Non-Nucleoside Reverse Transcriptase

Utah Medicaid Pharmacy and Therapeutics Committee

Single-Ingredient Antivirals for the Treatment of HIV-1 March 2017

Integrase Strand Transfer Inhibitors Dolutegravir (Tivicay®) Raltegravir (Isentress®)

Non-Nucleoside Reverse Transcriptase Inhibitors Delavirdine (Rescriptor®) Efavirenz (Sustiva®) Etravirine (Intelence®) Nevirapine (Viramune ®, Viramune XR ®) Rilpivirine (Edurant®)

Entry Inhibitors Enfuvirtide (Fuzeon®) Maraviroc (Selzentry®)

Review prepared by: Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrich, B.Pharm., Pharm.D., Clinical Pharmacist Elena Martinez Alonso, B.Pharm., Medical Writer Michelle Fiander, MA, MLIS, Systematic Review/Evidence Synthesis Scientist

Table of Contents

EXECUTIVE SUMMARY 3 INTRODUCTION 6 Table 1. Single-Ingredient INSTI, NNRTI, and EI Products FDA-Approved for the Treatment of HIV-1 7 DISEASE OVERVIEW 10 Table 2. Guidelines for HIV-1 Management with Antiretroviral Therapy 11 PHARMACOLOGY 14 INTEGRASE STRAND TRANSFER INHIBITORS 14 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS 14 ENTRY INHIBITORS 15 Table 3. Pharmacokinetics of Single-Ingredient INSTI, NNRTI, and EI Products FDA-Approved for the Treatment of HIV-1 16 SPECIAL POPULATIONS 19 INTEGRASE STRAND TRANSFER INHIBITORS 19 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS 19 ENTRY INHIBITORS 20 Table 4. Single-Ingredient INSTI, NNRTI, and EI Products: Applications in Special Populations 21 METHODS 25 CLINICAL EFFICACY AND SAFETY— INTEGRASE STRAND TRANSFER INHIBITORS 26 CLINICAL EFFICACY AND SAFETY— NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS 27 CLINICAL EFFICACY AND SAFETY— ENTRY INHIBITORS 30 Table 5. Single-Ingredient INSTI, NNRTI, and EI Products: Common Adverse Effects, Warnings/Precautions, and Safety Comparison 31 SUMMARY 34 APPENDIX A 35 Table 1. FDA-Approved Antiretroviral Agents for the Treatment of HIV-1 35 Table 2. Timing Concerns for Antiretroviral Therapy Initiation 36 APPENDIX B 37 Table 1. MEDLINE & EMBASE Literature Search Strategies for NNRTI Drug Class 37 Table 2. MEDLINE & EMBASE Literature Search Strategies for INSTI and EI Drug Classes 40 APPENDIX C 43 Table 1. Evidence for the Integrase Strand Transfer Inhibitor Drug Class 43 Table 2. Evidence for the Non-Nucleoside Reverse Transcriptase Inhibitor Drug Class 45 REFERENCES 51

2 Executive Summary Introduction: Treatment strategies for human immunodeficiency virus (HIV) must be fortified to maintain pace with the virus’s rapid rate of resistance development. The standard of care for initial therapy is a 3-drug containing regimen, employing agents from at least two different drug classes. Selection of the regimen is guided by pre-treatment resistance testing and carefully tailored to the patient’s comorbidities, co-infections, and concurrent medications. The goals of therapy include preserving and improving the patient’s immunologic function, along with aiming to suppress the plasma HIV load below detectable levels. The rate of newly-diagnosed cases in Utah during 2015 was 4 per 100,000 populations. With regard to children age 13 or younger, nine newly diagnosed cases were reported in Utah between 2005 and 2014. Data from 2013 last cited the prevalence of HIV cases in Utah to be 2,565 persons. This review evaluates the safety and efficacy of the single-active-ingredient containing products based on meta- analyses and randomized controlled trials (RCTs) assessing intra-class comparisons among the integrase strand transfer inhibitors (INSTIs), dolutegravir and elvitegravir; the non-nucleoside reverse transcriptase inhibitors (NNRTIs), delavirdine, efavirenz, etravirine, nevirapine and rilpivirine; and the entry inhibitors (EIs), enfuvirtide and maraviroc, used for the treatment of HIV-1 infection. The single-ingredient elvitegravir product, Vitekta®, was recently removed from the market in February 2017 due to low utilization. Within these drug classes, efavirenz, rilpivirine, dolutegravir, and elvitegravir are also available in complete-regimen combination products. According to the Department of Health and Human Services (DHHS) treatment guideline for HIV-1 infected, treatment-naïve patients, the place in therapy for these three drug classes is as follows: • Integrase Strand Transfer Inhibitors: All INSTIs are recommended as options among preferred initial combination regimens for adults and children. • Non-Nucleoside Reverse Transcriptase Inhibitors: Two of the NNRTIs, efavirenz and rilpivirine, are recommended among alternative-line regimens in adults and adolescents; nevirapine is not recommended in these two populations, however, is a second-line option for certain children. Etravirine is reserved for treatment-experienced patients and delavirdine is no longer recommended among the DHHS guidelines. • Entry Inhibitors: The entry inhibitors are not recommended for initial therapy and are reserved for salvage therapy in treatment-experience patients. A thorough evaluation of virological failure should be carried out for patients experiencing a decline in drug- response. For these patients, an entirely new antiretroviral (ARV) regimen including at least two, preferably three, fully-active agents should be employed as salvage therapy and is guided by the patient’s resistance analysis with expert advice. INSTI Clinical Efficacy & Safety: The efficacy and safety of dolutegravir (DTG) versus raltegravir (RAL) has been compared in two randomized controlled trials (SRING-2 and SAILING), each with different patient populations with respect to ARV-experience. A meta-analysis pooled data from these two trials. In addition, a network meta- analysis indirectly compared these two agents through efavirenz as a common comparator node. In the treatment-naive population, the virological efficacy of DTG was non-inferior to RAL at both 48 and 96 weeks. For the treatment-experienced population, the efficacy of DTG treatment was marginally superior compared to RAL. Although the two meta-analyses only included a small number of trials comparing DTG versus RAL, their findings support the results of the randomized-controlled trials (RCTs), with respect to the experimental population’s ARV-experience. With regard to safety, dolutegravir and raltegravir are comparable with respect to adverse events and discontinuation rates. Commonly reported side effects include diarrhea, upper respiratory tract infection, and

3 headache. In RCTs, rates of discontinuation due to adverse events (AEs) were similar and infrequent in both experimental arms (less than 4%). Reported central nervous system (CNS) adverse events were dizziness, depression, insomnia, and anxiety; the SPRING-2 study found these to be similar between treatment arms, with rates less than 6%. The meta-analyses, reported no difference in serious drug-related AEs or discontinuations due to adverse events at 48 weeks. In the RCTs, comparable, clinically-insignificant lipid effects were observed between the DTG and RAL regimens, suggesting overall that these two agents have a neutral effect on lipids. NNRTI Clinical Efficacy & Safety: Comparing the efficacy of efavirenz (EFV) to nevirapine (NVP), three meta- analyses found that nevirapine demonstrates similar virological success in initial ARV treatment. Meta-analyses found contradictory results with respect to virological failure; one found no difference between EFV and NVP and another found a significant difference in favor of EFV. In addition, two meta-analyses report resistance development to be significantly lower for EFV. One meta-analysis evaluated rash events and found no differences. Two meta-analyses resulted in conflicting outcomes regarding a difference in CNS risk. NVP was found more likely to raise transaminases and cause neutropenia where evaluated in a meta-analysis. Overall, the DHHS guideline recommends EFV in alternative-line options and has reserved recommending NVP-based regimens in adult and adolescents due to its associated risks of fatal hepatotoxicity and hypersensitivity reactions, in addition to having a history of failing to demonstrate non-inferiority with respect to EFV in several RCTs. Nonetheless, both nevirapine and efavirenz have a place in therapy for children according to the DHHS guideline. Comparing the efficacy of efavirenz to rilpivirine (RPV), a meta-analysis found no difference in viral response or change in baseline CD4 count at 48 weeks between EFV and RPV based regimens. A higher virological failure rate in the RPV group was identified. Results from more recent RCTs have demonstrated RPV to be non-inferior to EFV, however, in two subgroups, 1) with a baseline HIV RNA > 100,000 copies/mL and 2) with a baseline CD4 count<200 cells/mL, RPV failed to demonstrate non-inferiority when used as the single-ingredient containing product. Two meta-analyses addressing safety arrived at different conclusions with respect to CNS adverse events comparing EFV to RPV. One showed a lower risk of rash and pooled neurological events with RPV compared to EFV. These differences have also been demonstrated in more recent RCTs than these two meta- analyses, suggesting EFV treatment leads to higher occurrences of both CNS side effects and rash compared to RPV. Overall, randomized-controlled trials were in favor of RPV with respect to changes lipid measures. There were no head-to-head studies meeting inclusion/exclusion criteria that directly compared NVP versus RPV or etravirine and delavirdine versus another NNRTI. Etravirine is indicated for treatment-experienced patients and the DHHS comments that there is insufficient evidence to support its use in treatment-naïve patients. The DHHS guidelines do not recommend delavirdine due to its inferior virological efficacy compared to preferred regimens. The package insert warns of insufficient data comparing delavirdine regimens with currently preferred 3-drug regimens for initial treatment, in addition to mentioning its low performance and durability against 2- drug suboptimal regimens. EI Clinical Efficacy & Safety: There were no head-to-head studies found comparing the efficacy of the two FDA- approved entry inhibitors, maraviroc and enfuvirtide. The prescribing-information product insert highlights that injection-site reactions with enfuvirtide are common, occurring in 98% of patients treated in RCTs leading to the drug’s approval. Furthermore, administration with the needleless Biojector® system may result in neuralgia and/or paresthesia, and hematomas. The most common adverse events reported in the prescribing information for maraviroc are upper respiratory tract infections, cough, pyrexia, rash, dizziness, flatulence, bloating, and gastrointestinal atonic/hypomotility disorders.

4 Summary INSTIs: Of the single-ingredient INSTIs, dolutegravir is dosed once daily and has activity against some HIV strains resistant to raltegravir. Raltegravir is dosed twice daily and is the preferred INSTI during pregnancy. In the treatment-naive population, the virological efficacy of dolutegravir was non-inferior to raltegravir at both 48 and 96 weeks. For the treatment-experienced population, in addition to being non-inferior, DTG treatment resulted in a marginally superior virological-success efficacy compared to the raltegravir arm. With regard to safety, dolutegravir and raltegravir have comparable adverse event and discontinuation rates. All INSTIs are recommended as first-line options among initial ARV combination regimens. They are well-tolerated and have demonstrated durable efficacy and favorable toxicity profiles. NNRTIs: Both efavirenz and rilpivirine are recommended as alternative-line therapies for treatment-naïve adults. Nevirapine is not recommended for adults, however, it is indicated/recommended in some pediatric age groups. Meta-analyses report that NVP and RPV have similar efficacy compared to EFV in terms of virological success in initial HIV treatment. However, NVP has failed to meet non-inferiority in several RCTs; thus, the DHHS guideline reserves recommending it for adults and adolescents. Compared to efavirenz, rilpivirine has shortcomings for the subpopulation with a baseline HIV RNA >100,000 copies/mL or with a baseline CD4 count <200 cells/mL. Recent RCTs suggest RPV results in less rash and CNS toxicity compared to EFV. EFV and NVP rash risks are probably similar, however, NVP has a boxed warning for life-threatening hypersensitivity reactions. Nevirapine is also associated with an increased risk of neutropenia and elevated transaminases compared to efavirenz. No head-to-head intra-class comparison trials were identified for etravirine or delavirdine. Etravirine is indicated for HIV-1-infected treatment-experienced patients with resistance to other NNRTIs, since it has a higher barrier to resistance. There is insufficient evidence to support its use in treatment-naïve patients. The DHHS does not recommend delavirdine for any population since there is insufficient evidence comparing it to the recommended, initial therapies. EIs: No head-to-head trials were identified to directly compare the approved entry inhibitors. The DHHS guidelines reserve recommending the entry inhibitors for initial therapy; however, of the two, maraviroc’s labeling does not restrict its use to treatment-experienced patients as is the case for enfuvirtide. Both entry inhibitors are approved for use in the pediatric population, with maraviroc carrying approval for younger children. Maraviroc is administered orally, whereas enfuvirtide is administered via subcutaneous injection. Maraviroc, unlike enfuvirtide, undergoes metabolism via Cytochrome P450, posing a greater potential for drug interactions.

5 Introduction The present day human immunodeficiency virus type-1 (HIV-1) disease state is a chronic plight, challenged by the emergence of therapy-resistant strains, opportunistic infections, and medication complexities. Incidence in the United States is dominated by the HIV-1 subtype, whereas HIV-2 is most prevalent in West Africa.1 Transmission of HIV can occur through exposure to infected blood, reproductive fluids, and breast milk.2 Once infected, the HIV-1 disease path may vary between individuals. Generally the disease follows a multiphasic progression, where the primary infection event is often followed by acute HIV dissemination syndrome and then enters clinical latency.2 Severe damage to the host’s immune system may progress as virulence of the virus augments through rapid mutations conferring resistance to medications. Without an effective therapeutic regimen, the patient is burdened by constitutional symptoms and illness from opportunistic infections leading to the end-of-life. In order to limit failure from viral resistance, an approach termed “highly active antiretroviral therapy” is implemented, combining three agents from at least two different drug classes— the standard of care in first-line HIV-1 therapy.3 The multidrug regimen is tailored to the patient’s comorbidities and concurrent medications, with the goal of therapy to preserve and improve immunologic function, and ideally suppress the plasma viral ribonucleic acid (RNA) load below detectable levels (HIV RNA< 20 to 75 copies/mL, assay dependent). The precise cut-off used to define virological failure remains an area of debate and study. The guidelines by the Department of Health and Human Services (DHHS) and the AIDS Clinical Trials Group currently define virological failure as an HIV RNA load >200 copies/mL.3 The HIV-antiretroviral drug armada includes the nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors (EIs), integrase strand-transfer inhibitors (INSTIs), and two pharmacokinetic enhancers. Table 1 of Appendix A displays the currently available antiretroviral agents indicated/labeled for the treatment of HIV-1. This review will evaluate the safety and efficacy of the single-active-ingredient containing products among the INSTI, NNRTI, and EI drug classes for the treatment of HIV-1. The single-ingredient elvitegravir product, Vitekta®, was voluntarily removed from the market in February 2017 due to low utilization.4 It remains available in combination products as Genvoya® and Stribild®. Within these three drug classes, efavirenz, rilpivirine, and dolutegravir are also available in complete-regimen combination products. Combination products will be compared in a review separate from this document and presented in April. Table 1 provides a summary of the dosage forms and approved dosing for the single-ingredient products included in this review. The NNRTIs and the EI, enfuvirtide, are neither indicated nor effective for HIV-2 treatment. The INSTIs and the EI, maraviroc, may have activity against HIV-2, however, are not approved by the Federal Drug Administration (FDA) for this indication.3 Treatment of HIV-2 will not be a focus of this review and discussion will be referring to HIV-1 treatment hereinafter.

5-16 Table 1. Single-Ingredient INSTI, NNRTI, and EI Products FDA-Approved for the Treatment of HIV-1 Brand Name/Dosage Forms (generic available if italicized) Indication/Dose Integrase Strand Transfer Inhibitors

No generic available Labeled Indication: Treatment of HIV-1 in combination ARV therapy for treatment-naïve and experienced adults and children Dolutegravir Tivicay®: Adult Dose: DTG • 10mg tablet • 50mg QD; Increase to BID dosing when taken with UGT1A or CYP3A inducers, or with certain INSTI-resistant strains • 25mg tablet • 50mg tablet Pediatric Dose: for pediatric patients at least 30kg • If at least 40kg: dosed as 50mg QD • For 30kg to less than 40kg: dosed as 35mg QD • Increase frequency to BID with certain UGT1A or CYP3A inducers and with certain INSTI-associated resistance substitutions

No generic available Labeled Indication: Treatment of HIV-1 in combination ARV therapy for treatment-naïve and treatment-experienced patients 4-weeks or older Raltegravir Isentress®: RAL • 25mg chewable tablet Adult Dose: • 100mg chewable tablet • 400 mg tablet BID • 100 mg/5mL oral suspension • During co-administration with rifampin, increase to 800 mg BID. • 400mg tablet Pediatric Dose: • If at least 25kg: One 400mg tablet BID • If at least 11kg: Chewable tablets dosed between 75mg and 300mg BID based on weight • If at least 3 kg to less than 25 kg: Oral suspension dosed between 20mg and 100mg BID based on weight.

7 Brand Name/Dosage Forms Indication/Dose (generic available if italicized) Non-Nucleoside Reverse Transcriptase Inhibitors

No generic available Labeled Indication: Treatment of HIV-1 in combination with other ARV agents for patients as least 16 years old.

Package insert note: It is important to consider that there is insufficient data directly comparing delavirdine-based regimens Delavirdine Rescriptor®: with currently preferred 3-drug regimens for initial treatment of HIV. DLV • 100mg dispersible tablet

• 200mg tablet • Treatment guidelines no longer recommended this drug for treatment- naïve patients

Dose: 400mg TID

No generic available Labeled Indication: Treatment of HIV-1 in combined ARV therapy for adults and pediatric patients at least 3 months old and

weighing at least 3.5 kg Efavirenz Sustiva®: EFV • 50mg capsule Adult Dose: • 200mg capsule • 600mg QD on an empty stomach preferably at bedtime to limit CNS side effects • 600mg tablet Pediatric Dose: at least 3 months old and weighing at least 3.5kg • Sprinkle capsule in food; dosed between 100mg and 600mg QD, based on weight

No generic available Labeled Indication Treatment of HIV-1 in combination ARV therapy for treatment-experienced patients 6 years or older with

documented viral resistance to other NNRTI and ARV agents Etravirine Intelence®: Dispersible tablets ETR • 25mg tablet Adult Dose: • 100mg tablet • 200mg BID following a meal • 200 mg tablet Pediatric Dose: for age 6 up to 18 years old weighing at least 16kg

• May disperse tablet in water; dosed between 100mg and 200mg BID, based on weight

Generics available Labeled Indication: Treatment of HIV-1 in combined ARV therapy for patients at least 15 days old

•Must have CD4-count >250cells/mm3 for females and >400 cells/mm3 for males Viramune®: • A 14-day lead-in dosing should be carried out to reduce the risk of rash Nevirapine • 200 mg tablet NVP Dose: for patients at least 16 years old • 50mg/5mL oral • IR-tablet: 200mg QD x 14 days for lead-in period, then 200mg BID thereafter suspension • ER-tablet: 400mg QD for maintenance therapy Viramune XR: • 100mg tablet Pediatric Dose: for patients at least 15 days old • 400mg tablet • IR-tablet: 150mg/m2 QD x 14 days followed by 150mg/m2 BID thereafter, not to exceed 400mg per day • ER-tablet dosed between 200mg and 400mg QD based on body surface area Black Box Warning Key Concerns: Hepatotoxicity; Life-threatening skin reactions

No generic available Labeled Indication: Treatment of HIV-1 in combination ARV therapy for treatment-naive patients at least 12 years old, Rilpivirine weighing at least 35kg, and with HIV-1 RNA ≤100,000 copies/mL at baseline RPV Edurant®: • 25mg tablet Dose: 25mg QD with a meal

8 Brand Name/Dosage Forms Indication/Dose (generic available if italicized) Entry Inhibitors

No generic available Labeled Indication: Treatment of HIV-1 in combination ARV therapy for treatment-experienced patients 6 years or older

Enfuvirtide Fuzeon®: Dose: ENF • 90mg/mL • 90mg (1mL) injected subcutaneously BID SQ-solution Pediatric Dose: for patients 6 to 16 years old • 2mg/kg subcutaneously BID, up to a maximum dose of 90mg BID

No generic available Labeled Indication: Treatment of HIV-1 in combined ARV therapy for adults and pediatric patients at least 2 years old. Prior to

initiation patients must be tested for CCR5 tropism using a highly sensitive assay. Maraviroc Selzentry®: MVC • 150mg tablet Adult Dose • 300mg tablet’ • Dosed between 150mg and 600mg BID, depending on concomitant medications that the affect CYP3A4 Anticipated formulations: Pediatric Dose: for patients weighing at least 10kg 25mg tablet, 75mg tablet, and • Dosed between 50mg and 300mg BID, depending on weight and concomitant medications 20mg/mL oral solution15 Abbreviation key: ARV- antiretroviral, BID- twice daily, DVL- delavirdine, DTG-dolutegravir, EFV- efavirenz, ENF- enfuvirtide, ER- extended release, ETR- etravirine, EVG- elvitegravir, IR- immediate release, INSTI- integrase strand transfer inhibitor, MVC- maraviroc, NNRTI- non-nucleotide reverse transcriptase inhibitor, NVP-nevirapine, QD- once daily, RAL- raltegravir, RPV- rilpivirine, TID- three times daily

9 Disease Overview Epidemiology Although the nation’s annual rate of newly-diagnosed HIV cases declined by 19% from 2005 to 2014, the disease continues to affect more than 1.2 million people in the United States.17 Groups at highest risk of becoming infected include men who have sex with men, IV- drug users, African Americans, Hispanics, and Latinos.17 The rate of newly-diagnosed cases in Utah during 2015 was 4 per 100,000 populations (108 males and 12 females) and has fluctuated between 3.3 and 5 per 100,000 populations over the last ten years.18,19 Data from 2013 last cited the prevalence of HIV cases in Utah to be 2,565 persons.20 Considering the trend of an increasing male incidence rate in Utah, especially in the 35 and younger category (composing 53% of the newly-diagnosed male cases in 2015), the Utah Department of Health (UDH) has advocated targeting young men for HIV testing.18,21 In contrast, the incidence among females has remained steady and is more evenly distributed across age groups in Utah.18 With regard to children, nine newly-diagnosed cases were reported in Utah between 2005 and 2014 in the 13 and younger age group.19 Tracking and establishing a linkage-to-care goal upon a positive diagnosis is of particular importance considering the context of recently published guidelines highlighting evidence supporting prompt antiretroviral (ARV) therapy initiation for all infected individuals, with rare exceptions, regardless of the CD4 T lymphocyte (CD4) count.3,17,22 The UDH strives to have newly infected patients linked to care within three months. In 2015, 67% of newly diagnosed patients in Utah obtained care within a month of diagnosis, and by three months 88% were considered linked to care.23 Further background information concerning the timing of antiretroviral therapy (ART) initiation is outlined in Table 2 of Appendix A. HIV-1 Treatment Pharmacotherapy strategies target pivotal enzymes or receptors involved in the HIV infection cycle —fusion and entry into the host cell (via glycoprotein (gp) 41 and C-C chemokine type 5 receptor (CCR5)), conversion of HIV RNA into double-stranded deoxyribonucleic acid (DNA) (via reverse transcriptase), integration of viral-coded DNA into the host’s genome (via integrase), and cleavage of gag-pol polyprotein for viral maturation (via protease).24 Once integrated into the host’s genome, HIV causes a deficiency of helper T lymphocytes and a profound immunodeficiency.2 Consideration of both the extent of immunosuppression and the current presenting symptoms are important when deciding prophylactic treatment.3 When the CD4 count falls below 500 cells/µL, patients are at a high risk of developing opportunistic infections (OIs) including, but not limited to, P. jiroveci, Mycobacterium, and Cytomegalovirus. Prior to treatment, genotypic resistance testing is performed to guide medication selection. Patients are also screened for tuberculosis and hepatitis B and C viruses. A positive diagnosis will influence the selection of the appropriate ARV regimen. Other pre-treatment tests include a co-receptor tropism assay prior to maraviroc initiation and HLA-B*5701 screening to assess abacavir-hypersensitivity risk. Two surrogate markers, CD4-lymphocyte count and plasma HIV RNA, are used to assess the patient’s response to therapy and guide opportunistic prophylaxis. When treatment is expedited before resistance results are available, the NNRTI- based regimens should be avoided; pre-existing resistance to INSTIs and PI-based regimens is less likely and serve as better options in this situation.3 The guidelines published by the DHHS and the International Antiviral Society-USA Panel (IAS-USA), for the management of HIV infection in the United States, are congruent to one

10 another with respect to the preferred INSTI-based and NNRTI-based regimens.3,22 In general, the DHHS recommends that initial therapy for treatment-naïve adults and adolescents consist of two NRTIs combined with a third ARV agent from either the INSTI or PI drug classes.3 Alternative regimens, which involve the NNRTIs efavirenz and rilpivirine, are effective but may have considerable potential disadvantages concerning side effects, ease of administration, and limitations in certain patient populations. However, therapy is individualized, and in certain situations an alternative regimen may be optimal. Third-line, drug combinations are further outlined by the DHHS, which may be useful in situations where resistance or comorbidities preclude the use of preferred regimens. These “Other” classified regimens may be less effective, have greater toxicity risks, or impose a higher pill burden.3 Table 3 provides a summary of the described DHHS guideline in addition to guidelines for the pediatric and perinatal populations. As for initial ART in the pediatric population, the DHHS guideline has a place in therapy for the NNRTIs: nevirapine, efavirenz, and rilpivirine. Each of the INSTIs are also recommended either as first-line or as alternative-line initial-treatment options for particular age groups.25 The entry inhibitors have not been recommended among initial regimens for either adults or children, so are reserved for salvage therapy when patients have failed the preferred options.3,25

Table 2. Guidelines for HIV-1 Management with Antiretroviral Therapy Guideline Recommendations

Initial Regimens for Treatment-Naïve Patients Recommended Regimens Guidelines for the Use of • INSTI plus 2-NRTI Regimens: Antiretroviral Agents in ▬ Dolutegravir + ABC + (3TC or FTC) HIV-1-Infected Adults ▬ Dolutegravir plus either [TDF with (3TC or FTC)] or [TAF with FTC] and Adolescents, July ▬ Elvitegravir plus cobicistat + (TAF or TDF) + FTC Raltegravir plus either [TDF with (3TC or FTC)] or [TAF with FTC] 20163 ▬ • Boosted PI plus 2-NRTIs:

DRV/r plus either [TDF with (3TC or FTC)] or [TAF with FTC] Publishing Body: ▬ DHHS Panel on Alternative Regimens Antiretroviral Therapy • NNRTI plus 2NRTIs: National Institutes of Health ▬ Efavirenz plus either [TDF with (3TC or FTC)] or [TAF with FTC] Office of AIDS Research ▬ Rilpivirine plus either [TDF with (3TC or FTC)] or [TAF with FTC] only with 3 Advisory Council pre-treatment HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm • Boosted PI plus 2 NRTIs: Note: ▬ (ATV/r or ATV/c) plus either [TDF with (3TC or FTC)] or [TAF with FTC] Guideline applies to post- ▬ (DRV/c or DRV/r) plus [ABC with (3TC or FTC)] if HLA-B*5701 is negative pubertal adolescents, sexual ▬ DRV/c plus either [TDF with (3TC or FTC)] or [TAF with FTC] maturity rating 4 & 5 Other Regimens ▬ Raltegravir + ABC + (3TC or FTC) ▬ Efavirenz + ABC + (3TC or FTC) ▬ (ATV/c or ATV/r) + ABC + 3TC ▬ DRV/r + Raltegravir (twice daily): requires HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm3 ▬ LPV/r + (3TC or FTC) (twice daily)

Note: When choosing between an INSTI, NNRTI, or PI as the third drug, the patient’s comorbidities, concomitant medications, and the potential for non-adherence to the regimen should be considered.

11 Guideline Recommendations Children at least 14 days old and up to 3 years old: Guidelines for the Use of Recommended Initial Therapy: LPV/r plus two NRTIs (if at postmenstrual age Antiretroviral Agents in greater than 42 weeks) Alternative Options for Initial Therapy: Nevirapine plus two NRTIs Pediatric HIV Infection, 25 Children at least 4 weeks old and up to 2 years old weighting at least 3kg: March 2016 Raltegravir plus two NRTIs Children at least 3 months old and up to 3 years old weighting at least 10kg: ATV/r plus two NRTIs Publishing Body: Children at least 2 years old and up to 3 years old: DHHS Panel on Recommended Initial Therapy: (LPV/r or Raltegravir) plus two NRTIs Antiretroviral Therapy Children at least 3 years old and up to 12 years old: National Institutes of Health Recommended Initial Therapy: Office of AIDS Research - Raltegravir plus 2-NRTIs Advisory Council - Efavirenz plus 2NRTIs - (ATV/r or twice daily DRV/r or LPV/r) plus 2 NRTIs Children at least 12 years old and not sexually mature (SMR 1-3) Note: Guideline applies to Recommended Initial Therapy post-pubertal adolescents, - (Dolutegravir or Elvitegravir/c) plus 2-NRTIs sexual maturity rating - (ATV/r or once daily DRV/r) plus 2 NRTIs (SMR) 3 and below Alternative Option for Initial Therapy - Efavirenz or Rilpivirine plus 2NRTIs - Raltegravir plus 2NRTIs *Selection of 2-NRTI Backbone: Refer to the full guideline to view the recommended NRTI backbone for each age group First Line ART for Adults (including pregnant/nursing women) Consolidated Guidelines • Should include 2-NRTI backbone plus an NNRTI or INSTI on Antiretroviral Drugs • Fixed dose combinations and once-daily regimes are preferred for Treating and ▬ TDF +EFV + (3TC or FTC) • If the above is unavailable or contraindicated choose from the following: Preventing HIV - AZT + 3TC + (EFV or NVP) Infection: - TDF + (3TC or FTC) + NVP Recommendations for a - TDF + (3TC or FTC) + (DTG or EFV400mg/d) Public Health Approach, First Line ART for Adolescents (10 to 19 years) 201626 - Preferred: TDF + (3TC or FTC) + EFV as a fixed-dose combination - Alternative: TDF + (3TC or FTC) + (DTG or EFV400mg/d) • If the above regimens are unavailable or contraindicated then the Publishing Body: following are alternative options: World Health - ABC + 3TC + (EFV or NVP) - AZT + 3TC + (EFV or NVP) Organization - TDF + (3TC or FTC) + NVP First Line ART for Children (Age 3 and up to 10 years old, weighing <35 kg) - Preferred NRTI backbones: [ABC + 3TC] or [(AZT or TDF) + (3TC or FTC)] - Preferred NNRTI: EFV or Alternative NNRTI: NVP First Line ART for Children less than 3 years old - Preferred NRTI backbone (ABC or AZT) + 3TC combined with LPV/r - Alternative: (ABC or AZT) +3TC + NVP - Consider substituting LPV/r with EFV at 3 years-old NNRTI place in therapy when the above first line regimens have been exhausted: • May consider second-generation NNRTIs with minimal risk of cross- resistance as third-line (low-quality evidenced based recommendation) Infant Prophylaxis • Infants born to mothers with HIV at high risk of contracting HIV - AZT + NVP for first 6 weeks of life • Breastfed infants of mother with HIV receiving ART - NVP for 6 weeks

12 Guideline Recommendations Recommendations for INSTI, NNRTI, and EI Place in Therapy Use of Antiretroviral Preferred INSTI Regimen: Raltegravir plus 2 NRTIs Drugs in Pregnant HIV-1- Recommended as an alternative option, secondary to the preferred PI and INSTI- Infected Women for based regimens: • Efavirenz or Rilpivirine with a 2-NRTI backbone: Maternal Health and o Previous guideline of 2014 advised to avoid EFV until after 8 weeks Interventions to Reduce gestation age due to teratogenicity concerns which are also stated in the Perinatal HIV product’s package insert. However, more recent large meta-analyses have Transmission in the provided compelling evidence for the panel to lessen this concern. This is United States, October consistent with the WHO and British HIV guidelines which all suggest EFV 201627 therapy can be used throughout pregnancy.

DHHS Panel on Note: Other INSTIs, NNRTIs, and both of the approved EIs are not recommended as Antiretroviral Therapy initial therapy options National Institutes of Health

Department of Health and Human Services Other Guidelines • Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV- 28 Available: Infected Adults and Adolescents, Updated 11/2016 International Antiviral Society- USA Panel • Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults, 201622 World Health Organization • Consolidated Guidelines on the use of Antiretroviral drugs for treating and preventing HIV infection: Recommendations for a Public Health Approach, 201626 Center for Disease Control and Prevention29 • Recommendations for HIV Prevention with Adults and Adolescents with HIV in the United States, 2014 • Pre-exposure Prophylaxis for the Prevention of HIV in the United States: A Clinical Practice Guideline, 2014 • Updated Guidelines for Antiretroviral Prost-exposure Prophylaxis After Sexual, Injection Drug Use, or Other Non-occupational Exposure to HIV— United States, 2016 Infectious Disease Society of America30 • Clinical Practice Guideline for The Management of Chronic Kidney Disease in Patients Infected with HIV, 2014 • Primary Care Management of HIV-Infected Patients, 2013 • Prevention and Treatment of Opportunistic Infections, 2015 *Of note: the guidelines by the International Antiviral Society-USA Panel,22 are congruent with respect to the preferred initial regimens outlined in the DHHS guideline for the adult population.

Abbreviation key: 3TC-lamivudine, ABC-abacavir, ATV-atazanavir, AZT- zidovudine, c- cobicistat, COBI- cobicistat, d4T- stavudine, ddl-didanosine, DVL- delavirdine, DRV-darunavir, DTG-dolutegravir, EFV – efavirenz, ETR- etravirine, EVG- elvitegravir, FTC-emtricitabine, IDV- indinavir, LPV- lopinavir, MVC- maraviroc, NFV- nelfinavir, NIH- National Institutes of Health, NVP- Nevirapine, PI-protease inhibitor, RAL- raltegravir, RPV- rilpivirine, RTV- ritonavir, SAQ- saquinavir, TAF- tenofovir alafenamide, TDF- tenofovir disoproxil, TPV- tipranavir, ZDV-zidovudine

13 A thorough evaluation of virological failure is required for patients experiencing a decline in drug response. This involves assessment of the plasma HIV RNA load and CD4 trends over time, resistance results, medication history/adherence, and drug interactions. In these patients, an entirely new regimen including at least two, preferably three, fully-active agents should be initiated based on the patient’s resistance analysis.3

Pharmacology

Integrase Strand Transfer Inhibitors The INSTIs inhibit the HIV-integrase enzyme as it inserts HIV-DNA into the host’s genome. Since integrase is a unique target, INSTIs are active against many strains that have developed resistant mutations to the NRTI, NNRTI, and PI drug classes. Nonetheless, it has been reported that the combination of some NNRTI-resistance mutations can confer resistance to INSTIs and vice versa.31 Table 3 outlines the pharmacokinetic properties of the INSTIs available as single- ingredient products. The first generation INSTIs include elvitegravir and raltegravir. Raltegravir must be dosed twice daily and is the only INSTI unavailable in a combination product. Elvitegravir is only available in a combination product and must be taken with a pharmacokinetic booster (cobicistat) for once daily dosing. Extensive cross-resistance between these two first generation agents has been reported.32 Dolutegravir is a second-generation INSTI and is the first in its class with once-daily doing as a single-ingredient-containing product. Dolutegravir has a higher barrier to resistance,3,33 with efficacy demonstrated against strains resistant to the first- generation INSTIs in the VIKING-3 study.34,35 In consideration of drug interactions, both dolutegravir and raltegravir are metabolized primarily by UGT1A1 (uridine diphosphate glucuronosyltransferase family 1 member A1) and require dose adjustments when taken with the UGT1A1 strong inducer, rifampin. In addition, dolutegravir is subject to drug interactions with strong inducers of CYP3A (Cytochrome P450, family 3, subfamily A) requiring dose adjustment; whereas, raltegravir is not a substrate of CYP3A.

Non-Nucleoside Reverse Transcriptase Inhibitors The NNRTI drug class binds non-competitively to HIV reverse transcriptase and is heterogeneous with respect to chemical structure.24 Efavirenz, nevirapine extended-release, and rilpivirine are all dosed once daily. Etravirine is dosed twice daily, while delavirdine is most frequently dosed at three times-a-day. Rilpivirine and etravirine are administered with a meal, while efavirenz must be administered on an empty stomach. This group of drugs has many potential drug interactions since the CYP enzymes mediate their metabolism. Table 3 outlines the pharmacokinetic properties of the five FDA-approved NNRTIs. Cross-resistance among the NNRTIs can limit the utility of this drug class and is common among first-generation agents, efavirenz and nevirapine. High-level resistance can occur with a single mutation.3 In addition, signature mutations (involving E138K and M184I alleles) leading to virological failure while taking rilpivirine often leads to NNRTI and NRTI cross resistance.31,36 Etravirine is active against HIV strains with limited resistance to other NNRTI agents; thus, it is useful in salvage therapy.3

14 Entry Inhibitors The entry inhibitor drug class is heterogeneous with respect to chemical structure and site of action. Enfuvirtide inhibits gp41-mediated fusion, while maraviroc acts as an antagonist at the CCR5 receptor, inhibiting the gp120-CCR5 interaction. Prior to initiation of maraviroc, a tropism assay must be conducted to determine if a patient is likely to respond to the drug. Although the CCR5 receptor is predominantly used by HIV for entry, strains that utilize CXCR4 (C- X-C chemokine type 4 receptor) may also be present, especially in the treatment-experienced population; these patients will not respond to maraviroc.3 Both entry inhibitors are dosed twice daily. A major difference between the two is the route of administration. Maraviroc is taken orally, whereas enfuvirtide must be administered subcutaneously.14,15 In consideration of drug interactions, maraviroc is a substrate of P-glycoprotein and CYP3A4 is its major metabolizing enzyme; thus, maraviroc can be subject to many drug interactions. Dose adjustments must be made when maraviroc is administered in combination with potent CYP3A inhibitors and inducers. In contrast, enfuvirtide is not metabolized by the CYP enzymes nor is a substrate of P-glycoprotein.

Table 3. Pharmacokinetics of Single-Ingredient INSTI, NNRTI, and EI Products FDA-Approved for the Treatment of HIV-1 5-16

Bioavailability (BA) Protein T (hrs) bound Metabolism Drug Interaction Concerns* 1/2 Elimination Concerns (%)

Integrase Strand Transfer Inhibitors 14 • Administer with or 99 Primarily • 53% unchanged drug • Drugs that induce/or inhibit CYP3A, UGT1A, UGT1A9, and without food UGT1A1 eliminated through PGP may alter DTG plasma concentration; Must increase • Take 2 hours before or 6 Secondarily feces; 31% excreted DTG dose with strong UGT1A (rifampin) and CYP3A hours after taking cation CYP3A through the urine as inducers containing antacids or metabolites, <1% • DTG inhibits renal transporters, OCT2 and MATE; thus

laxatives, sucralfate, oral unchanged-drug DTG may increase dofetilide (contraindicated) and supplements with iron or eliminated through metformin (use with caution/dose adjust) calcium, or buffered urine • Reduced absorption of DTG by polyvalent cations; must medications. Alternatively, separate out dosing by 2 hours before or 6 hours after Dolutegravir take DTG with calcium or taking cation-containing antacids, laxatives, sucralfate, iron together with food. oral supplements with iron or calcium, or buffered medications. Alternatively, can take with DTG with supplements containing calcium or iron together with food

9 • Administer with or 83 Primarily • 51% and 32% of the • Drugs that inhibit or induce UGT1A1 may be problematic; without food UGT1A1 dose excreted into the must increase dose when used with rifampin, a UGT1A1 • Must avoid aluminum, feces and urine, strong inducer. and magnesium containing Not a CYP respectively. About 9% of • Coadministration with the proton pump inhibitor antacids and supplements substrate the dose was unchanged omeprazole increases RAL concentrations, thus the EU drug eliminated in the has recommended avoiding agents that increase gastric urine pH.37 • Since raltegravir does not affect the PGP, the CYP Raltegravir enzymes, or UGT1A1 and UGT2B7, it is not expected to interact with PIs, NNRTIs, methadone, opioid analgesics, statins, azole antifungals, oral contraceptives, proton pump inhibitors and anti-erectile dysfunction agents

16 Protein Bioavailability (BA) T 1/2 (hrs) bound Metabolism Elimination Drug Interaction Concerns* Concerns (%)

Non-Nucleoside Reverse Transcriptase Inhibitors

2-11 • BA ⇑ 20% upon water 98 CYP3A and • 44% through feces, 51% • Inhibitor of CYP3A, 2D6 & 2C19 dispersion possibly through urine, <5% • Many DDIs • Administer with or CYP2D6 unchanged-drug without food through urine Delavirdine

40-55MD • Food increases BA 99 CYP3A & • 16-61% through feces, • Inducer of CYP3A & 2B6

• Administer on an empty 2B6 14-34% through urine • Inhibitor of CYP2C9 & 2C19 stomach • Many DDIs Efavirenz

41 (±20) • BA ⇓ 50% in fasting 99 CYP3A, 2C9, • 94% through feces, 1% • Inducer of CYP3A conditions & 2C19 through urine • Inhibitor of CYP2C9, 2C19, and PGP •Administer with meal • Many DDIs

Etravirine

25-30MD • May administer with or 60 CYP3A & • 10% through feces, 90% • Inducer of CYP3A and 2B6 without food/antacids 2B6 through urine, <5% • Many DDIs unchanged-drug through urine Nevirapine

50 • BA reduced under fasting 99 CYP3A • 85% through feces, 6% • Co-administration with drugs that induce or inhibit CYP3A, or that increase gastric pH may affect rilpivirine

conditions and with a through urine protein-rich nutritional • Contraindicated with PPIs; use caution with H2- drink. antagonists or antacids • Administer with a meal Rilpivirine

17 Protein Bioavailability (BA) T 1/2 (hrs) bound Metabolism Elimination Drug Interaction Concerns* Concerns (%)

Entry Inhibitors

3.8 - 92 Hepatic • Elimination pathway • May increase tipranavir trough levels hydrolysis hasn’t been studied per package insert Enfuvirtide

14-18 • High fat meal reduces 76 Primarily • 20% of dose eliminated • Coadministration with CYP3A inhibitors, including

AUC and Cmax, however CYP3A through the urine (9% as protease inhibitors (except tipranavir/ritonavir) and package insert states unchanged drug), while delavirdine, will increase the concentration of maraviroc product can be 76% of the administered • Coadministration with CYP3A inducers, including administered with or dose was eliminated efavirenz, may decrease the concentration of maraviroc Maraviroc without food through feces • Coadministration with St. John’s wort is not recommended * Extensive drug-drug interaction lists are viewable among each package insert and DHHS treatment guidelines. Refer to the Professional Prescribing Information for other drugs that should not be co-administered with these medications or that may require a change in dosage or regimen. Abbreviation key: BA-bioavailability, CYP- Cytochrome P450, DDIs-drug-drug interactions, DTG- dolutegravir, EU- European Union, MATE- multidrug and toxin extrusion transporter, MD- multiple-dose data, OCT2- organic cation transporter 2, PGP- p-glycoprotein, PK- pharmacokinetics, PPI- proton pump inhibitors, RAL- raltegravir, UGT- uridine diphosphate glucuronosyltransferase,

18 Special Populations

Integrase Strand Transfer Inhibitors All three INSTIs are designated among the preferred first-line regimens for the treatment of ARV-naïve patients.3,22 In addition, raltegravir and dolutegravir are FDA approved for use in ARV-experienced patients.5,7 Table 4 addresses use in special populations. Each medication is approved for pediatric patients, with raltegravir carrying approval for a younger subset of this population (based on weight). Dosage forms of raltegravir (Isentress®) include chewable tablets and an oral suspension. Dolutegravir is available only as a film-coated tablet. Renal dose adjustments are not required for dolutegravir and raltegravir due to the negligible renal clearance of the parent molecules. In addition, hepatic dosing for these two INSTIs is unnecessary in the case of mild or moderate impairment. Use of dolutegravir with severe hepatic impairment is not recommended. Raltegravir has not been studied in patients with severe hepatic impairment; dose adjustment recommendations are not provided in the product’s prescribing information (PI) insert. The DHHS guideline recommends raltegravir as the preferred INSTI during pregnancy. Dolutegravir lacks adequate supporting evidence in this population and is not recommended.27 Both agents are used off-label for post-exposure prophylaxis as referred to in Table 4.

Non-Nucleoside Reverse Transcriptase Inhibitors FDA labeling for efavirenz and nevirapine, first-generation NNRTIs, does not restrict the indication based on the patient’s ARV-naïve or experienced history. Regarding the second- generation NNRTIs, rilpivirine is only approved for treatment-naive patients with a baseline HIV RNA of ≤100,000 copies/mL; etravirine is approved only for treatment-experienced patients with documented resistance to other NNRTI agents. Of the five NNRTIs, only efavirenz and rilpivirine are recommended by the DHHS as initial therapy options for adults and adolescents.3 Efavirenz, rilpivirine, and nevirapine are included in the regimen options outlined for the pediatric population.3,25 In addition to being excluded from the DHHS’s initial recommended adult regimens, nevirapine therapy has the following characteristics: a) the indication is limited to certain CD4- baseline requirements—refer to Table 1, b) complex lead-in dosing is required to reduce the risk of rash, and c) the patient must be closely monitored during the first 18 weeks of therapy due to the potential for hepatotoxicity and life-threatening hypersensitivity reactions, which are black box warnings.3,11 The other first-generation NNRTI, delavirdine, is not recommended in any DHHS guideline due to inadequate evidence supporting its efficacy. At one point, it was stated by the DHHS to be removed from the market.27 Efavirenz and nevirapine are approved for use in the youngest population, while etravirine and rilpivirine are indicated at 6 and 12 years of age, respectively.9,13 Dose adjustments are not required for mild or moderate renal impairment for the NNRTIs. Guidance is limited for the population with severe renal impairment for some agents. Dose adjustments for mild hepatic impairment are not necessary for this drug-class, however adjustments or avoidance (as with nevirapine and efavirenz) with more severe impairment may be required— refer to Table 4. 8,9,13

19 During pregnancy, both rilpivirine and efavirenz are recommended in alternative regimen options, secondary to the preferred INSTI and PI-based regimens.27 Other NNRTI agents are not recommended for reasons outlined in Table 4. With the exception of delavirdine, the NNRTI agents are used off-label for HIV-exposure prophylaxis.

Entry Inhibitors Although maraviroc is approved for both treatment-naïve and experienced patients, it is not recommended as initial therapy.3,25 Enfuvirtide is only approved for treatment-experienced patients, reserving its use for salvage therapy. Both entry inhibitors are approved for use in the pediatric population. Maraviroc is approved for a younger subset of this population, as young as 2 years old, in contrast to enfuvirtide approved for 10 years of age. No dosing adjustments are necessary for enfuvirtide with respect to renal and hepatic impairment.14 Maraviroc is primarily metabolized by the liver; serum concentrations will likely increase with hepatic impairment. Dose adjustment recommendations, however, are not provided in the PI. With regard to renal impairment, according to the PI, there is no data to guide dosing for pediatric patients with mild to moderate impairment. Dose adjustments for adults with mild or moderate renal impairment are not required for maraviroc and studies have not been conducted for severe renal impairment guidance.15 Usage data in the perinatal population is limited with respect to the entry inhibitors; thus the DHHS recommends considering their use only upon failure of preferred options and in consultation with an HIV specialist. Similarly, upon expert advice, these medications are alternative-line options, used off-label, for certain HIV-exposure prophylaxis situations.

Table 4. Single-Ingredient INSTI, NNRTI, and EI Products: Applications in Special Populations 5-16 Pediatric Hepatic and Renal Impairment Dosing Pregnancy & Nursing Concerns27 Off-Label Use: PrEP38 & PEP39,40 Use

Integrase Strand Transfer Inhibitors

• There is insufficient human data on the use of DTG during • No dosing adjustment required for mild pregnancy to inform a drug associated risk of birth Approved or moderate hepatic impairment (Child- defects and miscarriage. No evidence of teratogenicity in • Listed among the CDC’s 3-drug for pediatric Pugh Class A or B). Not recommended mice, rats, or rabbits containing preferred 28-day patients with severe hepatic impairment • Animal studies show drug excretion into milk regimens for nPEP in patients 13 weighing at years or older, including pregnant

Dolutegravir least 30kg • No dose adjustment needed for renal Mother to Child Transmission Prevention women impairment Not recommended since data is limited to support the use of DTG during pregnancy

• No dosing adjustment required for mild • Pregnancy Risk Category: C or moderate hepatic impairment (Child- Approved • Animal studies show drug excretion into milk Pugh Class A or B). • Listed among the CDC’s 3-drug for pediatric • Insufficient data to assess for teratogenicity in humans. • PKs have not been evaluated for more containing preferred regimens for patients at Increased skeletal variants in rats, no increase in defects severe hepatic impairment or for renal nPEP in patients 4 weeks or older, least 4 in rabbits impairment. including pregnant women weeks old

Raltegravir • Listed among the PHS’s preferred weighing Mother to Child Transmission Prevention • Renal dosing is not expected to be drug regimen for oPEP 3kg or more Preferred INSTI for use in pregnancy necessary considering the negligible No change in dose indicated renal clearance of the parent drug.10

21 Pediatric Hepatic and Renal Impairment Dosing Pregnancy & Nursing Concerns27 Off-Label Use: PrEP38 & PEP39,40 Use

Non-Nucleoside Reverse Transcriptase Inhibitors

Approved • Pregnancy Risk Category: C for • Excretion into breast milk unknown adolescent • PK in hepatic or renal impairment hasn’t • Not listed in CDC or PHS guideline patients been investigated. Mother to Child Transmission Prevention

Delavirdine over 16 • Not recommended in DHHS guidelines years of age

• Pregnancy Risk Category: D* • Fetal risk has been demonstrated; Avoid in 1st trimester • Not recommended with moderate or • Excretion into human breast milk occurs Approved severe hepatic impairment. • Listed among the CDC’s alternative

for pediatric • No dose adjustment necessary for mild Mother to Child Transmission Prevention options for nPEP only with expert patients hepatic impairment. • Recommended as an alternative option, secondary to the consultation older than 3 preferred PI and INSTI-based regimens • Listed among the PHS’s alternative months • Efavirenz Renal insufficiency dose adjustments • More recent large meta-analyses provided compelling drug regimens for oPEP only with weighing at haven’t been studied, however evidence for the DHHS panel to lessen this concern of expert consultation least 3.5kg adjustment is not expected to be necessary pregnancy risk. This is consistent with the WHO and British HIV guidelines which all suggest EFV therapy can be used throughout pregnancy.

• No dosing adjustment required for mild or moderate hepatic impairment (Child- • Pregnancy Risk Category: B Approved Pugh Class A or B). • Excretion into human breast milk occurs

for pediatric • Listed among the CDC’s 3-drug • Insufficient data to assess for teratogenicity in humans. patients alternative regimens for nPEP for • PKs haven’t been evaluated for more No evidence of teratogenicity in rats or rabbits. older than 6 patients severe hepatic impairment or for renal years • Listed among the PHS’s alternative Etravirine impairment. Nonetheless, renal dosing Mother to Child Transmission Prevention weighing at drug regimens for oPEP is not expected to be necessary • Not recommended in pregnant adults due to insufficient least 16kg considering the negligible renal PK and safety data. clearance of the drug.10

22 Pediatric Hepatic and Renal Impairment Dosing Pregnancy & Nursing Concerns27 Off-Label Use: PrEP38 & PEP39,40 Use

• Pregnancy Risk Category: B • Excretion into human breast milk occurs • No evidence of human teratogenicity

• Contraindicated with moderate or • Contraindicated in nPEP per CDC Approved Mother to Child Transmission Prevention severe hepatic impairment (Child-Pugh guideline for pediatric • Not recommended as initial ART in pregnancy do to Class B or C) • Recommended for infant patients potential adverse events, complex lead-in dosing, and prophylaxis (infants born to older than resistance concerns per DHHS; initiate in pregnant women

Nevirapine • No dose adjustment for CrCL>20mL. PKs mothers with HIV) per WHO 15 days with CD4 cell counts ≥250 cells/mm3 only if benefit clearly unknown in more severe renal function. outweighs risk (possible life-threatening hepatotoxicity in women with high CD4 cell counts). • Recommended as an option for initial ART per the WHO guideline

• No dose adjustment required for mild • Pregnancy Risk Category: B or moderate (Child-Pugh Class A or B) • Animal studies show drug excretion into milk hepatic impairment. PKs haven’t been • No evidence of teratogenicity in rats or rabbits. Insufficient Approved evaluated for more severe hepatic data to assess for teratogenicity in humans • Listed among the CDC’s 3-drug for impairment alternative regimens for nPEP for adolescent Mother to Child Transmission Prevention patients patients at • No dose adjustment is required in • Recommended as an alternative option, secondary to the • Listed among the PHS’s

Rilpivirine least 12 patients with mild or moderate renal preferred PI and INSTI-based regimens. alternative drug regimens for years old impairment. Use caution with severe • Routine dosing adjustment in all women is not oPEP renal impairment. recommended for RPV during pregnancy. Individual patients should be closely monitored.

23 Pediatric Hepatic and Renal Impairment Dosing Pregnancy & Nursing Concerns27 Off-Label Use: PrEP38 & PEP39,40 Use

Entry Inhibitors

• Pregnancy Risk Category: B • Minimal to low placental transfer to fetus. No data on human teratogenicity. • Listed among the CDC’s • Excretion into breast milk unknown Approved alternative options for nPEP only

for pediatric • No dose adjustment needed for hepatic with expert consultation Mother to Child Transmission Prevention patients at or renal impairment41 • Listed among the PHS’s • Safety and PK data in pregnancy are insufficient to least 6 years alternative drug regimens for

Enfuvirtide recommend for initial ART in ARV-naive women during old oPEP only with expert pregnancy. Consider for women who have failed therapy consultation with several other classes of ARV drugs after consultation with HIV and obstetric specialists. • Insufficient data to make dosing recommendation.

• Hepatic impairment is expected to • Pregnancy Risk Category: B affect maraviroc metabolism however • Insufficient data to assess for teratogenicity in humans. No dose adjustments are not provided in evidence of teratogenicity in rats or rabbits. the package insert. • Drug extensively excreted into animal milk. • Listed among the CDC’s

Approved alternative options for nPEP only • Dosing adjustment does not appear for pediatric Mother to Child Transmission Prevention with expert consultation necessary in adults with mild to patients at • Safety and PK data in pregnancy are insufficient to • Listed among the PHS’s moderate renal impairment. PK-studies least 2 years recommend for initial ART in ARV-naive women during alternative drug regimens for Maraviroc haven’t been conducted for severe old and 10kg pregnancy. Consider for women who have failed therapy oPEP only with expert impairment or in pediatric patients with with several other classes of ARV drugs after consultation consultation renal impairment; the medication is with HIV and obstetric specialists. contraindicated in patients with severe • Standard adult dosing adjusted for concomitant ARV use renal impairment concomitantly taking appears appropriate potent CYP3A inhibitors or inducers. Abbreviation key: ART- antiretroviral therapy, AVR-antiretroviral, CDC- Centers for Disease Control and Prevention, DHHS- Department of Health and Human Services, DTG- dolutegravir, EVG- elvitegravir, INSTI- Integrase Strand Transfer Inhibitor, nPEP- non-occupational post-exposure prophylaxis, oPEP- occupational post-exposure prophylaxis, PK- pharmacokinetic, PEP- post-exposure prophylaxis, PHS- Public Health Service, PrEP- pre-exposure prophylaxis, NVP- nevirapine, RPV- rilpivirine, WHO- World Health Organization

24 Methods

A systematic search was conducted using a strategy developed by an Informational Scientist (M.F.) for OVID Medline and EMBASE.com. Screening criteria was set to capture intra-class, head-to- head efficacy comparisons (with agents applied as part of triple ARV regimens) among the three HIV drug classes reviewed— 1) Integrase Strand Transfer Inhibitors, 2) Non-nucleoside Reverse Transcriptase Inhibitors, and 3) Entry Inhibitors. Systematic reviews (SRs) were first considered for inclusion. Prospective randomized controlled trails (RCTs) published during the time frame for which no robust SRs provided evidence were reviewed and included. Search Strategy— A search strategy for OVID Medline was developed, consisting of controlled vocabulary (e.g. MeSH) and keyword phrases; this strategy was peer reviewed and then translated for EMBASE.com. Two methodological filters were used, one for systematic reviews, another for randomized controlled trials. In Medline, the Cochrane precision and sensitivity maximizing RCT filter was used; the Medline systematic review filter and both filters used in EMBASE were ad hoc. Results were limited to English language. Databases were searched from date of inception forward. Complete search strategies and terms are available in Appendix B. Literature searches for the NNRTI drug class were conducted in December 2016. Searches pertaining to the INSTIs and EIs were conducted in January 2017. Screening— To minimize selection bias, a two-reviewer strategy was used to screen the resultant 3,766 unique title and abstracts identified. Full-text screening was performed by the review author (V.G.). Articles were included if they evaluated intra-class drug comparisons applied in triple-drug ARV treatment for HIV-1 and measured therapeutic efficacy outcomes (e.g. virological outcome endpoints, clinical progression of disease or death outcomes, etc.). Studies were excluded if they applied to non- FDA-approved indications such as HIV transmission prevention, exposure prophylaxis, monotherapy, or HIV-2. Dual therapy arms were also excluded since the standard of care is currently triple-therapy regimens for initial treatment of HIV. Opposing screening votes were resolved through discussion between reviewers. Results— Of the 3,766 unique title and abstracts identified, 54 were moved forward to full-text screening. Trials were excluded if the primary outcome did not measure efficacy.33,42-47 Reviews of commentary nature48 or that did not involve a thorough systematic search method to address the intra- class comparisons of interest were excluded.36,49-55 Systematic or randomized-controlled trials with a single experimental arm,35 only with a placebo comparator,56 or only with comparators from a different ARV class,37,57-59 such that an intra-class comparison was not evident, were excluded. Phase 2 studies,60 non-randomized,61 retrospective, and observational study designs were excluded. An SR with only one contributing RCT,62 where more robust SRs were available for the respective comparison of interest, was also excluded. Individual RCTs were excluded if a more recent robust SR was identified for inclusion, ultimately taking into account the excluded RCT in a meta-analysis approach.63-69

25 Clinical Efficacy and Safety— Integrase Strand Transfer Inhibitors

Evidence involving head-to-head INSTI comparisons is presented for the single-active-ingredient products currently available in the United States. Upon full-text screening, two systematic reviews and two randomized-controlled trials were included, comparing dolutegravir to raltegravir. Table 1 of Appendix C outlines the included studies described below.

INSTI Clinical Efficacy Dolutegravir (DTG) vs. Raltegravir (RAL) — The efficacy of DTG and RAL has been compared in two randomized, double-blinded, controlled trials which had different patient populations with respect to ART-experience. The SPRING-2 study applied to treatment-naive patients, whereas the SAILING study pertained to treatment-experienced patients with ARV-resistance who had not yet been tried on an INSTI. The primary efficacy endpoint in both trials was the proportion of participants with plasma HIV RNA <50 copies/mL.70,71 • The SPRING-2 trial included 822 treatment-naïve patients, where DTG 50 mg once daily was compared to RAL 400 mg twice daily; both arms were taken in combination with an investigator- selected 2-NRTI regimen (either abacavir/lamivudine or tenofovir disoproxil/emtricitabine). The backbone distribution among arms appears well-balanced between groups. Results showed DTG was non-inferior to RAL at both the 48 and 96 week time points. In addition, non-inferiority of DTG versus RAL at 48 weeks was maintained upon statistical stratification with respect to the backbone.70,72 Non-inferiority, however, was not maintained at 96 weeks for the strata receiving the abacavir/lamivudine backbone.70 However, upon an ad-hoc analysis excluding a group of patients who were all receiving abacavir-lamivudine and deemed as non-responders upon the permanent closure of their treatment site, non-inferiority was achieved at 96 weeks for this strata.70 • The SAILING study included 715 treatment-experienced patients, where DTG 50 mg once daily was compared to RAL 400 mg twice daily. These patients had resistance to at least two ARV drug classes, however were INSTI-naïve patients. Each INSTI was taken in combination with one to two fully active drugs, chosen by the investigator (most background regimens included a PI plus an NRTI or NNRTI). Baseline backbone distribution appears well-balanced between groups. At week 48, DTG was found to be non-inferior to RAL. In following, a superiority test was carried out finding DTG marginally superior to RAL (difference in proportions with virological success, DTG vs. RAL: 7.4%, 95% CI 0.7-14.2; superiority p value= 0.03). Stratification with respect to two versus fewer than two fully active background agents was assessed; the non-inferiority finding was maintained with respect to this strata.71 The efficacy of DTG and RAL has been compared in two systematic reviews: one meta-analysis by Jiang et al, pooling the two direct-comparator RCTs mentioned above, and a network meta-analysis by Patel et al, using an indirect comparison methodology (via network).34,73 • The meta-analysis by Jiang et al, pooled the SAILING and SPRING-2, 48-week data to compare DTG to RAL. A striking difference is the patient populations in each study with respect to ART- experience. The SPRING-2 study applied to treatment-naive patients, whereas the SAILING study pertained to treatment-experienced patients with ARV-resistance who had not yet been tried on an INSTI. Of note is that the individual meta-analysis-calculated Mantel-Haenszel (M-H) risk ratios for the SPRING-2 and SAILING studies were found to be non-significant, however, when pooled together demonstrated a marginal significant difference in efficacy favoring DTG (pooled effects M-H risk ratio, 1.06 95% CI 1.01 to 1.12).34

26 • Overall, the network meta-analysis by Patel et al, did not identify a significant difference in the virological-success efficacy of DTG versus RAL for the ARV-naïve population. Of note is that the network had limited connectedness of the INSTI nodes with the efavirenz node that was used to deduce an indirect-comparison (2 total trials; 1:1 ratio of connection). 73 INSTI Safety Dolutegravir (DTG) vs. Raltegravir (RAL)—The safety of DTG and RAL has been secondarily compared in the two randomized-controlled trials (SPRING-2 and SAILING) and two meta-analyses described in the section above. In the SAILING study, adverse event (AE) frequencies were similar between arms. The most common reported events for dolutegravir versus raltegravir were diarrhea (20% vs. 18% of patients), upper respiratory tract infection (11% vs. 8%), and headache (9% vs. 9%); statistical difference evaluation was not conducted for these outcomes.71 The SPRING-2 study also found these common AEs to be similar between the treatment groups. Rates of discontinuation (DC) were similar and infrequent in both arms of each RCT (DC rates were less than 4%).70,71 In addition, SPRING-2 tracked central-nervous-system AEs such as dizziness, depression, insomnia, and anxiety; all were found to be similar between groups with rates less than 6%.70 In the meta-analyses, no difference was found in serious drug-related AEs34 or discontinuations due to adverse events,73 with respect to the comparator arms at 48 weeks. In the RCT comparative analyses, similar lipid effects were observed between the dolutegravir and raltegravir regimens. Results from the SPRING-2 study showed minor, clinically-insignificant increases in TC, LDL-C, and TG levels in each arm at 48 weeks.42 SAILING only reported total cholesterol measures. The network meta-analysis by Patel el al, found no difference in HDL, LDL-C, and TC between groups, however found a marginal significant difference in mean TG change from baseline favoring RAL (mean difference 12.78 mg/dL; 95% CI 0.58 to 25.32).73

Clinical Efficacy and Safety— Non-Nucleoside Reverse Transcriptase Inhibitors

Upon full-text screening, four meta-analyses and five randomized-controlled trials were included, addressing head-to-head efficacy comparisons among the NNRTI drug class. The majority of evidence for NNRTI head-to-head comparisons pertains to efavirenz (EFV) versus nevirapine (NVP) or rilpivirine (RPV). No other intra-class comparisons meeting the inclusion/exclusion criteria were identified (e.g. NVP vs. RPV; etravirine or delavirdine vs. another NNRTI). Table 2 of Appendix C outlines the studies described below.

NNRTI Clinical Efficacy Efavirenz (EFV) vs. Nevirapine (NVP) — The efficacy of EFV and NVP has been directly compared in three meta-analyses44,74,75 which include RCTs published through August 12, 2016 (the search limit for Mbuagbaw et al). • The most recent met-analysis is by Mbuagbaw et al, was published in 2016. It included 12 RCTs involving treatment naïve populations where EFV 600mg once daily was compared to NVP 400mg once daily and NVP 200mg twice daily. Each treatment arm demonstrated similar efficacy with respect to virological suppression, mortality, and clinical progression to AIDS when used for initial treatment in combination with two NRTIs. Of note, however, was a difference in mortality outcome upon stratification of the NVP dose; mortality was lower for the EFV arm compared to the NVP 400mg once daily subgroup. No statistical differences were found for the secondary endpoints, change in CD4 count and treatment failure, with respect to EFV and NVP.

27 Development of resistance, however, was found to be lower in the EFV arm (RR 0.76, 95% CI 0.60 to 0.95, P=0.02).74 • Findings from the meta-analysis by Kawalec et al (2013), are congruent with Mbuagabaw et al; no statistical difference was found in virological response, or disease progression/or death with respect to EFV versus NVP in ARV-naïve patients.75 • The meta-analysis by Pillay et al (2013), is congruent with Mbuagabaw et al, with respect to virological response and development of resistance, however identified a significant difference in favor of EFV with less virological failure.44 Efavirenz (EFV) vs. Rilpivirine (RPV)— One meta-analysis76 evaluating the efficacy of efavirenz versus rilpivirine was identified and includes RCTs published up to October 2013. In addition, five RCTs published more recently than October 2013, pertaining to EFV versus RPV, were included. • The meta-analysis by Li et al, applied to an ARV-treatment naïve population and showed no difference in viral response or change in baseline CD4 count at 48 weeks between treatment arms. Nonetheless, a higher virological failure rate in the RPV group was identified (RR=1.70; 95% CI, 1.21 to 2.38).76 Of note is that this meta-analysis pools together studies with differing treatment arms with respect to complete-single-tablet regimens and multi-pill regimens. • Results from the STaR77 and the pooled THRIVE/ECHO study78 demonstrated RPV to be non- inferior to EFV at week 48 and 96 with respect to viral response. In the pooled results from the RCTs, where the single-ingredient products were compared, subpopulation analysis for baseline HIV RNA<100,000 copies/mL found efficacy of the two agents to be non-inferior both at 48 and 96 weeks.79,80 The single-tablet-regimen (STaR) study, however, showed that RPV outperformed EFV for this particular HIV RNA baseline population.77 Nonetheless, the single-ingredient RPV product has failed to demonstrate non-inferiority for the population with a baseline HIV RNA>100,000 copies/mL80 or HIV RNA>500,000 copies/mL in the pooled TRHIVE/ECHO studies.77,78,81 In addition, RPV failed to demonstrate non-inferiority for the population with a CD4 baseline count of ≤200 cells/µl at 96 weeks in the STaR study.77 Of note is the STaR study involved single-pill regimen arms, whereas, the THRIVE and ECHO studies involved multi-pill regimen arms. Thus, for the sake of this review considering single-ingredient products, the non- inferiority of RPV in the group with HIV RNA >100,000 copies/mL must be considered. Other background information on agents, for which intra-class head-to-head comparisons were not identified, is included: • Delavirdine: The DHHS does not recommend this agent in any guideline and generally states that it has inferior virological efficacy.3 Similarly, the package insert also warns, “There are insufficient data directly comparing antiretroviral regimens containing RESCRIPTOR with currently preferred 3-drug regimens for initial treatment of HIV. In studies comparing regimens consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) (currently considered suboptimal) to RESCRIPTOR plus 2 NRTIs, the proportion of patients receiving the regimen containing RESCRIPTOR who achieved and sustained an HIV-1 RNA level <400 copies/mL over 1 year of therapy was relatively low.”8 • Etravirine: This agent is approved only in ARV-experienced patients with resistance to other NNRTIs. The DHHS guideline states that there is insufficient data to support its use in ART-naïve patients, and reserves recommending it for this population.3

28 NNRTI Clinical Safety Efavirenz (EFV) vs. Nevirapine (NVP) —In Mbuagbaw et al, a statistical difference resulted for a few adverse reactions—EFV was more likely to cause central nervous system AEs and NVP more likely to raise transaminases, and cause neutropenia. There however was not a statistical difference with respect to all-pooled severe adverse events, ALT, TG, TC, rash events, and discontinuation rates between arms.74 Similarly, Kawalec et al, found no difference for discontinuation rates due to adverse events.75 Ford et al., resulted in a conflicting outcome with respect to Mbuagbaw et al, regarding drug discontinuation as a result of any adverse event (lower risk with EFV compared with NVP) and severe CNS events (no difference found between groups). Other findings with regard to risk of severe clinical adverse events were congruent with Mbuagbaw et al,82 Of note is the differing contributing RCTs and the details described for consideration of each outcome (the Ford et al, study was vague about which trials were used for secondary-outcome safety measures). Efavirenz (EFV) vs. Rilpivirine (RPV)— The meta-analyses by Ford et al, and Li et al, arrived at differing conclusions with respect to CNS adverse events. In Ford et al, no statistical difference was found with respect to drug discontinuation, severe CNS events, or severe laboratory events.82 Li et al, showed lower risk of rash and pooled neurological events with RPV compared to EFV.76 More recent randomized controlled trials suggest EFV has more CNS side effects and rash risks compared to RPV. The STaR study demonstrated significant differences in favor of RPV with regard to pooled nervous system events, pooled psychiatric events, and drug discontinuation due to AEs at 48 and 96 weeks. With regard to rash, a statistical difference was found at 96 weeks, however, not at the 48 week point.77 Trends of CNS event differences were similar in the pooled ECHO and THRIVE studies.78,80 Behrens et al, is consistent with above results favoring RPV with respect to pooled neurological AE, dizziness, psychiatric AEs, abnormal dreams/nightmares, and rash.79 Nelson et al, favors RPV with respect to the following AEs; Grade 2–4 AEs, neurological AE, somnolence, dizziness, disturbance in attention, psychiatric AEs, abnormal dreams/nightmares, and rash.78 Overall, these randomized controlled trials were in favor of RPV with respect to changes lipid measures. Efavirenz CNS side effects including dizziness, irritability, headache, impaired concentration, euphoria, and vertigo have been described to resolve or become more tolerable within a month of initiation with the majority of events occurring in the first four weeks of treatment.80 Less frequent intolerable psychiatric disturbances such as abnormal dreams, anxiety, aggression, paranoid/manic reactions, depression, and suicidal ideation can manifest years into treatment and may not subside until the agent is discontinued.9,83 Although there were no head-to-head studies included for direct comparison with etravirine and delavirdine based regimens, Table 5 includes information from tertiary sources concerning common adverse events and precautions outlined in the packaged inserts.

29 Clinical Efficacy and Safety— Entry Inhibitors Upon full-text screening, there were no head-to-head studies comparing the efficacy of the two FDA-approved entry inhibitors, maraviroc and enfuvirtide. Table 5 includes information from tertiary sources concerning common adverse events and precautions outlined in the product prescribing information (PI). The DHHS guideline notes that use of enfuvirtide in salvage regimens has declined with the availability of integrase inhibitors and maraviroc.25 Injection site reactions with enfuvirtide are common, occurring in 98% of patients (in RCTs, per PI). Administration via the needleless Biojector® system may result in neuralgia and/or paresthesia, bruising, and hematomas. Other common adverse effects are diarrhea, nausea, and fatigue. 14 The PI for maraviroc cites the most common adverse events (reported in >8% of patients in RCTs) as upper respiratory tract infections, cough, pyrexia, rash, dizziness, flatulence, bloating, and gastrointestinal atonic/hypomotility disorders.15

30 Table 5. Single-Ingredient INSTI, NNRTI, and EI Products: Common Adverse Effects, Warnings/Precautions, and Safety Comparison5,7-11,13-15 Common Adverse Reactions Warnings & Precautions Head-to-Head Study Safety Comparison

Integrase Strand Transfer Inhibitors

• Comparable common-reported events Prescribing Information Package Insert (>2%) included diarrhea, upper respiratory • Hypersensitivity reactions characterized by rash, constitutional tract infection, and headache, dizziness, findings, and sometimes organ dysfunction, including liver Prescribing Information Package Insert fatigue, depression, insomnia, rash, anxiety

injury, have been reported. and arthralgia in DTG and RAL based • Most common adverse reactions of • Redistribution/accumulation of body fat and immune treatment arms of the SAILING and SPRING- moderate to severe intensity and reconstitution syndrome have been reported in patients 2 studies.70,71 incidence at least 2% are insomnia, treated with combination antiretroviral therapy. fatigue, and headache. • Dolutegravir Rates of discontinuation due to adverse Other Source events were similar and infrequent in both • “Depression and suicidal ideation, primarily in patients with a arms in randomized studies (less than history of psychiatric illnesses, have rarely been reported in 4%).70,71 patients receiving INSTI-based regimens.”3

• Reported central nervous system adverse included dizziness, depression, insomnia, and anxiety; the SPRING-2 study found these to be similar between treatment arms, with rates less than 6%.70 In the meta-analyses, no difference was found in Prescribing Information Package Insert serious drug-related AEs34 or Prescribing Information Package Insert 73 • Life-threatening skin reactions have been reported, including discontinuations due to adverse events, • The most common adverse reactions cases of Stevens-Johnson syndrome and toxic epidermal with respect to the comparator arms at 48 of moderate to severe intensity (≥2%) necrolysis. weeks. are insomnia, headache, dizziness, • Monitor for Immune Reconstitution Syndrome. nausea and fatigue. • In the RCTs, comparable, clinically- • Myopathy, rhabdomyolysis, and insignificant lipid effects were observed Raltegravir Other Source increase in creatine kinase have been • “Depression and suicidal ideation, primarily in patients with a between the dolutegravir and raltegravir reported. history of psychiatric illnesses, have rarely been reported in regimens, suggesting overall that these two

patients receiving INSTI-based regimens.”3 agents have a rather neutral effect on lipids.42

31 Common Adverse Warnings & Precautions Head-to-Head Study Safety Comparison Reactions

Non-Nucleoside Reverse Transcriptase Inhibitors

Prescribing Information • Most common adverse Prescribing Information Package Insert

reaction is rash; (15% • Black Box Warning: Life-threatening hepatotoxicity and skin reactions • The most recent meta-analysis found that adult incidence versus • Fatal and non-fatal hepatotoxicity and skin reactions have been reported, EFV was more likely to cause CNS AEs and 6% with placebo) and including Stevens-Johnson syndrome and toxic epidermal necrolysis NVP more likely to raise transaminases, and cause neutropenia. No difference was Nevirapine (21% all causality • Monitor patients for immune re constitution syndrome and fat re distribution. incidence in pediatric found in rash events.74 However an older subjects) meta-analysis had found no difference in CNS events events between groups. 82 Prescribing Information Package Insert • QTc prolongation risk • Serious psychiatric symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. Prescribing Information • Nervous system symptoms are frequent and usually begin 1-2 days after • Most common adverse initiating therapy and resolve in 2-4 weeks. Dosing at bedtime may improve

reactions (>5%, tolerability. moderate-severe) are • Avoid administration in the first trimester of pregnancy as fetal harm may occur. impaired concentration, • Hepatotoxicity: Monitor liver function tests for patients with underlying hepatic • Published meta-analyses have arrived at abnormal dreams, rash, disease, including hepatitis B or C coinfection, or who are taking medications Efavirenz differing conclusions with respect to CNS dizziness, nausea, associated with liver toxicity. adverse events comparing efavirenz and headache, fatigue, • Rash usually begins within 1-2 weeks after initiating therapy and resolves within rilpivirine.76,82 Nonetheless, insomnia, and vomiting. 4 weeks. complementing the meta-analysis by Li, et • Convulsions: caution in patients with seizure history al., showing lower risk of rash and pooled • Lipids: Monitor total cholesterol and triglyceride elevations. neurological events with RPV compared to • Patients may develop redistribution/accumulation of body fat or immune EFV, more recent RCTs also suggest EFV reconstitution syndrome. treatment leads to higher occurrences of CNS side effects and rash compared to Prescribing Information Prescribing Information Package Insert RPV.77-79 • The most common • QTc-prolongation risk notated adverse drug reactions • Skin and hypersensitivity reactions have been reported, including cases of Drug • Overall, randomized controlled trials were

(incidence > 2%) of at Reaction with Eosinophilia and Systemic Symptoms (DRESS) in favor of RPV with respect to changes least moderate to • Severe depressive disorders have been reported. lipid measures. severe intensity (> • Hepatic adverse events have been reported in patients with underlying liver

Rilpivirine Grade 2) were disease, including hepatitis B or C coinfection, or in patients with elevated depressive disorders, baseline transaminases. A few cases of hepatotoxicity have occurred in patients headache, insomnia with no pre-existing hepatic disease. and rash. • Patients may develop redistribution/accumulation of body fat or immune reconstitution syndrome.

32 Common Adverse Reactions Warnings & Precautions

Non-Nucleoside Reverse Transcriptase Inhibitors

Prescribing Information Package Insert

Prescribing Information Package Insert • Life threatening skin reactions have been reported, including cases of • The most frequently reported drug-related adverse event was skin rash Stevens-Johnson syndrome and erythema multiforme. • Other common reported adverse events included: fatigue, headache, and • Use with caution with liver impairment and CYP

Delavirdine nausea • Patients may develop redistribution/accumulation of body fat or immune reconstitution syndrome.

Prescribing Information Package Insert

Prescribing Information Package Insert • The most common adverse drug reactions of moderate to severe intensity • Life threatening skin reactions have been reported, including cases of (at least 2%) which occurred at a higher rate than placebo in adults are Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema rash and peripheral neuropathy. multiforme. Etravirine • The most common adverse drug reactions in at least 2% of pediatric

patients are rash and diarrhea.

Entry Inhibitors Prescribing Information Package Insert

Prescribing Information Package Insert • Injection Site Reaction: 98% of subjects experienced at least one injection • Most common adverse reactions are local injection site reactions, site reaction in randomized, controlled, open-label, multicenter trials. diarrhea, nausea, and fatigue. • Administration with needleless Biojector® 2000 may result in neuralgia

Enfuvirtide and/or paresthesia, bruising and hematomas. • Antiretroviral therapy may result in immune reconstitution syndrome Prescribing Information Package Insert • The most common adverse events in treatment-experienced adult subjects (greater than 8% incidence) which occurred at a higher Prescribing Information Package Insert frequency compared with placebo are upper respiratory tract infections, • Hepatotoxicity accompanied by severe rash or systemic allergic reaction,

cough, pyrexia, rash, and dizziness. including potentially life-threatening events, has been reported. • Most common adverse events in treatment-naive adults (greater than 8% • Hypersensitivity reactions have been reported, including cases of Stevens- incidence) which occurred at a higher frequency than the comparator Johnson syndrome and toxic epidermal necrolysis. arm were upper respiratory tract infections, bronchitis, flatulence, Maraviroc • More cardiovascular events, including myocardial ischemia and/or infarction, bloating and distention, upper respiratory tract signs and symptoms, and were observed in treatment-experienced subjects gastrointestinal atonic and hypomotility disorders.

• Adverse reactions occurring in the pediatric ART-experienced population (greater than or equal to 3% incidence) were vomiting, abdominal pain, diarrhea, nausea, and dizziness. Abbreviation key: ART- antiretroviral therapy, AVR-antiretroviral, CDC- Centers for Disease Control and Prevention, DHHS- Department of Health and Human Services, DTG- dolutegravir, EVG- elvitegravir, INSTI- Integrase Strand Transfer Inhibitor, oPEP- occupational post-exposure prophylaxis, PK- pharmacokinetic, PEP- post-exposure prophylaxis, PHS- Public Health Service, PrEP- pre-exposure prophylaxis, NVP- nevirapine, RPV- rilpivirine, WHO- World Health Organization

33 Summary

INSTIs- The use of dolutegravir and raltegravir for induction of virological suppression is well- established.3 Studies have demonstrated that dolutegravir has a higher barrier of resistance compared to raltegravir.35,71 Studies using an INSTI in intensification and simplification strategies have been conducted,49 however, no direct comparisons of DTG and RAL were identified for these scenarios. Of the single-ingredient INSTIs, dolutegravir is dosed once daily and raltegravir is dosed twice daily. In the treatment-naive population, the virological-success efficacy of dolutegravir was non-inferior to raltegravir at both 48 and 96 weeks.70,72 For the treatment-experienced population, DTG treatment resulted in a marginally superior efficacy compared to RAL.71 The safety of dolutegravir and raltegravir are comparable with respect to adverse events and discontinuation rates.34,70,71,73 All INSTIs are recommended as first-line options among initial ARV-combination regimens since they are considered to be well-tolerated and provide durable efficacy and favorable toxicity profiles.3,25 NNRTIs—Meta-analyses have demonstrated similar efficacy of nevirapine and rilpivirine compared to efavirenz in terms of virological success in initial HIV treatment. 44,74,75 However, nevirapine has failed to meet non-inferiority in several RCTs, thus the DHHS guideline reserves recommending it for adults and adolescents.3,63,65,67 EFV and RPV are recommended as alternative-line options in initial therapy.3 RPV has shortcomings for the subpopulation with a baseline HIV RNA >100,000 copies/mL or with a baseline CD4 count <200 cells/mL.80 There is contradictory SR evidence to differentiate CNS and rash risk between EFV versus NVP and RPV, respectively. More recent RCTs suggest RPV produces less rash and CNS risk compared to EFV.77-80 EFV has demonstrated more impaired mental function risk compared to NVP, while rash risk is probably similar.74 Yet, NVP has a boxed warning for life-threatening hypersensitivity reactions.11,74 In addition, NVP seems to raise transaminases more significantly and is associate with a higher neutropenia risk than EFV.74 No head-to-head trials meeting the inclusion/exclusion criteria were identified to directly compare nevirapine versus rilpivirine. Etravirine is indicated in treatment-experienced patients with resistance to other NNRTIs, as it has a higher barrier to resistance. The DHHS comments that there is insufficient data to support its use in ART-naïve patients, and reserves recommending it for this population.3 No head-to-head trials meeting the inclusion/exclusion criteria were identified for etravirine versus another NNRTI. The DHHS does not recommend delavirdine-based regimens and generally considers it to be inferior to other recommended regimens.3 The PI insert warns of insufficient data comparing delavirdine regimens with currently preferred 3-drug regimens for initial treatment and warns of its low performance/durability against 2-drug suboptimal therapies.8 No head-to-head trials meeting the inclusion/exclusion criteria were identified for delavirdine versus another NNRTI. EIs— There were no head-to-head trials to directly compare the approved entry inhibitors. The DHHS guidelines reserve recommending the entry inhibitors for initial therapy; however, of the two, maraviroc’s labeling does not restrict its use to ARV-experienced patients.3,25 Both entry inhibitors are approved for use in the pediatric population, with maraviroc carrying approval for a younger subset of this population. A possible user advantage of maraviroc is that it is administered orally, whereas enfuvirtide is administered via subcutaneous injection. Maraviroc may pose more drug-interaction issues since it is metabolized by CYP enzymes, which are not involved in enfuvirtide’s metabolism.

34 Appendix A

Table 1. FDA-Approved Antiretroviral Agents for the Treatment of HIV-1 84,85

Nucleoside & Nucleotide Non-Nucleoside Reverse Integrase Strand Transfer Reverse Protease Inhibitors Entry Inhibitors Pharmacokinetic Enhancer Transcriptase Inhibitors Inhibitors Transcriptase Inhibitors Abacavir (ABC) Delavirdine (DLV) Dolutegravir (DTG) Atazanavir (ATV) Enfuvirtide (ENF) Cobicistat (c or COBI) • Ziagen: ABC • Rescriptor: DLV • Tivicay: DTG • Reyataz: ATV • Fuzeon: ENF •Tybost: c • Epzicom: ABC/3TC • Triumeq: ABC/3TC/DTG • Evotaz: ATV/c •Evotaz: ATV/c • Trizivir: ABC/ZDV/3TC • Genvoya: FTC/EVG/c /TAF • Triumeq: ABC/3TC/DTG • Prezcobix: DRV/c • Stribild: EVG/c /TDF/FTC Didanosine (ddl) Efavirenz (EFV) Elvitegravir (EVG) Darunavir (DRV) Maraviroc (MVC) Ritonavir (r or RTV) • Videx: ddl • Sustiva: EFV • Genvoya: FTC/EVG/c /TAF • Prezista: DRV • Selzentry: MVC • Norvir: r • Atripla: EFV/TDF/FTC • Stribild: FTC/EVG/c /TDF • Prezcobix: DRV/c • Kaletra: r/LPV

Emtricitabine (FTC) Etravirine (ETR) Raltegravir (RAL) Fosamprenavir (FPV) • Emtriva: FTC • Intelence: ETR • Isentress: RAL • Telzir: FPV • Atripla: EFV/TDF/ FTC • Complera: RPV/TDF/FTC • Descovy: FTC/TAF • Genvoya: FTC/EVG/COBI/TAF • Odefsey: RPV/TAF/FTC • Stribild: FTC/EVG/COBI/TDF • Truvada: FTC/TDF Lamivudine (3TC) Nevirapine (NVP) Indinavir (IDV) • Epivir: 3TC • Viramune: NVP • Crixivan: IDV • Combivir: 3TC/ZDV • Epzicom: 3TC/ABC • Trizivir: 3TC/ZDV/ABC • Triumeq: 3TC/ABC/DTG Stavudine (d4T) Rilpivirine (RPV) Lopinavir (LPV) • Zerit: d4T • Edurant: RPV • Kaletra: r/LPV • Complera: RPV/ TDF/FTC • Odefsey: RPV/ TAF/ FTC

35 Tenofovir alafenamide (TAF) Nelfinavir (NFV) • Vemlidy: TAF • Viracept: NFV • Descovy: FTC/TAF • Genvoya: FTC/EVG/COBI/TAF • Odefsey: RPV/TAF/FTC Tenofovir disoproxil (TDF) Ritonavir (r or RTV) • Viread: TDF • Norvir: r • Atripla: EFV/TDF/ FTC • Kaletra: r/LPV

• Complera: RPV/TDF/FTC • Stribild: FTC/EVG/COBI/TDF • Truvada: FTC/TDF Zidovudine (ZDV or AZT) Saquinavir (SQV) • Retrovir: ZDV • Invirase: SQV • Combivir: ZDV/3TC • Trizivir: ZDV/3TC/ABC Tipranavir (TPV) • Aptivus: TPV * Drug agents are grouped by generic name and abbreviation in bold; brand-names and constituents are listed in bullets. Abbreviation key: 3TC-lamivudine, ABC-abacavir, ATV-atazanavir, AZT-zidovudine, c-cobicistat, COBI-cobicistat d4T-stavudine, ddl-didanosine, DVL-delavirdine, DRV-darunavir, DTG-dolutegravir, EFV-efavirenz, ETR-etravirine, EVG-elvitegravir, FTC-emtricitabine, IDV- indinavir, LPV- lopinavir, MVC-maraviroc, NFV- nelfinavir, NVP- Nevirapine, RAL- raltegravir, RPV- rilpivirine, RTV-ritonavir, SAQ-saquinavir, TAF-tenofovir alafenamide, TDF tenofovir disoproxil, TPV-tipranavir, ZDV-zidovudine

Table 2. Timing Concerns for Antiretroviral Therapy Initiation 3,22

Consider Initiation Delays on a Conditions Increasing Urgency of Initiation Case-by-Case Basis Applicable Populations Applicable Populations • Pregnancy •Elite controllers, who are patients with confirmed HIV with persistent undetectable HIV • Acute HIV Infection RNA levels (without treatment) is a rare subgroup where antiretroviral initiation remains • HIV associated dementia/malignancies/neuropathy controversial. • Certain opportunistic infections •Rare exceptions may warrant a delay in initiation. Examples include: cryptococcal and • Hepatitis B or C coinfection tuberculous meningitis (at increased risk of serious Immune Reconstitution Inflammatory • Low CD4 T lymphocyte count Syndrome86)

36 Appendix B

Table 1. MEDLINE & EMBASE Literature Search Strategies for NNRTI Drug Class Ovid MEDLINE OVID Medline: Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to present> Systematic Review Search Strategy (December 8, 2016) 1 reverse transcriptase inhibitors/ or delavirdine/ or efavirenz, emtricitabine, tenofovir disoproxil fumarate drug combination/ or rilpivirine/ or Non- nucleoside reverse transcriptase inhibitor?.ti,ab,kw,kf,rn. (13852) 2 Efavirenz.ti. (1655) 3 Sustiva.ti. (54) 4 etravirine.ti. (335) 5 HIV reverse transcriptase/ (6009) 6 or/1-5 [Reverse Transcriptase Inhibitors] (17993) 7 (metaanaly$ or meta-analy$).ti,pt,ab. or (systematic adj2 review).ti. (174352) 8 6 and 7 (129) 9 exp HIV/ (105532) 10 (HIV or AIDS or acquired immuno$ deficiency or acquired immunodeficienc$).ti,ab. (384016) 11 8 and (or/9-10) (104) 12 8 not 11 (25) 13 remove duplicates from 11 (89) 14 from 13 keep 1-89 (89)

Randomized Controlled Trials Search Strategy (December 31, 2016) 1. reverse transcriptase inhibitors/ or "Emtricitabine, Rilpivirine, Tenofovir Drug Combination"/ or delavirdine/ or "Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination"/ or rilpivirine/ or HIV reverse transcriptase/ 2. ((Non-nucleosid$ or nonnucleosid$ or HIV) adj2 reverse transcriptas$).ti. or ((Non-nucleosid$ or nonnucleosid$ or HIV) adj2 reverse transcriptas$ inhibitors).ab,kw,kf. or reverse transcriptase inhibitors.ab,kw,kf. or reverse transcriptase inhibitor?.ti. 3. NNRTI.ti,ab,kw,kf,rn. 4. (delarvidin$ or delavirdin$ or delaviridin$ or "pnu 90152t" or pnu90152t or rescriptor or "u 90152" or "u 90152e" or "u 90152s" or "u 90152t" or "u90152" or "u90152e" or "u90152s" or "u90152t").ti,ab,kw,kf,rn. or "136817-59-9".rn. 5. (Efavirenz or efavir or filginase or stocrin or sustiva or virorrever or "l 743726" or l743726 or "L 743726" or "L-743,726" or "L-743726" or "L 743,726" or "dmp 266" or dmp266 or "dmp-266").ti,ab,kw,kf,rn. or JE6H2O27P8.rn. 6. (etravirine or intelence or "r 165335;" or "r165335" or "tmc 125" or "tmc125").ti,ab,kw,kf,rn. or ("269055-15-4" or "269055154").rn. 7. (rilpivirine or R278474 or "TMC 278" or (TMC adj "278") or TMC278 or TMC-278).ti,ab,kw,kf,rn. or FI96A8X663.rn. 8. or/1-7 [NNRTI] 9. exp HIV/

37 10. (HIV or (AIDS adj2 (lentivirus$ or retrovirus$ or viral$ or virus$))).ti,ab,kw,kf. 11. (Lymphadenopath$ adj2 (retrovirus$ or virus$)).ti,ab,kw,kf. 12. ((human or acquired) adj2 (immunodefc$ or immuno deficienc$ or immune deficienc$) adj virus$).ti,ab,kw,kf. 13. ((human immuno or immunodeficienc$) adj2 virus$).ti,ab,kw,kf. 14. ("Human T Cell Lymphotropic Virus$" or " Human T Cell Leukemi$ Virus$").ti,ab,kw,kf. 15. (LAV-HTLV or LAVHTLV or (LAV adj AIDS)).ti,ab,kw,kf. 16. or/9-15 [HIV/AIDS] 17. (randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.RCT Strategy 18. exp animals/ not humans.sh. 19. 17 not 18 [Cochrane RCT Filter 6.4.d Sens/Precision Maximizing] 20. 8 and 16 and 19 (2050) [Trial Results] EMBASE (via EMBASE.com)

Systematic Review Search Strategy (December 8th, 2016) ((((('efavirenz'/mj or 'delavirdine'/mj or 'etravirine'/mj or 'rilpivirine'/mj or 'nevirapine'/mj) or (efavirenz*:ti or delavirdin*:ti or etravirin*:ti or rilpivirin*:ti or nevirapin*:ti) or (efavirenz*:ab,tn,rn or delavirdin*:ab,tn,rn or etravirin*:ab,tn,rn or rilpivirin*:ab,tn,rn or nevirapin*:ab,tn,rn) or (sustiva*:ti,ab,tn,rn or je6h2o27p8:ti,ab,tn,rn or 'dmp 266':ti,ab,tn,rn or dmp266:ti,ab,tn,rn or efavir:ti,ab,tn,rn or filginase:ti,ab,tn,rn or 'l 743726':ti,ab,tn,rn or l743726:ti,ab,tn,rn or stocrin*:ti,ab,tn,rn or virorrever*:ti,ab,tn,rn) or (delarvidin*:ti,ab,tn,rn or delaviridin*:ti,ab,tn,rn or 'pnu 90152t':ti,ab,tn,rn or pnu90152t:ti,ab,tn,rn or 'u 90152*':ti,ab,tn,rn or u90152*:ti,ab,tn,rn) or ('tmc 278':ti,ab or tmc278:ti,ab or edurant*:ti,ab or r278474:ti,ab or 'r 278474':ti,ab,tn,rn) or 'nonnucleoside reverse transcriptase inhibitor'/mj or ('nonnucleoside reverse transcriptase inhibitor*':ti,ab or 'non nucleoside reverse transcriptase inhibitor*':ti,ab) or ('154598 52 4':rn or '136817 59 9':rn or '500287 72 9':rn or '700361 47 3':rn)) and ((randomi*:ti,ab or randomly:ti or crossover*:ti,ab or 'cross over*':ti,ab or placebo*:ti,ab or (blind* near/1 (doubl* or singl*)):ti,ab) or ('randomized controlled trial'/de or 'crossover procedure'/de or 'double blind procedure'/de or 'single blind procedure'/de) or (assign*:ti,ab or allocat*:ti,ab or volunteer*:ti,ab))) and ('human immunodeficiency virus'/exp/mj or (aids near/2 (lentivirus or retrovirus or virus)):ti,ab or (hiv:ti,ab or (lymphadenopathy near/2 (retrovirus* or virus*)):ti,ab) or ((human near/2 immuno):ti,ab and deficiency:ti,ab and virus*:ti,ab) or ((human near/2 'immuno deficiency virus*'):ti,ab or (human near/2 'immunodeficiency virus*'):ti,ab))) not ('book'/it or 'chapter'/it or 'conference abstract'/it or 'conference review'/it or 'short survey'/it)) and (('systematic review':ti or 'meta analys*':ti or metaanalys*:ti) or ('meta analysis'/de or 'systematic review'/de))

Randomized Controlled Trials Search Strategy (December 31st, 2016) (((((('efavirenz'/mj or 'delavirdine'/mj or 'etravirine'/mj or 'rilpivirine'/mj or 'nevirapine'/mj) or (efavirenz*:ti or delavirdin*:ti or etravirin*:ti or rilpivirin*:ti or nevirapin*:ti) or (efavirenz*:ab,tn,rn or delavirdin*:ab,tn,rn or etravirin*:ab,tn,rn or rilpivirin*:ab,tn,rn or nevirapin*:ab,tn,rn) or (sustiva*:ti,ab,tn,rn or je6h2o27p8:ti,ab,tn,rn or 'dmp 266':ti,ab,tn,rn or dmp266:ti,ab,tn,rn or efavir:ti,ab,tn,rn or filginase:ti,ab,tn,rn or 'l 743726':ti,ab,tn,rn or l743726:ti,ab,tn,rn or stocrin*:ti,ab,tn,rn or virorrever*:ti,ab,tn,rn) or (delarvidin*:ti,ab,tn,rn or delaviridin*:ti,ab,tn,rn or 'pnu 90152t':ti,ab,tn,rn or pnu90152t:ti,ab,tn,rn or 'u 90152*':ti,ab,tn,rn or u90152*:ti,ab,tn,rn) or ('tmc 278':ti,ab or tmc278:ti,ab or edurant*:ti,ab or r278474:ti,ab or 'r 278474':ti,ab,tn,rn) or 'nonnucleoside reverse transcriptase inhibitor'/mj or ('nonnucleoside reverse transcriptase inhibitor*':ti,ab or 'non nucleoside reverse transcriptase inhibitor*':ti,ab) or ('154598 52 4':rn or '136817 59 9':rn or '500287 72 9':rn or '700361 47 3':rn)) and ((randomi*:ti,ab or randomly:ti or crossover*:ti,ab or 'cross over*':ti,ab or placebo*:ti,ab or (blind* near/1 (doubl* or singl*)):ti,ab) or ('randomized controlled trial'/de or 'crossover procedure'/de or 'double blind procedure'/de or 'single blind procedure'/de) or (assign*:ti,ab or allocat*:ti,ab or volunteer*:ti,ab))) and ('human immunodeficiency virus'/exp/mj or (aids near/2 (lentivirus or retrovirus or virus)):ti,ab or (hiv:ti,ab or (lymphadenopathy near/2 (retrovirus* or virus*)):ti,ab) or ((human near/2 immuno):ti,ab and deficiency:ti,ab and virus*:ti,ab) or

38 ((human near/2 'immuno deficiency virus*'):ti,ab or (human near/2 'immunodeficiency virus*'):ti,ab))) not ('book'/it or 'chapter'/it or 'conference abstract'/it or 'conference review'/it or 'short survey'/it)) and (nct*:cn or eudra*:cn or isrctn*:cn) not (((((('efavirenz'/mj or 'delavirdine'/mj or 'etravirine'/mj or 'rilpivirine'/mj or 'nevirapine'/mj) or (efavirenz*:ti or delavirdin*:ti or etravirin*:ti or rilpivirin*:ti or nevirapin*:ti) or (efavirenz*:ab,tn,rn or delavirdin*:ab,tn,rn or etravirin*:ab,tn,rn or rilpivirin*:ab,tn,rn or nevirapin*:ab,tn,rn) or (sustiva*:ti,ab,tn,rn or je6h2o27p8:ti,ab,tn,rn or 'dmp 266':ti,ab,tn,rn or dmp266:ti,ab,tn,rn or efavir:ti,ab,tn,rn or filginase:ti,ab,tn,rn or 'l 743726':ti,ab,tn,rn or l743726:ti,ab,tn,rn or stocrin*:ti,ab,tn,rn or virorrever*:ti,ab,tn,rn) or (delarvidin*:ti,ab,tn,rn or delaviridin*:ti,ab,tn,rn or 'pnu 90152t':ti,ab,tn,rn or pnu90152t:ti,ab,tn,rn or 'u 90152*':ti,ab,tn,rn or u90152*:ti,ab,tn,rn) or ('tmc 278':ti,ab or tmc278:ti,ab or edurant*:ti,ab or r278474:ti,ab or 'r 278474':ti,ab,tn,rn) or 'nonnucleoside reverse transcriptase inhibitor'/mj or ('nonnucleoside reverse transcriptase inhibitor*':ti,ab or 'non nucleoside reverse transcriptase inhibitor*':ti,ab) or ('154598 52 4':rn or '136817 59 9':rn or '500287 72 9':rn or '700361 47 3':rn)) and ((randomi*:ti,ab or randomly:ti or crossover*:ti,ab or 'cross over*':ti,ab or placebo*:ti,ab or (blind* near/1 (doubl* or singl*)):ti,ab) or ('randomized controlled trial'/de or 'crossover procedure'/de or 'double blind procedure'/de or 'single blind procedure'/de) or (assign*:ti,ab or allocat*:ti,ab or volunteer*:ti,ab))) and ('human immunodeficiency virus'/exp/mj or (aids near/2 (lentivirus or retrovirus or virus)):ti,ab or (hiv:ti,ab or (lymphadenopathy near/2 (retrovirus* or virus*)):ti,ab) or ((human near/2 immuno):ti,ab and deficiency:ti,ab and virus*:ti,ab) or ((human near/2 'immuno deficiency virus*'):ti,ab or (human near/2 'immunodeficiency virus*'):ti,ab))) not ('book'/it or 'chapter'/it or 'conference abstract'/it or 'conference review'/it or 'short survey'/it)) and (('systematic review':ti or 'meta analys*':ti or metaanalys*:ti) or ('meta analysis'/de or 'systematic review'/de))) and [english]/lim)

39 Table 2. MEDLINE & EMBASE Literature Search Strategies for INSTI and EI Drug Classes Ovid MEDLINE OVID Medline: Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to present>

Systematic Review and Randomized Controlled Trials Search Strategy (January 26, 2017) 1 exp HIV/ (108790) 2 (HIV or (AIDS adj2 (lentivirus$ or retrovirus$ or viral$ or virus$))).ti,ab,kw,kf. (320167) 3 (Lymphadenopath$ adj2 (retrovirus$ or virus$)).ti,ab,kw,kf. (401) 4 ((human or acquired) adj2 (immunodefc$ or immuno deficienc$ or immune deficienc$) adj virus$).ti,ab,kw,kf. (602) 5 ((human immuno or immunodeficienc$) adj2 virus$).ti,ab,kw,kf. (99535) 6 ("Human T Cell Lymphotropic Virus$" or " Human T Cell Leukemi$ Virus$").ti,ab,kw,kf. (5959) 7 (LAV-HTLV or LAVHTLV or (LAV adj AIDS)).ti,ab,kw,kf. (228) 8 or/1-7 [HIV/AIDS] (355910) 9 (randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti. (1226256) 10 exp animals/ not humans.sh. (4860425) 11 9 not 10 [Cochrane RCT Filter 6.4.d Sens/Precision Maximizing] (1132816) 12 (metaanaly$ or meta-analy$).ti,kw,kf,pt,ab. (144422) 13 (systematic adj2 review).ti,kw,kf. (75921) 14 (or/12-13) not 10 [SR-Filter- not validated] (184094) 15 Integrase Inhibitors/ (125) 16 integrase inhibit$.ti,ab,kw,kf,rn. (1805) 17 Raltegravir Potassium/ (1105) 18 (raltegravir$ or isentress$).ti,ab,kw,kf,rn,nm,ps,px. (1902) 19 (Dolutegravir$ or tivicay).ti,ab,kw,kf,rn,nm,ps,px. (492) 20 (Elvitegravir$ or Vitekta$).ti,ab,kw,kf,rn,nm,ps,px. (505) 21 or/15-20 [Integrase Inhibitors] (3276) 22 HIV Integrase Inhibitors/ (1748) 23 (HIV? adj2 integrase?).ti,ab,kw,kf,rn,nm,ps,px. (3251) 24 or/22-23 [HIV Integrase Inhibitors] (3251) 25 HIV Fusion Inhibitors/ (1385) 26 (HIV adj2 (Fusion or entry) adj2 inhibitor?).ti,ab,kw,kf,rn,nm,ps,px. (1875) 27 (enfuvirtide? or fuzeon?).ti,ab,kw,kf,rn,nm,ps,px. (1140) 28 (maraviroc? or Selzentr$).ti,ab,kw,kf,rn,nm,ps,px. (1199) 29 or/22-25 [HIV Fusion/Entry Inhibitors] (4570) 30 (and/8,21) or (or/24,29) [ Results before filters: Integrase Inhibitors & HIV OR HIV Fusion or Integrase Inhibitors] (5971)

40 31 (30 and 14) not 10 [SR Results] (30) 32 (and/11,30) not 31 [RCT Results] (710) 33 remove duplicates from 31 [SR Results to Export] (22) 34 remove duplicates from 32 [RCT Results to Export] (539) 35 limit 34 to english language (501)

Secondary Search on “anti-HIV-agents” (January 26, 2017) 33 *Anti-HIV Agents/ or ((anti-hiv or antihiv) adj2 (agent? or drug?)).ti,kw,kf. (33332) 34 (and/14,33) not (or/10,31-32) [Anti-HIV Drugs SRs] (345) 35 remove duplicates from 31 [SR Results to Export] (22) 36 remove duplicates from 32 [RCT Results to Export] (539) 37 limit 36 to english language (501) EMBASE (via EMBASE.com)

Systematic Review Strategy (February 6th, 2017) (('integrase inhibitor'/mj or 'raltegravir'/mj or 'dolutegravir'/mj or 'dolutegravir plus rilpivirine'/mj or 'elvitegravir'/mj) or ('integrase inhibit*':ti,ab or raltegravir*:ti,ab or isentress*:ti,ab or dolutegravir*:ti,ab or tivicay:ti,ab or elvitegravir*:ti,ab or vitekta*:ti,ab) and ('human immunodeficiency virus'/exp/mj or (aids near/2 (hiv or lentivirus* or retrovirus* or viral* or virus*)):ti,ab or (('immun* deficiency' or immunodeficiency) next/2 virus*):ti,ab)) or ((hiv* next/2 integrase*):ti,ab or (hiv next/2 (fusion or entry) next/2 inhibitor*):ti,ab or (enfuvirtide*:ti,ab or fuzeon*:ti,ab or maraviroc*:ti,ab or selzentr*:ti,ab)) not ('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de not ('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de and ('human'/exp or 'human cell'/de))) and ((metaanaly*:ti,ab or 'meta analy*':ti,ab or (systematic near/2 review):ti) or ('systematic review'/de or 'meta analysis'/de)) and [2003-2017]/py

Randomized Controlled Trials Search Strategy (February 6th, 2017) ((('integrase inhibitor'/mj or 'raltegravir'/mj or 'dolutegravir'/mj or 'dolutegravir plus rilpivirine'/mj or 'elvitegravir'/mj) or ('integrase inhibit*':ti,ab or raltegravir*:ti,ab or isentress*:ti,ab or dolutegravir*:ti,ab or tivicay:ti,ab or elvitegravir*:ti,ab or vitekta*:ti,ab) and ('human immunodeficiency virus'/exp/mj or (aids near/2 (hiv or lentivirus* or retrovirus* or viral* or virus*)):ti,ab or (('immun* deficiency' or immunodeficiency) next/2 virus*):ti,ab)) or ((hiv* next/2 integrase*):ti,ab or (hiv next/2 (fusion or entry) next/2 inhibitor*):ti,ab or (enfuvirtide*:ti,ab or fuzeon*:ti,ab or maraviroc*:ti,ab or selzentr*:ti,ab)) not (('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de not ('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de and ('human'/exp or 'human cell'/de))) or ((('integrase inhibitor'/mj or 'raltegravir'/mj or 'dolutegravir'/mj or 'dolutegravir plus rilpivirine'/mj or 'elvitegravir'/mj) or ('integrase inhibit*':ti,ab or raltegravir*:ti,ab or isentress*:ti,ab or dolutegravir*:ti,ab or tivicay:ti,ab or elvitegravir*:ti,ab or vitekta*:ti,ab) and ('human immunodeficiency virus'/exp/mj or (aids near/2 (hiv or lentivirus* or retrovirus* or viral* or virus*)):ti,ab or (('immun* deficiency' or immunodeficiency) next/2 virus*):ti,ab)) or ((hiv* next/2 integrase*):ti,ab or (hiv next/2 (fusion or entry) next/2 inhibitor*):ti,ab or (enfuvirtide*:ti,ab or fuzeon*:ti,ab or maraviroc*:ti,ab or selzentr*:ti,ab)) not ('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de not ('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de and ('human'/exp or 'human cell'/de))) and ((metaanaly*:ti,ab or 'meta analy*':ti,ab or (systematic near/2 review):ti) or

41 ('systematic review'/de or 'meta analysis'/de)) and [2003-2017]/py)) and ('clinical study'/de or 'clinical trial'/de or 'controlled clinical trial'/de or 'controlled study'/de or 'major clinical study'/de or 'randomized controlled trial'/de or 'control group'/de or ((clinical or randomi* or controlled or multicentre or multicenter or 'multi centre' or 'multi center') near/3 (study or trial)):ti,ab or placebo:ab,ti) and [2003-2017]/py and [english]/lim) not (((('integrase inhibitor'/mj or 'raltegravir'/mj or 'dolutegravir'/mj or 'dolutegravir plus rilpivirine'/mj or 'elvitegravir'/mj) or ('integrase inhibit*':ti,ab or raltegravir*:ti,ab or isentress*:ti,ab or dolutegravir*:ti,ab or tivicay:ti,ab or elvitegravir*:ti,ab or vitekta*:ti,ab) and ('human immunodeficiency virus'/exp/mj or (aids near/2 (hiv or lentivirus* or retrovirus* or viral* or virus*)):ti,ab or (('immun* deficiency' or immunodeficiency) next/2 virus*):ti,ab)) or ((hiv* next/2 integrase*):ti,ab or (hiv next/2 (fusion or entry) next/2 inhibitor*):ti,ab or (enfuvirtide*:ti,ab or fuzeon*:ti,ab or maraviroc*:ti,ab or selzentr*:ti,ab)) not (('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de not ('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de and ('human'/exp or 'human cell'/de))) or ((('integrase inhibitor'/mj or 'raltegravir'/mj or 'dolutegravir'/mj or 'dolutegravir plus rilpivirine'/mj or 'elvitegravir'/mj) or ('integrase inhibit*':ti,ab or raltegravir*:ti,ab or isentress*:ti,ab or dolutegravir*:ti,ab or tivicay:ti,ab or elvitegravir*:ti,ab or vitekta*:ti,ab) and ('human immunodeficiency virus'/exp/mj or (aids near/2 (hiv or lentivirus* or retrovirus* or viral* or virus*)):ti,ab or (('immun* deficiency' or immunodeficiency) next/2 virus*):ti,ab)) or ((hiv* next/2 integrase*):ti,ab or (hiv next/2 (fusion or entry) next/2 inhibitor*):ti,ab or (enfuvirtide*:ti,ab or fuzeon*:ti,ab or maraviroc*:ti,ab or selzentr*:ti,ab)) not ('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de not ('animal'/exp or 'invertebrate'/exp or 'animal experiment'/exp or 'animal model'/exp or 'animal tissue'/exp or 'animal cell'/exp or 'nonhuman'/de and ('human'/exp or 'human cell'/de))) and ((metaanaly*:ti,ab or 'meta analy*':ti,ab or (systematic near/2 review):ti) or ('systematic review'/de or 'meta analysis'/de)) and [2003-2017]/py)) and ('clinical study'/de or 'clinical trial'/de or 'controlled clinical trial'/de or 'controlled study'/de or 'major clinical study'/de or 'randomized controlled trial'/de or 'control group'/de or ((clinical or randomi* or controlled or multicentre or multicenter or 'multi centre' or 'multi center') near/3 (study or trial)):ti,ab or placebo:ab,ti) and [2003-2017]/py) and ('chapter'/it or 'conference abstract'/it))

42 Appendix C

Table 1. Evidence for the Integrase Strand Transfer Inhibitor Drug Class

Patient Treatment Study Design N Efficacy Results Safety & Discontinuation Endpoints Population Interventions Systematic Reviews Jiang et al.; 201634 1537 • Treatment naïve [DTG 50mg QD vs. Virological Response: proportion of Serious Drug-Related Adverse Reactions: and experienced RAL 400mg BID]+ patients achieving HIV RNA, 50 Results showed no statistically significant difference Meta-Analysis patients—see BB copies/mL between DTG 50mg QD vs. RAL 400mg BID sub-analysis • Pooled two non- individual RCT Results showed as statistically significant inferior RCTs studies below difference of the treatment effects in comparing DTG to • Studies with Used fixed effects favor of DTG RAL containing efficacy outcomes of Mantel–Haenszel M-H, fixed, ITT (RR 1.06 95% CI 1.01– regimens; outcomes interest after at 48 model to obtain 1.12), Z = 2.23 (p = 0.02), I2 = 54 % (p = were at the 48 week weeks of treatment weight-related 0.14) time point • Excluded non- risks • Included the randomized SAILING and SPRING- observational 2 studies outlined studies, studies with below structured treatment • Literature searched interruptions, switch up to July, 2013 studies

Patel, et al.; 201473 RAL arm: • ART-treatment [DTG 50mg QD vs. Primary Efficacy Endpoints Safety Endpoints N= 692 naïve patients >13 RAL 400mg BID]+ • Probability of HIV suppression below • Adverse Events and Discontinuations due to AEs years old infected BB 50copies/mL at 48 weeks; backbone - DTG vs RAL: no significant difference Meta-Analysis DTG arm: with HIV-1 adjusted results • Lipid changes: No significant differences were found • Bayesian fixed- N= 825 • Studies with - DTG vs RAL: no significant (based on backbone adjusted results) between treatment effect network meta- efficacy outcomes of difference found arms DTG vs RAL with respect to TC, HDL, LDL, analysis Node interest after at 48 • Statistically • CD4 cell increase at 48 weeks; • TG increase; backbone adjusted results evaluating 48 week Connections: weeks of treatment adjusted results to backbone adjusted results DTG vs RAL (12.78, 95% CI 0.58, 25.32), in favor of RAL efficacy, comparing 1:1 indirect • Excluded non- account for the - DTG vs RAL: no significant DTG to RAL nodes ratio & randomized variation of NRTI difference found containing regimens 1 direct node observational backbones used • Literature searched of connection studies, studies with up to August, 2013 structured treatment interruptions, switch studies,

43 Randomized Controlled Trials Cahn, et al.; 201471 715 • ART-treatment [DTG 50mg QD vs. Primary Efficacy Endpoint Adverse Events SAILING study experienced adults, RAL 400mg BID]+ • Virological Response: proportion of AE frequencies were similar between arms; the most INSTI naïve, with BB patients achieving HIV RNA<50 common reported events for DTG vs. RAL were: • Non-inferior with resistance to > 2 ARV copies/mL • Diarrhea (20% vs 18% of patients) superiority drug classes, taking 1 Investigator DTG demonstrated non-inferiority and • Upper respiratory infection (11% vs 8%) assessment, to 2 fully active selected BBs (i.e. superiority to RAL • Headache (9% vs 9%) multinational, background drugs NRTI + PI, NNRTI + (Adjusted Difference: 7.4%, 95% CI 0.7 Select grade 3-4 laboratory abnormalities randomized- • Excluded PI, etc.) were well- to 14.2; superiority test with p=0.03) • Alanine aminotransferase (3% vs 2%) controlled, double- pregnancy, moderate balanced between • Cholesterol (2% vs 4%) blind trial comparing or severe hepatic groups Secondary Efficacy Endpoint • Creatinine (<1% vs <1%) DTG to RAL impairment, need for • Virological Failure: • Hyperglycemia (1% vs 2%) regimens; outcomes hepatitis C virus Stratified results (Adjusted Difference: -3.7.%, 95% CI -6.1 • Creatinine Phosphate (11% vs 8%) were surveyed at 48 therapy, malignancy, based # of active to -1.2.; p=0.003) • Headache (9% vs 9%) weeks or recent HIV background AEs Leading to Discontinuation: Rates were infrequent in vaccines, radiation agents both groups, DTG vs RAL (3% vs 4%) therapy, cytotoxic chemotherapy, or Non-inferior *Statistical difference evaluation was not conducted for immunomodulators margin: 12% these outcomes Raffi, et al.; 201370,72 822 • ART-treatment [DTG 50mg QD vs. Primary Efficacy Endpoint Adverse Events SPRING-2 study naïve adults, with no RAL 400mg BID]+ Virological Response: proportion of AE frequencies were similar between arms; the most primary resistance to 2NRTIs patients achieving HIV RNA< 50 commonly reported events for dolutegravir versus • Non-inferior reverse transcriptase copies/mL raltegravir were: double-blind, or protease enzymes Investigator Non-inferiority of DTG was • Nausea (15% vs. 14%) multinational RCT • Excluded selected TDF/FTC demonstrated at 48 and 96 weeks; ITT • Nasopharyngitis (13% vs. 14%) comparing DTG to pregnancy, moderate or ABC/3TC results • Diarrhea (14% vs. 13%) RAL regimens; or severe hepatic backbone; • 48 Week: DTG vs RAL (88% vs 86%; • Upper respiratory infection (8% vs 7%) outcomes were impairment, Baseline backbone adjusted difference: 2.5%; 95% CI • Headache (14% vs 13%) 72 surveyed at 48 and CrCL<50mL/min, distribution was -2.2 to 7.1) • Dizziness (6% vs. 6%) 96 weeks expected need for well-balanced • 96 Week: DTG vs RAL (81% vs 76%; • Fatigue (5% vs. 6%) hepatitis C virus between groups adjusted difference in proportion: • Depression (6% vs. 5%) 70 therapy, malignancy, and statistical 4.5%; 95% CI -1.1 to 10.0) • Insomnia (6% vs 5%) or recent treatment stratification with • Rash (5% vs 5%) with HIV vaccines, or respect to BB was Secondary Efficacy Endpoint • Anxiety (4% vs. 5%) immunomodulators. carried out Virological Failure: defined as confirmed • Lipids: no clinically significant changes in the fasting lipids HIV-1 RNA ≥50 copies/mL on or after Mean Increase in Serum Creatinine: DTG vs RAL (µmol/L) Non-inferior week 24.(Adjusted Difference: -3.7.%, • 48 wks: 12.3 vs. 4.7 µmol/L margin: 10% 95% CI -6.1 to -1.2.; p=0.003) • 96 wks: 14.6 vs. 8.2 µmol/L

• 96 wks: eCrCl change -19.6 vs. -9.3 mL/min

AEs Leading to Discontinuation: Rates were infrequent in both groups, DTG vs RAL (2% in both arms) Abbreviation key: 3TC-lamivudine, ABC-abacavir, ART-antiretroviral therapy, ARV- antiretroviral, BB-backbone, CI-confidence interval, CrCL-creatinine clearance, DTG- dolutegravir, EFV-efavirenz, eGFR-estimated glomerular filtration rate, ENF-enfuvirtide, ER-extended release, ETR-etravirine, EVG-elvitegravir, FTC-emtricitabine, HDL- high density lipoprotein, INSTI-integrase strand transfer inhibitor, LDL-low density lipoprotein, M-H-Mantel Haenzel, MVC-maraviroc, NNRTI- non-nucleotide reverse transcriptase inhibitor, NRTI-nucleoside reverse transcriptase inhibitor, NVP-nevirapine, PI- protease inhibitor, QD- once daily, RAL- raltegravir, RPV- rilpivirine, TC-total cholesterol, TG- triglycerides, TID- three times daily, wks-weeks

Table 2. Evidence for the Non-Nucleoside Reverse Transcriptase Inhibitor Drug Class

Patient Treatment Safety & Discontinuation Study Design N Efficacy Results Population Interventions Endpoints Systematic Reviews Mbuagbaw et al.; See individual • ART-naiive or limited [EFV vs. NVP]+ Primary Efficacy Endpoints Primary Safety Endpoints 201674 endpoints for N pre-exposure, adults 2NRTIs • Proportion of patients achieving • All severe adverse events; 8 trials, N=2329 and children infected undetectable plasma HIV RNA; 10 trials, N= • Discontinuation rate; 9 trials, N=2384 with HIV 2438 No statistical difference between groups for Meta-Analysis • Excluded children • Mortality; 8 trials, N=2317 primary safety endpoints • Included 12 RCTs under 5, pregnant or Data analyzed on • Clinical progression to AIDS; 5 trials, N= 2005 comparing EFV and nursing women, and intention to treat basis Comparable findings resulted with no statistical Secondary Endpoints NVP containing studies assessing first difference between groups for all primary • Individual adverse events: No statistical regimens line ARV treatments endpoints difference found between groups when • Literature searched with a non-3-drug- considering the following adverse events: up to August 12th, containing ART Secondary Endpoints gastrointestinal (6 trial), pyrexia (3 trials), 2016 regimen. • Change in mean CD4 count; 9 trials, N= 1829 raised alkaline phosphatases (1 trial), • Treatment failure; 5 trials, N=737 elevated amylase (2 trials), elevated • Available studies Comparable findings resulted with no statistical triglycerides (2 trials), elevated SGOT (1 included were mostly difference between groups for the secondary trial), elevated SGPT (1 trial), and elevated applied to ages 18 and endpoints above cholesterol (1 trial) older • Development of ART resistance; 4 trials, • Risk of central nervous system adverse • Assessments on N=988 events; 6 trials, N= 2049 subpopulations with Resulted in slightly lower incidence in EFV arm Higher in the EFV arm (RR 4.46, 95% CI hepatitis B/C and (RR 0.76, 95% CI 0.60 to 0.95, P=0.02) 1.65 to 12.03; P = 0.003) tuberculosis were • Risk of raised transaminase; 3 trials, N= carried out Subgroup Analyses 1299 • Hepatitis co-morbidity: data was insufficient Lower in the EFV arm than in the NVP arm to make assessments (RR 0.52, 95% CI 0.35 to 0.78; P = 0.001) • Concurrent treatment for tuberculosis: no • Risk of neutropenia; 3 trials, N= 1799 significant subgroup effects for tuberculosis Lower in the EFV arm (RR 0.48, 95% CI treatment with regard to any of the primary 0.28 to 0.82; P = 0.007) efficacy endpoints • Risk of Rash; 7 trials, N= 2277 • Dosage effect: Mortality was lower in the Lower trend in the EFV arm, however EFV arm than in the NVP 400 mg subgroup statistical significance was not met (RR (RR 0.34, 95% CI 0.13 to 0.90; P = 0.03) 0.58, 95% CI 0.34 to 1.00; P = 0.05) Ford et al.; 201582 See individual • ART treatment naïve [EFV vs. NVP] in a 3- NONE Primary Endpoint: Drug discontinuation as a treatment arms HIV positive children drug ART regimen result of treatment related adverse events: Meta-Analysis for N and adults N= 2,936, 9 studies - Lower risk with EFV compared with NVP • Included RCTs and • Excluded switch (RR=0.7, 95% CI 0.5 to 0.9; RD: -3.6) quasi-RTCs studies, and studies [EFV vs. RPV]+ BB - Statistical difference not found for EFV comparing EFV to that only included N= 2,522, 4 studies compared to RPV (RR=2.0, 95% CI: 1.0 to NVP and RPV patients with specific 3.8; RD: 4.1, 95% CI: 1.3 to 6.8) comorbidities

45 • Literature Secondary Endpoint searched up to • Risk of severe clinical adverse events (not October 2014 reported for RPV comparison) • Risk of severe CNS events • Risk of severe laboratory events No significant difference between groups was found for the secondary safety endpoints Li et al.; 201576 2522 • ART treatment naïve [EFV vs. RPV] in a 3- Primary Endpoints Treatment Related Adverse Events HIV positive adults with drug ART regimen • Proportion of patients with HIV-1 RNA <50 • Treatment related rash (any grade): Meta-Analysis viral sensitivity to TDF copies/mL at 48 weeks Lower with RPV than with EFV group • Included 4 RCTs and FTC RPV demonstrated non-inferior antiviral (RR=0.11; 95% CI, 0.03-0.33) comparing EFV and • Exclusion criteria: Outcome is based on efficacy. Study heterogeneity was not • Pooled neurological events of interest NVP containing documented NNRTI pooled data from significant (I2=0%) Lower with RPV than with EFV regimens resistance mutations, studies with both (RR, 0.52; 95% CI, 0.45-0.60) • Literature active clinically complete single-tablet Secondary Endpoint searched up to significant disease, regimens (STaR study) Virological failure rates: October 2013 pregnancy or nursing and multi-pill RPV group demonstrated higher failure rates regimens (ECHO and compared to the EFV group TRHIVE studies) (RR=1.70; 95% CI, 1.21-2.38).

Kawalec et al.; See individual • ART treatment naïve [EFV vs. NVP] in a 3- Efficacy Endpoints Discontinuation due to adverse events; 4 201375 endpoints for N or limited pre- drug ART regimen • Proportion of patients with disease trials, N= 1,360 exposure, HIV positive progression or death; 3 trials, N=1,253 No statistical difference was found between Meta-Analysis adults • Virological response (HIV RNA< 50 and groups with respect to discontinuation of • Included 6 RCTs • Excluded patients A fixed effects model <400 copies/mL) in weeks 48-52; 5 trials, therapy due to adverse events. comparing EFV and with documented was used in absence N=1,970 NVP containing clinically significant of heterogeneity; No statistical difference between groups for regimens disease state, otherwise the random the above efficacy endpoints • Literature searched concurrent effects model was up to December opportunistic infection, used 2012 pregnant or nursing patients Pillay et al.; 201344 See individual • ART treatment naïve [EFV vs. NVP] + 2 Primary Endpoints Discontinuation due to any cause; 5 RCTs, N endpoints for N patients NRTIs EFV vs NVP =1648 Meta-Analysis • Excluded pregnancy, • Proportion of patients achieving virological No significant difference found • Included 10 RCTs ART experienced, Outcomes based on success; 8 RCTs, N= 2550, all NVP 200mg BID - The majority of treatment comparing EFV and virological rebound, ITT and pooled using 73.7% vs. 70.4% (RR 1.04 95%CI 1.00–1.08) discontinuations were driven by adverse NVP containing studies lacking where random effects meta- • Virologic failure; 6 RCTs, N= 1572 events. regimens viral load measures, analysis 16.7% vs 20.7% failed treatment (RR 0.85 • Literature searched and switch studies [0.73– 0.99], I2 = 0%) in favor of EFV up to May 2013 • Proportion of TB-coinfected patients achieving virological success; 6 RCTs, N=1187 No statistical difference found between arms

46 Secondary Endpoint EFV vs NVP • Mortality rate; 4 RCTs, N= 1067 No significant difference found Randomized Controlled Trials van Lunzen et al.; 786 • ART treatment (RPV 25mg QD vs. Primary Endpoint Treatment-emergent Adverse Events 201677 naïve HIV-1- EFV 600mg QD)/FTC • Successful virological suppression (HIV-1 RNA • Pooled nervous system events (dizziness, [STaR study-week 96] infected adults with 200mg/TDF 300mg < 50 copies/mL) at week 96 (using Snapshot somnolence, headache) favored RPV HIV RNA> 2500 algorithm) • (RPV 27.2% vs. EFV 47.4%, p<0.001) • Non-inferiority copies/ml at Each arm consisted of Non-inferiority was demonstrated for RPV vs. • Pooled psychiatric events (abnormal RCT, multicenter, screening; with single tablet regimens EFV (77.9% vs. 72.4% respectively; difference dreams, depression, anxiety, insomnia) international, open- sensitivity to EFV, with administration 5.5%, 95% CI -0.6 to 11.5%); Superiority was favored RPV label; superiority was FTC, and TDF, and instructions— to take tested, however, was not significant. • (RPV 28.2% vs. EFV 49%, p< 0.001) tested when non- absence of the RPV with a 500kcal meal • Rash events: favored RPV inferiority was resistance at entry for the RPV group and Stratified Groups: • (RPV 15.7% vs. EFV 24.2%, p= 0.003) demonstrated (i.e. K101E/P, to take on an empty 1. By baseline HIV RNA • Study drug discontinuation due to AEs E138A/G/K/Q/R, stomach for EFV group • Baseline HIV RNA <100,000 copies/mL favored RPV Y181C/I/V, and Statistically significant difference in • (RPV 3.0% vs. EFV 11.0%, p<0.001) H221Y mutations); Margin of non- virological suppression favoring RPV group • Mean changes in fasting lipids from eGFR > 50 ml/min inferiority was set to - (RPV 78.8% vs. EFV 71.2% at week 96; baseline: statistically significant 12% difference 7.2%, 95% CI -1.1–13.4%; differences in most lipid measures (TC, Superiority demonstrated with P=0.046) LDL, HDL) with the exception of TGs • Baseline HIV RNA >100,000 copies/mL favored RPV RPV was non-inferior to EFV group, however, • eGRF change from baseline favored EFV not superior. • (RPV -5.4ml/min vs. EFV +4.6ml/min, • Baseline HIV RNA 100,000 to 500,000 p<0.0001) copies/mL: RPV was non-inferior to EFV • Baseline HIV RNA >500,000/mL: The non- inferiority margin was not met 2. By baseline CD4 Count • CD4 baseline >200 cells/µl; RPV was non- inferior to EFV group • CD4 baseline <200 cells/µl; The non- inferiority margin was not met Cohen et al.; 201481 786 • ART-treatment (RPV 25mg QD vs. Primary Endpoint Treatment-emergent Adverse Events [STaR study-week 48] naïve HIV-1- EFV 600mg QD)/FTC • Successful virological suppression (HIV-1 RNA • Pooled nervous system events (i.e. infected adults with 200mg/TDF 300mg < 50 copies/mL) at week 48 (using Snapshot dizziness, insomnia, somnolence, • Non-inferiority HIV RNA> 2500 algorithm) headache) favored RPV RCT, multicenter, copies/ml at Each arm consisted of Non-inferiority was demonstrated for RPV vs • (RPV 29.7% vs. EFV 50.5%, p<0.001) international, open- screening; single tablet regimens EFV (85.8% vs. 81.6%, respectively; difference • Pooled psychiatric events (i.e. abnormal label; superiority was sensitivity to EFV, with administration 4.1%, 95% CI -1.1 to 9.2%) dreams, depression, anxiety) favored RPV tested when non- FTC, and TDF, and instructions— to take Superiority was tested however, was not • (RPV 15.7% vs. EFV 37.5%, p< 0.001) inferiority was absence of the RPV with a 500kcal meal significant. • Rash events: no statistical difference demonstrated resistance for the RPV group and between groups mutations known at to take on an empty Secondary Endpoint • (RPV 6.1% vs. EFV 12%, p= 0.17) entry (i.e. K101E/P, stomach for EFV group • CD4 count change from baseline E138A/G/K/Q/R, • Time to loss of virological response

47 Y181C/I/V, and • Margin of non- No statistical difference found for these • Study drug discontinuation due to AEs H221Y mutations); inferiority was set secondary endpoints favored RPV eGFR) > 50 ml/min to -12% • (RPV 2.5% vs. EFV 8.7%, p<0.001) Stratified Groups: By baseline HIV RNA • Mean changes in fasting lipids from • Baseline HIV RNA <100,000 copies/mL baseline: statistically significant Statistically significant difference in differences in all measures (TC, LDL, TG, virological suppression favoring RPV (RPV HDL) favored RPV 88.8% vs. EFV 81.6% at week 48; difference • eGRF change from baseline favored EFV 7.2%, 95% CI -1.1–13.4%, Superiority • (RPV -5.4ml/mon vs. EFV +4.6ml/min, demonstrated with P=0.02) p<0.0001) • Baseline HIV RNA >100,000 copies/mL RPV was non-inferior to EFV group (79.9% vs. 81.7%, respectively; difference -1.8%, 95% CI -11.1 to 7.5%) • Baseline HIV RNA 100,000 to 500,000 copies/mL: RPV was non-inferior to EFV • Baseline HIV RNA >500,000/mL: The non- inferiority margin was not met Behrens et al.; 543 patients RCT studies were [RPV 25mg QD vs. Primary Endpoints Treatment Related Adverse Events 201479 included in the double-blind, double EFV 600mg QD] + • Successful virological response (HIV-1 RNA < RPV vs. EFV, Week 96 Results: subsidy analysis dummy design. FTC/TDF 50 copies/mL) at 48 and 96 weeks: • Any AEs (46.9% vs 62.0%, p < 0.001) Sub-study • Included HIV-1 Non-inferiority was demonstrated for both • Grade 2–4 AEs (17.4% vs 30.2%, p < 0.001) • Pooled results from infected ART-naı¨ve Baseline time points • Neurological AEs (19.1% vs 38.4%, p < two non-inferiority adults with any CD4 demographics and - (48-week treatment difference of RPV vs. 0.001) RCTs (THRIVE and cell count, baseline HIV disease characteristics EFV: 4.8%, 95% CI -0.8 to 10.5) • Dizziness (10.4% vs 27.8%, p < 0.001) ECHO) with RNA <100,000 were - (96-week treatment difference of RPV vs. • Psychiatric AEs (16.3% vs 24.7%, p= 0.018) multinational study copies/mL, and similar between the EFV: 2.9%, 95% CI -3.6 to 9.3) • Abnormal dreams/nightmares (7.6% vs sites demonstrated viral RPV + FTC/TDF and 13.7%, p=0.025) sensitivity to the EFV + FTC/TDF groups • Rash (2.1% vs 10.6%, p < 0.001) background NRTIs. No statistical difference for the following: • Excluded patients • ITT-Analysis • Any serious adverse events with known NNRTI • Margin of non- • Adverse events leading to discontinuation resistance, 8 active inferiority was set • Somnolence clinically significant to -12% • Disturbance in attention diseases, renal • Depressive disorder impairment, eGFR < • Sleep disorder 50mL/min, or • pregnant/or Anxiety breastfeeding Laboratory Abnormalities RPV vs. EFV, Week 96 Results: No significant difference between groups with respect to: • hypophosphatemia • pancreatic amylase • AST Significant difference for: • Grade 2-3 LDL (8.7% vs 18.9%, p=0.001)

48 • Grade 2-3 TC (7% vs. 22%, p<0.001) • Grade 2-4 TG (0.7% vs. 3.6%, p=0.028) • Grade 2-4 ALT (6.6% vs. 12.9%, p=0.018) • Grade 2-4 Hyperbilirubinemia (4.2% vs. 0%, p=0.001)

Adherence Through Week 96, a similar proportions of subjects on RPV (85%) and EFV (81%) had adherence levels > 95% using the ITT analysis Nelson et al.; 201378 1,096 patients RCT studies were [RPV 25mg QD vs. Primary Endpoint Treatment Related Adverse Events • double-blind, double EFV 600mg QD] + Successful virological response (HIV-1 RNA < RPV vs. EFV, Week 96 Results • Pooled 96 week dummy design. FTC/TDF 50 copies/mL) at 48 and 96 weeks: • Grade 2–4 treatment-related AEs (17% vs results from two • Included HIV-1 Non-inferiority was demonstrated for both 33%, p < 0.001) non-inferiority RCTs infected ART-naı¨ve • ITT-Analysis time points • Treatment-related Neurological AE (17% (THRIVE and ECHO) adults with any CD4 • Margin of non- - 96 Week Result, 77% RPV vs. 77% EFV vs 37%, p < 0.001) with multinational cell count, with inferiority was set (treatment difference -0.4%, 95% CI -5.4 to • Somnolence (3% vs 6%, p= 0.0159) study sites pretreatment HIV to -12% 4.6) • Dizziness (8% vs 26%, p<0.001) RNA> 5,000 copies/ml, • Disturbance in attention (1% vs 2%, and demonstrated viral Stratified Groups: By baseline HIV RNA p=0.029) sensitivity to the • Baseline HIV RNA <100,000 copies/mL: • Psychiatric AEs (16% vs 27%, p<0.001) background NRTIs. outcome was within non-inferiority margin • • Excluded patients (RPV 83% vs. EFV 80% at week 96, 95% CI - Abnormal dreams/nightmares (9% vs 15%, with known NNRTI 3.9 to 9.1) p=0.003) • resistance, 8 active • Baseline HIV RNA 100,001 to 500,000 Rash (0.2% vs 2%, p = 0.003) clinically significant copies/mL: outcome at 96 weeks was also • Discontinued due to AE (4% vs 9%, diseases, renal within non-inferiority margin p=.001) impairment, eGFR < • For baseline HIV RNA> 500,000, RPV did not No statistical difference between groups 50mL/min, or demonstrate non-inferiority with respect to: depression pregnant/or breastfeeding Laboratory Abnormalities RPV vs. EFV, Week 96 Results No significant difference between groups with respect to: • hypophosphatemia • pancreatic amylase • hyperglycemia Significant difference in ALT, AST, hyperbilirubinemia, LDL and TC, Grade 2-4 lab abnormality

Cohen et al.; 201380 N= 1,368 RCT studies were [RPV 25mg QD vs. Primary Endpoint Treatment Related Adverse Events • double-blind, double EFV 600mg QD] + 2 Successful virological response (HIV-1 RNA < RPV vs. EFV, Week 96 Results Pooled 96 week dummy design. N(t)RTIs 50 copies/mL) • Treatment-related Grade 2–4 AEs (17% vs results from two • Included HIV-1 Non-inferiority was demonstrated for both 33%, p < 0.001) non-inferiority RCTs infected ART-naı¨ve • ITT-Analysis time points

49 (THRIVE and ECHO) adults with any CD4 • Model-adjusted - 96 Week, 78% RPV vs. 78% EFV (treatment • Any Neurological AE (17% vs 38%, p < with multinational cell count, with factors: baseline difference 0%, 95% CI -4.4 to 4.4) 0.001) study sites pretreatment HIV viral load, • Dizziness (8% vs 27%, p<0.001) RNA> 5,000 copies/ml, background N[t]RTI Stratified Groups: • Any Psychiatric AEs (16% vs 24%, p<0.001) and demonstrated viral regimen, and study By baseline HIV RNA with >95% adherence rate • Abnormal dreams/nightmares (8% vs 13%, sensitivity to the as factors • Baseline HIV RNA <100,000 copies/mL: p=0.004) background NRTIs. • Margin of non- outcome was within non-inferiority margin • Rash (4% vs 15%, N < 0.001) • Excluded patients inferiority was set (RPV 86% vs. EFV 86% at week 96, difference No statistical difference between groups with known NNRTI to -12% 0.2 95% CI -5.6 to 6) with respect to: any serious adverse event, resistance, 8 active • For baseline HIV RNA> 100,000, RPV did not deaths, discontinuations due to AEs clinically significant Baseline demographic demonstrate non-inferiority diseases, renal and disease “Most rashes, neurologic adverse impairment, eGFR < characteristics events, and psychiatric adverse events 50mL/min, or were well balanced occurred during the first 4 weeks of pregnant/or between the treatment and were transient. All of these breastfeeding treatment groups adverse events were rare (occurring in _1% of patients) in either group during the The proportions of second year of treatment. The majority of patients receiving rashes were grade 1–2 in severity and there each N(t)RTI were no reported grade 4 events. Most background regimen neurologic and psychiatric adverse events were well balanced were grade 1.” between treatment groups Laboratory Abnormalities RPV vs. EFV, Week 96 Results No significant difference between groups with respect to: • hypophosphatemia • pancreatic amylase • hyperglycemia Lipids: Rilpivirine was associated with a significantly smaller increase from baseline in the following: RPV vs EFV • TC [0.12 vs 0.74 mmol/l] • LDL [0.03 vs 0.37 mmol/l] • TG [0.07 vs 0.14) mmol/l] • HDL [0.11 vs 0.29)mmol/l]

Abbreviation key: 3TC-lamivudine, ABC-abacavir, ART-antiretroviral therapy, ARV- antiretroviral, BB-backbone, CI-confidence interval, CrCL-creatinine clearance, DTG- dolutegravir, EFV-efavirenz, eGFR-estimated glomerular filtration rate, ENF-enfuvirtide, ER-extended release, ETR-etravirine, EVG-elvitegravir, FTC-emtricitabine, HDL- high density lipoprotein, INSTI-integrase strand transfer inhibitor, LDL-low density lipoprotein, M-H-Mantel Haenzel, MVC-maraviroc, NNRTI- non-nucleotide reverse transcriptase inhibitor, NRTI-nucleoside reverse transcriptase inhibitor, NVP-nevirapine, PI- protease inhibitor, QD- once daily, RAL- raltegravir, RPV- rilpivirine, TC-total cholesterol, TG- triglycerides, TID- three times daily, wks-weeks

50 References

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