.

With respect to laboratory safety, changes from baseline in hemoglobin by background regimen showed a transient mean hemoglobin decrease in the AZT/3TC subgroup consistent with the known hematotoxic effect of AZT.

A mean increase in serum creatinine and consequently a decrease in eGFRcreat were seen at the first on-treatment assessment in the TMC278 treatment group, but these remained stable over time. In line with the known effect of TDF, these changes were more pronounced in the FTC/TDF subgroup. There were no treatment discontinuations due to renal impairment or elevated serum creatinine. Estimating GFR with the more appropriate marker of cystatin C, there was an increase in eGFRcyst at Week 2 and at Week 24 in both treatment groups, indicating that there is no TMC278-induced nephrotoxicity.

Mean total and LDL cholesterol values over time remained close to baseline in TMC278 group, while mean values for these lipids increased significantly in the control group. The increase in HDL cholesterol over time was less pronounced with TMC278 than with control subjects, and there was no difference between treatment groups at Week 48 in decrease from baseline of the total cholesterol/HDL ratio. Mean triglyceride values remained close to baseline throughout the trial in both treatment groups, showing a small decrease with TMC278 and a small increase with control. Changes over time in the hepatic, pancreatic and other laboratory parameters were modest in both treatment groups with no substantial difference between the treatment groups and none were considered clinically relevant.

The majority of treatment-emergent laboratory abnormalities were Grade 1 or 2 in severity. The incidence of Grade 3 or 4 laboratory abnormalities was lower with TMC278 (10.9%) than with control (17.6%). The difference between the treatment groups in the incidence of Grade 3 or 4 increases was statistically significant in favor of TMC278 for total cholesterol, LDL cholesterol, and triglycerides. No Grade 4 laboratory abnormalities were reported in more than 2 subjects (0.3%) in the TMC278 group, with the exception of AST (0.7%) and ALT (0.4%).

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There were no consistent or clinically relevant changes in vital signs with TMC278. There was a gradual increase over time in the mean QTcF interval in both treatment groups with no gender difference. This increase was less pronounced in the FTC/TDF subgroup than in the AZT/3TC subgroup. The incidence of prolonged QTcF interval (>480 ms) was low with TMC278 (0.3%) and with control (0.2%). There were no QTcF increases > 500 ms, a typical proarrhythmic threshold. No AEs suggestive of ventricular tachyarrhythmia were reported. There was no relationship between exposure to TMC278 (AUC24h) at a dose of 25 mg once daily and the maximum change from baseline in QTcF interval.

Small variations in adrenal and gonadal parameters indicate that neither TMC278 nor control had a clinically relevant inhibitory effect on 21-hydroxylase or on 17-hydroxylase. There were no clinically relevant changes in any of the adrenal safety parameters. There were no clinical signs or symptoms suggestive of an adrenal or gonadal dysfunction.

Subgroup analyses by background N(t)RTI regimen, gender, race, age, hepatitis B/C coinfection, Center for Disease Control and Prevention (CDC) category at screening and CD4+ cell count at baseline did not reveal any notable or unexpected differences between subgroups. TMC278 was safe and well tolerated with all of the background regimens studied. Differences between the background regimen subgroups were generally consistent with the established safety profile of the individual NRTIs used. As would be expected, subjects with hepatitis B and/or C coinfection had a higher incidence of hepatic events of interest and elevated hepatic parameters, mostly increases in AST and ALT.

In the Phase 3 analysis, a smaller proportion of subjects in the TMC278 group experienced an ADR (51.6% on TMC278 versus 67.9% on control) when compared with the control group. The most common ADRs of at least Grade 2 reported with TMC278 treatment were depression (3.5%), insomnia (2.9%), headache (2.6%), transaminases increased (2.5%) and rash (2.2%). The greatest differences between the treatment groups in the incidence of ADRs of at least Grade 2 were seen for rash (2.2% on TMC278 versus 9.4% on control) and dizziness (0.7% on TMC278 versus 6.6% on control). Although the incidence was low in both treatment groups, there was a trend for a higher incidence in the control group of Grade 3 and 4 ADRs (3.1% on TMC278 versus 5.6% on control) and ADRs leading to permanent discontinuation (1.6% versus 4.0%). There were no additional preferred terms identified as ADRs from the (pooled) Phase 1, Phase 2a and Phase 2b trials that were not listed for the pooled Phase 3 ADR analysis.

In conclusion, TMC278 treatment in the Phase 3 trials was generally safe and well tolerated when administered for up to 48 weeks to HIV-infected, treatment-naive adults at a dose of 25 mg once daily combined with FTC/TDF, AZT/3TC or ABC/3TC. The incidence was lower with TMC278 than with control for Grade 3 or 4 AEs, AEs leading to permanent discontinuation, treatment-related AEs, skin events of interest, i.e., rash (grouped term), neurologic events of interest (particularly dizziness), and Grade 3 or 4 lipid-related laboratory abnormalities. There were no laboratory, cardiovascular, or endocrine safety signals with TMC278. The adverse reaction profile of TMC278, based on thorough review of clinical safety data, reflects the safety and tolerability of the product and offers benefits over EFV.

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The once-daily regimen of EFV + FTC + TDF in Study GS-01-934 demonstrated a preferential safety profile compared with the EFV plus Combivir regimen, as evidenced by the significantly lower rate of study drug discontinuation due to an AE. No new adverse reactions associated with the regimen of EFV + FTC + TDF were identified from AEs and laboratory abnormalities during 144 weeks of treatment.

The 144-week safety data for Study GS-99-903 demonstrate an acceptable safety profile for the regimen of TDF + 3TC + EFV during long-term treatment in HIV-1 infected subjects. The regimen was well tolerated with no clinically significant renal or bone toxicity and no evidence of any other significant drug-related toxicity emerging. The results of several key measures used to assess safety and tolerability indicate that the TDF regimen has a more favorable safety profile than the d4T regimen. No new safety issues have emerged with longer-term treatment in Study GS-99-903 (up to 240 weeks).

The main conclusions in relation to specific safety issues are as follows:

x There was no evidence of renal toxicity during long-term clinical trials of TDF. Postmarketing safety data indicate that TDF therapy may cause renal adverse reactions. These reactions include acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, and polyuria. The following adverse reactions may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalemia, muscular weakness, myopathy, and hypophosphatemia. These events are not considered to be causally associated with TDF therapy in the absence of proximal renal tubulopathy.

x The risk of renal toxicity associated with TDF is increased in patients with underlying renal impairment and those taking nephrotoxic agents. FTC/RPV/TDF FDC tablets are not recommended for patients with moderate and severe renal impairment (CLcr < 50 mL/min). Patients with moderate or severe renal impairment require dose interval adjustment of FTC and TDF that cannot be achieved with the combination tablet. It is recommended that CLcr be calculated in all patients prior to initiating therapy with FTC/RPV/TDF FDC tablets and that renal function (CLcr and serum phosphate) also be monitored every 4 weeks during the first year and then every 3 months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function. x Long-term clinical safety data demonstrate a minimal risk of bone toxicity with prolonged administration of TDF. The clinical relevance of the changes in surrogate bone biomarkers and BMD in treatment-naive subjects is not known. Postmarketing safety data indicate that osteomalacia (manifested as bone pain and infrequently contributing to fractures) may occur in some patients experiencing TDF-associated proximal renal tubulopathy.

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x Clinical trial safety data and postmarketing experience demonstrate a low risk of mitochondrial toxicity (lactic acidosis, hepatic steatosis, pancreatitis, peripheral neuropathy, lipodystrophy, and lipid abnormalities) with FTC and TDF. x Due to the lack of safety and efficacy information, the FTC/RPV/TDF FDC tablet is not recommended for use in children ( 18 years). Only limited data are available to assess safety in the elderly. x The safety of the FTC/TDF tablet or the FTC/RPV/TDF FDC tablet has not been established in patients with HIV/HBV coinfection. Hepatitis flares, or possible signs and symptoms of hepatitis flares, have been observed following withdrawal of treatment with FTC/TDF tablet in subjects coinfected with HIV-1 and HBV.

In conclusion, the NRTI/NtRTI backbone of FTC + TDF has demonstrated an acceptable safety profile in HIV-1 infected patients that compares favorably with the safety profile of other NRTI backbones, particularly with respect to mitochondrial toxicity. The clinical trial and postmarketing safety experience for each agent, together with the substantial clinical trial data from use of these agents in combination, provide adequate assurance regarding the safe use of these agents in the FTC/RPV/TDF FDC tablet.

The safety database for TMC278 is robust in terms of numbers of subjects receiving the recommended dose and formulation and in terms of the cumulative exposure to TMC278. Conclusions regarding the safety profile of TMC278 are made based on the large double-blind active-controlled data set. No new or unexpected safety signals were observed with long-term treatment of TMC278 up to 192 weeks.

Safety information on FTC/RPV/TDF FDC is limited. Two Phase 1 bioequivalence studies showed that the FDC was well tolerated. No additional adverse drug reactions were identified in an analysis of the safety database for subjects receiving RPV in combination with FTC/TDF in Trials C209 and C215.

2.5.6. Benefits and Risks Conclusions

The therapeutic need remains for new antiretroviral therapies with practical and convenient dosing regimens that combine potent and sustained efficacy with acceptable tolerability and minimal long-term toxicity. The most significant challenge in achieving successful long-term treatment is the prevention of drug resistance. Incomplete adherence to treatment regimens is probably the most important factor contributing to the development of resistance and treatment failure. The development of fixed-dose combination products is a strategy employed to simplify regimens and improve adherence to therapy. The FDC of FTC/RPV/TDF has the potential to combine a next generation NNRTI, having an improved safety profile, with the standard-of-care, preferred-agent NRTIs FTC and TDF. Therapy with FTC/RPV/TDF should be initiated by a physician experienced in the management of HIV infection. The following considerations support the positive benefit:risk profile for the FTC/RPV/TDF FDC tablet for the treatment of adult HIV-1 infected patients.

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Benefits

Emtricitabine and TDF are potent and selective HIV-1 reverse transcriptase inhibitors, each of which has been approved individually for use once-daily in combination with other antiretroviral agents for the treatment of HIV-1 infection. The long-term clinical benefits of these agents in combination regimens have been demonstrated in both treatment-naive (including subjects with a high viral load, i.e., ! 100,000 copies/mL) and treatment-experienced subjects.

Emtricitabine and TDF is a preferred NRTI/NtRTI backbone for initial therapy of HIV-1 infection, as recommended in international treatment guidelines, on the basis of the significant clinical efficacy and preferential long-term toxicity profile demonstrated in controlled clinical trials. Clinical effectiveness was demonstrated by statistically significant and clinically relevant changes in plasma HIV-1 RNA and CD4 cell counts. The degree of viral load suppression and virologic response rates indicate potent and durable antiviral efficacy with a low level of resistance development.

With respect to treatment-experienced patients, the clinical data and resistance profiles for the individual agents provide adequate assurance that the FTC/RPV/TDF FDC tablet effectively maintains control of plasma HIV-1 RNA levels with appropriate consideration of the pattern of mutations and treatment history.

FTC and TDF are the only 2 preferred NRTIs listed in the DHHS Guidelines for nonpregnant, antiretroviral-naive patients {15207}.

In a Phase 2b trial, TMC278 25 mg had similar efficacy as TMC278 75 mg or 150 mg, or EFV. The durable antiviral effect of TMC278 containing regimens was shown in the results of the long-term efficacy analyses of the Phase 2b trial, which demonstrated a persistent long-term decrease from baseline in viral load and an immunological benefit. The vast majority of subjects with undetectable viral load (< 50 copies/mL) at Week 96 maintained this level of virologic suppression to at least 192 weeks of treatment. The controlled safety data up to 192 weeks of treatment from the Phase 2b trial in which many subjects received doses of TMC278 higher than 25 mg defined the longer-term safety and tolerability profile of TMC278. Administration of TMC278 for this longer treatment period did not reveal any additional or unexpected safety issues than were observed within the first 48 weeks of the study.

Clinical trial data from 2 Phase 3 studies demonstrate that TMC278 dosed at 25 mg once daily (with a meal) with a background regimen consisting of 2 N(t)RTIs (approximately 80% was FTC/TDF), demonstrated substantial and sustained efficacy in a manner that was noninferior to EFV 600 mg once daily with a similar background regimen.

Response rates in the Phase 3 trials were as high as in recent clinical trials {15040}, {15966}, {15968}, {12654} in this population of ARV treatment-naive HIV-1 infected adult patients.

There were a limited number of virologic failures in the Phase 3 trials C209 and C215, with a difference in proportion of virologic failures between treatment groups (10.5% with TMC278

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and 5.7% with control). Among virologic failures on TMC278, 62.9% developed NNRTI mutations, 67.7% had N(t)RTI mutations and 50.0% lost susceptibility to TMC278. Among TMC278-treated patients who develop resistance to TMC278, cross resistance developed against EFV (87.1%), ETR (90.3%) and NVP (45.2%). Among virologic failures in the control group, 53.6% had NNRTI RAMs, 32.1% had N(t)RTI RAMs and 42.9% had phenotypic resistance to EFV. Among the control virologic failures resistant to EFV, none were cross-resistant to ETR or TMC278 whereas all demonstrated cross-resistance to NVP.

For the FTC/TDF pooled subset, of the 54 subjects with virologic failure and available phenotypic resistance data, 37 lost susceptibility to FTC, 29 lost susceptibility to RPV, and 2 lost susceptibility to TDF. Among these subjects, 37 were resistant to lamivudine, 28 were resistant to etravirine, 26 to efavirenz, and 12 to nevirapine. Reduced susceptibility was observed to abacavir and/or ddI in some cases.

Based on the resistance results, the overall consequences of virologic failure with TMC278, irrespective of the comparative frequency of such failure, are similar to that of virologic failure on other first line NNRTI containing regimens. Given the current availability of treatment options from multiple ARV classes, a variety of active second line ARV treatment options could generally be constructed for the limited number of patients who might be expected to virologically fail TMC278 with the extent and type of drug resistance observed in Phase 2b and Phase 3 clinical trials. Current practice when selecting a subsequent ARV regimen can be applied, including the use of viral genotyping and drug resistance assessment. Specifically ETR, the only NNRTI approved for patients with evidence of NNRTI resistance, would likely not be an option when selecting a second treatment regimen following TMC278 virologic failure (or virologic failure of any other NNRTI). This is consistent with the label indication for ETR, which recommends not using ETR with only 2 N(t)RTIs in patients who have virologically failed a previous NNRTI-containing regimen.

The FDC of FTC/RPV/TDF has the potential to combine a next generation NNRTI, having an improved safety profile compared to EFV, with the standard-of-care, preferred-agent NRTIs FTC and TDF. This fixed-dose regimen would potentially be the second highly active, once daily FDC regimen, and will address limitations with the only other fixed-dose regimen (EFV/FTC/TDF).

The FDC of FTC/RPV/TDF will provide an attractive treatment option to a significant number of patients who may wish to avoid using EFV-containing regimens such as Atripla. Patients may wish to avoid EFV-containing regimens due to tolerability concerns, including CNS adverse reactions, or the reproductive risk potential associated with EFV in women of childbearing potential. Thus, there remains a need for new combinations of potent agents exhibiting favorable tolerability, minimal short and long-term toxicity, and convenient dosing to maximize patient adherence.

Risk

The individual agents of the FTC/RPV/TDF FDC tablet have each demonstrated acceptable tolerability and long-term safety profiles to support their use in the adult HIV-1 infected

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population. Clinical experience with FTC/TDF and RPV tablets in subjects in C209 and C215 demonstrated acceptable safety that demonstrated benefits compared to subjects treated with FTC/TDF and EFV. Adverse reactions reported in clinical trials and postmarketing experience are included in the proposed FTC/RPV/TDF FDC tablet prescribing information.

The principal warnings or precautions applicable to the individual agents are provided in the proposed FTC/RPV/TDF FDC tablet prescribing information. The FTC/RPV/TDF FDC tablet is proposed for treatment of HIV-1 infection in adults and is not recommended for pediatric patients. No additional warnings or precautions are proposed for use of the FTC/RPV/TDF FDC tablet. As a fixed-dose combination, the FTC/RPV/TDF FDC tablet should not be administered with other medicinal products containing the same active components, or with other cytidine analogues such as 3TC, or with adefovir dipivoxil.

Based on preclinical findings that identified the gastrointestinal tract, the renal tubular epithelium, and bone as target organs of toxicity associated with TDF treatment, safety monitoring relevant to these organ systems has been extensively conducted and evaluated during the clinical development of TDF. Overall, the clinical assessment does not reveal significant clinical toxicity associated with TDF therapy even with prolonged administration.

Long-term safety data from clinical trials do not demonstrate a causal association between renal events and TDF therapy. Postmarketing safety data indicate that TDF therapy may cause renal adverse reactions. These reactions include acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, and polyuria. The following adverse reactions may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalemia, muscular weakness, myopathy, and hypophosphatemia. These events are not considered to be causally associated with TDF therapy in the absence of proximal renal tubulopathy.

Controlled 48-week safety data from the Phase 3 trials demonstrate that TMC278 in an ARV treatment regimen resulted in a favorable safety and tolerability profile with clinically relevant tolerability advantages (neurologic, rash and serum lipids) over EFV.

The most common AEs with TMC278 were headache, nausea, diarrhea, and nasopharyngitis, and these were reported at rates similar to those with EFV. Dizziness, rash and abnormal dreams/nightmare, which were common in the control group, were reported at a significantly lower rate with TMC278. Incidences of hepatic events with TMC278 were low and similar to those with EFV. Grade 3 or 4 laboratory abnormalities in lipids (increases in total cholesterol, LDL cholesterol and triglycerides) were significantly more common with EFV than with TMC278.

Importantly, fewer subjects on TMC278 discontinued because of AEs (3.4%) than subjects in the control group (7.6%). TMC278-treated subjects who discontinued due to AEs did so later than subjects in the control group and this difference was sustained throughout the treatment period. The most common AEs leading to discontinuation on TMC278 belonged to the SOC

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psychiatric disorders (1.5% versus 2.2% on control). In the control group, subjects mostly discontinued due to AEs in the SOCs of skin and subcutaneous tissue disorders (0.3% on TMC278 versus 1.8% on control), all related to rash, infections and infestations (0.3% on TMC278 versus 1.3% on control), and psychiatric disorders (1.5% on TMC278 versus 2.2% on control).

Based on the nonclinical safety studies, adrenal function was carefully monitored in the clinical trials. However, Phase 3 and Phase 2b trials did not highlight any safety concerns with respect to adrenal function or endocrine events.

TMC278 has a good safety profile over the dose range tested and the exposures achieved. TMC278 at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. At supratherapeutic doses of 75 mg and 300 mg once daily in healthy volunteers, a dose-related prolongation of corrected QT intervals was seen. The clinical significance of this is unknown. Therefore a warning is included in the prescribing information that the FTC/RPV/TDF FDC tablet should be used with caution when coadministered with a medicinal product with a known risk of Torsade de Pointes.

Small mean increases in creatinine and mean decreases in eGFRcreat were seen over time with TMC278, but not with EFV. There were no treatment discontinuations due to renal impairment or elevated creatinine. Using creatinine as a marker for eGFR, there was a mean decrease from baseline in eGFRcreat in the TMC278 group. Estimating GFR with the more appropriate marker of cystatin C, there was an increase in eGFRcyst at Week 2 and at Week 24 in both treatment groups, indicating that there is no TMC278-induced nephrotoxicity. Subjects with renal impairment are not expected to have altered disposition of TMC278, as renal elimination is a negligible (<1%) route of excretion. No special precautions or dose adjustments are required in patients with renal impairment.

Subgroup analyses of AEs by age, race and gender did not reveal any clinically meaningful differences in AE profile. TMC278 was generally safe and well-tolerated after 48 weeks of treatment.

TMC278 can be used in special populations without increased risk. Hepatitis B and/or C coinfected subjects can be treated with TMC278 at the recommended dose, with the standard clinical monitoring for HIV/hepatitis coinfected patients. A clinical trial indicated that the tolerability profile of TMC278 was not altered in non-HIV infected subjects with mild or moderate hepatic impairment. TMC278 can be used in patients with mild to moderate hepatic impairment without dose adjustment. Coadministration of TMC278 in healthy volunteers on a stable methadone maintenance therapy was generally safe and well tolerated and it did not have a clinically relevant effect on pharmacodynamic parameters of the treatment of opiate dependence.

From genetic toxicology studies it was concluded that there was no potential for carcinogenicity by a direct interaction of TMC278 or its metabolites with DNA, at exposures up to 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily).

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Data from nonclinical trials have shown that fertility, early embryonic development, pre- and postnatal development were not affected by TMC278. Phase 1 drug-drug interaction trials showed there is no pharmacokinetic interaction between TMC278 and ethinylestradiol/ norethindrone-based oral contraceptives. The gender subgroup analysis of the Phase 3 safety data indicated that there were no gender-specific safety signals for women. Unlike efavirenz, TMC278 may therefore represent a good therapeutic option for women of childbearing potential. Until more clinical data are generated, TMC278 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No clear relationship was observed between TMC278 pharmacokinetics at a dose of 25 mg once daily and the occurrence of AEs of special interest or changes in relevant laboratory parameters with the TMC278 25 mg once daily dose. There was also no relationship between exposure to TMC278 and the maximum change from baseline in QTcF interval, over the exposures achieved with the TMC278 25 mg once daily dose.

The following conditions that are likely to result in decreased TMC278 exposure (sub-optimal adherence, intake without food, missing doses, coadministration with exposure-lowering drugs) should be avoided during treatment with TMC278. Drugs that alter intra-gastric pH may affect the solubility of TMC278, therefore, TMC278 should not be coadministered with proton pump inhibitors since coadministration may cause significant decreases in TMC278 plasma concentrations. For drugs with a short-lived effect on intra-gastric pH, such as the H2-antagonists and antacids, an effect on TMC278 exposure can be circumvented by separating the intake of the drugs in time. TMC278 should not be taken with CYP3A inducers as these could decrease TMC278 plasma concentrations, and potentially reduce the therapeutic effect of TMC278. TMC278 can be used with many other medications generally used in HIV-1 infected patients.

The risk assessments, based on the currently available clinical and preclinical data, indicate that continued monitoring of the safety profile during ongoing and planned clinical trials and routine pharmacovigilance activities provide sufficient tools to manage the potential risks for TMC278. The long-term data of the Phase 2b trial, which contributed to the understanding of the safety of TMC278, did not identify any new types of AEs emerging from 192 weeks of treatment with TMC278. Moreover, TMC278 is an NNRTI, a well-characterized class of HIV compounds that has had extensive use for over 10 years. Therefore, no additional risk minimization activities are proposed.

Appropriate guidance is included in the proposed FTC/RPV/TDF FDC tablet prescribing information to reduce the risk for development of renal events, notably with respect to patients with pre-existing renal impairment and concomitant use with nephrotoxic agents and agents that are eliminated by active tubular secretion. It is recommended that CLcr is calculated in all patients prior to initiating therapy and, as clinically appropriate, during FTC/RPV/TDF therapy. Routine monitoring of calculated CLcr and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil. Renal toxicity remains under constant review in the pharmacovigilance setting. FTC/RPV/TDF tablets are not recommended for patients with moderate or severe renal impairment (CLcr < 50 mL/min).

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Patients with moderate or severe renal impairment require a dose adjustment of FTC and TDF that cannot be achieved with the combination tablet.

Based on clinical trial data, there appears to be a minimal risk of bone toxicity with prolonged administration of TDF. Long-term safety evaluations in both treatment-experienced and treatment-naive subjects have demonstrated no increased risk of bone fracture. The clinical significance of changes in bone biomarkers or BMD in treatment-naive subjects is unknown. Postmarketing safety data indicate that osteomalacia (manifested as bone pain and infrequently contributing to fractures) may occur in some patients experiencing TDF–associated proximal tubulopathy. Postmarketing bone AEs remain under close monitoring. The proposed FTC/RPV/TDF FDC tablet prescribing information indicates that if bone abnormalities are suspected then appropriate consultation should be obtained.

Emtricitabine and TDF appear to have a low potential for mitochondrial toxicity, as demonstrated by enzyme and cell analyses in vitro and by markers of mitochondrial injury. Rilpivirine does not inhibit the mitochondrial DNA polymerase Ȗ. Overall, assessment of clinical safety data from ongoing clinical studies and during postmarketing experience continues to demonstrate a low risk of mitochondrial toxicity (lactic acidosis, hepatic steatosis, pancreatitis, peripheral neuropathy, lipodystrophy, and lipid abnormalities) with FTC, RPV, and TDF. Nonetheless, nucleoside analog class-related warnings regarding lactic acidosis and hepatic steatosis are included in the proposed FTC/RPV/TDF FDC tablet prescribing information.

The safety and efficacy of the FTC/RPV/TDF FDC tablet have not been established in patients with significant underlying liver disorders. The pharmacokinetics of FTC have not been studied in patients with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, and so the impact of liver impairment should be limited. A clinical trial indicated that the tolerability profile of TMC278 was not altered in non-HIV infected subjects with mild or moderate hepatic impairment. TMC278 can be used in patients with mild to moderate hepatic impairment without dose adjustment (CPT Grade A or B). TMC278 has not been studied in patients with severe hepatic impairment (CPT Grade C). The pharmacokinetics of TFV have been studied in patients with hepatic impairment and no dosage adjustment is required in these patients. It is therefore unlikely that a dose adjustment would be required for the FTC/RPV/TDF FDC tablet in patients with mild to moderate hepatic impairment.

The FTC/RPV/TDF FDC tablet is not indicated for the treatment of chronic HBV infection, and safety and efficacy have not been established in patients coinfected with HBV and HIV-1. Since TDF and FTC demonstrate anti-HBV activity, there is a potential risk of hepatitis flare following discontinuation of these agents, not unlike that observed with other agents with anti-HBV activity (e.g., adefovir dipivoxil and 3TC). No activity of RPV was observed against HBV at concentrations up to 10 PM. Although the postmarketing data are limited, hepatitis flares, or possible signs and symptoms of hepatitis flares, have been observed following withdrawal of treatment with Truvada in patients with HBV. Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of

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Truvada in patients coinfected with HIV-1 and HBV; a warning related to the risk of hepatic flare following discontinuation of treatment in these patients is provided in the proposed FTC/RPV/TDF FDC prescribing information.

No adequate and well-controlled studies of the FTC/RPV/TDF FDC tablet or its components have been conducted in pregnant women. The FTC/RPV/TDF FDC tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Due to the lack of safety and efficacy information, the FTC/RPV/TDF FDC tablet is not recommended for use in children.

A number of reports of overdose have occurred during postapproval use of FTC and TDF. The individual component agents of the fixed-dose combination product (i.e., FTC, RPV, or TDF) or any other combination containing these agents should not be administered concurrently with the FTC/RPV/TDF FDC tablet. A warning has therefore been included in the prescribing information advising not to coadminister with other medicinal products containing the same components as the FTC/RPV/TDF FDC tablet. If overdose occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary including observation of the clinical status of the patient and monitoring of vital signs and ECG (QT interval).

In conclusion, the therapeutic efficacy and acceptable tolerability and safety profiles established for the individual agents support the clinical utility and acceptable benefit:risk profile of the FTC/RPV/TDF FDC tablet in HIV-1 infected patients.

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2.5.7. References

Copies of the references cited in this document are provided in Module 5.4.

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2226 Fischl MA, Richman DD, Hansen N, Collier AC, Carey JT, Pra MF, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with midly symptomatic human immunodeficiency virus type 1 (HIV) infection. A double- blind, placebo-controlled trial. Ann Intern Med 1990;112 (10):727-37.

2368 Ying C, De Clercq E, Nicholson W, Furman P, Neyts J. Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir. J Viral Hepat 2000;7 (2):161-5.

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2522 Brinkman K, Ter Hofstede HJ, Burger DM, Smeitink JAM, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998;12 (14):1735-44.

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2537 Palella FJ, Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338 (13):853-60.

3320 Birkus G, Hitchcock MJM, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002;46 (3):716-23.

3467 Cooper D, Coakley DF, Sayre J, Mittan A, Zhong L, Chen S-S, et al. Anti-hepatitis B virus (HBV) activity of tenofovir disoproxil fumarate (TDF) in lamivudine (LAM) experienced HIV/HBV co-infected patients [poster]. XIV International AIDS Conference; 2002 Jul 7-12; Barcelona, Spain. Poster Number 6015.

3940 Nunez M, Perez-Olmeda M, Diaz B, Rios P, Gonzalez-Lahoz J, Soriano V. Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients failing or partially responding to lamivudine. AIDS 2002;16 (17):2352-4.

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4249 Wilson JE, Martin JL, Borroto-Esoda K, Hopkins S, Painter G, Liotta DC, et al. The 5'-triphosphates of the (-) and (+) enantiomers of cis-5-fluoro-1-[2- (hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine equally inhibit human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1993;37 (8):1720-2.

4256 Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis 2000;30 (Suppl 2):S171-S6.

4266 Stone VE, Jordan J, Tolson J, Pilon T. Potential impact of once daily regimens on adherence to HAART [abstract]. 40th Annual Meeting of the Infectious Disease Society of America; 2002 Oct 24-27; Chicago, Ill. p. 129. Abstract 486.

4343 McColl DJ, Margot NA, Cheng AK, Miller MD. Development of K65R versus thymidine analogue-associated mutations (TAMs) in antiretroviral-treated patients. In: Abstracts of the 6th International Congress on Drug Therapy in HIV Infection; 2002 Nov 17-21; Glasgow, UK. Abstract P206.

4376 Bruno R, Sacchi P, Zocchetti C, Ciappina V, Puoti M, Filice G. Rapid hepatitis B virus-DNA decay in co-infected HIV-hepatitis B virus 'e-minus' patients with YMDD mutations after 4 weeks of tenofovir therapy. AIDS 2003;17 (5):783-4.

4526 Jeong LS, Schinazi RF, Beach JW, Kim HO, Nampalli S, Shanmuganathan K, et al. Asymmetric synthesis and biological evaluation of beta-L-(2R,5S)- and alpha- L-(2R,5R)-1,3-oxathiolane-pyrimidine and -purine nulceosides as potential anti- HIV agents. J Med Chem 1993;36 (2):181-95.

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4527 Paff MT, Averett DR, Prus KL, Miller WH, Nelson DJ. Intracellular metabolism of (-)- and (+)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine in HepG2 derivative 2.2.15 (subclone P5A) cells. Antimicrob Agents Chemother 1994;38 (6):1230-8.

4534 Schinazi RF, McMillan A, Cannon D, Mathis R, Lloyd RM, Peck A, et al. Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother 1992;36 (11):2423-31.

4535 Furman PA, Davis M, Liotta DC, Paff M, Frick LW, Nelson DJ, et al. The anti- hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother 1992;36 (12):2686-92.

4541 Painter G, St. Clair MH, Chingm S, Noblin J, Wang L, Furman PA. 524W91. Anti-HIV, Anti-Hepatitis B Virus. Drugs of the Future 1995;20 (8):761-5.

4620 Kaul S, Damle B, Bassi K, Xie J, Gale J, Ryan K, et al. Pharmacokinetic evaluation of reduced doses of didanosine enteric coated capsules (ddI-EC) in combination with tenofovir disoproxil fumarate (TDF) and food for a once-daily antiretroviral regimen [poster]. 4th International Workshop on Clinical Pharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. Poster 8.1.

4630 Benhamou Y, Tubiana R, Thibault V. Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus. N Engl J Med 2003;348 (2):177-8.

5010 Miller MD, Margot N, Lu B, Zhong L, Chen S-S, Cheng A, et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis 2004;189 (5):837-46.

5024 Thio CL, Seaberg EC, Skolasky R, Jr, Phair J, Visscher B, Munoz A, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002;360 (9349):1921-6.

5044 Palmer S, Margot N, Gilbert H, Shaw N, Buckheit R, Jr, Miller M. Tenofovir, adefovir, and zidovudine susceptibilities of primary human immunodeficiency virus type 1 isolates with non-B subtypes or nucleoside resistance. AIDS Res Hum Retroviruses 2001;17 (12):1167-73.

5125 Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. Lancet 1998;352 (9142):1725-30.

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5482 Wolf K, Walter H, Beerenwinkel N, Keulen W, Kaiser R, Hoffmann D, et al. Tenofovir resistance and resensitization. Antimicrob Agents Chemother 2003;47 (11):3478-84.

6043 Taburet AM, Piketty C, Gerard L, Vincent I, Chazallon C, Clavel F, et al. Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir in HIV infected patients with multiple treatment failures: a sub-study of Puzzle2- ANRS 107 Trial [poster]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 February 10-14; Boston, Mass, USA. Poster 537.

6054 Ray A, Olson L, Fridland A. Role of purine nucleoside phosphorylase in drug interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir or tenofovir. Antimicrob Agents Chemother 2004;48 (4):1089-95.

6074 Domingo P, Labarga P, Llibre JM, Guerrero MF, Terron JA, Elias MJP, et al. Dyslipidaemia improvement in patients switching from D4T to tenofovir. (Recover Study) [abstract]. 9th Conference of the European AIDS Clinical Society; 2003 October 24-28; Warsaw, Poland.

6133 Glesby MJ. Bone disorders in human immunodeficiency virus infection. Clin Infect Dis 2003;37 (Suppl 2):S91-S5.

6134 DeJesus E, Grinsztejn B, Rodriguez C, Nieto L, Coco J, Lazzarin A, et al. Efficacy and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) vs lopinavir/ritonavir (LPV/RTV) in patients who have experienced virologic failure on multiple HAART regimens: 48-week results from BMS AI424-045 [abstract]. 11th Conference on Retroviruses and Opportunistic Infections; 2004 February 8- 11; San Francisco, Calif, USA.

6137 Cheng AK, Chen SS, Wulfsohn M, Toole JJ. 2 year long term safety profile of tenofovir DF (TDF) in treatment-experienced patients from randomized, double- blind, placebo-controlled clinical trials [poster]. 9th European AIDS Conference (EACS); 2003 October 25-29; Warsaw, Poland. Poster Number 7.3/7.

6180 Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001;32 (3):492-7.

6181 Dore GJ, Cooper DA. The impact of HIV therapy on co-infection with hepatitis B and hepatitis C viruses. Curr Opin Infect Dis 2001;14 (6):749-55.

6266 Videx EC (SmPC). Bristol-Myers Squibb Pharmaceuticals. Hounslow. 06 January 2003.

6379 Benhamou Y, Piketty C, Katlama C, Rozembaum W, Neau D, Lafeuillade C, et al. Anti-hepatitis B virus (HBV) activity of tenofovir disoproxil fumarate (TDF) in

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human immunodeficiency virus (HIV) co-infected patients [poster]. 54th Annual Meeting of the AASLD; 2003 October 24-28; Boston, Mass, USA. Poster 1155.

6389 Lok ASF, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology 2004;39 (3):857-61.

6586 Dore GJ, Cooper DA, Pozniak AL, DeJesus E, Zhong L, Miller MD, et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis 2004;189 (7):1185-92.

6772 Jones R, Stebbing J, Nelson M, Moyle G, Bower M, Mandalia S, et al. Renal dysfunction with tenofovir DF containing HAART regimens is not observed more frequently: a cohort and case control study [poster]. 10th Anniversary Conference of the British HIV Association (BHIVA); 2004 April 15-17; Cardiff, United Kingdom.

6837 Stephan C, Berger A, Lutz T, Stuermer M, Nisius G, Carlebach A, et al. Impact of tenofovir on chronic hepatitis B in HIV co-infected individuals: The Frankfurt Cohort Study Experience [poster]. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2003 September 14-17; Chicago, Ill, USA. Poster V- 784.

6849 Park J, Braun J, Kreiswirth S, Goldman D, Mullen M, Dieterich D. Co-infection with HIV and HBV: The Effect of Tenofovir Disoproxil Fumarate in Lamivudine and Famciclovir Experienced Patients [AASLD Abstract No. 1911]. Hepatology 2002;36 (4, Pt. 2):641A.

6923 Podzamczer D, Ferrer E, Gatell JM, Niubo J, Dalmau D, Leon A, et al. Early virologic failure with a combination of tenofovir, didanosine and efavirenz [Poster]. International Resistance Workshop; 2004 June; Tenerife, Spain.

7013 Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JMAH, Miller MD, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004;292 (2):191- 201.

7034 Maggiolo F, Migliorino M, Maserati R, Rizzi L, Pan A, Rizzi A, et al. Once-a-day treatment for HIV infection: Final 48-week results. 8th Conference on Retroviruses and Opportunistic Infections; 2001 February 4-8; Chicago, IL. Abstract 320.

7035 Felizarta F, Becker S, Bellos N, Jayaweera D, Sands M, Slater L, et al. Adherence and efficacy with a once-daily efavirenz-based regimen: 48-week results from the Daily Antiretroviral Therapy II (DART II) Study [poster 5842]. XV International AIDS Conference; 2004 July 11-16; Bangkok, Thailand.

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7036 Arribas JR, Iribarren JA, Knobel H, Ribera E, Rubio R, Viciana P, et al. Adherence, treatment satisfaction and effectiveness of once-daily (QD) vs twice- daily (BID) antiretroviral therapy (AT), in a large prospective observational cohort (CUVA Study) [poster WePeB5780]. XV International AIDS Conference; 2004 July 11-16; Bangkok, Thailand.

7299 Cihlar T, Bleasby K, Roy A, Pritchard J. Antiviral acyclic nucleotide analogs tenofovir and adefovir are substrates for human kidney organic anion, but not cation transporters: implications for potential renal drug interactions [poster A- 443]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 October 30-November 2; Washington, DC, USA.

7325 Moyle G, Maitland D, Hand J, Mandalia S, Nelson M, Gazzard B. Early virological failure in persons with viral loads >100000 copies/ml and CD4 counts <200/mm3 receiving didanosine/tenofovir/efavirenz as initial therapy: 12 week results from a randomized comparative trial [poster H-566]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 October 30- November 2; Washington, DC, USA.

7358 Johnson M, DeJesus E, Grinsztejn B, Rodriguez C, Nieto-Cisneros, Coco J, et al. Long-term efficacy and durability of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in HIV-infected patients with multiple virologic failures: 96-week results from a randomized, open-label trial, BMS A1424045 [poster #PL14.4]. Seventh International Congress on Drug Therapy in HIV Infection; 2004 November 14-18; Glasgow, UK.

7374 Johnson M, De Jesus E, Grinsztein B. Comparison of Atazanavir (ATV) with Ritonavir or Saquinavir vs Lopinavir/ritonavir in Patients with Multiple Virologic Failures: BMS AI424-045 96 Week Results. Long-term Efficacy and Durability of Atazanavir With Ritonavir or Saquinavir vs Lopinavir/Ritonavir in HIV-Infected Patients With Multiple Virologic Failures (Oral presentation PL14.4). 7th International Congress on Drug Therapy in HIV Infection; 2004 November 14-18; Glasgow, UK.

7399 Hodder SL. Bristol-Myers Squibb Company letter to physicians about clinical data: Potential Early Virologic Failure Associated with the Combination Antiretroviral Regimen of Tenofovir Disoproxil Fumarate, Didanosine, and Either Efavirenz or Nevirapine in HIV Treatment-Naive Patients with High Baseline Viral Loads. November 2004.

7469 Peters M, Andersen J, Lynch P, Jacobson JM, Sherman K, Alston-Smith B, et al. Tenofovir disoproxil fumarate is not inferior to adefovir dipivoxil for the treatment of Hepatitis B virus in subjects who are co-infected with HIV: Results of ACTG A5127 [oral abstract 124]. 12th Conference on Retroviruses and Opportunistic Infections (CROI); 2005 February 22-25; Boston, MA.

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7625 Becker SL, Balu RB, Fusco JS, Fusco GP. Beyond serum creatinine: Identification of renal insufficiency using GFR: Implications for clinical research and care [poster 819]. 12th Conference on Retroviruses and Opportunistic Infections; 2005 February 22-25; Boston, Mass, USA.

7672 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40 (8):1194-8.

7725 Harris M, Zalunardo N, Yip B, Werb R, Valyi M, Hogg R, et al. Nephrotoxicity of tenofovir DF in an expanded access program [oral presentation]. Presented at the 12th Annual Canadian Conference on HIV/AIDS Research; 2003 April 10-13; Nova Scotia, Canada.

7760 Llibre JM, Domingo P, Perez MJ, Labarga P, Palacios R, Ruiz MI, et al. Continuous improvement of dyslipidemia in patients with baseline hyperlipidemia switching from D4T to tenofovir: 24 week data (Recover Study) [poster abstract 268]. 7th International Congress on Drug Therapy in HIV Infection; 2004 November 14-18; Glasgow, UK.

7932 Palacios R, Santos J, Domingo P, Elizas MJP, Arazo P, Miralles C, et al. Impact of switching from stavudine (d4T) to tenofovir DF (TDF) on cardiovascular (CV) risk factors in patients with lipoatrophy (LIPO-REC study) [poster TuPe2.3C15]. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; 2005 July 24-27; Rio de Janeiro, Brazil.

7974 Molina JM, Wilkin A, Domingo P, Myers R, Hairrell J, Naylor C, et al. Once-daily vs. twice-daily lopinavir/ritonavir in antiretroviral-naïve patients: 96-week results [poster WePe12.3C12]. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; 2005 July 24-27; Rio de Janeiro, Brazil.

7987 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function in patients treated with Tenofovir DF (TDF) compared to nucleoside reverse transcriptase inhibitors (NRTIs) [abstract]. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; 2005 July 24-27; Rio de Janeiro, Brazil.

8056 Jones R, Stebbing J, Nelson M, Moyle G, Bower M, Mandalia S, et al. Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case- control study. J Acquir Immune Defic Syndr Hum Retrovirol 2004;37 (4):1489-95.

8115 Powderly W, Cohen C, Gallant J, Lu B, Enejosa J, Cheng AK, et al. Similar incidence of osteopenia and osteoporosis in antiretroviral-naïve patients treated with tenofovir DF or stavudine in combination with lamivudine and efavirenz over 144 weeks [poster number 823]. 12th Conference on Reteroviruses and Opportunistic Infections; 2005 February 22-25; Boston, Mass, USA.

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8284 Sterne JAC, Hernán MA, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long- term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet 2005;366 (9483):378-84.

8344 Zerai T, El-Sahly H, Andrade R, Munoz C, Nnabuife C, Hunter R. Effects of tenofovir DF on the kidney [poster 093]. 43rd Annual Meeting of the Infectious Diseases Society of America (IDSA); 2005 October 6-9; San Francisco, Calif, USA.

8414 Staszewski S, Pozniak AL, Lu B, Cotton G, Enejosa J, Cheng AK. Similar Renal Safety Profile Between Tenofovir DF (TDF) and Stavudine (d4T) Using Modification of Diet in Renal Disease (MDRD) and Cockroft-Gault (CG) Estimation of Glomerular Filtration Rate (GFR) in Antiretroviral-Naïve Patients Through 144 Weeks [poster]. 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2005 November 13-16; Dublin, Ireland. Poster Number 93.

8418 Ray AS, Vela JE, Robinson KL, Cihlar T, Rhodes GR. Efflux of Tenofovir by the Multidrug Resistance-Associated Protein 4 (MRP4) is not Affected by HIV Protease Inhibitors [poster]. 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2005 November 13-16; Dublin, Ireland. Poster Number 91.

8646 Mallants R, Van Oosterwyck K, Van Vaeck L, Mols R, De Clercq E, Augustijns P. Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites. Xenobiotica 2005;35 (10-11):1055-66.

8715 Heffelfinger JD, Hanson DL, Voetsch AC, McNaghten AD, Sullivan PS. Renal impairment associated with the use of tenofovir [poster 779]. 13th Conference on Retroviruses and Opportunistic Infections; 2006 February 5-9; Denver, Colo, USA.

8904 Ray AS, Tong L, Robinson KL, Kearney BP, Rhodes GR. Role of intestinal absorption in increased tenofovir exposure when tenofovir disoproxil fumarate is co-administered with atazanavir or lopinavir/ritonavir [poster number 49]. 7th International Workshop on Clinical Pharmacology of HIV Therapy; 2006 April 20-22; Lisbon, Portugal.

8920 Walker UA, McComsey GA. Mitochondrial Toxicity of Nucleoside Analogs. In: Hoffmann C, Rockstroh JK, Kamps BS, eds. HIV Medicine 2005. Paris, France: Flying Publisher; 2005: 299-309.

9005 Cote HC, Magil AB, Harris M, Scarth BJ, Gadawski I, Wang N, et al. Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy. Antivir Ther 2006;11 (1):79-86.

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9023 Winston A, Amin J, Mallon P, Marriott D, Carr A, Cooper DA, et al. Minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. HIV Med 2006;7 (2):105-11.

9115 O'Flaherty EJ. Modeling normal aging bone loss, with consideration of bone loss in osteoporosis. Toxicol Sci 2000;55 (1):171-88.

9116 Powderly WG. Bone disorders in HIV-infected patients. Medscape General Medicine 2001; 3(1). Available at:. http://www.medscape.com/viewarticle/403863_print. Accessed June 16, 2006.

9161 Moreno S, Domingo P, Palacios R, Santos J, Falco V, Murillas J, et al. Renal Safety of Tenofovir Disoproxil Fumarate in HIV-1 Treatment-experienced Patients with Adverse Events Related to Prior NRTI Use: Data from a Prospective, Observational, Multicenter Study. J Acquir Immune Defic Syndr Hum Retrovirol 2006;42 (3):385-7.

9266 Delaney WE, IV, Ray AS, Yang H, Qi X, Xiong S, Zhu Y, et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother 2006;50 (7):2471-7.

9318 Ray AS, Cihlar T, Robinson KL, Tong L, Vela JE, Fuller MD, et al. Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother 2006;50 (10):3297-304.

9334 Buchacz K, Brooks JT, Tong T, Moorman AC, Baker RK, Holmberg SD, et al. Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed and TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy. HIV Med 2006;7 (7):451-6.

9863 Cihlar T, Ray A, Laflamme G, Vella J, Tong L, Fuller M, et al. Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors. Antivir Ther 2007;12 (2):267-72.

9864 Vidal F, Domingo JC, Guallar J, Saumoy M, Cordobilla B, Sanchez de la Rosa R, et al. In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in combination with other antiretrovirals in human renal proximal tubule cells. Antimicrob Agents Chemother 2006;50 (11):3824-32.

10259 Izzedine H, Hulot JS, Villard E, Goyenvalle C, Dominguez S, Ghosn J, et al. Association between ABCC2 Gene Haplotypes and Tenofovir-Induced Proximal Tubulopathy. J Infect Dis 2006;194 (11):1481-91.

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10260 Imaoka T, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y. Functional involvement of multidrug resistance associated protein 4 (MRP4/ABCC4) in the renal elimination of the anti-viral drugs, adefovir and tenofovir. Mol Pharmacol 2007;71 (2):619-27.

10394 Buchacz K, Young B, Baker RK, Moorman A, Chmiel JS, Wood KC, et al. Renal Function in Patients Receiving Tenofovir With Ritonavir/Lopinavir or Ritonavir/Atazanavir in the HIV Outpatient Study (HOPS) Cohort. J Acquir Immune Defic Syndr 2006;43 (5):626-8.

10610 Tong L, Phan TK, Robinson KL, Rhodes GR, Ray AS. Role of intestinal absorption in changes in tenofovir exposure when tenofovir disoproxil fumarate is co-administered with certain HIV protease inhibitors [abstract]. AAPS Workshop on Drug Transporters in ADME: From the Bench to the Bedside; 2007 March 5-7; North Bethesda, Md, USA.

10611 Tong L, Phan TK, Robinson KL, Rhodes GR, Ray AS. Role of intestinal absorption in changes in tenofovir exposure when tenofovir disoproxil fumarate is co-administered with certain HIV protease inhibitors [poster number 59]. AAPS Workshop on Drug Transporters in ADME: From the Bench to the Bedside; 2007 March 5-7; North Bethesda, Md, USA.

10921 Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 2007;21 (10):1273-81.

10960 de la Prada FJ, Prados AM, Tugores A, Uriol M, Saus C, Morey A. Insuficiencia renal aguda y disfuncíon tubular proximal en paciente diagnosticado de infeccíon VIH tratado con tenofovir [Spanish]. Nefrologia 2006;26 (5):626-30.

11255 Tong L, Phan TK, Robinson KL, Babusis D, Strab R, Bhoopathy S, et al. Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro. Antimicrob Agents Chemother 2007;51 (10):3498-504.

11576 Andreev E, Koopman M, Arisz L. A rise in plasma creatinine that is not a sign of renal failure: which drugs can be responsible? J Intern Med 1999;246 (3):247-52.

12007 Hynes P, Urbina A, McMeeking A, Barisoni L, Rabenou R. Acute renal failure after initiation of tenofovir disoproxil fumarate. Renal failure 2007;29 (8):1063-6.

12230 Kiser JJ, Aquilante CL, Anderson PL, King TM, Carten ML, Fletcher CV. Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J Acquir Immune Defic Syndr 2008;47 (3):298-303.

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12344 Kiser JJ, Carten ML, Aquilante CL, Anderson PL, Wolfe P, King TM, et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther 2008;83 (2):265-72.

12554 Ortiz R, Dejesus E, Khanlou H, Voronin E, van Lunzen J, Andrade-Villanueva J, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008;22 (12):1389-97.

12654 ZIAGEN“ (abacavir sulfate) Tablets. ZIAGEN“ (abacavir sulfate) Oral Solution. US Prescribing Information. GlaxoSmithKline. Research Triangle Park, NC. July 2008

12702 Gallant JE, Pozniak AL, DeJesus E, Chen SS, Cheng AK, Enejosa J. Renal safety profile of tenofovir DF (TDF)-containing vs. thymidine analog-containing regimens through 144 weeks in antiretroviral-naive patients [poster number THPE0186]. XVII International AIDS Conference; 2008 August 3-8; Mexico City, Mexico.

12716 Hammer SM, Eron JJ, Jr., Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008;300 (5):555-70.

12896 UNAIDS. Report on the global AIDS epidemic: Executive summary. July, 2008.

13428 Johnson VA, Brun-Vezinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, et al. Update of the Drug Resistance Mutations in HIV-1:December 2008. Top HIV Med 2008;16 (5):138-45.

13786 Lebrecht D, Venhoff AC, Kirschner J, Wiech T, Venhoff N, Walker UA. Mitochondrial Tubulopathy in Tenofovir Disoproxil Fumarate-Treated Rats. J Acquir Immune Defic Syndr 2009;00 (0).

14064 Levin J. The effect of different types of food on the bioavailability of TMC278, an investigational NNRTI. 9th International Workshop on Clinical Pharmacology of HIV Therapy; 2008 April 7-9; New Orleans, Louisiana, USA.

14065 Gazzard BG. British HIV Association Guidelines for the treatment of HIV-1- infected adults with antiretroviral therapy 2008. HIV Med 2008;9 (8):563-608.

14196 Woodward CL, Hall AM, Williams IG, Madge S, Copas A, Nair D, et al. Tenofovir-associated renal and bone toxicity. HIV Med 2009;10 (8):482-7.

14246 Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double- blind randomised controlled trial. Lancet 2009;374 (9692):796-806.

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14978 Rodriguez-Novoa S, Labarga P, Soriano V, Egan D, Albalater M, Morello J, et al. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study. Clin Infect Dis 2009;48 (11):e108-16.

15040 ATRIPLA“ (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets. US Prescribing Information. Gilead Sciences and Bristol-Myers Squibb, LLC. Foster City, CA. January 2010.

15207 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

15280 Kirk O, Mocroft A, Reiss P, De Wit S, Sedlacek D, Beniowski M, et al. Chronic Kidney Disease and Exposure to ART in a Large Cohort with Long-term Follow- up: The EuroSIDA Study [Abstract 107LB]. 17th Conference on Retroviruses and Opportunistic Infections (CROI); 2010 February 16-19; San Francisco, CA.

15430 Pushpakom S, Liptrott N, Rodríguez-Nóvoa S, Labarga P, Soriano V, Albalater M, et al. Genetic Variants of ABCC10 Are Associated with Kidney Tubular Dysfunction in Patients Treated with Tenofovir-containing Regimens [Poster 742]. 17th Conference on Retroviruses and Opportunistic Infections (CROI); 2010 February 16-19; San Francisco, CA.

15541 Azijn H, Tirry I, Vingerhoets J, de Béthune M, Kraus G, Boven K, et al. TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1. Antimicrob Agents Chemother 2010;54 (2):718-27.

15807 SUSTIVA“ (efavirenz) capsules and tablets. US Prescribing Information. Bristol- Myers Squibb Company. Princeton, NJ. March 2010.

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15864 Katlama C, Haubrich R, Lalezari J, Lazzarin A, Madruga JV, Molina JM, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS 2009;23 (17):2289- 300.

15869 Lima VD, Gill VS, Yip B, Hogg RS, Montaner JS, Harrigan PR. Increased resilience to the development of drug resistance with modern boosted protease inhibitor-based highly active antiretroviral therapy. J Infect Dis 2008;198 (1):51-8.

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15873 Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr 2010;53 (3):323-32.

15884 Swan SK. The search continues--an ideal marker of GFR. Clin Chem 1997;43 (6 Pt 1):913-4.

15965 European AIDS Clinical Society (EACS) Guidelines for the Clinical Management and Treatment of HIV Infected Adults in Europe. Version 5.2. 1-25.

15966 ISENTRESS (raltegravir) Tablets. US Prescribing Information. Merck & Co., Inc. Whitehouse Station, NJ. Revised December 2009.

15967 RESCRIPTOR“ (brand of delavirdine mesylate tablets), US Prescribing Information. Agouron Pharmaceuticals Inc. LaJolla, CA, Revised May 2001.

15968 SELZENTRY• (maraviroc) tablets. US Prescribing Information. Pfizer Labs, New York, NY. November 2009.

15969 Viramune“ (nevirapine) tablets, 200 mg. US Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. Revised January 2010.

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2.5.8. List of Gilead Nonclinical and Clinical Reports

Table 31 provides a list of all Gilead nonclinical studies for FTC, TDF, FTC/TDF, and EFV/FTC/TDF. All nonclinical studies considered pivotal to support this MAA are provided within Module 4 as outlined within the table. Table 32 provides a list of all clinical studies conducted for FTC, TDF, FTC/TDF, and EFV/FTC/TDF. All clinical studies considered pivotal to support this MAA are provided within Module 5 as outlined within the table.

Reports for studies that are not provided in this submission are available on request within 48 hours (as they are not considered pivotal to the FTC/RPV/TDF FDC and have previously been submitted and reviewed within the context of the MAAs for Emtriva [EMEA/H/C/533], Viread [EMEA/H/C/419], Truvada [EMEA/H/C/594] and Atripla [EMEA/H/C/797]). Reports for studies relating to RPV and the FTC/RPV/TDF FDC (all considered pivotal to this submission) are located in Modules 4 (nonclinical) and 5 (clinical) are not included within these tables.

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Table 31. Gilead Nonclinical Reports

Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TESF/91/0014 Phosphorylation of 523W91 and Truvada Available Original MAA March 2004 Module 4 Volume 3 524W91 by calf thymus upon request (EMEA/H/C/594) deoxycytidine kinase TESF/92/0002 Kinetic constants for 523W91 and Truvada Available Original MAA March 2004 Module 4 Volume 3 524W91 with calf thymus upon request (EMEA/H/C/594) deoxycytidine kinase TEIT/92/0005 Phosphates of 523W91 and 524W91: Truvada Available Original MAA March 2004 Module 4 Volume 3 results with dCPMP kinase upon request (EMEA/H/C/594) TGZZ/93/0025 Phosphorylation of the 5’ Truvada Available Original MAA March 2004 Module 4 Volume 3 monophosphate of 524W91 to the upon request (EMEA/H/C/594) 5’-Di-and 5’triphosphates by cellular enzymes TPI 15883 Activity of emtricitabine on the HIV- Truvada Available Original MAA March 2004 Module 4 Volume 1 1 reverse transcriptase mutant K65R; upon request (EMEA/H/C/594) biochemical and phenotypic analysis TEZA/92/0062 Anabolism of (-) 3’Thia-2’,3’- Truvada Available Original MAA March 2004 Module 4 Volume 3 dideoxy-5-[6-3H]fluorocytidine upon request (EMEA/H/C/594) (524W91,(-) FTC) and (+)3’-Thia- 2’,3’-dideoxy-5-[6-3H]fluorocytidine (524W91, (+)FTC) in Hep G2 2.2.15 (P5A) Cells

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TEZA/92/0103 Anabolism of (-) 3’-Thia-2’,3’- Truvada Available Original MAA March 2004 Module 4 Volume 3 dideoxy-5-[6-3H]fluorocytidine upon request (EMEA/H/C/594) (524W91, (-) FTC) in CEM T- lymphoblast cells TEZA/92/0111 Anabolism of (-) 3’-Thia-2’,3’- Truvada Available Original MAA March 2004 Module 4 Volume 3 dideoxy-5-[6-3H]fluorocytidine upon request (EMEA/H/C/594) (524W91, (-) FTC) in Hep G2 (human hepatocellular carcinoma) cells TEZZ/93/0007 Inhibition of HeLa DNA Emtriva Avaliable Original MAA December Part III Volume 21 polymerases Į, ȕ, Ȗ and İ and HIV-1 upon request (EMEA/H/C/533) 2002 reverse transcriptase by the triphosphates of ddC (16Y82), (+) FTC (523W91), (-) FTC (524W91), (+) 3TC (1960U90) and (-)3TC (1961U90) TPI 11985 Effect of orally administered Truvada Available Original MAA March 2004 Module 4 Volume 3 emtricitabine [(-)-FTC] and upon request (EMEA/H/C/594) lamivudine [3TC] in the HuPBMC- SCID mouse model of HIV-1 infection TPI 462 v2 Antiviral activity of FTC, (2R-cis)-4- Truvada Available Original MAA March 2004 Module 4 Volume 1 amino-5-fluoro-1-[2- upon request (EMEA/H/C/594) (hydroxymethyl)-1,3-oxathiolan-5- yl]-2(1H)-pyrimidinone against HIV-1

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TPI 10498 v2 Evaluation of the antiviral activity of Truvada Available Original MAA March 2004 Module 4 Volume 1 emtricitabine against HIV-1 (Group upon request (EMEA/H/C/594) M and Subtype O) and HIV-2 10518-v2 MAGI-LU assay validation 1: Truvada Available Original MAA March 2004 Module 4 Volume 3 Inhibitory effect of FTC on HIV-1 upon request (EMEA/H/C/594) xxLAI viral infection is independent of multiplicity of infection (MOI) of the infecting virus 11773 Effect of multiplicity of infection on Truvada Available Original MAA March 2004 Module 4 Volume 3 inhibition of HIV-1 replication by upon request (EMEA/H/C/594) FTC 10247 DXG, FTC, and AZT: time of Truvada Available Original MAA March 2004 Module 4 Volume 3 addition upon request (EMEA/H/C/594) 463 Effect of human serum on the anti- Truvada Available Original MAA March 2004 Module 4 Volume 3 HIV-1 activity of FTC, (2R-cis)-4- upon request (EMEA/H/C/594) amino-5-fluoro-1-[2- (hydroxymethyl)-1,3-oxathiolan-5- yl]-2(1H)-pyrimidinone TPI 11419 v2 Evaluation of the antiviral activity of Truvada Available Original MAA March 2004 Module 4 Volume 1 emtricitabine against HIV-1 (group upon request (EMEA/H/C/594) M and subtype O) and HIV-2 using the MAGI-LU assay in cMAGI cells TPI 11148 Phenotypic evaluation of FTC, DXG Truvada Available Original MAA March 2004 Module 4 Volume 2 and MKC442 on recombinant upon request (EMEA/H/C/594) clinical isolates of HIV-1

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TPI 9501 Inhibition of human mitochondrial Truvada Available Original MAA March 2004 Module 4 Volume 5 DNA polymerase by (+) FTC, (-) upon request (EMEA/H/C/594) FTC, and DXG triphosphates P4331-00035 In vitro drug sensitivity of Viread Module Original MAA May 2001 Part III Volume 24 nucleoside and non-nucleoside 4.2.1.1 (EMEA/H/C/ 419) reverse transcriptase inhibitor resistant clinical HIV-1 isolates to tenofovir PC-104-2003 In vitro activity of tenofovir against Truvada Module Original MAA March 2004 Module 4 Volume 1 HIV-2 4.2.1.1 (EMEA/H/C/594) PC-104-2004 Effects of the K65R mutation on Truvada Module Original MAA March 2004 Module 4 Volume 1 HIV-1 replication capacity 4.2.1.1 (EMEA/H/C/594) PC-104-2008 In vitro phosphorylation of tenofovir Viread Available Provided in 3rd February 2005 3rd Annual Volume 5 and abacavir upon request Annual Risk Risk Benefit Benefit (EMEA/H/C/419/S/ 48) PC-104-2013 Antiviral activity vs. HIV-1 & HIV- Viread Module Previously not 2 4.2.1.1 submitted. PC-104-2017 Susceptibility to tenofovir and Viread Module Previously not tenofovir disoproxil fumarate 4.2.1.1 submitted. (tenofovir DF) of virologic failure isolates from study GS-01-934

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume PC-164-2007 Week 144 virology report of study Truvada Available Provided in Type II October 2007 Module 5 Volume 1 GS-01-934 upon request variation (EMEA/H/C/594 II/036) P0393-00025 Tenofovir, adefovir and zidovudine Viread Available Original MAA May 2001 Part III Volume 23 susceptibilities of human upon request (EMEA/H/C/419) immunodeficiency virus type I isolates with non-B subtypes or nucleoside resistance PC-164-2001 In vitro phosphorylation of tenofovir Truvada Module Original MAA March 2004 Module 4 Volume 2 and emtricitabine 4.2.1.1 (EMEA/H/C/594) PC-164-2005 In vitro resistance selection with Truvada Available Submitted in PSUR September PSUR Volume 2 tenofovir and emtricitabine upon request (03 February 2005 2005 to 12 August 2005) 233 Data from clonogenic assays CFU- Truvada Available Original MAA March 2004 Module 4 Volume 4 GM and BFU-E and mitochondrial upon request (EMEA/H/C/594) assays for TP0001 and TP0004 as compared to AZT TPI 11963 An in vitro evaluation of the effects Truvada Available Original MAA March 2004 Module 4 Volume 4 on cell growth and mitochondrial upon request (EMEA/H/C/594) functions in the MT2 cell line after long term exposure to antiviral xenobiotics

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TGZZ/93/0016 Effect of antiviral nucleoside Truvada Module Original MAA March 2004 Module 4 Volume 5 analogues on mitochondrial DNA 4.2.2.4 (EMEA/H/C/594) synthesis in Molt-4 cells TGZZ/93/0023 Effect of 524W91 on mitochondrial Truvada Module Original MAA March 2004 Module 4 Volume 5 DNA synthesis on Molt-4 cells 4.2.3.1 (EMEA/H/C/594) P4331-00038 Activity of tenofovir and tenofovir Viread Module Original MAA May 2001 Part III Volume 24 disoproxil fumarate against hepatitis 4.2.1.2 (EMEA/H/C/419) B virus in cell culture PC-104-2012 Antiviral activity against hepatitis B Viread Module Provided in Type II October 2007 Module 5 Volume 1 virus with the rtA194T mutation 4.2.1.2 variation (EMEA/H/C/419 /II/75) PC-174-2003 In vitro susceptibility of HBV Viread Module Provided in Type II October 2007 Module 5 Volume 1 rtA194T mutants to tenofovir 4.2.1.2 variation (EMEA/H/C/419 /II/75) C4331-00013 In vitro cytotoxicity of tenofovir in Viread Available Original MAA May 2001 Part III Volume 24 (P4331-00037) various human cell types - upon request (EMEA/H/C/419) comparison with other NRTIs P1278-00042 In vitro assessment of tenofovir Truvada Module Original MAA March 2004 Module 4 Volume 4 mitochondrial toxicity – comparison 4.2.1.2 (EMEA/H/C/594) with approved NRTIs

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TX-104-2001 Mitochondrial toxicity of Viread Module Provided in July 2005 Response Volume 1 combinations of nucleoside and 4.2.1.2 response to CHMP document nucleotide analogue reverse- request transcriptase inhibitors in HepG2 EMEA/CPMP cells /5836/03 PC-174-2004 A 48-week oral dosing study of Viread Module Provided in Type II February 2007 Type II Volume 1 adefovir dipivoxil (ADV), tenofovir 4.2.1.2 variation variation disoproxil fumarate (TDF), (EMEA/H/C/419/ emtricitabine (FTC), and lamivudine II/75) 93TC) alone and in combination using the woodchuck model of hepatitis B virus infection PC-164-2004 In vitro combination testing of Viread Available Provided in Type II October 2007 Module 5 Volume 1 tenofovir and emtricitabine against upon request variation hepatitis B virus (EMEA/H/C/419/ II/75) TPZZ/93/0002 In vitro receptor binding potencies of Truvada Module Original MAA March 2004 Module 4 Volume 6 524W91 4.2.1.3 (EMEA/H/C/594) TPZZ/92/0055 In vitro autonomic pharmacology of Truvada Module Original MAA March 2004 Module 4 Volume 6 524W91 and its effects on peripheral 4.2.1.3 (EMEA/H/C/594) autonomic receptors TPZZ/92/0056 Effects of 524W91 on isolated Truvada Module Original MAA March 2004 Module 4 Volume 6 cardiac muscle of rat, guinea-pig and 4.2.1.3 (EMEA/H/C/594) cat

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 477 General high dose testing results for Truvada Module Original MAA March 2004 Module 4 Volume 6 FTC 4.2.1.3 (EMEA/H/C/594) TPZZ/93/0001 General pharmacology of 524W91 Truvada Module Original MAA March 2004 Module 4 Volume 6 over an extended dose range in mice 4.2.1.3 (EMEA/H/C/594) and rats TPZZ/93/0119 Effects of 524W91 on conditioned Truvada Available Original MAA March 2004 Module 4 Volume 6 avoidance responce in rats upon request (EMEA/H/C/594) TPZZ/92/0057 Effects of 524W91 on systolic blood Truvada Module Original MAA March 2004 Module 4 Volume 6 pressure and heart rate of conscious 4.2.1.3 (EMEA/H/C/594) normotensive rats TPZZ/92/0076 Effects of intravenous injection of Truvada Module Original MAA March 2004 Module 4 Volume 6 524W91 on cardiovascular, 4.2.1.3 (EMEA/H/C/594) respiratory and autonomic function in anaesthetized dogs V2000020 Spectrum screen of GS-4331-05 and Truvada Module Original MAA March 2004 Module 4 Volume 5 GS-1278 4.2.1.3 (EMEA/H/C/594) V2000009 Guinea pig ileum contractile Truvada Module Original MAA March 2004 Module 4 Volume 5 response 4.2.1.3 (EMEA/H/C/594) R990152 A pharmacological safety assessment Truvada Module Original MAA March 2004 Module 4 Volume 5 of the effect of tenofovir DF (GS- 4.2.1.3 (EMEA/H/C/594) 4331-05) on the central nervous system of the rat

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume R990153 A pharmacological assessment of the Truvada Module Original MAA March 2004 Module 4 Volume 6 effect of tenofovir DF (GS-4331-05) 4.2.1.3 (EMEA/H/C/594) on gastrointestinal motility in the rat R990154 A pharmacological assessment of the Truvada Module Original MAA March 2004 Module 4 Volume 6 effect of tenofovir DF (GS-4331-05) 4.2.1.3 (EMEA/H/C/594) on the renal system of the rat D990155 Cardiovascular profile study Truvada Module Original MAA March 2004 Module 4 Volume 6 following a single oral 4.2.1.3 (EMEA/H/C/594) administration of tenofovir DF in the unrestrained conscious beagle dog 470 In vitro synergy studies of FTC in Truvada Module Original MAA March 2004 Module 4 Volume 2 combination with MKC 442, AZT, 4.2.1.4 (EMEA/H/C/ 594) nelfinavir (NELF) and nevirapine (NEV) against HIV 10804 In vitro synergy studies with FTC Emtriva Module Included in May 2003 Response to Volume 3 and other anti-HIV compounds 4.2.1.4 response to CPMP Questions Day 120 List of Questions (EMEA/H/C/533) 12207 Synergy of emtricitabine (FTC) and Truvada Module Original MAA March 2004 Module 4 Volume 6 lamivudine (3TC) in combination 4.2.1.4 (EMEA/H/C/594) with stavudine (d4T) and nevirapine (NVP) against HIV C1278-00005 In vitro synergy of tenofovir Viread Module Original MAA May 2001 Part III Volume 23 combinations against HIV-1 4.2.1.4 (EMEA/H/C/419)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume PC-104-2005 Tenofovir, abacavir and lamivudine; Truvada Module Original MAA March 2004 Module 4 Volume 2 evaluation of the in vitro anti-HIV 4.2.1.4 (EMEA/H/C/594) activity of the combination in PBMC PC-104-2006 Tenofovir, didanosine and Truvada Module Original MAA March 2004 Module 4 Volume 2 lamivudine; evaluation of the in vitro 4.2.1.4 (EMEA/H/C/594) anti-HIV activity of the combination in PBMC PC-104-2007 In vitro combination studies of Truvada Module Original MAA March 2004 Module 4 Volume 6 tenofovir and other nucleoside 4.2.1.4 (EMEA/H/C/594) analogs with ribavirin against HIV-1 PC-183-2004 Antiviral activity in combination Viread Module Previously not with other antiretroviral drugs 4.2.1.4 submitted 14379 In vitro synergy studies with Emtriva Module Included in May 2003 Follow-up Volume 3 emtricitabine and tenofovir 4.2.1.4 Response to CPMP Measure Day 120 List of Questions (EMEA/H/C/533) PC-164-2002 In vitro anti-HIV synergy studies of Truvada Module Original MAA March 2004 Module 4 Volume 2 tenofovir and emtricitabine 4.2.1.4 (EMEA/H/C/594) 1010 Determination of TP-0006/96 in Truvada Available Original MAA March 2004 Module 4 Volume 8 human, mouse and monkey plasma upon request (EMEA/H/C/594) and human urine by HPLC-MS (SIM)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 6159v1 Determination of emtricitabine in Truvada Available Original MAA March 2004 Module 4 Volume 8 mouse, monkey and rabbit plasma by upon request (EMEA/H/C/594) LC/MS/MS 7582v1 Determination of emtricitabine in Truvada Available Original MAA March 2004 Module 4 Volume 8 human or monkey urine by upon request (EMEA/H/C/594) LC/MS/MS 6447v5 Determination of emtricitabine in Truvada Available Original MAA March 2004 Module 4 Volume 8 human and rat plasma using upon request (EMEA/H/C/594) LC/MS/MS P4331-00009 Validation of a high performance Truvada Available Original MAA March 2004 Module 4 Volume 7 liquid chromatographic method for upon request (EMEA/H/C/594) the determination of GS-4331-05 in dose formulations P4331-00008: Cross-validation of an HPLC method Truvada Available Original MAA March 2004 Module 4 Volume 7 97-TOX-4331- for the quantitation of GS-1278 upon request (EMEA/H/C/594) 008 (PMPA) in mouse plasma and determination of PMPA in mouse plasma samples P1278-00001 Validation of an HPLC assay for the Truvada Available Original MAA March 2004 Module 4 Volume 7 (OLI-VRA- quantitation of GS-1278 (PMPA) in upon request (EMEA/H/C/594) 144.1) rat plasma and cross-validation in cynomolgus monkey plasma

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume P1278-00028 Validation of a high performance Truvada Available Original MAA March 2004 Module 4 Volume 8 (001097/NDK) liquid chromatographic mass upon request (EMEA/H/C/594) spectrometric method for the determination of GS-1278 (R- PMPA) in rat plasma (sodium citrate) - cross validation of GS-1278 (R-PMPA) in rat plasma (heparin) - cross validation of GS-1278 (R-PMPA) in mouse plasma (sodium heparin) P1278-00034: Validation of a high performance Truvada Available Original MAA March 2004 Module 4 Volume 8 Project No. liquid chromatographic mass upon request (EMEA/H/C/594) 003105OU1 spectrometric method for the determination of GS-1278 in rat milk P4331-035-3 Cross validation of an HPLC method Truvada Available Original MAA March 2004 Module 4 Volume 8 (Oread No: for the quantitation of GS-1278 upon request (EMEA/H/C/594) OLI-RE748- (PMPA) in rabbit plasma and 9901-DNS-1) determination of PMPA in rabbit samples (from study 98-TOX-4331- 005) P1278-00017 Cross-validation of an HPLC assay Truvada Available Original MAA March 2004 Module 4 Volume 8 for the quantitation of GS-1278 upon request (EMEA/H/C/594) (PMPA) in dog plasma

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume P4331-0037 Mini-validation of a high Truvada Available Original MAA March 2004 Module 4 Volume 8 (MDS Project performance liquid chromatographic upon request (EMEA/H/C/594) No. mass spectrometric method for the 003296OTN) determination of GS-1278 (R- PMPA) in dog plasma (EDTA) P1278-00029 Validation of a high performance Truvada Available Original MAA March 2004 Module 4 Volume 8 (MDSPS liquid chromatographic mass upon request (EMEA/H/C/594) Project No: spectrometric method for the 002092OFH) determination of GS-1278 (R- PMPA) in monkey plasma (EDTA) TEIN/93/0003 Pharmacokinetics of 524W91 in Emtriva Module Original MAA December Part III Volume 22 male CD-1 mice following oral and 4.2.2.2 (EMEA/H/C/533) 2002 intravenous administration TEIN/93/0004 Pharmacokinetics of 100 mg/kg oral Emtriva Module Original MAA December Part III Volume 22 and intravenous 524W91 in male 4.2.2.2 (EMEA/H/C/533) 2002 CD-1 mice IUW00101 Pharmacokinetic study in male mice Truvada Module Original MAA March 2004 Module 4 Volume 10 following single oral and intravenous 4.2.2.2 (EMEA/H/C/594) administration of L-(-)-2’3’-dideoxy- 5-fluoro-3’-thiacytidine TEZZ/93/0019 A pharmacokinetic study of 524W91 Emtriva Module Original MAA December Part III Volume 22 in cynomolgus monkeys following 4.2.2.2 (EMEA/H/C/533) 2002 oral and intravenous administration

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume IUW00301 Pharmacokinetic study in Emtriva Module Original MAA December Part III Volume 22 cynomolgus monkeys following 4.2.2.2 (EMEA/H/C/533) 2002 single oral and intravenous administration of L-(-)-2’,3’- dideoxy-5-fluoro-3’- thiacytidine W2000108 Single dose oral bioavailability of Truvada Module Original MAA March 2004 Module 4 Volume 3 tenofovir DF in woodchucks 4.2.2.2 (EMEA/H/C/594) D2000076 Single dose oral bioavailability of Viread Module Original MAA May 2001 Part III Volume 29 tenofovir DF in beagle dogs 4.2.2.2 (EMEA/H/C/ 419) P2000031 A single dose oral bioavailability Viread Module Original MAA May 2001 Part III Volume 30 study of tenofovir DF in rhesus 4.2.2.2 (EMEA/H/C/ 419) monkeys PC-174-2006 Anti-HBV activity of in vitro Viread Module Provided in Type II October 2007 Module 5 Volume 1 combinations of tenofovir with 4.2.2.2 variation nucleoside analogs (EMEA/H/C/419/ II/75) TBZZ/93/0025 Protein binding of 524W91 in Emtriva Module Original MAA December Part III Volume 25 human, monkey, mouse and rabbit 4.2.2.3 (EMEA/H/C/533) 2002 plasma (PDM-037) TOX103 Toxicokinetic study to determine Emtriva Module Original MAA December Part III Volume 25 fetal exposures in CD-1 mice given 4.2.2.3 (EMEA/H/C/533) 2002 TP-0006 orally

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TOX103 Addendum to TOX103: Truvada Module Original MAA March 2004 Module 4 Volume 11 [Addendum] toxicokinetic study to determine fetal 4.2.2.3 (EMEA/H/C/594) exposures in CD-1 mice given TP- 0006 orally TOX092 [14C]TP-0006: A tissue distribution Emtriva Module Original MAA December Part III Volume 24 and excretion study in rats 4.2.2.3 (EMEA/H/C/533) 2002 P0504-00039.1 Protein binding of cidofovir, cyclic Viread Module Original MAA May 2001 Part III Volume 35 HPMPC, PMEA and PMPA in 4.2.2.3 (EMEA/H/C/419) human plasma and serum 95-DDM- Determination of distribution of Truvada Module Original MAA March 2004 Module 4 Volume 10 1278-002 [14C]-PMPA in male rats following 4.2.2.3 (EMEA/H/C/594) single administration using whole body autoradiography 97-DDM- Tissue distribution of [14C] Viread Module Original MAA May 2001 Part III Volume 35 4331-001 GS-4331 in beagle dogs following 4.2.2.3 (EMEA/H/C/419) oral administration 96-DDM- Placental transfer and Viread Module Original MAA May 2001 Part III Volume 35 1278-005 pharmacokinetics of PMPA (GS- 4.2.2.3 (EMEA/H/C/ 419) 1278) in infant rhesus monkeys P2000116 Pharmacokinetics of tenofovir in Viread Module Original MAA May 2001 Part III Volume 35 healthy adult female lactating rhesus 4.2.2.3 (EMEA/H/C/419) monkeys following a single 30 mg/kg subcutaneous dose of tenofovir

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume Doc #15247 In vitro evaluation of emtricitabine Truvada Module Original MAA March 2004 Module 4 Volume 3 (FTC) as an inhibitor of human 4.2.2.4 (EMEA/H/C/594) cytochrome P-450 enzymes and 5’- uridine diphosphate glucuronosyl transferase (UGT) (CTBR Project No. 48171) 15396 v1 Identification of the principal human Emtriva Module Included in May 2003 Response to Volume 2 cytochrome P-450 isoenzyme(s) and 4.2.2.4 response to CPMP Questions potential glucuronidation responsible Day 120 List of for the metabolism of emtricitabine Questions (FTC) using pooled human liver (EMEA/H/C/533) microsomes and bactosomes containing cDNA-expressed human cytochrome P-450 (CYP) isoenzymes TEIN/93/0015 Metabolic disposition and balance Emtriva Module Original MAA December Part III Volume 24 studies in male CD-1 mice following 4.2.2.4 (EMEA/H/C/533) 2002 oral administration of 120 mg/kg [6- 3H]524W91 (EXT020) TOX063 Metabolism and excretion of Emtriva Module Original MAA December Part III Volumes 22- [14C]TP-0006 following oral 4.2.2.4 (EMEA/H/C/533) 2002 -23 administration to male cynomolgus monkeys TEIN/93/0016 Metabolic disposition of 80 mg/kg Emtriva Module Original MAA December Part III Volume 25 orally administered [6-3H]524W91 4.2.2.4 (EMEA/H/C/533) 2002 in cynomolgus monkeys

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume P1278-00008; In vitro metabolism of 14C-PMPA in Truvada Available Original MAA March 2004 Module 4 Volume 12 96-DDM- human and animal tissues upon request (EMEA/H/C/594) 1278-003 P4331-00003; In vitro stability of bis-POC PMPA Truvada Available Original MAA March 2004 Module 4 Volume 12 97-VIT-1278- (GS-4331) in biological fluids upon request (EMEA/H/C/594) 001 P4331- Epithelial transport and metabolism Truvada Available Original MAA March 2004 Module 4 Volume 12 00015.1; 98- of tenofovir disoproxil (Bis-POC upon request (EMEA/H/C/594) VIT-4331-001 PMPA; GS-4331) in caco-2 cell monolayers V990172-104 The effect of tenofovir and tenofovir Truvada Module Original MAA March 2004 Module 4 Volume 3 DF on the activities of the 4.2.2.4 (EMEA/H/C/594) cytochrome P-450 isoforms in human hepatic microsomes R2001024 GLP ex-vivo rat cytochrome P-450 Truvada Module Original MAA March 2004 Module 4 Volume 12 induction study following treatment 4.2.2.4 (EMEA/H/C/594) with tenofovir DF 96-DDM- Effect of dose on the recovery of Viread Module Original MAA May 2001 Part III Volume 36 1278-001 [14C]-PMPA following intravenous 4.2.2.5 (EMEA/H/C/ 419) administration to Sprague-Dawley rats

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 97-DDM- Determination of tenofovir Viread Module Original MAA May 2001 Part III Volume 36 4331-003/4; disoproxil and metabolite 4.2.2.5 (EMEA/H/C/419) P4331-00014 concentrations in bile and gastrointestinal tract, following oral administration of tenofovir disoproxil to rats (Gilead Study Nos. 97-DDM-4331-003 and 97-DDM- 4331-004) P1278-00011; A pilot study of biliary excretion of Truvada Module Original MAA March 2004 Module 4 Volume 14 96-DDM- 14C-PMPA in the beagle dog 4.2.2.3 (EMEA/H/C/594) 1278-002 PC-104-2018 Effect of HIV protease inhibitors on Viread Module Submitted in April 2007 Follow-up Volume 1 MRP4-mediated efflux of tenofovir 4.2.2.5 response to Measure Follow-up Measure (EMEA/H/C/419) PC-104-2019 In vitro effect of HIV protease Viread Module Submitted in June 2008 Follow-up Volume 1 inhibitors on the accumulation of 4.2.2.5 response to Measure tenofovir in fresh human kidney Follow-up Measure tissue (EMEA/H/C/419) PC-103-2001 In vitro interactions of acyclic Viread Module Submitted in December Follow-up Volume 1 nucleoside phosphonate analogs with 4.2.2.6 response to 2003 Measure human organic cation and anion Follow-up Measure transporters (EMEA/H/C/419)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume AD-104-2001 Effect of HIV protease inhibitors on Viread Available Submitted in June 2005 Follow-up Volume 1 the transport of tenofovir by the upon request Response to Measure multidrug resistance related proteins Follow-Up Measure 2 and 4 (EMEA/H/C/419) AD-104-2002 Lack of contribution from P- Viread Module Submitted in December Follow-up Volume 1 glycoprotein (Pgp) in the active 4.2.2.5 Response to 2005 Measure tubular secretion of tenofovir Follow-up Measure (EMEA/H/C/ 419) PC-104-2010 Effect of HIV protease inhibitors and Viread Module Provided in Type II June 2005 Type II Volume 1 other therapeutics on the transport of 4.2.2.6 Variation variation tenofovir by human renal organic (EMEA/H/C/419/ anion transporter type I (hOAT1) II/29) PC-104-2011 Effect of HIV protease inhibitors on Viread Module Provided in Type II June 2005 Type II Volume 1 the transport of tenofovir by human 4.2.2.6 Variation variation renal organic anion transporter type (EMEA/H/C/419/ 3 (hOAT3) II29) PC-104-2014 Lack of contribution from MRP1 in Viread Module Submitted in March 2006 Follow-up Volume 1 tubular re-absorption of tenofovir 4.2.2.6 Response to Measure Follow-up Measure (EMEA/H/C/419) AD-104-2010 Effect of HIV protease inhibitors on Viread Module Submitted in September Follow-up Volume 1 the intestinal absorption of tenofovir 4.2.2.5 Response to 2010 Measure disoproxil fumarate in vitro Follow-up Measure (EMEA/H/C/419)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume PC-177-2001 The triple combination of tenofovir, Atripla Module Submitted in PSUR September Module 5 Volume 1 emtricitabine and efavirenz shows 4.2.2.6 (13 January 2009 to 2009 synergistic anti-HIV-1 activity in 12 July 2009) vitro: a mechanism of action study PC-180-2018 Effect of increasing multiplicity of Viread Module Previously Not infection on the EC50 of GS-9131 4.2.2.6 Submitted and GS-9148 R2000075 Single-dose iv PK of tenofovir at Truvada Module Original MAA March 2004 Module 4 Volume 14 two doses in Sprague-Dawley rats 4.2.2.7 (EMEA/H/C/594) P2001025 Intracellular kinetics of 14C – PMPA Truvada Available Original MAA March 2004 Module 4 Volume 14 in rhesus monkeys upon request (EMEA/H/C/594) P2000117 Pharmacokinetics of tenofovir in Truvada Available Original MAA March 2004 Module 4 Volume 15 healthy and infected rhesus monkeys upon request (EMEA/H/C/594) administered chronic subcutaneous doses of tenofovir R2000065 Comparison of plasma Truvada Available Original MAA March 2004 Module 4 Volume 15 pharmacokinetics in rats of tenofovir upon request (EMEA/H/C/594) following oral administration of GS-7340-02 or tenofovir DF as either a suspension in CMC or a solution in citric acid TTEP/93/0020 An acute oral toxicity study in the Emtriva Module Original MAA December Part III Volume 1 mouse with 524W91 4.2.3.1 (EMEA/H/C/533) 2002

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TTEP/93/0023 An acute intravenous toxicity study Emtriva Module Original MAA December Part III Volume 1 in the mouse with 524W91 4.2.3.1 (EMEA/H/C/533) 2002 TTEP/93/0021 An acute oral toxicity study in the rat Emtriva Module Original MAA December Part III Volume 1 with 524W91 4.2.3.1 (EMEA/H/C/533) 2002 TTEP/93/0024 An acute intravenous toxicity study Emtriva Module Original MAA December Part III Volume 1 in the rat with 524W91 4.2.3.1 (EMEA/H/C/533) 2002 R990200 An acute oral gavage toxicity study Viread Module Original MAA May 2001 Part III Volume 1 of tenofovir DF (GS-4331-05) in the 4.2.3.1 (EMEA/H/C/ 419) albino rat followed by a 14-day observation period (ClinTrials BioResearch Ltd Report No. 89285) D990201 An acute oral gavage toxicity study Viread Module Original MAA May 2001 Part III Volume 1 of tenofovir DF (GS-4331-05) in the 4.2.3.1 (EMEA/H/C/419) beagle dog followed by a 14-day observation period (ClinTrials BioResearch Ltd Report No. 89286) IUW00701 Fourteen-day oral (Gavage) toxicity Truvada Module Original MAA March 2004 Module 4 Volume 30 study in mice given FTC 4.2.3.2 (EMEA/H/C/594) TOX599 A 30-day oral toxicity study in mice Emtriva Module Original MAA December Part III Volumes 3-4 given 524W91 4.2.3.2 (EMEA/H/C/533) 2002 TOX599 Addendum - A 30-day oral toxicity Emtriva Module Original MAA December Part III Volume 4 [Addendum] study in mice given 524W91 4.2.3.2 (EMEA/H/C/533) 2002

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TOX022 Toxicokinetic report for a 6-month Emtriva Module Original MAA December Part III Volumes 5-6 (IUW01001) oral (gavage) toxicity study in mice 4.2.3.2 (EMEA/H/C/533) 2002 given FTC with a 3-month interim kill TOX022 Toxicokinetic report for a 6-month Truvada Module Original MAA March 2004 Module 4 Volume 32 [Addendum] oral (gavage) toxicity study in mice 4.2.3.2 (EMEA/H/C/594) given FTC with a 3-month interim kill TOX628 A 6-month oral toxicity study (with a Emtriva Module Original MAA December Part III Volumes 7-9 3-month interim sacrifice) in mice 4.2.3.2 (EMEA/H/C/533) 2002 given 524W91 TOX097 A 3-month oral gavage study for Emtriva Module Original MAA December Part III Volumes bioassay dose selection in CD rats 4.2.3.2 (EMEA/H/C/533) 2002 9-10 TOX600 A 30-day oral toxicity study in Emtriva Module Original MAA December Part III Volumes cynomolgus monkeys given 524W91 4.2.3.2 (EMEA/H/C/533) 2002 11-12 TOX600 Addendum - A 30-day oral toxicity Emtriva Module Original MAA December Part III Volume 12 study in cynomolgus monkeys given 4.2.3.2 (EMEA/H/C/533) 2002 524W91 TOX627 A 3-month oral toxicity study in Emtriva Module Original MAA December Part III Volumes cynomolgus monkeys given 524W91 4.2.3.2 (EMEA/H/C/533) 2002 12-13 TOX032 52-week oral toxicity study with Emtriva Module Original MAA December Part III Volumes TP-006 in cynomolgus monkeys 4.2.3.2 (EMEA/H/C/533) 2002 13-14 with a 4-week recovery period

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume M990191 A 14-day repeat dose oral toxicity Truvada Module Original MAA March 2004 Module 4 Volume 17 study of tenofovir DF in ICR CD-1® 4.2.3.2 (EMEA/H/C/594) mice M990203 A 13-week oral gavage toxicity Viread Module Original MAA May 2001 Part III Volumes 2-3 (T4331- study of tenofovir disoproxil 4.2.3.2 (EMEA/H/C/419) 00017.1) fumarate (Tenofovir DF) in the albino mouse M990203-PK A 13-week oral gavage toxicity Viread Module Original MAA May 2001 Part III Volume 30 study of tenofovir disoproxil 4.2.3.2 (EMEA/H/C/ 419) fumarate (tenofovir DF) in the albino mouse (Gilead Study #M990203) 96-TOX-4331- 5-day repeated dose oral toxicity Truvada Available Original MAA March 2004 Module 4 Volume 18 002 study of GS-4331-02 in male upon request (EMEA/H/C/594) Sprague-Dawley rats 98-TOX-4331- A 14-day oral gavage toxicity study Truvada Module Original MAA March 2004 Module 4 Volume 18 004 of bis-POC PMPA fumarate 4.2.3.2 (EMEA/H/C/594) (GS-4331-05; PMPA prodrug) in the albino rat 98-TOX-4331- Toxicokinetic report for a 14-day Truvada Module Original MAA March 2004 Module 4 Volume 18 004-PK oral gavage toxicity study of bis- 4.2.3.2 (EMEA/H/C/594) POC PMPA fumarate [GS-4331- 05; PMPA prodrug] in the albino rat (98-TOX-4331-004)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 96-TOX-4331- A 28-day oral gavage toxicity study Viread Module Original MAA May 2001 Part III Volume 7 003 (T4331- of GS-4331-05 in the albino rat 4.2.3.2 (EMEA/H/C/ 419) 00003.2) 96-TOX-4331- Pharmacokinetics of tenofovir Viread Module Original MAA May 2001 Part III Volume 32 003-PK following oral gavage of tenofovir 4.2.3.2 (EMEA/H/C/ 419) (P4331-00004) DF in a 28-day toxicity study in albino rats (A report on the analysis of plasma concentration data from Toxicity Study #96-TOX-4331-003) 97-TOX-4331- A 13- and 42-week oral gavage Viread Module Original MAA May 2001 Part III Volumes 002 toxicity study (with a 13-week 4.2.3.2 (EMEA/H/C/ 419) 8-12 recovery period) of BIS-POC PMPA (GS-4331-05) in the albino rat 97-TOX-4331- Pharmacokinetics of tenofovir in a Viread Module Original MAA May 2001 Part III Volume 33 002-PK 13 and 42-week oral gavage Toxicity 4.2.3.2 (EMEA/H/C/419) study (with a 13-week recovery period) of tenofovir DF (GS-4331- 05) in rats (A report on the analysis of plasma concentration in data from toxicity study #97-TOX-4331-002) 96-TOX-4331- 5-day repeated oral dose toxicity Truvada Available Original MAA March 2004 Module 4 Volume 25 001 study with GS-4331 in dogs upon request (EMEA/H/C/594)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 96-TOX-4331- Pharmacokinetics of tenofovir in a Viread Module Original MAA May 2001 Part III Volume 33 001-PK pilot five day oral toxicity study of 4.2.3.2 (EMEA/H/C/ 419) tenofovir DC (GS-4331-02) in beagle dogs (Toxicity Study #96- TOX-4331-001) 96-TOX-4331- A 28-day oral gavage toxicity study Viread Module Original MAA May 2001 Part III Volume 14 004 (T4331- of GS-4331-05 in the beagle dog 4.2.3.2 (EMEA/H/C/419) 00004.2) 96-TOX-4331- Pharmacokinetics of tenofovir Viread Module Original MAA May 2001 Part III Volume 33 004-PK following oral gavage of tenofovir 4.2.3.2 (EMEA/H/C/ 419) (P4331-00005) DF in a 28-day repeat dose toxicity study in beagle dogs (Gilead Sciences Study #96-TOX-4331-004- PK) 98-TOX-4331- A 28-day oral gavage toxicity study Truvada Available Original MAA March 2004 Module 4 Volume 26 003 of GS-4331-05 (bis-POC PMPA; upon request (EMEA/H/C/594) PMPA Prodrug) in the beagle dog 98-TOX-4331- Pharmacokinetics of tenofovir in a Viread Module Original MAA May 2001 Part III Volume 33 003-PK 28-day repeated dose oral gavage 4.2.3.2 (EMEA/H/C/ 419) toxicity study of tenofovir DF in beagle dogs (A report on analysis of data from toxicity study 98-TOX- 4331-003)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 97-TOX-4331- A 13- and 42-week oral gavage Viread Module Original MAA May 2001 Part III Volumes 001 toxicity study (with a 13-week 4.2.3.2 (EMEA/H/C/ 419) 15-17 recovery period) of Bis-POC PMPA (GS-4331-05) in the beagle dog 97-TOX-4331- Pharmacokinetics of tenofovir Viread Module Original MAA May 2001 Part III Volume 34 001-PK following oral gavage of tenofovir 4.2.3.2 (EMEA/H/C/ 419) (P4331-00006) DF in a 13- and 42-week repeat dose toxicity study in beagle dogs (A report on analysis of plasma concentration data from toxicity study #97-TOX-4331-001) TX-164-2001 A 14-day oral gavage toxicity study Truvada Module Original MAA March 2004 Module 4 Volumes 4-5 comparing non-degraded and 4.2.3.2 (EMEA/H/C/594) degraded TDF/FTC in Sprague- Dawley rats TX-164-2004 4-week oral gavage toxicity and Truvada Module Provided in Type II August 2005 Module 4 Volumes 1-2 toxicokinetic study with 4.2.3.2 Variation emtricitabine/tenofovir disoproxil (EMEA/H/C/594 fumarate (FTC/TDF) in male dogs /II/010) with a 4-week recovery period 18637-0-409R Mutagenicity test with FTC in the Emtriva Module Original MAA December Part III Volume 24 Salmonella - Escherichia 4.2.3.3.1 (EMEA/H/C/533) 2002 coli/mammalian-microsome reverse mutation assay with a confirmatory assay

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume MUT203 Salmonella/mammalian-microsome Emtriva Module Original MAA December Part III Volume 20 assays with 524W91 4.2.3.3.1 (EMEA/H/C/533) 2002 K01-3154 Mutagenicity test of FTC using Truvada Module Submitted in PSUR April 2006 PSUR Volume 2 microorganisms 4.2.3.3.1 (03 August 2005 to 02 February 2006) TOX012 In vitro mammalian cell gene Emtriva Module Original MAA December Part III Volume 20 mutation test (mouse lymphoma 4.2.3.3.1 (EMEA/H/C/533) 2002 assay) 96-TOX-4331- Mutagenicity test with GS-4331-05 Viread Module Original MAA May 2001 Part III Volume 23 005 in the Salmonella- escherichia coli 4.2.3.3.1 (EMEA/H/C/ 419) mammalian microsome reverse mutation assay 97-TOX-1278- Mutagenicity test with GS-1278 Viread Module Original MAA May 2001 Part III Volume 23 003 (PMPA) Lot no. KH01603, GS-1278 4.2.3.3.1 (EMEA/H/C/ 419) (PMPA) Lot No. 1278-B-1, GS- 4331-05 (PMPA prodrug, bis-POC PMPA) Lot no. 4331-05-XA-1 (2nd crop) in the Salmonella mammalian reverse mutation assay K01-3037 Mutagenicity test of tenofovir using Viread Available Provided in 3rd February 2005 3rd Annual Volume 2 microorganisms upon request Annual Risk Risk Benefit Benefit (EMEA/H/C/419/S/ 48)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 97-TOX-4331- Mutagenicity test on GS-4331-05 in Viread Module Original MAA May 2001 Part III Volume 23 007 the L5178Y/TK+/- mouse lymphoma 4.2.3.3.1 (EMEA/H/C/ 419) forward mutation assay TX-164-2002 Bacterial reverse mutation assay Truvada Available Submitted in March 2005 Follow-up Volume 1 with emtricitabine/tenofovir upon request Response to Measure disoproxil fumarate Follow-up Measure (EMEA/H/C/594) TX-164-2003 In vitro mammalian cell gene Truvada Module Submitted in March 2005 Follow-up Volume 1 mutation test (L5178Y/TK+/- mouse 4.2.3.3.1 Response to Measure lymphoma assay) with Follow-up Measure emtricitabine/tenofovir disoproxil (EMEA/H/C/594) fumarate TOX011 In vivo mammalian erythrocyte Emtriva Module Original MAA December Part III Volume 20 micronucleus assay 4.2.3.3.2 (EMEA/H/C/533) 2002 97-TOX-4331- Mutagenicity test on GS-4331-05 in Viread Module Original MAA May 2001 Part III Volume 23 008 the in vivo mouse micronucleus 4.2.2.1 & (EMEA/H/C/419) assay Module 4.2.3.3.2 97-TOX-4331- Tenofovir levels in mouse plasma: Viread Module Original MAA May 2001 Part III Volume 28 008-PK pharmacokinetics from a single dose 4.2.3.3.2 (EMEA/H/C/419) micronucleus study in mice (97-TOX-4331-008)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 23291-0- In vivo/in vitro unscheduled DNA Viread Module Submitted in February 2002 Specific Volume 1 494OECD synthesis in rat primary hepatocyte 4.2.3.3.2 Response to Obligation cultures at two time points Specific Obligation (EMEA/H/C/ 419) TOX109 Two-year oral oncogenicity study in Emtriva Module Original MAA December Part III Volume 20 CD-1 mice 4.2.3.4.1 (EMEA/H/C/533) 2002 TOX108 TP-0006: two-year oral oncogenicity Emtriva Module Original MAA December Part III Volume 20 study in CD rats 4.2.3.4.1 (EMEA/H/C/533) 2002 M990205 An oral carcinogenicity study of Viread Module Provided in Type II September Type II Volumes 1- tenofovir disoproxil fumarate 4.2.3.4.1 Variation 2003 variation 10 (tenofovir DF) in the albino mouse (EMEA/H/C/419 /II/32 R990204 An oral carcinogenicity study of Viread Module Submitted in March 2003 Specific Volumes 1-8 tenofovir disoproxil fumarate 4.2.3.4.1 Response to Obligation (tenofovir DF) in the albino rat Specific Obligation (EMEA/H/C/ 419) TOX036 Study of fertility and early Emtriva Module Original MAA December Part III Volume 15 embryonic development of TP-0006 4.2.3.5.1 (EMEA/H/C/533) 2002 administered by gavage to CD-1 mice (segment 1) TTEP/95/0028 A fertility study in male rats given Emtriva Module Original MAA December Part III Volume 15 524W91 by gavage 4.2.3.5.1 (EMEA/H/C/533) 2002

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 98-TOX-4331- Oral (gavage) fertility and general Viread Module Original MAA May 2001 Part III Volume 19 006 reproduction toxicity study of GS- 4.2.3.5.1 (EMEA/H/C/ 419) 4331-05 (bis-POC PMPA) in Sprague-Dawley rats TOX033 A dose range-finding study of the Truvada Module Original MAA March 2004 Module 4 Volume 85 effects of TP-0006 on embryo/fetal 4.2.3.5.2 (EMEA/H/C/594) development in mice TOX037 A study of the effects of TP-0006 Emtriva Module Original MAA December Part III Volumes (FTC) on embryo/fetal development 4.2.3.5.2 (EMEA/H/C/533) 2002 16-17 in mice TOX037 Addendum to document No: Truvada Module Original MAA March 2004 Module 4 Volume 85 TOX037 4.2.3.5.2 (EMEA/H/C/594) TOX034 A dose range-finding study of the Truvada Module Original MAA March 2004 Module 4 Volume 85 effects of TP-0006 on embryo/fetal 4.2.3.5.2 (EMEA/H/C/594) development in rabbits TOX038 A study of the effects of TP-0006 on Emtriva Module Original MAA December Part III Volumes embryo/fetal development in rabbits 4.2.3.5.2 (EMEA/H/C/533) 2002 18-19 TOX038 Addendum to TOX038: A study of Truvada Module Original MAA March 2004 Module 4 Volume 86 [Addendum] the effects of TP-0006 on 4.2.3.5.2 (EMEA/H/C/594) embryo/fetal development in rabbits 97-TOX-4331- Oral (gavage) developmental toxicity Viread Module Original MAA May 2001 Part III Volume 20 004 study of GS-4331-005 in rats 4.2.3.5.2 (EMEA/H/C/ 419)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 98-TOX-4331- Oral (stomach tube) developmental Viread Module Original MAA May 2001 Part III Volume 22 005 toxicity study of GS-4331-05 in 4.2.3.5.2 (EMEA/H/C/ 419) rabbits 98-TOX-4331- Pharmacokinetics of tenofovir in an Truvada Module Original MAA March 2004 Module 4 Volume 85 005-PK oral (stomach tube) developmental 4.2.3.5.2 (EMEA/H/C/594) toxicity study of GS-4331-05 (bis- POC PMPA) in rabbits (A report on analysis of data from toxicity study 98-TOX-4331-005) TOX039 Pre- and postnatal development Emtriva Module Original MAA December Part III Volume 19 study in CD-1 mice given TP-0006 4.2.3.5.3 (EMEA/H/C/533) 2002 by gavage (segment III) R990202 Oral (gavage) developmental and Viread Module Provided in Type II August 2002 Type II Volumes 1-2 perinatal/postnatal reproduction 4.2.3.5.3 Variation variation toxicity study of GS-4331-05 (bis- (EMEA/H/C/419/ POC PMPA) in rats including a II/10) postnatal behavioural / functional evaluation R990202-PK Tenofovir (GS-1278) plasma Viread Module Provided in Type II August 2002 Type II Volume 2 toxicokinetics from a developmental 4.2.3.5.3 Variation variation and perinatal/postnatal reproduction (EMEA/H/C/419 toxicity study of tenofovir DF in /II/10) female rats B990165 A primary eye irritation study in Truvada Module Original MAA March 2004 Module 4 Volume 89 rabbits with tenofovir DF 4.2.3.6 (EMEA/H/C/594) (GS-4331-05)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume B990166 A primary skin irritation study in Truvada Module Original MAA March 2004 Module 4 Volume 89 rabbits with tenofovir DF 4.2.3.6 (EMEA/H/C/594) (GS-4331-05) G990167 A dermal sensitization study in Truvada Module 4.2. Original MAA March 2004 Module 4 Volume 89 guinea pigs with tenofovir DF 3.7.1 (EMEA/H/C/594) (GS-4331-05) - modified Buehler design TOX146 TP-0006 28-day oral (gavage) Truvada Module Original MAA March 2004 Module 4 Volume 27 immunotoxicity study in rats. 4.2.3.7.2 (EMEA/H/C/594) R2000096 A 28-day oral repeat dose study to Viread Module Submitted in January 2002 Specific Volume 1 evaluate the toxicity of adefovir 4.2.3.7.3 Response to Obligation dipivoxil (GS-0840), tenofovir DF Specific Obligation (GS-4331-05), or adefovir dipivoxil (EMEA/H/C/419) in combination with tenofovir DF in male Sprague-Dawley rats W2000042 A 90-day repeat dose oral toxicity Viread Module Submitted in January 2002 Specific Volume 4 study of tenofovir DF in woodchucks 4.2.3.7.3 Response to Obligation Specific Obligation (EMEA/H/C/ 419) W2000042-PK Toxicokinetics of tenofovir Truvada Module Original MAA March 2004 Module 4 Volume 91 following daily oral administration 4.2.3.7.3 (EMEA/H/C/594) of tenofovir DF to male and female woodchucks for 90 days V2000122 Human osteoblast calcium Truvada Module Original MAA March 2004 Module 4 Volume 89 deposition in vitro 4.2.3.7.3 (EMEA/H/C/594)

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume R2000095 A 3-day oral repeat dose study to Truvada Module Original MAA March 2004 Module 4 Volume 89 evaluate serum and urine phosphorus 4.2.3.7.3 (EMEA/H/C/594) levels in tenofovir DF (GS-4331- 05)-treated male Sprague-Dawley rats supplemented, following the final dose, with intraperitoneal or oral phosphate R2000099 A 3-day oral or intravenous repeat Truvada Module Original MAA March 2004 Module 4 Volume 89 dose study to evaluate serum and 4.2.3.7.3 (EMEA/H/C/594) urine phosphate concentrations in male Sprague-Dawley rats treated with tenofovir (GS-1278) or tenofovir DF (GS-4331-05) and supplemented with oral phosphate R2000043 A 6-day repeat dose oral exploratory Truvada Module Original MAA March 2004 Module 4 Volume 89 study of tenofovir DF in male 4.2.3.7.3 (EMEA/H/C/594) Sprague-Dawley rats R2000036 A 28-day study to evaluate the Truvada Module Original MAA March 2004 Module 4 Volume 90 effects of tenofovir disoproxil 4.2.3.7.3 (EMEA/H/C/594) fumarate (tenofovir DF) on bone following daily administration by gavage in the Sprague-Dawley rat

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume R2000036-PK A 28-day study to evaluate the effect Viread Module Original MAA May 2001 Part III Volume 32 of tenofovir disoproxil fumarate 4.2.3.7.3 (EMEA/H/C/419) (tenofovir DF) on bone following daily administration by gavage in the Sprague-Dawley rat P2000078 A 56-day study of tenofovir DF Viread Module Submitted in January 2002 Specific Volume 2 administered orally and of PMPA 4.2.3.7.3 Response to Obligation administered by subcutaneous Specific Obligation injection to rhesus monkeys (EMEA/H/C/ 419) P2000078-PK Toxicokinetics of tenofovir DF Viread Module Provided in Type II August 2002 Type II Volume 1 administered orally and tenofovir 4.2.3.7.3 Variation variation administered by subcutaneous (EMEA/H/C/419/ injection to rhesus monkeys for 56- II/10) days TOX 153 A 1-month mouse oral qualification Truvada Module Original MAA March 2004 Module 4 Volumes 95- study of TP-0006 and TP-0296 4.2.3.7.6 (EMEA/H/C/594) 96 (degradant) TX-162-2001 A 1-month oral qualification study of Truvada Module Original MAA March 2004 Module 4 Volumes 97- TP-0006 produced by the menthol 4.2.3.7.6 (EMEA/H/C/594) 98 process in CD-1 mice TOX151 Bacterial reverse mutation assay of Truvada Module Original MAA March 2004 Module 4 Volume 95 TP-0006 to qualify degradant TP- 4.2.3.7.6 (EMEA/H/C/594) 0296

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume TOX152 In vitro mammalian chromosome Truvada Module Original MAA March 2004 Module 4 Volume 95 aberration study of TP-0006 to 4.2.3.7.6 (EMEA/H/C/594) qualify degradant TP-0296 R2000081 14-day oral toxicity study comparing Truvada Module Original MAA March 2004 Module 4 Volume 93 tenofovir DF and degraded tenofovir 4.2.3.7.6 (EMEA/H/C/594) DF in Sprague-Dawley rats R2000081-PK 14-day oral toxicity study comparing Truvada Module Original MAA March 2004 Module 4 Volumes 30- tenofovir DF and degraded tenofovir 4.2.3.7.6 (EMEA/H/C/594) 94 DF in Sprague-Dawley rats Safepharm 28-day repeated dose oral (gavage) Truvada Available Original MAA March 2004 Module 4 Volume 99 Laboratories toxicity study in the rat Upon (EMEA/H/C/594) 1432/009 Request Safepharm 28-day repeated dose oral (gavage) Truvada Available Original MAA March 2004 Module 4 Volume 99 Laboratories toxicity study in the rat Upon (EMEA/H/C/594) 1432/021 Request Safepharm CMIC: Reverse mutation assay Truvada Available Original MAA March 2004 Module 4 Volume 98 Laboratories “Ames Test” using Salmonella Upon (EMEA/H/C/594) 1432/022 typhimurium and Eschericha coli Request Safepharm CMIC: L5178Y/TK+/- mutation Truvada Available Original MAA March 2004 Module 4 Volume 99 Laboratories assay Upon (EMEA/H/C/594) 1432/023 Request

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Cross-Reference to Study Report Nonclinical Location Report within FDC EU Procedure Date Dossier Number Study Title Product MAA (& number) Submitted Number/Type Volume 95-TOX-1278- Mutagenicity test with GS-1278 Truvada Module Original MAA March 2004 Module 4 Volume 98 006 (PMPA) lot #1016-56-26 in the 4.2.3.7.7 (EMEA/H/C/594) Salmonella-Escherrichia coli mammalian-microsome reverse mutation assay 95-TOX-1278- Mutagenicity test on GS-1278 Truvada Module Original MAA March 2004 Module 4 Volume 98 007 (PMPA) in the L5178Y/TK+/- 4.2.3.7.7 (EMEA/H/C/594) mouse lymphoma forward mutation assay T1278-00034 PMPA in SIV-infected and Viread Available Original MAA May 2001 Part III Volume 26 uninfected rhesus macaques: studies upon request (EMEA/H/C/419) from Martin and Tsai Laboratories. T1278-00030 The effects of PMPA treatment on Truvada Module Original MAA March 2004 Module 4 Volume 98 cortical bone strength in rhesus 4.2.3.7.7 (EMEA/H/C/594) monkeys (Macaca mulatta).Thesis, University of California, Davis

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Table 32. Gilead Clinical Reports

Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-110 A study to evaluate the relative and Emtriva Module 5.3.1.1 Original MAA December Module 5 Volumes absolute bioavailability of emtricitabine (EMEA/H/C/533) 2002 1–4 in healthy volunteers FTC-109 A pilot study to evaluate the Emtriva Module 5.3.1.2 Original MAA December Module 5 Volumes bioavailability/bioequivalence between (EMEA/H/C/533) 2002 5-6 the 100 mg and 200 mg capsule formulations of emtricitabine in healthy volunteers. FTC-111 An open-label study to compare the Emtriva Module 5.3.1.2 Original MAA December Module 5 Volumes bioavailability/bioequivalence of two (EMEA/H/C/533) 2002 7–9 dosage forms of emtricitabine (100 mg capsules and 200 mg capsules) and the effect of food on the bioavailability of emtricitabine administered as a 200 mg capsule in healthy volunteers. FTC-112 An open-label study to determine the Truvada Available upon Original MAA March 2004 Module 5 Volumes bioequivalence between Epivir“ tablets request (EMEA/H/C/594) 54-55 and encapsulated Epivir“ tablets in healthy volunteers. FTC-113 An open-label study to determine the Truvada Available upon Original MAA March 2004 Module 5 Volumes bioequivalence between Zerit“ request (EMEA/H/C/594) 16-18 capsules and over-encapsulated Zerit“ capsules in healthy volunteers.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-US-162-0101 A phase 1, open-label, randomized, Emtriva Available upon Submitted in June 2004 Follow-Up Volume 1 three-way crossover study to evaluate request Response to Measure the effect of food on the bioavailability Follow-Up of emtricitabine administered as Measure Emtriva• oral solution in healthy (EMEA/H/C/ 533) volunteers.

GS-00-914 A phase 1, randomized, open label, Viread Module 5.3.1.2 Original MAA May 2001 Part IV Volume 8 pharmacokinetic study in healthy (EMEA/H/C/419) volunteers to assess the 1) bioequivalence of the clinical and intended commercial formulations of tenofovir disoproxil fumarate and the 2) effect of food on the bioavailability and pharmacokinetics of the intended commercial formulation of tenofovir disoproxil fumarate 300 mg tablets. GS-US-104-0172 A phase 1 pharmacokinetic study in Truvada Module 5.3.1.2 Original MAA March 2004 Module 5 Volume healthy volunteers to evaluate the (EMEA/H/C/594) 19 bioequivalence of the combined formulated tablet of tenofovir disoproxil fumarate and emtricitabine compared to tenofovir disoproxil fumarate and emtricitabine administered concurrently and the effect of food on pharmacokinetics.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume P1278-00030 Validation of an HPLC Truvada Available upon Original MAA March 2004 Module 5 Volume chromatographic method for the request (EMEA/H/C/594) 20 quantitation of PMPA (GS-1278) in human serum (Harris Laboratories Project 18758_1.01) P1278-00031 Validation of a high performance liquid Truvada Available upon Original MAA March 2004 Module 5 Volume chromatographic mass spectrometric request (EMEA/H/C/594) 20 method for the determination of GS- 1278 (R-PMPA) in human urine (Phoenix Project 001324NRO). P1278-00032 Validation of a high performance liquid Truvada Available upon Original MAA March 2004 Module 5 Volume chromatographic mass spectrometric request (EMEA/H/C/594) 21 method for the determination of GS- 1278 (R-PMPA) in human serum (Phoenix Project 993679NHC). P1278-00033 Validation of a liquid chromatographic Truvada Available upon Original MAA March 2004 Module 5 Volume method for the quantitation of PMPA request (EMEA/H/C/594) 21 in urine (Harris Laboratories Project 18758_2.01). November 1996, amended December 1996, April 1997, January 1999 and July 1999 20143v3 Validation of a Method for the Truvada Module 5.3.1.4 Previously not Determination of Emtricitabine and submitted. Tenofovir in Human Plasma by LC-MS/MS.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-106 An evaluation of the absorption, Emtriva Module 5.3.3.1 Original MAA December Module 5 Volumes distribution, metabolism and excretion (EMEA/H/C/533) 2002 17–20 (ADME) of C14 labelled emtricitabine (FTC) in healthy male volunteers. 143-001 A phase 1, randomized, single-dose Truvada Module 5.3.3.2 Original MAA March 2004 Module 5 Volume placebo-controlled trial to evaluate the (EMEA/H/C/594) 27 safety and pharmacokinetics of 524W91 (Emtricitabine). FTC-116 A study to evaluate the Emtriva Available upon Submitted in June 2006 Follow-up Volume 1 pharmacokinetics of emtricitabine request response to Measure following multiple-dose administration Follow-Up in HIV-exposed neonates receiving Measure prophylactic zidovudine therapy for (EMEA/H/C/533) perinatal HIV transmission. FTC-101 Phenotypic and genotypic analysis of Emtriva Module 5.3.1.2 Original MAA December Module 5 Volumes recombinant HIV-1 clinical isolates. (EMEA/H/C/ 533) 2002 22-27 FTC-101 A dose-escalation study to investigate Emtriva Module 5.3.3.2 Original MAA December Module 5 Volumes the safety, tolerance, pharmacokinetics (EMEA/H/C/533) 2002 22–27 and antiviral activity of multiple repeat doses of emtricitabine in patients who are infected with HIV-1.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-102 A Randomized, Comparative Trial of Emtriva Module 5.3.3.2 Original MAA December Module 5 Volumes FTC Administered Once-Daily vs 3TC (EMEA/H/C/533) 2002 28-31 Administered Twice-Daily to HIV-1 Infected Subjects in a 10-day Dosing Regimen FTC-105 An evaluation of the safety and Truvada Available upon Original MAA March 2004 Module 5 Volumes pharmacokinetics of single, escalating request (EMEA/H/C/594) 32-38 oral doses of emtricitabine (FTC) in HIV-1 infected or exposed paediatric patients aged < 18 years old. FTC-107 An evaluation of the pharmacokinetics Emtriva Module 5.3.3.3 Original MAA December Module 5 Volumes of emtricitabine in volunteers with (EMEA/H/C/533) 2002 39–43 varying degrees of renal impairment. FTC-107 Investigation of the use of dosing Emtriva Module 5.3.3.3 Included in May 2003 Response to Volume 2 interval as a means of normalizing Response to Questions emtricitabine exposure in patients with CHMP Day 120 varying degrees of renal impairment List of Questions (Analyses and simulations based on (EMEA/H/C/533) data for study FTC-107). 13542v1 Statistical analysis of emtricitabine Truvada Available upon Original MAA March 2004 Module 5 Volume pharmacokinetic parameter estimates request (EMEA/H/C/594) 73 vs. demographic variables in adult healthy and HIV infected populations evaluated in emtricitabine HIV clinical program.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-01-919 A phase 1, open-label, parallel-group Viread Module 5.3.3.3 Provided in Type II August 2002 Type II Volumes study to evaluate the pharmacokinetics variation Variation 1–2 of tenofovir disoproxil fumarate in (EMEA/H/C/419/ subjects with normal and impaired II/09) renal function. GS-01-931 A/B A phase 1 open-label, parallel-group, Viread Module 5.3.3.3 Provided in Type II July 2003 Module 5 Volumes single-dose study to evaluate the variation 1–2 pharmacokinetics of tenofovir DF in (EMEA/H/C/419 subjects with normal and impaired II/030) hepatic function. GS-01-926 A Phase I Study of Tenofovir Viread Available upon Submitted in March 2006 Follow-up Volumes Disoproxil Fumarate (PMPA Prodrug), request response to a Measure 1–6 a Novel Nucleotide Analog Reverse Follow-Up Transcriptase Inhibitor, in Children Measure with HIV Infection (EMEA/H/C/419) GS-01-927 A Phase 1í2, Open-Label, Dose- Viread Available upon Submitted in September Follow-up Volumes Finding, Multiple Center Study of the request response to a 2005 Measure 1–3 Pharmacokinetics and Safety of Follow-Up Tenofovir Disoproxil Fumarate Measure Administered in Combination with (EMEA/H/C/ 419) Other Antiretroviral Agents as Advanced Therapy in HIV-1 Infected Children and Adolescents (Aged 4í17)

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-02-983 A phase 1, open-label, single-dose, Viread Available upon Submitted in November Follow-up Volume 1 single center study of the request response to 2005 Measure pharmacokinetics of tenofovir Follow-up Measure disoproxil fumarate oral suspension (EMEA/H/C/419) administered in combination with other antiretroviral agents in HIV-1 infected children. GS-US-104-0235 Open-Label, Single-Group, 48-Week, Truvada Module 5.3.3.3 Submitted in April 2007 Follow-up Volumes Phase 4 Study to Evaluate the Safety response to Measure 16 And Tolerability of Tenofovir DF in Follow-Up Combination With Emtricitabine in Measure Treatment-Naïve or (EMEA/H/C/594) Treatment-Experienced HIV-

1Infected Patients With Varying Degrees of Renal Impairment. FTC-103 An open-label study to evaluate Emtriva Module 5.3.3.4 Original MAA December Module 5 Volumes pharmacokinetic interactions of (EMEA/H/C/533) 2002 44–46 emtricitabine, Retrovir and Zerit in healthy male and female volunteers. FTC-104 A study to evaluate the potential Emtriva Module 5.3.3.4 Original MAA December Module 5 Volumes pharmacokinetic interactions of (EMEA/H/C/533) 2002 47–50 emtricitabine with indinavir and MKC- 442 (emivirine).

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-108 An open-label, randomized crossover Emtriva Module 5.3.3.4 Original MAA December Module 5 Volumes study to evaluate the pharmacokinetics (EMEA/H/C/533) 2002 51–55 of emtricitabine and famciclovir administered alone or in combination in healthy volunteers. FTC-115 An open label, randomized, three way Truvada Module 5.3.3.4 Original MAA March 2004 Module 5 Volume crossover study to evaluate the steady- (EMEA/H/C/594) 72 state pharmacokinetics of emtricitabine and zidovudine when administered alone and in combination in healthy volunteers. FTC-114 An open-label, randomised, three-way Truvada Module 5.3.3.4 Original MAA March 2004 Module 5 Volume crossover study to evaluate the steady- (EMEA/H/C/594) 73 state pharmacokinetics of emtricitabine and tenofovir disoproxil fumarate when administered alone and in combination in healthy volunteers. GS-01-932 A phase 1, open-label, drug-drug Viread Module 5.3.3.4 Submitted in June 2002 Follow-up Volumes interaction study to assess the response to Measure 1–2 pharmacokinetics of tenofovir Follow-Up disoproxil fumarate and enteric-coated Measure from the didanosine capsules in healthy original Letter of volunteers. Undertaking (EMEA/H/C/419)

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-02-984 A phase 1, open label, drug-drug Viread Module 5.3.3.4 Provided in Type II February Type II Volume 1 interaction study to assess the variation 2003 Variation pharmacokinetics of tenofovir (EMEA/H/C/419/ disoproxil fumarate, dose reduced II/18) didanosine delayed release capsules and abacavir sulfate in healthy volunteers. GS-01-943 A phase 1, randomised, open label Viread Module 5.3.3.4 Submitted in March 2003 Follow-up Volumes multi-dose, drug interaction study to response to Measure 1–2 assess the pharmacokinetics of Follow-Up tenofovir disoproxil fumarate and Measure from the lopinavir/ritonavir under fed conditions revised Letter of in healthy volunteers. Undertaking (EMEA/H/C/419) GS-01-930 A phase 1, open label, drug interaction Truvada Module 5.3.3.4 Original MAA March 2004 Module 5 Volumes study evaluating the effect of tenofovir (EMEA/H/C/594) 56-57 disoproxil fumarate on the pharmacokinetics of norgestimate/ethinyl estradiol in healthy females. GS-01-929 A phase 1, open label study evaluating Truvada Module 5.3.3.4 Original MAA March 2004 Module 5 Volumes the effect of tenofovir disoproxil (EMEA/H/C/594) 54-55 fumarate on methadone pharmacokinetics in opiate-maintained subjects.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-01-940 A phase 1, open-label, drug interaction Truvada Module 5.3.3.4 Original MAA March 2004 Module 5 Volume study to assess the pharmacokinetic and (EMEA/H/C/594) 58 drug interaction potential between tenofovir disoproxil fumarate (TDF) and adefovir dipivoxil (ADV) in healthy volunteers. GS-02-1037 A phase 1, open-label, drug interaction Truvada Available upon Original MAA March 2004 Module 5 Volume study to assess the pharmacokinetics of request (EMEA/H/C/594) 59 tenofovir disoproxil fumarate and ribavirin in healthy volunteers. GS-02-1038 A Phase 1, Open-Label, Study on Truvada Module 5.3.3.4 Provided in Type II November Type II Volume 1 Pharmacokinetic Interaction between variation 2006 Variation Tenofovir DF and Rifampin in Healthy (EMEA/H/C/594/ Subjects II/025) GS-US-104-0236 A Phase 1, Open-Label, Single- and Truvada Module 5.3.3.4 Provided in a Type October Type II Volume 1 Multiple-Dose, Drug-Drug Interaction II variation 2005 Variation Study to Assess the Pharmacokinetics (EMEA/H/C/594/ of Tenofovir Disoproxil Fumarate and II/011) Unboosted and Ritonavir-Boosted Saquinavir Mesylate in Healthy Volunteers

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-US-104-0237 A Phase 1, Randomized, Open-Label, Truvada Module 5.3.3.4 Provided in a Type October Type II Volume 1 Multi-Dose, Safety and II variation 2005 Variation Pharmacokinetic Drug Interaction (EMEA/H/C/594 Study of Tenofovir Disoproxil /II/011) Fumarate and Nelfinavir Mesylate in Healthy Subjects GS-00-909 A phase 1, randomized, open-label, Viread Module 5.3.3.4 Original MAA May 2001 Part IV Volumes multiple-dose, drug interaction study to (EMEA/H/C/419) 5 – 7 assess the pharmacokinetics of tenofovir disoproxil fumarate (TDF), lamivudine (3TC), didanosine (ddI), indinavir (IDV), ABT-378/ ritonavir and efavirenz (EFV) in healthy volunteers. GS-US-174-0105 A Open-label, Randomized, three-way, Truvada Module 5.3.3.4 Submitted with March 2007 PSUR Volume 2 Crossover Study to Evaluate the PSUR potential for and extent of (03 August 2006 to Pharmacokinetic Interactions Between 02 February 2007) the Combination of Emtricitabine and Tenofovir Disoproxil Fumarate and Tacrolimus when administered alone and together in Health Volunteers.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume TDF-06-063 Renal Impairment Data Summary Viread Module 5.3.3.5 Provided April 2006 Data Volume 1 (Gilead subsequent to the Summary Submission Updated Reference) Cumulative Review of Renal Events submitted in response to the CHMP Assessment Report of the PSUR (01 November 2004 to 30 April 2005) (EMEA/H/C/419) GS-96-701 A phase 1-2, randomized, double-blind, Viread Module 5.3.4 Original MAA May 2001 Part IV Volumes placebo-controlled study of the safety, (EMEA/H/C/419) 1-2 tolerance, pharmacokinetics, and antiviral activity of 9-[(R)-2- (phosphonomethoxy)propyl]adenine (PMPA) in HIV infected patients. GS-97-901 A Phase 1-2 randomized, double-blind, Viread Module 5.3.4 Original MAA May 2001 Part IV Volumes placebo-controlled study of the safety, (EMEA/H/C/419) 2-3 tolerance, pharmacokinetics, and antiviral activity of tenofovir disoproxil fumarate in HIV-infected patients.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-301A A randomized, double-blind, Emtriva Module 5.3.5.1 Original MAA December Module 5 Volumes equivalence trial comparing (EMEA/H/C/533) 2002 57-66 emtricitabine to stavudine within a triple drug combination containing didanosine plus efavirenz in antiretroviral-drug naïve HIV-1 infected patients. (24 week clinical study report [with 319 evaluable patients at week 48]) FTC-301A A randomized, double-blind, Emtriva Module 5.3.5.1 Included in May 2003 Response to Volume equivalence trial comparing Response to Questions 10 emtricitabine to stavudine within a CHMP Day 120 triple drug combination containing List of Questions didanosine plus efavirenz in (EMEA/H/C/533) antiretroviral-drug naïve HIV-1 infected patients. (Final 48 week clinical/statistical report [with 571 evaluable patients at Week 48]) FTC-302 A randomized, double-blind Emtriva Module 5.3.5.1 Original MAA December Module 5 Volumes equivalence trial comparing (EMEA/H/C/533) 2002 67–74 emtricitabine to lamivudine within a triple combination in antiretroviral- drug naïve HIV 1 infected patients.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-303 (PK A randomized, open-label equivalence Emtriva Module 5.3.5.1 Original MAA December Module 5 Volumes substudy) study of FTC vs. lamivudine in patients (EMEA/H/C/533) 2002 75–80 on a stable triple antiretroviral therapy regimen containing lamivudine, stavudine or zidovudine, and a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. FTC-303 A randomized, open-label equivalence Emtriva Module 5.3.5.1 Original MAA December Module 5 Volumes study of FTC vs. lamivudine in patients (EMEA/H/C/533) 2002 75–80 on a stable triple antiretroviral therapy regimen containing lamivudine, stavudine or zidovudine, and a protease inhibitor or nonnucleoside reverse transcriptase inhibitor. FTC-303 Phenotypic analysis of recombinant Truvada Available upon Original MAA March 2004 Module 5 Volume HIV-1 clinical isolates. request (EMEA/H/C/594) 153 FTC-303 Addendum to clinical/statistical report Emtriva Module 5.3.5.1 Included in May 2003 Response to Volume 1 (ie TLOVR analysis) response to CHMP Questions Day 120 List of Questions (EMEA/H/C/533) FTC-303 Addendum 2 – Medical narrative for all Truvada Available upon Included in September Response to Volume 6 patients who discontinued for any request response to CHMP 2004 Questions reason. Day 120 List of Questions (EMEA/H/C/594)

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-303 Incidence of adverse events (• 5%) in Emtriva Available upon Included in May 2003 Response to Volume 3 emtricitabine patients coadministered request Response to Questions zidovudine compared with CHMP Day 120 emtricitabine patients who did not take List of Questions zidovudine. (EMEA/H/C/533) FTC-303 (ANRS- Randomized Phase 3 study comparing Emtriva Available upon Original MAA December Module 5 Volume 099/ALIZE) the efficacy and the tolerance of request (EMEA/H/C/533) 2002 80 maintaining an antiprotease tritherapy versus changing to a combination of FTC/ddI/Efavirenz administered once daily in the treatment of HIV-1 infected patients with an undetectable viral load.). FTC-301 A randomized, open-label superiority Truvada Available upon Original MAA March 2004 Module 5 Volume trial comparing emtricitabine to request (EMEA/H/C/594) 154 abacavir within a triple drug combination in antiretroviral-drug naïve HIV-1 infected patients. MKC-401 A randomized, open-label study of Truvada Available upon Original MAA March 2004 Module 5 Volumes Emivirine combined with Stavudine request (EMEA/H/C/594) 156-161 and Emtricitabine versus Abacavir combined with Stavudine and Emtricitabine in HIV-infected patients who are treatment naïve.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-98-902 A phase 2, randomized, double-blind, Viread Module 5.3.5.1 Original MAA May 2001 Part IV Volumes placebo-controlled study of the safety (EMEA/H/C/419) 9–12 and antiviral activity of the addition of tenofovir disoproxil fumarate (PMPA Prodrug) to combination antiretroviral regimens in treatment-experienced HIV-infected patients (48 week clinical study report) Version 2. GS-98-902 A phase 2, randomized, double-blind, Viread Module 5.3.5.1 Original MAA May 2001 Part IV Volumes placebo-controlled study of the safety (EMEA/H/C/419) 13-14 and antiviral activity of the addition of tenofovir disoproxil fumarate (PMPA Prodrug) to combination antiretroviral regimens in treatment-experienced HIV-infected patients (Interim extension report). GS-98-902 Genotypic and phenotypic analyses of Viread Module 5.3.5.1 Original MAA May 2001 Part IV Volume HIV-1 from patients in a phase 2 study (EMEA/H/C/419) 13 of tenofovir disoproxil fumarate for the treatment of HIV-1 infection (Final 48 week virology study report).

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-98-902 A phase 2, randomized, double-blind, Viread Module 5.3.5.1 Submitted in January Specific Volumes placebo-controlled study of the safety response to 2002 Obligation 1–3 and antiviral activity of the addition of Specific Obligation tenofovir disoproxil fumarate (PMPA from the Letter of Prodrug) to combination antiretroviral Undertaking regimens in treatment-experienced (EMEA/H/C/419) HIV-infected patients (Final clinical study report). GS-98-902 Genotypic & phenotypic analyses of Viread Module 5.3.5.1 Submitted in January Specific Volumes HIV-1 from patients in the 48 week response to 2002 Obligation 1–3 extension phase of a phase 2 study of Specific Obligation tenofovir disoproxil fumarate for the from the Letter of treatment of HIV-1 infection. (Final Undertaking extension phase virology study report) (EMEA/H/C/419) GS-99-907 Genotypic and phenotypic analyses of Viread Module 5.3.5.1 Original MAA May 2001 Part IV Volume HIV-1 from patients in a phase 3 study (EMEA/H/C/419) 19 of tenofovir disoproxil fumarate for the treatment of HIV-1 infection. (Interim 24 week virology study report) GS-99-907 A phase 3, double-blind, randomized, Viread Module 5.3.5.1 Original MAA May 2001 Part IV Volumes placebo-controlled multicenter study of (EMEA/H/C/419) 15–18 the safety and efficacy of tenofovir disoproxil fumarate administered in combination with other antiretroviral agents for the treatment of HIV 1 infected patients. (Interim 24 week clinical study report)

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-99-907 A phase 3, double-blind, randomized, Viread Module 5.3.5.1 Submitted in January Specific Volumes placebo-controlled multicenter study of response to 2002 Obligation 1–3 the safety and efficacy of tenofovir Specific Obligation disoproxil fumarate administered in from the Letter of combination with other antiretroviral Undertaking agents for the treatment of HIV 1 (EMEA/H/C/419) infected patients. (Final 48 week clinical study report) GS-99-907-PK A phase 3, double-blind, randomized, Viread Module 5.3.5.1 Submitted in March 2002 Specific Volumes placebo-controlled multicenter study of response to Obligation 1–3 the safety and efficacy of tenofovir Specific Obligation disoproxil fumarate administered in from the Letter of combination with other antiretroviral Undertaking agents for the treatment of HIV-1 (EMEA/H/C/419) infected patients. (Final 48 week clinical study report) GS-99-907 Genotypic and phenotypic analyses of Viread Module 5.3.5.1 Submitted in April 2002 Specific Volume 1 HIV-1 from patients in a phase 3 study response to Obligation of tenofovir disoproxil fumarate for the Specific Obligation treatment of HIV-1 infection. from the Letter of (48 week virology study report) Undertaking (EMEA/H/C/419)

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-02-1008 A phase II, open-label, multicentre, Viread Available upon Submitted in PSUR June 2006 PSUR Volume 2 (RAVE) randomised, comparator study of request (01 November substitution with tenofovir or abacavir 2005 to 30 April in HIV̂1 infected individuals, with a 2006) viral load < 50 copies/mL, receiving a (EMEA/H/C/419) thymidine analogue (zidovudine or stavudine) as part of their highly active antiretroviral therapy (HAART) GS-99-903 A phase 3, randomized, double-blind, Viread Module 5.3.5.1 Provided in Type II August 2002 Part IV Volumes multicenter study of the treatment of variation 1–4 antiretroviral-naive, HIV 1 infected (EMEA/H/C/ patients comparing tenofovir disoproxil 419/II/08 fumarate administered in combination with lamivudine and efavirenz versus stavudine, lamivudine, and efavirenz. (48 week clinical study report) GS-99-903 A phase 3, randomized, double-blind, Viread Module 5.3.5.1 Provided in Type II May 2004 Module 5 Volumes multicenter study of the treatment of variation 1-6 antiretroviral-naive, HIV 1 infected (EMEA/H/C/419/ patients comparing tenofovir disoproxil II/039) fumarate administered in combination with lamivudine and efavirenz versus stavudine, lamivudine, and efavirenz. (144 week clinical study report)

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-99-903 (240- A open-label extension 96-week Viread Available upon Submitted in August 2006 Follow-up Volume 1 week clinical study interim study report); A phase 3, request response to a measure report) randomized, double-blind, multicenter Follow-Up study of the treatment of antiretroviral- Measure naive, HIV 1 infected patients (EMEA/H/C/419) comparing tenofovir disoproxil fumarate administered in combination with lamivudine and efavirenz versus stavudine, lamivudine, and efavirenz. GS-99-903 (Open- A Phase 3, randomized, double-blind, Viread Available upon Submitted in December Follow-up Volume 1 label extension multicenter study of the treatment of request response to a 2008 measure phase) antiretroviral-naïve, HIV1 infected Follow-Up patients comparing tenofovir disoproxil Measure fumarate administered in combination (EMEA/H/C/419) with lamivudine and efavirenz versus stavudine, lamivudine, and efavirenz. (192-week extension phase). GS-01-934 White paper including 8-16 week Truvada Available upon Original MAA March 2004 Module 5 Volume efficacy and safety data in a Phase 3, request (EMEA/H/C/594) 153 randomized, open label, multicenter study of the treatment of antiretroviral- naïve, HIV-1 infected patients comparing tenofovir disoproxil fumarate and emtricitabine in combination with efavirenz with lamivudine and zidovudine in combination with efavirenz.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-01-934 (Interim 24-week data); A Phase 3, Truvada Available upon Submitted in September Response to Volume 4 randomized, open-label, multicenter request Response to 2004 Questions study of the treatment of antiretroviral- CHMP D120 List naive, HIV-1-infected subjects of Questions comparing tenofovir disoproxil (EMEA/H/C/594) fumarate and emtricitabine in combination with efavirenz versus combivir (lamivudine/zidovudine) and efavirenz. GS-01-934 A Phase 3, Randomized, Open-Label, Truvada Module 5.3.5.1 Provided in Type II June 2005 Type II Volumes Multicenter Study of the Treatment of variation Variation 1-8 Antiretroviral-Naive, HIV-1 Infected (EMEA/H/C/594/ Subjects Comparing Tenofovir II/03) Disoproxil Fumarate and Emtricitabine in Combination with Efavirenz Versus Combivir (lamivudine/zidovudine) and Efavirenz (48 Weeks) GS-01-934 A Phase 3, Randomized, Open-Label, Truvada Available upon Original MAA October Module 5 Volumes Multicenter Study of the Treatment of request (EMEA/H/C/797) 2006 1012 Antiretroviral-Naive, HIV-1 Infected Subjects Comparing Tenofovir Disoproxil Fumarate and Emtricitabine in Combination with Efavirenz Versus Combivir (lamivudine/zidovudine) and Efavirenz (96-week data).

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-01-934 A Phase 3, Randomized, Open-Label, Truvada Module 5.3.5.1 Included in August 2007 Response to Volumes Multicenter Study of the Treatment of Response to questions 212 Antiretroviral-Naive, HIV-1 Infected CHMP D180 List Subjects Comparing Tenofovir of Outstanding Disoproxil Fumarate and Emtricitabine Issues in Combination with Efavirenz Versus (EMEA/H/C/594) Combivir (lamivudine/zidovudine) and Efavirenz (144-week data). GS-01-934 (168-week clinical efficacy and safety Atripla Available upon Included in July 2007 Response to Volume 1 summary); A phase 3, randomized, request Response to questions open-label, multicenter study of the CHMP D180 List treatment of antiretroviral-naive, HIV-1 of Outstanding infected subjects comparing tenofovir Issues disoproxil fumarate and emtricitabine (EMEA/H/C/797) in combination with efavirenz versus combivir (lamivudine/zidovudine) and efavirenz. GS-01-934 (240/288 week data); A phase 3, Atripla Available upon Submitted in January Follow-up Volume 1 randomized, open-label, multicenter request Response to 2010 Measure study of the treatment of antiretroviral- Follow-Up naïve, HIV-1 infected subjects Measure comparing tenofovir disoproxil (EMEA/H/C/797) fumarate and emtricitabine in combination with efavirenz versus combivir (lamivudine/zidovudine) and efavirenz,

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume M02-418 (48 week interim report); A Viread Module 5.3.5.1 Submitted in Type December Type II Volumes (GS-02-982) randomized, open-label study of 800 II Variation 2004 Variation 1–7 mg lopinavir/200 mg ritonavir QD in (EMEA/H/C/419/ combination with tenofovir DF and II/29) emtricitabine vs. 400 mg lopinavir/100 mg ritonavir BID in combination with tenofovir DF and emtricitabine in HIV- infected antiretroviral-naïve patients M02-418 (96 week report); A randomized, open- Viread Module 5.3.5.1 Submitted in PSUR December PSUR Volume 1 (GS-02-982) label study of 800 mg lopinavir/200 mg (01 May 2005 to 2005 ritonavir QD in combination with 30 October 2005) tenofovir DF and emtricitabine vs. 400 mg lopinavir/100 mg ritonavir BID in combination with tenofovir DF and emtricitabine in HIV-infected antiretroviral-naïve patients

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-MC-164-0111 A Phase 3, Open-label, Multi-center, Truvada Module 5.3.5.1 Submitted with June 2009 PSUR Volume 1 Randomized, 48 Week Study to PSUR Compare the Effect on Prevention and (03 April 2008 to Resolution of Treatment Related 02 April 2009) Adverse Events of a Simplified, Once Daily Regimen of a Fixed Dose Combination Tablet of Emtricitabine and Tenofovir DF Versus Twice Daily Co-formulated Zidovudine and Lamivudine (Combivir®) or Zidovudine and Lamivudine, in Virologically Suppressed, HIV Infected Patients Taking Efavirenz. GS-ES-164-0154 Pilot phase IV, multicenter, Truvada Module 5.3.5.1 Previously not randomized, open-label and controlled submitted. study to assess the evolution of peripheral body fat distribution after switching from AZT containing backbone to Truvada in HIV-1-infected patients on HAART (RECOMB Study)

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-202 Final Report; An open-label study to Emtriva Available upon Submitted with May 2010 PSUR Volume 1 evaluate the safety, tolerance, antiviral request PSUR activity and pharmacokinetics of (03 April 2001 to emtricitabine in combination with 02 April 2010) efavirenz and didanosine in a once- daily regimen in HIV-infected antiretroviral therapy naïve or very limited antiretroviral exposed pediatric subjects. Analysis Report of Age Group 1. FTC-202 Final Report; An open-label study to Emtriva Available upon Submitted with May 2010 PSUR Volume 1 evaluate the safety, tolerance, antiviral request PSUR activity and pharmacokinetics of (03 April 2009 to emtricitabine in combination with 02 April 2010) efavirenz and didanosine in a once- daily regimen in HIV-infected antiretroviral therapy naïve or very limited antiretroviral exposed pediatric subjects. Statistical Report of the Final Analysis Report Groups 2 & 3 (Ages 3- 12 and 13-21 years). FTC-203 An Open-Label Study of a Once Daily Truvada Available upon Provided in a Type November Type II Volume 1 Dose of Emtricitabine in Combination request II variation 2005 Variation with Other Antiretroviral Agents in (EMEA/H/C/594/ HIV-Infected Pediatric Subjects II/013)

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume FTC-203 (Updated 24 week report); An open- Truvada Available upon Original MAA March 2004 Module 5 Volume label study of a once daily dose of request (EMEA/H/C/594) 162-164 emtricitabine in combination with other antiretroviral agents in HIV-infected paediatrics. FTC-203 (48 week analysis); An open-label Emtriva Available upon Provided in a Type April 2005 Type II Volumes study of a once daily dose of request II variation Variation 1-7 emtricitabine in combination with other EMEA/H/C/553/ antiretroviral agents in HIV-infected II/23 pediatric subjects. FTC-211 An Open-label Study of a Once-daily Truvada Available upon Provided in a Type November Type II Volume 1 Dose of Emtricitabine in Combination request II variation 2005 Variation with Other Antiretroviral Agents in (EMEA/H/C/594/ HIV-infected Pediatric Subjects II/013) FTC-350 An open-label, extension study of Truvada Available upon Original MAA March 2004 Module 5 Volume emtricitabine (Emtriva/FTC) in patients request (EMEA/H/C/594) 155 who are a virologic success and currently enrolled in FTC-303. FTC-201 Pilot study evaluating the efficacy and Truvada Available upon Original MAA March 2004 Module 5 Volume tolerance of the combination FTC + ddI request (EMEA/H/C/594) 154 + Efavirenz administered once daily in the treatment of HIV-1 infected antiretroviral naïve patients (ANRS 091 - Montana Study).

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume ACTG 5015 A Phase II exploratory study examining Truvada Available upon Original MAA March 2004 Module 5 Volume immunologic and virologic indices in request (EMEA/H/C/594) 155 two age-differentiated cohorts of HIV- infected subjects to explore the basis of accelerated HIV-disease progression associated with aging. GS-00-917 An open-label study to assess the anti- Truvada Available upon Submitted in March 2006 Specific Volume 1 HIV-1 activity of tenofovir disoproxil request response to Obligation fumarate (TDF) in antiretroviral-naive Specific Obligation patients who are chronically infected from the revised with HIV-1. Letter of Undertaking (EMEA/H/C/594) GS-02-1015 (“3 O Open-label multicenter study to assess Viread Available upon Submitted in PSUR December Module 5 Volume 1 D & opiate the efficacy, the tolerability and the request (01 November 2007 substitution”) adherence of an once daily (QD) taken 2006 to 31 October antiretroviral therapy (ART) containing 2007) the NtRTI tenofovir DF 300 mg in combination with the best suitable once a day regimen being 1 NRTI plus 1 PI or 1 NRTI plus 1 NNRTI in HIV-1- infected IVDU-patients with opiate substitution being either antiretroviral- naive or with suppressed viral load and without a history of virological failure

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-99-908 An open-label, multicenter, Truvada Available upon Original MAA March 2004 Module 5 Volumes (Interim clinical compassionate access study of the request (EMEA/H/C/594) 136-137 study report) safety of tenofovir disoproxil fumarate administered in combination with other antiretroviral agents for the treatment of HIV-1 infected patients. GS-99-908 (Final An open-label, multicenter, Truvada Available upon Original MAA March 2004 Module 5 Volumes clinical study compassionate access study of the request (EMEA/H/C/594) 138-139 report) safety of tenofovir disoproxil fumarate administered in combination with other antiretroviral agents for the treatment of HIV-1 infected patients. GS-99-910 A phase 3 open-label multicenter study Viread Module 5.3.5.2 Submitted in August 2003 Specific Volumes of the safety of tenofovir disoproxil response to Obligation 1–3 fumarate administered in combination Specific Obligation with other antiretroviral agents for the from the revised treatment of HIV-1 infected patients. Letter of Undertaking (EMEA/H/C/ 419) ACTG A5127 ACTG 5127 Executive Summary: A Viread Available upon Submitted in May 2005 Follow-up Volume 1 Randomised, Phase II Controlled Trial request response to a Measure Comparing the Efficacy of Adefovir Follow-Up Dipivoxil and Tenofovir Disoproxil Measure Fumarate for the Treatment of Hepatitis (EMEA/H/C/419) B Virus in Subjects who are Co- infected with HIV (Based on preliminary data for CROI 2005).

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume GS-US-164-0107 Combination of Efavirenz and Truvada Module 5.3.5.2 Submitted in September Follow-up Volumes (COMET) Truvada“ (The COMET Study): A response to 2006 measure 1-6 Phase 4 Evaluation of Switching from Follow-Up Twice Daily Zidovudine and Measure Lamivudine (Combivir“) to a (EMEA/H/C/594) Simplified, Once-Daily Regimen of Co-formulated Emtricitabine and Tenofovir Disoproxil Fumarate (Truvada“), in Virologically Suppressed, HIV- Infected Patients Taking Efavirenz GS-DE-164-0106 A Phase 3, prospective, Truvada Module 5.3.5.2 Submitted in June 2007 Follow-Up Volume 1 nonrandomized, single-group, response to Measure open-label, 48-week, pilot study of Follow-Up

treatment switch from a regimen with Measure zidovudine and lamivudine plus a third (EMEA/H/C/594) partner to a once-daily regimen containing the fixed-dose combination of tenofovir DF and emtricitabine in combination with a third once-daily partner in HIV infected subjects. GS-US-164-0115 A Phase 4, Prospective, Open-Label, Truvada Module 5.3.5.2 Submitted with June 2009 PSUR Volume 1 Multicenter Study of the Safety, PSUR Efficacy, and Adherence in (03 April 2008 to HIV-Infected, Antiretroviral-Naïve 02 April 2000) Subjects Treated with Simple Once-Daily Regimen.

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Cross-reference to Study Report Dossier Clinical Study Location within EU Procedure (& Date Number/ Number Study Title Product FDC MAA number) Submitted Type Volume C0840-00011 Adefovir and tenofovir susceptibilities Truvada Available upon Original MAA March 2004 Module 5 Volume of HIV-1 after 24-48 weeks of adefovir request (EMEA/H/C/594) 150 dipivoxil therapy: genotypic and phenotypic analyses of study GS-96-408.

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SECTION 2.5 – CLINICAL OVERVIEW- NOTE TO REVIEWER

The section 2.5 clinical overview document content submitted for Eviplera and Edurant are the same apart from the following differences as outlined here:

 Descriptions of changes proposed in the Eviplera product annexes are aligned with the Eviplera proposed amendments. These descriptions differ slightly from Edurant.

 The following additions to the Eviplera clinical overview were made. These changes were made to further explain the adverse event of decreased lymphocytes that was seen in this study (based on the data in the clinical study report). Additions are shown in underline and deletions in strikethrough from Edurant overview:

5 Overview of Safety

5.1 TMC278IFD1003

No deaths, serious adverse events (SAEs), or Grade 4 adverse events (AEs) were reported during this study. Grade 3 AEs were reported in 6 (30%) subjects during the whole study. The most frequent Grade 3 AEs (reported in >1 subject in any treatment phase) were lymphopenia (2 [18.2%] subjects during treatment with RPV 25 mg qd + rifabutin 300 mg qd [Treatment C]] and none during Treatments A and B) and myalgia (2 [10.0%] subjects during treatment with RPV 50 mg qd + rifabutin 300 mg qd [Treatment B]).

The only grade 4 laboratory toxicity was grade 4 decreased absolute lymphocyte count, which was reported in 4 (20.0%) subjects during Treatment B, and in 1 (9.1%) subject during Treatment C compared to none during Treatment A. DecreasedTime to onset of the Grade 4 events of decreased lymphocytes ranged from 11 to 14 days following initiation of Treatment B or 18 days following initiation of Treatment C. In 4 subjects (3 on Treatment B, 1 on Treatment C), Grade 4 decreased lymphocyte countcounts had normalized within 6 to 8 days (coinciding with 6 to 8 days after last dose of study drug). In one further subject on Treatment B, lymphocyte counts had improved to below normal 7 days after the Grade 4 event (while still on Treatment B) and normalized at the next assessment (while no longer on study drug due to finishing the treatment cycle). No concomitant treatment was administered to treat the decreased lymphocyte counts in these subjects. Leukopenia is a knownvery common (=> 10%) adverse effect for Rifabutin rifabutin, while lymphopenia and white blood cell decreased are uncommon (=> 0.1% to < 1%) adverse effects for rifabutin {24950}. The rifabutin SmPC recommends monitoring of white blood cell and platelet counts periodically during treatment in Section 4.4, Special warnings and precautions for use {24950}. SECTION 2.5 CLINICAL OVERVIEW

SECTION 2.5 – CLINICAL OVERVIEW

EMTRICITABINE/RILPIVIRINE/TENOFOVIR DISOPROXIL FUMARATE SINGLE-TABLET REGIMEN

Gilead Sciences International Ltd

26 JUNE 2013

CONFIDENTIAL AND PROPRIETARY INFORMATION Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate 2.5 Clinical Overview Addendum Final

TABLE OF CONTENTS

SECTION 2.5 – CLINICAL OVERVIEW ...... 1 TABLE OF CONTENTS ...... 2 LIST OF IN-TEXT TABLES...... 2 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ...... 3 INTRODUCTION...... 4 1. PRODUCT DEVELOPMENT RATIONALE...... 5 2. OVERVIEW OF BIOPHARMACEUTICS...... 6 3. OVERVIEW OF CLINICAL PHARMACOLOGY ...... 7 3.1. Pharmacology/Virology...... 7 3.2. Clinical Pharmacodynamics...... 7 3.3. Clinical Pharmacokinetics...... 7 3.4. Potential for Drug Interactions...... 7 3.4.1. Rilpivirine ...... 7 3.4.1.1. Potential for RPV to Affect Other Drugs...... 8 3.4.1.2. Potential for Other Drugs to Affect RPV...... 8 4. OVERVIEW OF EFFICACY...... 11 5. OVERVIEW OF SAFETY ...... 12 6. BENEFITS AND RISKS CONCLUSIONS ...... 14 7. REFERENCES ...... 16

LIST OF IN-TEXT TABLES

Table 3-1. Coadministration Recommendations Based on Drug-Drug Interaction Trials or Predicted Interaction (Rilpivirine)...... 10

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS

AE adverse event ARV antiretroviral CI confidence interval

Cmax maximum plasma concentration

Cmin minimum plasma concentration CYP450 cytochrome P450 enzyme(s) ECG electrocardiogram HIV(-1) human immunodeficiency virus (-type 1) MAH Marketing Authorization Holder QD once daily RPV rilpivirine RNA ribonucleic acid SAE serious adverse event TB tuberculosis

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INTRODUCTION

This document is an addendum to the initial Clinical Overview for Eviplera (0000/Module 2.5 - Clinical Overview [18 August 2010]). It summarizes the data from a completed Phase 1 clinical pharmacology study (TMC278IFD1003) in healthy subjects, investigating the drug-drug interaction of rilpivirine (RPV) 25 mg once daily (qd) with rifabutin.

Tuberculosis (TB) coinfection is highly prevalent in the population infected with the human immunodeficiency virus (HIV) and disease management may require therapy for HIV infection as well as TB. The rifamycins, rifampin and rifapentine, in combination with other drugs, are part of preferred regimens for tuberculosis therapy {24933}. Drug-drug interactions between rifamycins and antiretrovirals (ARVs) are, however, widespread, and it can be difficult to design satisfactory concurrent regimens against TB and HIV {24951}. Rifabutin (Mycobutin ®) is an antimycobacterial agent, structurally similar to rifampicin, with high in vitro activity against many strains of Mycobacterium tuberculosis. {24950}. Rifabutin is a less potent inducer of cytochrome P450 (CYP)3A enzyme activity than rifampin, and therefore drug-drug interactions can be reduced as compared to those with rifampin. Rifabutin is sometimes used in lieu of rifampin for treatment of TB, e.g., in cases where drug-drug interactions preclude the use of rifampin {24931}.

A previously conducted study (TMC278-C125) with RPV 150 mg qd and rifabutin 300 mg qd in healthy subjects, established the extent of the drug-drug interaction between RPV (a CYP3A substrate) and rifabutin. Since the data from this study showed a substantial reduction in RPV exposure, currently, coadministration of RPV (at the recommended dose of 25 mg qd) and rifabutin is contraindicated.

The current study (TMC278IFD1003) was conducted to further investigate the interaction profile between rifabutin and RPV 25 mg qd and ways to overcome the interaction. It aimed to evaluate different dosing regimens for RPV in combination with rifabutin in order to provide guidance on dosing recommendations for the concurrent administration of RPV and rifabutin in HIV-1 infected subjects.

The data described in this document support an update of the prescribing information for Eviplera to provide guidance for the coadministration of Eviplera with rifabutin, i.e., when Eviplera is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration of rifabutin coadministration.

Titles of all main sections of the Clinical Overview, with an indication of whether the section required an update, are included in this addendum. Throughout the Clinical Overview, “TMC278” was changed to “RPV”. This change has not been consistently indicated in this addendum.

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1. PRODUCT DEVELOPMENT RATIONALE

No update is required for this section. Refer to the initial Clinical Overview for details (0000/Module 2.5/Clinical Overview - Section 1 [18 August 2010]),

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2. OVERVIEW OF BIOPHARMACEUTICS

No update is required for this section. Refer to the initial Clinical Overview for details (0000/Module 2.5/Clinical Overview - Section 2 [18 Aug 2010]).

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3. OVERVIEW OF CLINICAL PHARMACOLOGY

Refer to the initial Clinical Overview for details (0000/Module 2.5/Clinical Overview - Section 3 [18 August 2010]),

This section has been updated with the following additional information:

3.1. Pharmacology/Virology

No update is required for this section.

3.2. Clinical Pharmacodynamics

No update is required for this section.

3.3. Clinical Pharmacokinetics

No update is required for this section.

3.4. Potential for Drug Interactions

3.4.1. Rilpivirine

TMC278IFD1003

Study Design

This was a Phase 1, open-label study in 20 healthy subjects, to explore the pharmacokinetics of different dosing regimens of RPV in combination with rifabutin, at steady-state.

All subjects were scheduled to receive 3 different treatments (Treatments A, B, and C):

 Treatment A: RPV 25 mg qd administered on Days 1 to 11;

 Treatment B: RPV 50 mg qd administered on Days 1 to 11 + rifabutin 300 mg qd administered on Days 1 to 17;

 Treatment C: RPV 25 mg qd administered on Days 1 to 11 + rifabutin 300 mg qd administered on Days 1 to 17 (this RPV regimen was determined based on an interim pharmacokinetic analysis of Treatments A and B).

Further details on the design of this study are available in the Clinical Study Report (Module 5.3.3.4/TMC278IFD1003-CSR - Section 3.1) and the addendum to the Summary of Clinical Pharmacology Studies (Module 2.7.2/Summary of Clinical Pharmacology Studies Addendum - Section 2.2.8).

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Results

While the RPV 25 mg qd exposure was significantly reduced by rifabutin (a potent CYP3A enzyme activity inducer) doubling the RPV dose (50 mg qd) was able to overcome this, relative to RPV 25 mg qd alone.

For RPV 25 mg qd in the presence of rifabutin, the minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the plasma-concentration time curve from time of intake until 24 hours after dosing (AUC24h) of RPV were 48%, 31%, and 42% lower, respectively, compared to RPV alone at the same dose level. Similar results were obtained in a previous study (TMC278-C125) with RPV at 150 mg qd.

For RPV 50 mg qd in the presence of rifabutin, Cmin was similar (90% confidence interval [CI] within 80% to 125%) compared to RPV 25 mg qd alone, while Cmax and AUC24h were 43% and 16% higher, respectively, compared to RPV 25 mg qd alone, with the upper limit of the 90% CI just above 125%. These increases in Cmax and AUC24h are not considered clinically relevant.

Further details on the pharmacokinetic results of this study are available in the Clinical Study Report (Module 5.3.3.4/TMC278IFD1003-CSR - Section 5) and the addendum to the Summary of Clinical Pharmacology Studies (Module 2.7.2/Summary of Clinical Pharmacology Studies Addendum - Section 2.2.8).

Conclusion

In conclusion, the pharmacokinetic data (Module 2.7.2/Summary of Clinical Pharmacology Studies Addendum- Section 2.2.8) indicate that, throughout coadministration with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration of rifabutin coadministration.

3.4.1.1. Potential for RPV to Affect Other Drugs

This section has been updated with the following additional information:

Rifabutin The pharmacokinetics of rifabutin were not evaluated in the current study. However, it has been previously shown (in study TMC278-C125) that the pharmacokinetics of rifabutin were not affected by coadministration with RPV 150 mg qd (0000/Module 2.7.2/Summary of Clinical Pharmacology Studies - Section 2.2.8.7 [19 Aug 2010]). No different results for rifabutin pharmacokinetics are anticipated with lower RPV doses.

3.4.1.2. Potential for Other Drugs to Affect RPV

This section has been updated with additions to the existing text indicated in bold and deletions in strikethrough:

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In general, the exposure to RPV can be affected by modulators of CYP3A enzyme activity and by drugs that increase the gastric pH.

The primary metabolism of RPV is mainly catalyzed by CYP3A enzymes. Therefore, coadministration of RPV and drugs that induce CYP3A could decrease RPV plasma concentrations, which could potentially reduce the therapeutic effect of RPV.

This decrease in exposure was indeed shown in vivo by the results of drug-drug interaction studies with rifampin and rifabutin, which both significantly decreased the exposure to RPV. Based on this, RPV should not be used in combination with inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, St John’s wort, systemic dexamethasone, carbamazepine, oxcarbazepine, phenobarbital, phenytoin). For rifabutin, an alternative dosing regimen has been established, i.e., when Eviplera is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration of rifabutin coadministration.

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Table 3-1. Coadministration Recommendations Based on Drug-Drug Interaction Trials or Predicted Interaction (Rilpivirine)

Coadministration without Dose Coadministration with specific Coadministration Not Adjustment instructions Recommended  N(t)RTIs, other than ddI  ddI (which should be  inducers of CYP3A (e.g. TDF, ABC, administered on an empty (e.g., rifampin, rifabutin, emtricitabine, 3TC, stomach) should be administered rifapentine, St John’s wort, stavudine, AZT) separated in time from TMC278 systemic dexamethasone,  boosted PIs LPV/rtv and RPV (which should be carbamazepine, DRV/rtv1 administered with a meal). oxcarbazepine, phenobarbital, phenytoin).  raltegravir, maraviroc  when coadministering with methadone, dose adjustment is  proton pump inhibitors  ribavirin not needed when initiating (e.g. omeprazole,  azole antifungal agents treatment with TMC278 RPV but lansoprazole, rabeprazole, (including ketoconazole) clinical monitoring for methadone pantoprazole, esomeprazole)  atorvastatin withdrawal symptoms is recommended. Methadone  estrogen-and/or maintenance therapy may need to progesterone-based be adjusted in some patients. contraceptives  H2-antagonists (e.g. famotidine)  paracetamol or antacids, can be coadministered if separated in time.  clarithromycin, erythromycin, and troleandomycin may cause an increase in the plasma concentrations of RPV. Where possible, alternatives such as azithromycin should be considered.  When Eviplera is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration of rifabutin coadministration. 1 The combination of RPV with other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) or unboosted PIs (atazanavir, indinavir, nelfinavir) has not been studied; coadministration may cause an increase in the plasma concentrations of RPV.

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4. OVERVIEW OF EFFICACY

No update is required for this section. Refer to the initial Clinical Overview for details (0000/Module 2.5/Clinical Overview - Section 4 [18 August 2010]),

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5. OVERVIEW OF SAFETY

This section has been updated with the following additional information:

5.1 TMC278IFD1003

For detailed information on the safety data described in this section, refer to the Clinical Study Report (Module 5.3.3.4/TMC278IFD1003-CSR - Section 6).

No deaths, serious adverse events (SAEs), or Grade 4 adverse events (AEs) were reported during this study. Grade 3 AEs were reported in 6 (30%) subjects during the whole study. The most frequent Grade 3 AEs (reported in >1 subject in any treatment phase) were lymphopenia (2 [18.2%] subjects during treatment with RPV 25 mg qd + rifabutin 300 mg qd [Treatment C] and none during Treatments A and B) and myalgia (2 [10.0%] subjects during treatment with RPV 50 mg qd + rifabutin 300 mg qd [Treatment B]).

Eight (40.0%) subjects stopped RPV as well as rifabutin intake and discontinued the study due to AEs. The most frequent AEs leading to discontinuation (reported in >1 subject in any treatment phase) were headache, myalgia, pyrexia, and arthralgia. None of these AEs occurred during treatment with RPV 25 mg qd alone (Treatment A). Headache was reported in 3 (15.0%) and 1 (9.1%) subjects during Treatment B and Treatment C, respectively, myalgia in 3 (15.0%) and 1 (9.1%) subjects, respectively, and pyrexia in 2 (10.0%) and 1 (9.1%) subjects, respectively.

The most frequently reported AEs (reported in >3 subjects in any treatment phase) were headache, myalgia, pyrexia, diarrhea, influenza-like illness, pruritus, and dizziness. None of these AEs occurred in Treatment A, except for headache in 1 (5.6%) subject. Headache was reported in 9 (45.0%) and 2 (18.2%) subjects during Treatment B and Treatment C, respectively, myalgia in 6 (30.0%) and 5 (45.5%) subjects, respectively, and pyrexia in 5 (25.0%) and 1 (9.1%) subjects, respectively. Diarrhea was reported in in 4 (20.0%) and 3 (27.3%) subjects, respectively, influenza-like illness in 5 (25.0%) and 1 (9.1%) subjects, pruritus in 4 (20.0%) and 1 (9.1%) subjects, and dizziness in 4 (20.0%) and 1 (9.1%) subjects, respectively.

Most of these AEs reported during the coadministration phase are AEs known to have been reported with RPV in other Phase 1 studies (headache, dizziness, pruritus) and/or rifabutin (headache, myalgia, pyrexia, diarrhea, flu-like syndrome). Most of these AEs were also reported during the coadministration phase of a previous study (TMC278-C125) with rifabutin and 150 mg qd RPV, with similar or lower frequencies.

The only grade 4 laboratory toxicity was grade 4 decreased absolute lymphocyte count, which was reported in 4 (20.0%) subjects during Treatment B, and in 1 (9.1%) subject during Treatment C compared to none during Treatment A. Time to onset of the Grade 4 events of decreased lymphocytes ranged from 11 to 14 days following initiation of Treatment B or 18 days following initiation of Treatment C. In 4 subjects (3 on Treatment B, 1 on Treatment C), Grade 4 decreased lymphocyte counts had normalized within 6 to 8 days (coinciding with 6

CONFIDENTIAL Page 12 26 June 2013 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate 2.5 Clinical Overview Addendum Final to 8 days after last dose of study drug). In one further subject on Treatment B, lymphocyte counts had improved to below normal 7 days after the Grade 4 event (while still on Treatment B) and normalized at the next assessment (while no longer on study drug due to finishing the treatment cycle). No concomitant treatment was administered to treat the decreased lymphocyte counts in these subjects. Leukopenia is a very common (=> 10%) adverse effect for rifabutin, while lymphopenia and white blood cell decreased are uncommon (=> 0.1% to < 1%) adverse effects for rifabutin {24950}. The rifabutin SmPC recommends monitoring of white blood cell and platelet counts periodically during treatment in Section 4.4, Special warnings and precautions for use {24950}.

Abnormalities in ECG parameters were scarce and no AEs related to vital signs parameters were reported.

The safety and tolerability of RPV 25 mg qd administered alone for 11 days was better than that of RPV 25 or 50 mg qd administered for 11 days together with rifabutin 300 mg qd for 17 days. There was a higher frequency and grading of AEs and laboratory abnormalities as well as a higher number of dropouts when RPV was coadministered with rifabutin, as compared to RPV alone. However, no new safety issues were identified for RPV alone or in combination with rifabutin, taking into account the known safety and tolerability profiles of both RPV and rifabutin.

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6. BENEFITS AND RISKS CONCLUSIONS

This section has been updated with the following additional information:

No new safety issues were identified for RPV alone or in combination with rifabutin, taking into account the known safety and tolerability profiles of both RPV and rifabutin.

The pharmacokinetic findings of this drug-drug interaction study with RPV and rifabutin indicate that when Eviplera is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration of rifabutin coadministration. The product information is proposed to be updated with the new pharmacokinetic data of this drug-drug interaction study in order to provide appropriate guidance to prescribers regarding the coadministration of Eviplera and rifabutin.

The Marketing Authorization Holder (MAH), therefore, proposes to update the Summary of Product Characteristics for Eviplera as follows:

 The Posology section is updated to reflect the appropriate dose for Eviplera when coadministered with rifabutin i.e., when Eviplera is coadministered with Rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration of rifabutin coadministration.

Rifabutin is removed from the Contraindications section.

 The concomitant use not recommended section is revised to allow Eviplera to be administered concomitantly with RPV in the case of dose adjustment due to rifabutin.

 Table Interactions and dose recommendations with other medicinal products is updated with pharmacokinetic data for RPV and rifabutin obtained in the drug-drug interaction study TMC278IFD1003.

In the Package leaflet, the following changes are proposed:

 Rifabutin is deleted from the list of medicines that should not be taken in combination with Eviplera.

 Rifabutin is added to the list of medicines that may influence the effects of Eviplera or other medicines, when taken together with Eviplera.

 Information that your doctor may need to give you an additional dose of rilpivirine to treat your HIV infection is added.

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Guidance for Clinical Use of FTC/RPV/TDF Drug Interactions

A previous study (TMC278-C125) with RPV 150 mg qd (a CYP3A substrate) and rifabutin (a CYP3A inducer) showed a substantial reduction in RPV exposure when combined. Based on these earlier results, the coadministration of Eviplera (containing 25 mg RPV) qd and rifabutin was contraindicated.

The current study (TMC278IFD1003) was conducted to further establish the interaction profile between rifabutin and RPV 25 mg qd and ways to overcome the interaction. While the RPV 25 mg qd exposure was significantly reduced by rifabutin, doubling the RPV dose (50 mg qd) was able to overcome this relative to RPV 25 mg qd alone. Therefore when Eviplera is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration of rifabutin coadministration.

Exposure Response Relationship

This section has been updated with additions to the existing text indicated in bold and deletions in strikethrough:

Coadministration of RPV with CYP3A inducers may cause significant decreases in RPV plasma concentrations, as was shown in drug-drug interaction studies with rifampin and rifabutin, which decreased the mean exposure to RPV by 80% and 42%, respectively. Therefore, RPV should not be coadministered with CYP3A inducers (e.g. rifampin, rifabutin, rifapentin, phenytoin, carbamazepine, oxcarbamazepine, phenobarbital, systemic dexamethasone and products containing St John’s wort). For rifabutin, an alternative dosing regimen has been established, i.e., when Eviplera is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration of rifabutin coadministration.

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7. REFERENCES

24931 Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000;49 (RR-6):1-51.

24933 Norton BL, Holland DP. Current management options for latent tuberculosis: a review. Infection and drug resistance 2012;5:163-73.

24950 Mycobutin (Rifabutin) Capsule (150 mg) for oral administration. Summary of Product Characteristics (United Kingdom). Pfizer, March 2012.

24951 Walubo A. The role of cytochrome P450 in antiretroviral drug interactions. Expert Opin Drug Metab Toxicol 2007;3 (4):583-98.

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