Drug Class Review

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Drug Class Review

HIV Protease Inhibitors 8:18.08.08 HIV Protease Inhibitors

Atazanavir (Reyataz®) Atazanavir/Cobicistat (Evotaz®) Darunavir (Prezista®) Darunavir/Cobicistat (Prexcobix®) Fosamprenavir (Lexiva®) Indinavir (Crixivan®) Lopinavir/Ritonavir (Kaletra®) Nelfinavir (Viracept®) Ritonavir (Norvir®) Saquinavir (Invirase®) Tipranavir (Aptivus®)

Final Report August 2015

Review prepared by: Melissa Archer, PharmD, Clinical Pharmacist Natalia Ruiz, PharmD Candidate 2016 Candice Nielson, PharmD Candidate 2016 Devin Stock, PharmD Candidate 2016 Gary Oderda, PharmD, MPH, Professor

Table of Contents

Executive Summary ...... 3

Introduction ...... 5 Table 1. Comparison of the HIV Protease Inhibitor Agents ...... 6 Disease Overview ...... 11 Table 2. Summary of HIV Treatments ...... 12 Table 3. HIV/AIDS Disease Staging Systems ...... 21 Table 4. Most Current Clinical Practice Guidelines for the Treatment of HIV ...... 22

Pharmacology ...... 26 Table 5. Pharmacokinetic Properties of the HIV Protease Inhibitor Agents ...... 27

Methods ...... 28

Clinical Efficacy ...... 28 Special Populations ...... 32

Safety ...... 33 Table 6. Adverse Events Reported with the HIV Protease Inhibitor Agents ...... 36

References ...... 40

Appendix: Evidence Tables ...... 56 Evidence Table 1. Systematic Reviews Evaluating the HIV Protease Inhibitors ...... 56 Evidence Table 2. Clinical Trials Evaluating the HIV Protease Inhibitors ...... 57 Evidence Table 3. Excluded Clinical Trials ...... 67

2 Executive Summary

Introduction: Agents used in the treatment of human immunodeficiency virus (HIV) infection include nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), entry inhibitors, fusion inhibitors and integrase inhibitors. Successful treatment of an HIV infection involves combination therapy with multiple direct antiviral agents. This report evaluates the safety and efficacy of the HIV protease inhibitors. Currently, 8 single agent protease inhibitors, one combination agent containing two protease inhibitors and two combination agents containing a protease inhibitor with a pharmacologic booster are available for use in the US: atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir and tipranavir, lopinavir/ritonavir, atazanavir/cobicistat and darunavir/cobicistat.

HIV, the virus that causes acquired immune deficiency syndrome (AIDS), is a worldwide health challenge and is the world’s leading cause of death from infection. The virus causes a chronic infection with a gradual onset of clinical symptoms starting with general malaise and illness, progressing to the development of opportunistic diseases and ultimately death. The goal of HIV therapy is to decrease viral load, increase CD4+ T cell count and prevent opportunistic infections. The biggest challenge to treatment of HIV/AIDS infection is the development of resistance to drug therapy. To prevent viral resistance, an approach called highly active antiretroviral therapy (HAART), combining agents from at least two different drug classes, is recommended for treatment of HIV infection. In general, standard combination therapy consists of two nucleoside reverse transcriptase inhibitors (NRTI) combined with a third antiretroviral agent from one of the other direct-acting antiviral drug classes, such as a protease inhibitor. The US Department of Health and Human Services recommends darunavir/ritonavir in combination with tenofavir and lamivudine or emtricitabine as their preferred PI-based regimen.

Clinical Efficacy: One meta-analysis and 20 comparative clinical trials comparing the efficacy of the HIV protease inhibitors were identified for evaluation. Of the 20 clinical trials identified, 14 evaluated the efficacy of the PI agents in treatment-naïve patients and 6 evaluated the efficacy of the agents in treatment-experienced patients. Each of the HIV protease inhibitors was studied in at least one comparative clinical trial. Overall, the evidence suggests, when used in combination regimens, the protease inhibitors are efficacious in the treatment of HIV-1. The combination protease therapies demonstrated efficacy in treatment-naïve and treatment-resistant patients with treatment durations ranging from 6-192 weeks.

Special Populations: The HIV protease inhibitors demonstrated safety and efficacy in the treatment of HIV in special populations. The PI agents have differing indications but, in general, are recommended in pediatric patients (age <18 years), older adults (age >50 years), pregnant women and in patients with co-infections (hepatitis, tuberculosis, etc.) Of note, adverse events may occur more frequently in pediatric patients and older adults and careful monitoring of bone, kidney, metabolic, cardiovascular and liver health in these patient populations is recommended.

Adverse Drug Reactions: The protease inhibitors are associated with short- and long-term toxicities, which may limit use. The most common adverse events reported with protease inhibitor therapy vary between the agents and may include gastrointestinal irritation, skin 3 reactions and metabolic disturbances. The metabolic disturbances reported with PI use include hyperlipidemia, lipodystrophy and impaired glucose tolerance. Some of the agents cause unconjugated hyperbilirubinemia which is asymptomatic and not generally associated with serious hepatic disease. Clinicians should monitor patients receiving protease inhibitors carefully for adverse events, especially those at risk for altered lipid and glucose metabolism.

Summary: The HIV PI agents are recommended for use in the treatment of HIV/AIDS as part of a comprehensive combination therapy regimen. All patients with HIV should receive Antiretroviral Therapy (ART) to reduce the risk of disease progression and to prevent transmission. Before initiation of ART, genotypic drug-resistance testing is recommended to help guide therapy decisions. In an attempt to reduce or avoid drug-resistance, patients should receive education outlining the benefits and risks of therapy and the importance of adherence before initiation of therapy.

4 Introduction

Human immunodeficiency virus (HIV) is a lentivirus within the family of mammalian retroviruses.1 The virus causes a chronic infection with a gradual onset of clinical symptoms starting with general malaise and illness, progressing to the development of opportunistic diseases and ultimately death.1 Successful treatment of HIV infection involves combination therapy with direct antiviral agents. Agents used in the treatment of HIV infection include nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), entry inhibitors, fusion inhibitors and integrase inhibitors.2,3 This report will evaluate the safety and efficacy of the HIV protease inhibitors. Currently, there are 8 single agent protease inhibitors (atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir and tipranavir), one combination agent containing two protease inhibitors (lopinavir/ritonavir) and two combination agents containing a protease inhibitor with a pharmacologic booster (atazanavir/cobicistat and darunavir/cobicistat).2,3 Table 1 provides a summary of the agents included in this drug class review.

5 Table 1. Comparison of the HIV Protease Inhibitor Agents2,3 Product Route of Available Doses Dosing Generic Administration Available Single Agents Atazanavir Oral capsule 150 mg, 200 mg, Adult dosing (treatment naïve): No (REYATAZ®) 300 mg  300 mg daily w/ritonavir 100 mg daily; 400 mg daily alone

Adult dosing (treatment experienced): Oral powder 50 mg per packet  300 mg daily w/ritonavir 100 mg daily (packet) Pediatric dosing (treatment naïve or experienced):  3 mo‐5 yo ▬ 10‐14.9 kg: 200 mg powder daily w/ritonavir 80 mg daily ▬ 15‐24.8 kg: 250 mg powder daily w/ritonavir 80 mg daily  6‐17 yo ▬ 15‐19.9 kg: 150 mg daily w/ritonavir 100 mg daily ▬ 20‐39.9 kg: 200 mg daily w/ritonavir 100 mg daily ▬ >40 kg: 300 mg daily w/ritonavir 100 mg daily; 400 mg daily alone

Darunavir Oral tablet 75 mg, 150 mg, Adult dosing (treatment naïve): No (PREZISTA®) 400mg, 600mg,  800 mg daily w/ritonavir 100 mg daily 800 mg Adult dosing (treatment experienced; w/o darunavir resistance substitution):  800 mg daily w/ritonavir 100 mg daily

Oral suspension 100 mg/mL Adult dosing (treatment experienced; w/darunavir resistance substitution):  600 mg twice daily w/ritonavir 100 mg twice daily

Pediatric dosing (treatment naïve or experienced w/o darunavir resistance substitution):  3‐17 yo ▬ 10‐10.9 kg: 350 mg daily w/ritonavir 64 mg daily

6 Product Route of Available Doses Dosing Generic Administration Available ▬ 11‐11.9 kg: 385 mg daily w/ritonavir 64 mg daily ▬ 12‐12.9 kg: 420 mg daily w/ritonavir 80 mg daily ▬ 13‐13.9 kg: 455 mg daily w/ritonavir 80 mg daily ▬ 14‐14.9 kg: 490 mg daily w/ritonavir 96 mg daily ▬ 15‐29 kg: 600 mg daily w/ritonavir 100 mg daily ▬ 30‐39 kg: 675 mg daily w/ritonavir 100 mg daily ▬ >40 kg: 800 mg daily w/ritonavir 100 mg daily

Pediatric dosing (treatment experienced w/darunavir resistance substitution):  3‐17 yo ▬ 10‐10.9 kg: 200 mg twice daily w/ritonavir 32 mg twice daily ▬ 11‐11.9 kg: 220 mg twice daily w/ritonavir 32 mg twice daily ▬ 12‐12.9 kg: 240 mg twice daily w/ritonavir 40 mg twice daily ▬ 13‐13.9 kg: 260 mg twice daily w/ritonavir 40 mg twice daily ▬ 14‐14.9 kg: 280 mg twice daily w/ritonavir 48 mg twice daily ▬ 15‐29 kg: 375 mg twice daily w/ritonavir 48 mg twice daily ▬ 30‐39 kg: 450 mg twice daily w/ritonavir 60 mg twice daily ▬ 600 mg twice daily w/ritonavir 100 mg twice daily

Fosamprenavir Oral tablet 700 mg Adult dosing (treatment naïve): No (LEXIVA®)  1400 mg twice daily  Alternate: 1400 mg daily w/ritonavir 100‐200 mg  Alternate: 700 mg twice daily w/ritonavir 100 mg twice daily Oral suspension 50 mg/mL Adult dosing (treatment experienced):  700 mg twice daily w/ritonavir 100 mg

Pediatric dosing (treatment naïve):  >38 wk gestation, > 4wk old ▬ <11 kg: 45 mg/kg twice daily w/ritonavir 7 mg/kg twice daily ▬ 11‐14 kg: 30 mg/kg twice daily w/ritonavir 3 mg/kg twice daily ▬ 15‐19 kg: 23 mg/kg twice daily w/ritonavir 3 mg/kg twice daily ▬ >20 kg: 18 mg/kg (up to 700 mg) twice daily w/ritonavir 3 mg/kg (up to 100 mg) twice daily  >38 wk gestation, > 2 yo, w/o ritonavir

7 Product Route of Available Doses Dosing Generic Administration Available ▬ 11‐19 kg: 30 mg/kg twice daily ▬ >20 kg: 30 mg/kg (up to 1400 mg) twice daily

Indinavir (CRIXIVAN®) Oral capsule 200 mg, 400 mg Adult dosing (treatment naïve): No  800 mg every 8 hours

Adult dosing (treatment experienced):  800 mg every 8 hours

Pediatric dosing:  Limited experience, no current recommendation

Nelfinavir Oral tablet 250 mg, 625 mg Adult dosing (treatment naïve): No (VIRACEPT®)  1250 mg twice daily or 750 mg three times daily

Adult dosing (treatment experienced): Oral powder 50 mg/g  1250 mg twice daily  Alternate: 750 mg three times daily

Pediatric dosing:  2‐13 yo ▬ 45‐55 mg/kg twice daily ▬ Alternate: 25‐35 mg/kg three times daily ▬ Max: 2500 mg/day  >13 yo ▬ 1250 mg twice daily ▬ Alternate: 750 mg three times daily

Ritonavir (NORVIR®) Oral capsule 100 mg Adult dosing: No  600 mg twice daily  Not preferred as primary PI Oral tablet 100 mg  Start at 300 mg twice daily and titrate up

Pediatric dosing:

8 Product Route of Available Doses Dosing Generic Administration Available Oral solution 80 mg/mL  350‐400 mg/m2 twice daily  Not preferred as primary PI  Start at 250 mg/m2 twice daily and titrate up)

Saquinavir Oral capsule 200 mg Adult dosing (treatment naïve): No (INVIRASE®)  1000 mg twice daily w/ritonavir 100 mg twice daily

Adult dosing (treatment experienced): Oral tablet 500 mg  1000 mg twice daily w/ritonavir 100 mg twice daily

Pediatric dosing:  >16 yo; 1000 mg twice daily w/ritonavir 100 mg twice daily

Tipranavir Oral capsule 250 mg Adult dosing (treatment naive): No (APTIVUS®)  500 mg twice daily w/ritonavir 200 mg twice daily

Adult dosing (treatment experienced): Oral solution 100 mg/mL  500 mg twice daily w/ritonavir 200 mg twice daily

Pediatric dosing (treatment experienced):  2‐18 yo ▬ 14 mg/kg twice daily w/ritonavir 6 mg/kg twice daily ▬ Alternate: 375 mg/m2 twice daily w/ritonavir 150 mg/m2 twice daily ▬ Max: tipranavir: 1000 mg/day; ritonavir: 400 mg/day

Dual Protease Inhibitor Lopinavir and Oral tablet 100mg/25mg; Adult dosing (treatment naïve or experienced; w/o efavirenz, nelfinavir, or nevirapine): No Ritonavir (KALETRA®) 200mg/50mg  400 mg/100 mg twice daily

Adult dosing (treatment naïve or experienced; if given w/efavirenz, nelfinavir, or nevirapine; or w/lopinavir resistance substitutions): Oral suspension 80mg/20mg per  Tablet: 500 mg/125 mg twice daily mL  Suspension: 533 mg/133 mg twice daily

Pediatric dosing (w/o efavirenz, nelfinavir, or nevirapine):

9 Product Route of Available Doses Dosing Generic Administration Available  2 wk old‐6 mo ▬ 16 mg/4 mg/kg twice daily ▬ Alternate: 300 mg/75 mg/m2 twice daily  6 mo‐18 yo ▬ <15 kg: 12 mg/3 mg/kg twice daily ▬ 15‐40 kg: 10 mg/2.5 mg/kg twice daily (do not exceed 400 mg/100 mg twice daily) ▬ >40 kg: 400 mg/100 mg twice daily

Pediatric dosing (if given w/efavirenz, nelfinavir, or nevirapine):  6 mo‐18 yo ▬ <15 kg: 13 mg/3.25 mg/kg twice daily ▬ >15 kg: 11 mg/2.75 mg/kg twice daily

Combination Protease Inhibitor and Cytochrome Inhibitor Atazanavir and Oral tablet 300 mg/150 mg Adult dosing (treatment naïve): No Cobicistat (EVOTAZ®)  300 mg/150 mg daily

Adult dosing (treatment experienced):  300 mg/150 mg daily

Pediatric dosing:  Not currently recommended in pediatric patients

Darunavir and Oral tablet 800 mg/150 mg Adult dosing (treatment naïve): No Cobicistat  800 mg/150 mg daily (PREXCOBIX®) Adult dosing (treatment experienced w/o darunavir resistance substitution):  800 mg/150 mg daily

Pediatric dosing:  Not currently recommended in pediatric patients

10 Disease Overview

HIV, the virus that causes acquired immune deficiency syndrome (AIDS), is a worldwide health challenge with approximately 35 million people infected. HIV/AIDS is the world’s leading cause of death from infection.4 Of those infected, over 3 million are children (<15 years old) and the vast majority of those infected live in low- and middle-income countries, with sub- Saharan Africa the most affected region (24.7 million people). In the United States, an estimated 1.2 million people have HIV and up to 14% of those infected are unaware.4,5 Those who are unaware of being infected are a large source of disease transmission and are at risk for developing complications. The diagnosis of new HIV infections in the US has remained relatively constant at 50,000 per year. In Utah, over 100 new cases are diagnosed each year and, in total, nearly 3,000 people are infected.6 HIV is transmitted through exposure to infected blood, reproductive fluids, breast milk and the infection may be transmitted from mothers with an HIV infection to the child during the birthing process. Groups at highest risk of becoming infected with HIV include: men who have sex with men (MSM), African Americans and IV drug users (IDU).1,4

The HIV virus causes infection by fusing with the host cell, sending RNA into the cytoplasm for replication and integrating the subsequent full-length double-stranded DNA virus copy into the host chromosome.1 Once integrated into the host cell, HIV causes a deficiency of helper T cells, a loss of cell mediated immunity and a profound immunodeficiency. Helper T cells with the CD4 molecule on the cell surface act as the primary cellular receptor for HIV. When CD4+ T cell count falls below 500/µL, patients are at a much higher risk of developing opportunistic infections.1 Opportunistic infections which may cause serious disease in patients with HIV infection include P. jiroveci, mycobacterium and cytomegalovirus (CMV).7

Three key enzymes are required for successful HIV viral host infection: reverse transcriptase, integrase and protease. Reverse transcriptase converts the viral RNA into full- length double-stranded DNA, integrase is required for viral DNA insertion into the host genome and the protease enzymes cleave essential virus proteins required for host infection. These enzymes are the sites of action for HIV treatment therapy.1 To prevent viral resistance, an approach called highly active antiretroviral therapy (HAART), combining agents from at least two different drug classes, is recommended for treatment of HIV infection. In general, standard combination therapy in treatment-naïve patients with HIV consists of two nucleoside reverse transcriptase inhibitors (NRTI) combined with a third antiretroviral agent from one of the following classes: a non-nucleoside reverse transcriptase inhibitor (NNRTI), an integrase inhibitor (II) or a protease inhibitor (PI) boosted with ritonavir or cobicistat. Agents used to interfere with the virus' ability to enter the host cell (entry inhibitors and fusion inhibitors) may be considered as part of HAART. Table 2 provides a summary of the drug classes used in the treatment of HIV infection. Overall, the goal of HIV therapy is to decrease viral load, increase CD4+ T cell count and prevent opportunistic infections.7-11

11 Table 2. Summary of HIV Treatments2,3 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Nucleoside Reverse Combivir®: Treatment of HIV infection GlaxoSmithKline, Black Box: Associated with hematologic toxicity, Transcriptase Inhibitors lamivudine and Oral: one tablet twice daily 9/27/97; Generic including neutropenia and anemia, particularly in (NRTI) zidovudine Not recommended in patients requiring Available patients with advanced HIV‐1 disease; Prolonged dosage reduction including pediatric use of zidovudine has been associated with Black Box: Lactic acidosis patients <30 kg, renally‐impaired symptomatic myopathy; Severe, acute and severe hepatomegaly patients with a creatinine clearance <50 exacerbations of hepatitis B have been reported with steatosis, including mL/minute, patients with hepatic in patients who are coinfected with hepatitis B fatal cases, have been impairment virus (HBV) and HIV‐1 and have discontinued reported with the use of lamivudine nucleoside analogs in combination with other Emtriva®: Treatment of HIV infection in Gilead Sciences, Black Box: Severe acute exacerbations of antiretrovirals. emtricitabin (FTC) combination with at least two other 7/2/2003 hepatitis B have been reported in patients who antiretroviral agents have discontinued emtricitabine. Oral: Capsule‐ 200 mg once daily; Solution‐ 240 mg once daily

Epivir®: lamivudine HIV: Treatment of HIV infection in GlaxoSmithKline, Black Box: Severe, acute exacerbations of (3TC) combination with other antiretroviral 11/17/1995; Generic hepatitis B have been reported in patients who agents Available are coinfected with hepatitis B virus (HBV) and Oral: 150 mg twice daily or 300 mg once HIV‐1 and have discontinued lamivudine daily

HBV: Treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation

Epzicom®: abacavir Treatment of HIV infections in GlaxoSmithKline, Black Box: Serious and sometimes fatal and lamivudine combination with other antiretroviral 8/2/2004 hypersensitivity reactions have been associated agents with abacavir; Severe, acute exacerbations of Oral: One tablet (abacavir 600 mg and hepatitis B have been reported in patients who lamivudine 300 mg) once daily are coinfected with hepatitis B virus (HBV) and HIV‐1 and have discontinued lamivudine

12 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Hivid®: zalcitabine, Treatment of HIV infection in Hoffmann‐La Roche, Black Box: Severe peripheral neuropathy dideoxycytidine (ddC) conjunction with other antiretrovirals 6/19/1992 reported; Pancreatitis reported rarely; Hepatic *no longer marketed Oral: 0.75 mg every 8 hours failure and death reported rarely

Retrovir®: zidovudine Treatment of HIV‐1 infection in GlaxoSmithKline, Black Box: Zidovudine has been associated with (ZDV, azidothymidine, combination with at least two other 3/19/1987; May be hematologic toxicity, including neutropenia and AZT) antiretroviral agents; Prevention of generic depending on severe anemia; Prolonged use of zidovudine has perinatal HIV‐1 transmission product been associated with symptomatic myopathy Oral: 300 mg twice daily, IV: 1 mg/kg/dose administered every 4 hours around‐the‐clock

Trizivir®: abacavir, Treatment of HIV‐1 infection in GlaxoSmithKline, Black Box: Serious and sometimes fatal zidovudine, and combination with other antiretroviral 11/14/2000; Generic hypersensitivity reactions have been associated lamivudine agents or alone in patients weighing Available with abacavir; Zidovudine has been associated more than 40 kg with hematologic toxicity; Prolonged use of Oral: One tablet twice daily zidovudine has been associated with symptomatic myopathy; Severe, acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV‐1 and have discontinued lamivudine

Truvada®: tenofovir Treatment of HIV‐1 infection in Gilead Sciences, Black Box: Risk of drug resistance with use for disoproxil fumarate combination with other antiretroviral 8/2/2004 preexposure prophylaxis and emtricitabine agents in adults and pediatric patients ≥12 years of age Oral: One tablet (emtricitabine 200 mg and tenofovir 300 mg) once daily

Pre‐exposure prophylaxis (PrEP) for prevention of HIV‐1 infection in adults who are at high risk for acquiring HIV Oral: One tablet (emtricitabine 200 mg and tenofovir 300 mg) once daily

13 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Videx®: didanosine Treatment of HIV‐1 infection in Bristol Myers‐Squibb; Black Box: Fatal and nonfatal pancreatitis have (ddI) combination with other antiretroviral 10/9/1991, enteric occurred during therapy with didanosine used agents coated 10/31/2000; alone or in combination regimens Oral: <60 kg: 125 mg twice daily May be generic (preferred) or 250 mg once daily, ≥60 depending on product kg: 200 mg twice daily (preferred) or 400 mg once daily; Delayed release capsule (Videx EC): 25 kg to <60 kg: 250 mg once daily, ≥60 kg: 400 mg once daily

Viread®: tenofovir Treatment of HIV‐1 infection in Gilead Sciences, disoproxil fumarate combination with other antiretroviral 10/26/2001 (TDF) agents in adults and pediatric patients ≥2 years of age Oral: 300 mg once daily Treatment of chronic hepatitis B virus (HBV) in patients ≥12 years of age

Zerit®: stavudine Treatment of HIV infection in Bristol Myers‐Squibb, Black Box: Fatal and nonfatal pancreatitis has (d4T) combination with other antiretroviral 6/24/1994; Generic occurred during therapy when stavudine was agents Available part of a combination regimen that included Oral: didanosine <60 kg: 30 mg every 12 hours ≥60 kg: 40 mg every 12 hours

Ziagen®: abacavir Treatment of HIV‐1 infection in GlaxoSmithKline, Black Box: Serious and sometimes fatal sulfate (ABC) combination with other antiretroviral 12/17/1998; May be hypersensitivity reactions have been associated agents generic depending on with abacavir therapy Oral: 300 mg twice daily or 600 mg once product daily

14 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Non‐Nucleoside Reverse Edurant®: rilpivirine Treatment of HIV‐1 infection in Tibotec Therapeutics, Transcriptase Inhibitors combination with other agents 5/20/2011 (NNRTI) Oral: 25 mg once daily

Intelence®: etravirine Treatment of HIV‐1 infection in Tibotec Therapeutics, combination with at least two additional 1/18/2008 antiretroviral agents in treatment‐ experienced patients exhibiting viral replication with documented non‐ nucleoside reverse transcriptase inhibitor (NNRTI) resistance Oral: 200 mg twice daily

Rescriptor®: Treatment of HIV‐1 infection in Pfizer, 4/4/1997 delavirdine (DLV) combination with at least two additional antiretroviral agents Oral: 400 mg 3 times/day

Sustiva®: efavirenz Treatment of HIV‐1 infection in Bristol Myers‐Squibb, (EFV) combination with other antiretroviral 9/17/1998 agents in adults and pediatric patients at least 3 months old and weighing at least 3.5 kg Oral: 600 mg once daily

Viramune®: Treatment of HIV‐1 infection in Boehringer Ingelheim; Black Box: Severe, life‐threatening, and, in some nevirapine (NVP) combination with additional 6/21/1996, XR cases, fatal hepatotoxicity, particularly in the first antiretroviral agents 3/25/2011; Generic 18 weeks, has been reported in patients treated Oral: Immediate release: 200 mg twice Available with nevirapine; Severe, life‐threatening skin daily; Extended release: 400 mg once reactions, including fatal cases, have occurred in daily patients treated with nevirapine; Patients must be monitored intensively during the first 18 weeks of therapy with nevirapine to detect potentially life‐threatening hepatotoxicity or skin reactions

15 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Protease Inhibitors (PI) Agenerase®: Treatment of HIV Infection GlaxoSmithKline, Black Box: The oral solution is contraindicated in amprenavir (APV) Oral: 1.2 g once to twice daily 4/15/1999 infants and children <4 years of age, pregnant *no longer marketed women, patients with hepatic or renal failure, and those receiving metronidazole or disulfiram and should be used with caution in others In August 2007, the manufacturer of amprenavir announced that sales of the drug would be discontinued as of October 2007. This action was taken because demand for amprenavir had declined substantially and because of the availability of other treatment options

Aptivus®: tipranavir Treatment of HIV‐1 infection in Boehringer Ingelheim, Black Box: Clinical hepatitis and hepatic (TPV) combination with ritonavir and other 6/22/2005 decompensation, including some fatalities, have antiretroviral agents; limited to been reported; Both fatal and nonfatal treatment‐experienced or intracranial hemorrhage have been reported. multiprotease inhibitor resistance. Oral: 500 mg twice daily

Crixivan®: indinavir Treatment of HIV infection; should Merck, 3/13/1996 (IDV) always be used as part of a multidrug regimen (at least 3 antiretroviral agents) Oral: 800 mg two to three times daily

Evotaz®: atazanavir Treatment of HIV‐1 infection in adults in Bristol‐Myers Squibb, and cobicistat combination with other antiretroviral 1/29/2015 agents Oral: One tablet (atazanavir 300 mg/cobicistat 150 mg) once daily

Invirase®: saquinavir Treatment of HIV infection; used in Hoffmann‐La Roche, mesylate (SQV; combination with ritonavir and other 12/6/1995 previously antiretroviral agents Fortovase®) Oral: 1000 mg twice daily

16 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Kaletra®: lopinavir Treatment of HIV‐1 infection in Abbott Laboratories, and ritonavir combination with other antiretroviral 9/15/2000 (LPV/RTV) agents Oral: Lopinavir 400 mg/ritonavir 100 mg twice daily

Lexiva®: Treatment of HIV infections in GlaxoSmithKline, fosamprenavir combination with at least two other 10/20/2003 calcium (FOS‐APV) antiretroviral agents Oral: 700‐1,400 mg once to twice daily

Norvir®: ritonavir Treatment of HIV infection; should Abbott Laboratories, Black Box: Coadministration with sedative (RTV) always be used as part of a multidrug 3/1/1996 hypnotics, antiarrhythmics, or ergot alkaloid regimen preparations may result in potentially serious Oral: 600 mg twice daily and/or life‐threatening adverse reactions due to possible effects of ritonavir on the hepatic metabolism of certain drugs

Prezcobix®: darunavir Treatment of HIV‐1 infection, Janssen Therapeutics, and cobicistat coadministered with other antiretroviral 1/29/2015 agents, in treatment‐naive and in treatment‐experienced patients without darunavir resistant‐associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) Oral: One tablet (darunavir 800 mg/cobicistat 150 mg) once daily

Prezista®: darunavir Treatment of HIV‐1 infection, Tibotec Therapeutics, coadministered with ritonavir and other 6/23/2006 antiretroviral agents, in adults and pediatric patients 3 years and older Oral: 800 mg once daily

17 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Reyataz®: atazanavir Treatment of HIV‐1 infections in Bristol‐Myers Squibb, sulfate (ATV) combination with other antiretroviral 6/20/2003 agents in patients ≥3 months weighing ≥10 kg Oral: 300‐400 mg once daily

Viracept®: nelfinavir Treatment of HIV infection in Agouron mesylate (NFV) combination with other antiretroviral Pharmaceuticals, therapies 3/14/1997 Oral: 750 mg 3 times daily or 1250 mg twice daily

Entry Inhibitors Selzentry®: maraviroc Treatment of only CCR5‐tropic HIV‐1 Pfizer, 8/6/2007 Black Box: Hepatotoxicity has been reported with infection, in combination with other maraviroc use antiretroviral agents Oral: 300 mg twice daily

Fusion Inhibitors Fuzeon®: enfuvirtide Treatment of HIV‐1 infection in Hoffmann‐La Roche & (T‐20) combination with other antiretroviral Trimeris, 3/13/2003 agents in treatment‐experienced patients with evidence of HIV‐1 replication despite ongoing antiretroviral therapy SubQ: 90 mg twice daily

Integrase Inhibitors Isentress®: raltegravir Treatment of HIV‐1 infection in Merck & Co.: combination with other antiretroviral 10/21/2007 agents in patients 4 weeks and older and weighing at least 3 kg Oral: Film‐coated tablet: 400 mg twice daily; chewable tablet and oral suspension available for pediatric, weight‐based dosing

18 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Tivicay®: dolutegravir Treatment of HIV‐1 infection in GlaxoSmithKline, combination with other antiretroviral 8/13/2013 agents in adults and children and adolescents ≥12 years of age and weighing ≥40 kg Oral: 50 mg once to twice daily

Vitekta®: Elvitegravir Treatment of HIV‐1 infection in Gilead Sciences, combination with other antiretroviral 9/24/14 agents Oral: 85‐150 mg once daily

Multi‐Class Combination Atripla®: efavirenz, Treatment of HIV‐1 infection Bristol‐Myers Squibb, Moderate‐to‐severe renal OR hepatic Agents emtricitabine, Oral: One tablet once daily 7/12/2006 impairment: Use not recommended tenofovir disoproxil Recommended as an initial regimen for fumarate antiretroviral‐naive patients (HHS [adult], 2014)

Complera®: Treatment of HIV‐1 infection Gilead Sciences, Dosage adjustment required for concomitant emtricitabine, Oral: One tablet once daily 8/10/2011 therapy with rifabutin rilpivirine, tenofovir Recommended as a complete regimen disoproxil fumarate in antiretroviral treatment‐naive adult patients with HIV‐1 RNA ≤100,000 copies/mL at the start of therapy and in certain virologically suppressed (HIV‐1 RNA <50 copies/mL) adult patients

Stribild®: elvitegravir, Treatment of HIV‐1 infection Gilead Sciences, CrCl <70 mL/minute: Use not recommended cobicistat, Oral: One tablet once daily 8/27/2012 emtricitabine, Recommended in adults who are tenofovir disoproxil antiretroviral treatment‐naïve and in fumarate certain virologically suppressed (HIV‐1 RNA <50 copies/mL) adult patients

19 Drug Class Agents in the class Indications & Use Manufacturer & Safety Approval date Triumeq®: Abacavir, Treatment of HIV‐1 infection ViiV Healthcare, Black Box: Serious and sometimes fatal Dolutegravir, Oral: One tablet daily 8/22/2014 hypersensitivity reactions, with multiple organ Lamivudine involvement, have been associated with abacavir; Severe, acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV‐1 and have discontinued lamivudine

20 Both the United States Centers for Disease Control and Prevention (CDC)12 and the World Health Organization (WHO)13 have published staging systems for adolescent and adult patients with HIV/AIDS to help identify disease severity and guide treatment. See Table 3 for a summary of the disease classifications. Consideration of both the extent of immunosuppression and the current presenting symptoms are important when deciding therapeutic and prophylactic treatment therapies.12 Resistance to current HIV treatment in patients may manifest as lower CD4+ counts, thus prompting addition or change of therapy. Patients with additional bacterial and/or viral coinfections (such as hepatitis C virus (HCV), hepatitis B virus (HBV), tuberculosis (TB), etc.) may require specific drug therapies and additional monitoring. In addition, lower CD4+ levels increase risk of opportunistic infection, prompting initiation of prophylactic antimicrobial treatments.12-14

Table 3. HIV/AIDS Disease Staging Systems12-14 Classification System Description U.S. Centers for Disease CD4+ T Cell Count Category A Category B (Symptomatic) Category C Control and Prevention (Asymptomatic) (AIDS‐indicator symptoms) >500/µL A1 B1 C1 (CDC) 200‐499/ µL A2 B2 C2 <200/ µL A3 B3 C3 World Health Organization Stage Symptoms (WHO) Clinical Staging and Primary HIV Infection Asymptomatic, Acute retroviral syndrome Disease Classification Stage 1 Asymptomatic, Persistent generalized lymphadenopathy Stage 2 Moderate unexplained weight loss, Recurrent respiratory infections, Herpes zoster, Angular System cheilitis, Recurrent oral ulceration, Papular pruritic eruptions, Seborrheic dermatitis, Fungal nail infections Stage 3 Unexplained severe weight loss, Unexplained chronic diarrhea for >1 month, Unexplained persistent fever for >1 month, Persistent oral candidiasis, Oral hairy leukoplakia, Pulmonary tuberculosis, Severe presumed bacterial infections, Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis, Unexplained anemia, Neutropenia, Chronic thrombocytopenia Stage 4 HIV wasting syndrome, Pneumocystis pneumonia, Recurrent severe bacterial pneumonia, Chronic herpes simplex infection, Esophageal candidiasis, Extrapulmonary tuberculosis, Kaposi sarcoma, Cytomegalovirus infection, Toxoplasmosis, Encephalopathy, Cryptococcosis, Disseminated nontuberculosis mycobacteria infection, Progressive multifocal leukoencephalopathy, Candida of the trachea/bronchi/lungs, Chronic cryptosporidiosis, Chronic isosporiasis, Disseminated mycosis, Recurrent nontyphoidal Salmonella bacteremia, Lymphoma, Invasive cervical carcinoma, Atypical disseminated leishmaniasis, Symptomatic HIV‐associated nephropathy/ cardiomyopathy, Reactivation of trypanosomiasis

The US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (2015)15 recommends all patients receive Antiretroviral Therapy (ART) to reduce the risk of disease progression and to prevent transmission. Before initiation of ART, genotypic drug-resistance testing is recommended to help guide therapy decisions. In an attempt to reduce or avoid drug-resistance, the guidelines recommend patients receive education outlining the benefits and risks of therapy and the importance of adherence before initiation of therapy. If the benefits do not outweigh the risks or if adherence will be a significant challenge, patients may decide to postpone therapy or providers may recommend deferring therapy. In treatment-naïve adults and adolescent patients with HIV, ART should consist of three active antiretroviral agents. Table 4 provides a summary of the ART combination therapy recommendations published by the most recent clinical practice guidelines. In general, both HIV-1 and HIV-2 infections are treated the same as they are transmitted in the same fashion and are associated with similar rates of

21 opportunistic infections and development of AIDS. Although HIV-2 infections tend to be associated with slower development of immunodeficiency, treatment should be initiated before disease progression. In treatment-experienced patients, a thorough evaluation of virologic failure including an assessment of HIV-RNA and CD4+ T cell count trends over time, treatment history, drug-resistance testing results, medication adherence and drug-drug/drug-food interactions is recommended. In these patients, an entirely new regimen including at least two, preferably three, antiretroviral agents should be initiated; simply adding an additional antiretroviral agent to the current regimen is not recommended as this may lead to increased resistance and drug inefficacy.15

In general, the recommendations for initiation of ART and goals of therapy in adults and adolescents are the same for special populations of patients with HIV infection. Initiation of ART is recommended as soon as possible in all pregnant women to prevent perinatal transmission. Pharmacokinetic changes in pregnancy may lead to lower plasma levels of drugs and necessitate increased dosages, more frequent dosing, or boosting, especially of protease inhibitors. All patients >50 years of age should receive ART, regardless of CD4+ T cell count, due to increased risk of non-AIDS related complications and reduced response to ARV in this patient population.15 ART is recommended in patients with HIV-coinfections as the benefits of antiretroviral therapy almost always outweigh the risks (drug-induced liver injury, drug-drug interactions, etc.) In patients with HIV and a TB-coinfection, both ART and TB treatments should be initiated immediately. All patients with an HIV/HCV-coinfection, including those with cirrhosis, should receive ART, regardless of CD4+ T cell count. Patients with an HIV/HBV- coinfection should receive an ART regimen with an NRTI backbone including tenofovir (TDF) and either emtricitabine (FTC) or lamivudine (3TC), as this regimen has activity against both HIV and HBV infections. In pediatric patients, ART is recommended in all children < 12 months old and in children > 1 year old, depending on CDC stage and CD4+ T cell count.15,16 Table 4 provides a summary of the ART combination therapy recommendations in special populations.

Table 4. Most Current Clinical Practice Guidelines for the Treatment of HIV Guideline Recommendations Guidelines for the Use of Treatment naïve patients, recommended regimens: Antiretroviral Agents in HIV‐1‐  INSTI‐based regimens: Infected Adults and ▬ DTG/ABC/(3TC or FTC) only for patients who are HLA‐B*5701 negative Adolescents (US Department of ▬ DTG plus TDF/(3TC OR FTC) Health and Human Services; ▬ AVG/c/TDF/(3TC OR FTC) only for patient with pre‐treatment estimated CrCl ≥70 2015) 15 mL/min ▬ RAL plus TDF/(3TC OR FTC)  PI‐based regimens: ▬ DRV/r plus TDF/(3TC OR FTC)

Treatment naïve patients, alternative regimens:  NNRTI‐based regimens: ▬ EFV/TDF/(3TC OR FTC) ▬ RPV/TDF/(3TC OR FTC) only for patients with pre‐treatment HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/mm3  PI‐based regimens: ▬ ATV/c plus TDF/(3TC OR FTC) only for patients with pre‐treatment estimated CrCl ≥70 mL/min 22 ▬ ATV/r plus TDF/(3TC OR FTC) ▬ (DRV/c or DRV/r) plus ABC/(3TC or FTC) only for patients who are HLA‐B*5701 negative ▬ DRV/c plus TDF/(3TC OR FTC) only for patients with pre‐treatment estimated CrCl ≥70 mL/min

Treatment naïve patients, other regimens:  INSTI‐based regimen: ▬ RAL plus ABC/(3TC or FTC) only for patient who are HLA‐B*5701 negative  NNRTI‐based regimen: ▬ EFV plus ABC/(3TC or FTC) only for patients who are HLA‐B*5701 negative and pre‐ treatment HIV RNA <100,000 copies/mL  PI‐based regimens: ▬ (ATV/c or ATV/r) plus ABC/(3TC or FTC) only for patients who are HLA‐B*5701 negative and pre‐treatment HIV RNA <100,000 copies/mL ▬ LPV/r (once or twice daily) plus ABC/(3TC or FTC) only for patients who are HLA‐ B*5701 negative ▬ LPV/r (once or twice daily) plus TDF/(3TC OR FTC)  Other regimens when TDF or ABC cannot be used: ▬ DRV/r plus RAL only for patients with pre‐treatment HIV RNA <100,000 copies/mL and CD4 cell count >200 cells/mm3 ▬ LPV/r (twice daily) plus (3TC or FTC) (twice daily)

Guidelines for the Use of Pediatric initial therapy recommendations: Antiretroviral Agents in  2‐NRTI backbone: Pediatric HIV Infection ▬ <3 months: AZT plus (3TC or FTC) (National Institutes of Health ▬ ≥3 months: ABC plus (3TC or FTC) OR AZT plus (3TC or FTC); ABC only if HLA‐B*5701 Office of AIDS Research negative 16 Advisory Council; 2015) ▬ ≥12 years: ABC plus 3TC or plus FTC ▬ Adolescents at Tanner Stage 4 or 5: ABC plus 3TC or plus FTC or TDF plus 3TC or plus FTC

 Alternative 2‐NRTI backbone: ▬ ≥2 weeks: ddI plus (3TC or FTC) OR AZT plus ddI ▬ ≥3 months: AZT plus ddI ▬ Children and adolescents at Tanner Stage 3: TDF plus (3TC or FTC) ▬ ≥13 years: AZT plus (3TC or FTC)

 Agents to combine with backbone: ▬ ≥42 weeks postmenstrual and >14 days postnatal and children <3 years: LPV/r ▬ 3 to < 6 years: EFV or LPV/r ▬ ≥6 years: ATV/r or EFV or LPV/r

 Alternative agents to combine with backbone: ▬ >14 days old: NVP ▬ ≥3 months to <6 months & ≥10 kg: ATV/r ▬ ≥2 years: RAL ▬ ≥3 years to <12 years: DRV (twice daily)/r ▬ ≥12 years: DRV (once daily)/r or DTG

23 Recommendations for Use of  Generally, the same regimens used in non‐pregnant adults are used in pregnant women Antiretroviral Drugs in unless there are known risks to the fetus or mother during pregnancy Pregnant HIV‐1‐Infected  Avoid EFV containing regimens until after 8 weeks gestation (may be continued if Women for Maternal health started if woman present in first trimester and it is achieving virologic suppression) and Interventions to Reduce  Avoid combination of d4T and ddI Perinatal HIV Transmission in  PI‐based regimens present a small risk of preterm birth the United States (National Institutes of Health Office of AIDS Research Advisory Council; 2014)17

Antiretroviral therapy for HIV Infants, first‐line treatment: infection in infants and  No prior exposure to ARVs: children: towards universal ▬ NVP + 2 NRTIs access (World Health  Prior exposure to NVP or other NNRTIs: 18 Organization; 2010) ▬ LPV/r + 2 NRTIs  Unknown ARV exposure status: ▬ NVP + 2 NRTIs

Children, first‐line treatment:  12‐24 months, not exposed to NNRTIs: ▬ NVP + 2 NRTIs  12‐24 months, prior exposure to NVP or other NNRTIs: ▬ LPV/r + 2 NRTIs  24 months‐3 years: ▬ NVP + 2 NRTIs  3 years plus: ▬ (NVP or EFV) + 2 NRTIs

Preferred NRTI backbones: 1. 3TC + AZT 2. 3TC + ABC 3. 3TC + d4T

Guide for HIV/AIDS Clinical Treatment naïve patients, preferred regimens: Care (Health Resource and  INSTI‐based regimens: Services Administration ▬ RAL + TDF/(FTC or 3TC) 19 (HRSA); 2011) ▬ Elvitegravir/cobicistat/TDF/(FTC or 3TC) only if CrCl ≥70 mL/min ▬ Dolutegravir (once daily) +ABC/(FTC or 3TC) only for patients who are HLA‐B*5701 negative and pre‐treatment HIV RNA <100,000 copies/mL ▬ Dolutegravir (once daily) + TDF/(FTC or 3TC)  PI‐based regimens: ▬ ATV/r + TDF/(FTC or 3TC) ▬ DRV (once daily) + TDF/(FTC or 3TC)  NNRTI‐based regimens: ▬ EFV/TDF/FTC

Treatment naïve patients, alternative regimens:  NRTI‐based regimens: ▬ EFV + ABC/(FTC or 3TC) only for patients who are HLA‐B*5701 negative; caution with pre‐treatment HIV RNA <100,000 copies/mL ▬ Rilpivirine/TDF/(FTC or 3TC) only for patients with pre‐treatment HIV RNA

24 <100,000 copies/mL and CD4 cell count >200 cells/mm3 ▬ Rilpivirine +ABC/(FTC or 3TC) only for patients with CD4 cell count >200 cells/mm3 and are HLA‐B*5701 negative; caution with pre‐treatment HIV RNA <100,000 copies/mL  PI‐based regimens: ▬ ATV + ABC (FTC or 3TC) only for patients who are HLA‐B*5701 negative; caution with pre‐treatment HIV RNA <100,000 copies/mL ▬ DRV + ABC (FTC or 3TC) only for patients who are HLA‐B*5701 negative; caution with pre‐treatment HIV RNA <100,000 copies/mL ▬ FPV (once or twice daily) + (ABC or TDF)/(FTC or 3TC) ▬ LPV/r (once or twice daily) + (ABC or TDF)/(FTC or 3TC)  INSTI‐based regimens: ▬ RAL + ABC/3TC

Consolidated guidelines on HIV Adults (including pregnant/breastfeeding women and adults with TB or HBV coinfection), prevention, diagnosis, first‐line regimens: treatment and care for key ▬ TDF + 3TC (or FTC) + EFV populations (World Health ▬ Alternate: AZT + 3TC + EFV Organization (WHO); 2014)20 ▬ Alternate: AZT + 3TC + NVP ▬ Alternate: TDF + 3TC (or FTC) + NVP

Adolescents (10 to 19 years) ≥35 kg, first‐line regimens: ▬ TDF + 3TC (or FTC) + EFV ▬ Alternate: AZT + 3TC + EFV ▬ Alternate: AZT + 3TC + NVP ▬ Alternate: TDF + 3TC (or FTC) + NVP ▬ Alternate: ABC + 3TC + EFV (or NVP)

Children 3 years to less than 10 years and adolescents <35 kg), first‐line regimens: ▬ ABC + 3TC + EFV ▬ Alternate: ABC + 3TC + NVP ▬ Alternate: AZT + 3TC + EFV ▬ Alternate: AZT + 3TC + NVP ▬ Alternate: TDF + 3TC (or FTC) + EFV ▬ Alternate: TDF + 3TC (or FTC) + NVP

Children < 3 years, first‐line regimens: ▬ ABC (or AZT) + 3TC + LPV/r ▬ Alternate: ABC + 3TC + NVP ▬ Alternate: AZT + 3TC + NVP Key: NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors) = 3TC: lamivudine, ABC: abacavir, AZT: zidovudine, d4T: stavudine, ddI: didanosine, FTC: emtricitabine, TDF: tenofovir; NNRTIs (non‐nucleoside reverse transcriptase inhibitors): EFV: efavirenz, RPV: rilpivirine; PIs (protease inhibitors): ATV: atazanavir, ATV/c: atazanavir + cobicistat, DRV: darunavir, FPV: fosamprenavir, LPV/r: lopinavir + ritonavir, /r: ritonavir for boosting; INSTIs (integrase strand transfer inhibitors): DTG: dolutegravir, RAL: raltegravir

25 Pharmacology

The HIV protease inhibitors (PIs) are a class of active antiretroviral agents used in combination with other antiretroviral agents in the treatment of HIV/AIDS infections. The protease inhibitors competitively inhibit the action of viral protease enzyme action by binding to HIV protease active sites and inhibiting the cleavage of Gag-Pol polyprotein precursors. This competitive inhibition results in failure of infectious viral protein activation and renders the virus particles immature and noninfectious.21,22 Due to differences between viral and human protein polypeptide chains, the protease inhibitors are only active in HIV cells and do not cause protease inhibition in human cells, thereby reducing the risk for adverse effects.22,23 Table 6 provides a list of the adverse events associated with each of the HIV protease inhibitor agents. Viral resistance, as a result of alterations in the virus genome, is common with the PI agents and monotherapy is contraindicated. Resistance to one protease inhibitor is often associated with resistance to all protease inhibitors; although, darunavir and lopinavir/ritonavir have demonstrated effectiveness against resistant HIV strains in clinical trials.24

The HIV protease inhibitors are similar in structure but pharmacokinetic properties vary between the agents. See Table 5 for a summary of the pharmacokinetic data available for each of the HIV protease inhibitors. In general, the protease inhibitors are metabolized by CYP3A4. The exception is nelfinavir, which is metabolized by CYP2C19 and CYP3A4.21,22 Ritonavir has the greatest inhibitory effect on CYP3A4 and may be taken in combination with other PI agents in an effort to decrease metabolism and increase half-life of the agent. In general, PI half-lives range from 1-15 hours. The PI drugs with shorter half-lives (i.e. indinavir, nelfinavir) may require more frequent dosing, up to three times daily, compared to those with longer half-lives (i.e. atazanavir, darunavir; both dosed once daily). Amprenavir (Agenerase®, GlaxoSmithKline) is a protease inhibitor approved for use by the FDA in 1999, for twice-a-day dosing instead of needing to be taken every eight hours.2,3 However, the twice daily dosing required 1,200 mg, administered in 8 large 150 mg gel capsules twice daily. Production of amprenavir was eventually discontinued and a prodrug version (fosamprenavir) is now available. All of the protease inhibitors are classified as high alert medications by the Institute for Safe Medication Practices (ISMP) as the risk of causing significant harm is high if the agent is used inappropriately. Tipranavir carries a black box warning for hepatitis, hepatic decompensation, deaths from hepatic failure and fatal cranial hemorrhage. Due to its significant cytochrome inhibitory affect, ritonavir carries a black box warning for drug-drug interactions which may cause life-threatening adverse reactions when coadministered with sedative hypnotics, antiarrhythmics, or ergot alkaloids. Protease inhibitors are also P-glycoprotein efflux pump substrates which may be a source of drug-interactions. Table 6 provides a summary of the most significant drug interactions associated with HIV protease inhibitor use.22,23

26 Table 5. Pharmacokinetic Properties of the HIV Protease Inhibitor Agents2,3,22 Agent Half‐life Bioavailability Effect of Protein Renal Metabolism Autoinduction Inhibition (h) (%) meals on AUC binding Excretion of of metabolism of CYP3A4 (%) parent drug (%) Atazanavir 6.5‐7.9 low ↑70% (light 86 7 CYP3A4 No ++ meal) Darunavir 15 82 ↑30% 95 8 CYP3A4 NA +++ Fosamprenavir 7.7 20‐80 ↔ 90 4 CYP3A4 No ++ Indinavir 1.8 60‐65 ↓77% 60 9‐12 CYP3A4 No ++ Lopinavir 5‐6 low ↑27% 98‐99 <3 CYP3A4 Yes +++ (Moderate fat) Nelfinavir 3.5‐5 20‐80 (food ↑100‐200% >98 1‐2 CYP2C19 > Yes ++ and CYP3A4 formulation dependent) Ritonavir 3‐5 >60 ↑13% 98‐99 3.5 CYP3A4 > Yes +++ (capsule) CYP2D6 Saquinavir 1‐2 13 ↑570% (high 98 <3 CYP3A4 No + fat) Tipranavir 4.8‐6.0 NA ↔ 99.9 0.5 CYP3A4 Yes +++ Key: NA = not available

27 Methods

A literature search was conducted to identify articles addressing each key question, searching the MEDLINE database (1950 – 2015), the Cochrane Library and reference lists of review articles. For the clinical efficacy section, only clinical trials published in English and indexed on MEDLINE, evaluating efficacy of the HIV protease inhibitors are included. Trials evaluating the agents as monotherapy or combination therapy where adjunctive medications remained constant throughout the trial are included. Trials comparing monotherapy with combination regimens are excluded.25-32 The following reports were excluded (note: some were excluded for more than 1 reason, see table in appendix for additional exclusions):28,33-49

 Individual clinical trials which evaluated endpoints other than reduction of HIV symptoms, such as: pharmacologic characteristics33,50-82, safety83-90, adherence91- 96, resistance,53,97-99 metabolic effects 100 or cost analysis.101  Individual trials comparing the SGLT2 inhibitors in dose-finding studies or in healthy volunteers.54,102-110  Individual clinical trials evaluating formulations not currently available in the US111 or clinical trials without access to the full article.112,113

Clinical Efficacy

One meta-analysis and 20 comparative clinical trials comparing the efficacy of the HIV protease inhibitors were identified for evaluation. The meta-analysis114 identified trials evaluating the efficacy of two protease inhibitors, tipranavir and darunavir, in patients with HIV who had previously received antiretroviral therapy. In total, 14 trials were identified for analysis. According to the study, both tipranavir and darunavir-based antiretroviral regimens are similarly effective in reducing viral load in patients who were ART experienced. The authors concluded that second generation non-peptidic HIV protease inhibitors, tipranavir and darunavir, demonstrate improved resistance profiles in treatment-experienced patients.

Of the 20 clinical trials identified for evaluation, 14 evaluated the efficacy of the PI agents in treatment-naïve patients and 6 evaluated the efficacy of the agents in treatment-experienced patients. Each of the HIV protease inhibitors was studied in at least one comparative clinical trial. Saquinavir was studied in 8 of the identified clinical trials, while tipranavir was studied in only one of the trials. For a complete summary of the included clinical trials, see the Evidence Tables in the appendix.

Treatment-Naïve Patients Atazanavir was compared to darunavir in two clinical trials. Lennox et al (2014)115 evaluated the efficacy of the agents in treatment naïve adult patients in 57 sites across the US and Puerto Rico. A total of 1,809 patients were randomized to receive

28 tenofovir and emtricitabine in combination with atazanavir/ritonavir, darunavir/ritonavir or raltegravir. At 96 weeks, all treatment groups achieved high and similar rates of virologic success. No differences in efficacy were reported between the protease inhibitor treatment groups. Adverse event rates were similar between treatment groups. However, adverse event-related discontinuation rate was higher in the atazanavir treatment group compared to the darunavir treatment group, likely due to the higher rate of hyperbilirubinemia reported in the atazanavir group. Aberg et al (2012)116 evaluated the efficacy of atazanavir and darunavir in treatment-naïve adult patients in centers across the US. Sixty-five patients were randomized to receive tenofovir and emtricitabine in combination with atazanavir/ritonavir or darunavir/ritonavir for up to 48 weeks. At the end of the study period, virologic response was similar for the atazanavir (71%) and darunavir (76.5%) treatment groups. Again, overall adverse event rates were similar between treatment groups; however, hyperbilirubinemia was reported more frequently in the atazanavir treatment group.

Atazanavir was also compared to lopinavir in one clinical trial and fosamprenavir in one clinical trial. Molina at al (2008)117 evaluated the efficacy of atazanavir and lopinavir in treatment-naïve patients in 134 sites across the world. A total of 883 patients were randomized to receive tenofovir and emtricitabine in combination with atazanavir/ ritonavir or lopinavir/ritonavir with a follow-up of 48-96 weeks. At 48-weeks, atazanavir (78% and lopinavir (76%) demonstrated similar rates of virologic response. At 96 weeks, the atazanavir treatment group (74%) demonstrated higher rates of virologic response compared to the lopinavir treatment group (68%, p < 0.05). Smith et al (2008)118 evaluated the efficacy of atazanavir and fosamprenavir in 106 treatment-naïve adult patients in a 48-week study. At the end of the study period, the proportion of patients with HIV-RNA < 50 copies/mL was similar across the atazanavir (83%) and fosamprenavir (75%) treatment groups. The most frequently reported adverse events reported varied between the agents with diarrhea and nausea being reported more frequently in the fosamprenavir treatment group and hyperbilirubinemia, fatigue and jaundice are reported more frequently in the atazanavir treatment group.

Darunavir and lopinavir were compared in one long-term clinical trial. A total of 689 treatment-naïve patients were randomized to receive tenofovir and emtricitabine in combination with darunavir/ritonavir or lopinavir/ritonavir with a follow-up time of 192 weeks. The darunavir treatment group demonstrated higher rates of virologic response at 96 weeks and 192 weeks (p < 0.05). Incidence of adverse events was similar across treatment groups (darunavir- 23%, lopinavir- 34%) and the most frequently reported events were diarrhea, nausea and rash. Treatment-related discontinuation rate occurred more frequently in the lopinavir group (p = 0.005), in part due to recommendation to discontinue lopinavir in pregnancy.

Fosamprenavir was compared to saquinavir in one comparative clinical trial and to nelfinavir in one comparative clinical trial. Landman et al (2009)119 conducted a small trial evaluating the efficacy of fosamprenavir and saquinavir in treatment-naïve patients. A total of 61 patients were randomized to receive fosamprenavir/atazanavir/ritonavir or saquinavir/atazanavir/ritonavir for up to 16 weeks. At the end of the study period, rate of

29 early virologic response (< 50 copies/mL) was similar between the fosamprenavir (40%) and saquinavir (42%) treatment groups. Gastrointestinal adverse events were reported more frequently in the fosamprenavir treatment group (30% vs. 16%, p = NS) and hyperbilirubinemia was reported more frequently in the saquinavir treatment group (23% vs. 10%, p = NS). Gathe et al (2002)120 evaluated the safety and efficacy of fosamprenavir and nelfinavir in 649 treatment-naïve patients. Patients were randomized to receive abacavir and lamivudine in combination with fosamprenavir/ritonavir or nelfinavir for up to 48 weeks. Magnitude and durability of virologic response was similar between treatment groups. No differences in total adverse event rates were reported between treatment groups; although, diarrhea occurred more frequently in the nelfinavir treatment group (p < 0.05).

Nelfinavir was also evaluated in one clinical trial compared to saquinavir and one clinical trial compared to ritonavir. Kirk et al (2003)121 evaluated the efficacy nelfinavir and saquinavir in 233 treatment-naïve patients in Denmark. Patients were randomized to receive two NRTIs in combination with saquinavir/ritonavir or nelfinavir/nevirapine for up to 48 weeks. At the end of the study period, the proportion of patients with HIV-RNA < 20 copies/mL was greater in the nelfinavir/nevirapine treatment group (69%) compared to the saquinavir/ritonavir treatment group (56%, p = 0.037). No differences in overall adverse event rate were reported between treatment groups and gastrointestinal effects were the most frequently reported events throughout the study. Of note, skin reactions were reported more frequent in the nelfinavir/nevirapine treatment arm (p < 0.05). Gulick et al (2000)122 evaluated the efficacy of nelfinavir and ritonavir in NNRTI treatment- naïve patients. A total of 277 patients were randomized to receive delaviridine and/or adefovir in combination with ritonavir/saquinavir or nelfinavir/saquinavir for 16 weeks. No differences in efficacy or safety were reported between treatment groups.

Indinavir, ritonavir and saquinavir were evaluated in two clinical trials. Kirk et al (2001)123 evaluated the efficacy of the agents in patients aged > 16 years with HIV. A total of 2708 patients taking indinavir, ritonavir or saquinavir in addition to at least 3 additional antiretroviral agents as part of a complete combination ART were evaluated. With a median follow-up period of 30 months, the proportion of patients who experienced clinical progression at 12 months was similar between the ritonavir (11.9%) and saquinavir (11.9%) treatment groups. The proportion of patients who experienced clinical progression at 12 months was lower in the indinavir treatment group (9.2%) when compared to the saquinavir treatment group (11.9%, p = 0.043). Katzenstein et al (1999)124 evaluated the efficacy of the agents in 318 adult patients with 0-13 days of prior use of a PI. Patients were randomized to receive indinavir, ritonavir or saquinavir/ritonavir with a follow-up of up to 72 weeks. At the end of the study period, no statistically significant differences in treatment success rate were reported between the indinavir (52%), ritonavir (41%) and saquinavir/ritonavir (58%) treatment groups. However, patients in the saquinavir/ ritonavir treatment group (58%) demonstrated a higher rate of HIV-RNA <20 copies/mL count when compared to ritonavir alone (41%, p < 0.05).

30 Indinavir was compared to saquinavir in two additional clinical trials. Dragsted et al (2003)125 evaluated the efficacy of the agents in treatment-naïve adult patients in 28 sites around the world. A total of 306 patients were randomized to receive 2 NRTIs or NNRTIs in combination with indinavir/ritonavir or saquinavir/ritonavir. At 48 weeks, no significant differences in virologic failure rates (~25%) were reported between indinavir and saquinavir treatment groups. However, adverse event-related discontinuation rate was higher in the indinavir treatment group compared to the saquinavir treatment group, reportedly due to the higher rate of renal, skin/hair and gastrointestinal adverse events reported in the indinavir treatment group. Cohen-Stuart et al (1999)126 evaluated the efficacy of the agents in 70 treatment-naïve patients with a diagnosis of HIV and demonstration of HIV-related symptoms. Patients were randomized to receive zidovudine and lamivudine in combination with indinavir or saquinavir for up to 24 weeks. No differences in decreased HIV-RNA counts were reported between treatment groups. Increased CD4+ cell counts occurred more frequently in the saquinavir treatment group compared to the indinavir treatment group (p = 0.01). Overall adverse event rate and discontinuation rate were similar across treatment groups.

Treatment-Experienced Patients Antoniou et al (2010)127 evaluated the efficacy of combination therapy tipranavir/ritonavir or darunavir/ritonavir in 85 patients with multi-drug resistant HIV infection. No differences in virologic response or sustained virologic suppression were reported between treatment groups. In addition, no differences in safety were reported between the agents. Johnson et al (2005)128 evaluated the efficacy of atazanavir, ritonavir, saquinavir and lopinavir in treatment-experienced patients aged 16-18 years in Europe and North/South America. A total of 358 patients were randomized to receive tenofovir and one additional NRTI in combination with atazanavir/ritonavir, atazanavir/saquinavir or lopinavir/ritonavir for up to 96 weeks. No differences in magnitude/durability of viral load reduction or in rate of adverse events were reported between treatment groups.

Haas et al (2003)129 evaluated the efficacy of atazanavir and ritonavir in the treatment of HIV in 85 patients who had demonstrated a response to a prior ART regimen. Patients were randomized to receive two NRTIs in combination with atazanavir/saquinavir or ritonavir/saquinavir. At 48 weeks, no significant differences in virologic response were reported between atazanavir treatment groups (29-41%) and the ritonavir treatment group (35%). No differences in adverse event-related discontinuation rate were reported between treatment groups (9-30%). However, increases in cholesterol were significantly more frequent in the ritonavir treatment group (p < 0.05). Roca et al (2000)130 evaluated the efficacy of indinavir and nelfinavir in patients with active HIV infection who received ART previously. A total of 112 patients were randomized to receive stavudine and lamivudine in combination with indinavir or nelfinavir for up to 9 months. No differences in CD4 cell count or HIV-RNA count were reported between treatment groups. Frequency of treatment-related adverse events was similar between treatment groups; although, adverse event-related discontinuation rate was higher in the indinavir treatment group (60%) compared to the nelfinavir treatment group (38%, p < 0.05)

Chavanet et al (2001)131 evaluated the efficacy of nelfinavir and ritonavir in treatment-experienced adult patients with previous PI exposure > 6 months. A total of 31 patients were randomized to receive NRTI therapy in combination with ritonavir/saquinavir or nelfinavir/saquinavir for 3 months. No differences in viral load stabilization or decrease were reported between treatment groups. Para et al (2000)132conducted a similar trial comparing indinavir to saquinavir in 89 adult patients who have received previous ART. Patients were randomized to receive a complete ARV therapeutic regimen in combination with indinavir or saquinavir for up to 24 weeks. According to the data, indinavir was associated with higher rates of viral load decreases (49%) when compared to the saquinavir treatment group (4-8%, p < 0.001). This data suggests indinavir may be more effective in treatment-experienced patients.

Some trials comparing dual therapy to monotherapy are available. In general, these trials demonstrated similar or increased rates of efficacy with dual PI therapy compared to mono-PI therapy. This suggests that twice-daily indinavir-ritonavir and, to a lesser extent, amprenavir-ritonavir may be effective for many patients with viruses resistant to protease inhibitors.53 Quadruple therapy, including SQV-SGC and NFV, gave a more durable response than triple therapy with either single protease inhibitor. Quadruple therapy might particularly benefit NRTI-experienced patients and those with high baseline viral loads.29 The overall efficacy of ritonavir-boosted protease inhibitor monotherapy is inferior to HAART.32

Special Populations

Some data is available for the evaluation of the HIV protease inhibitors in the treatment of HIV in the pediatric population. Rusconi et al (2012)133 reported “dual- boosted protease inhibitor therapy was virologically and immunologically effective and it could be considered as a possible alternative to a rescue regimen in children and adolescents.” However, hypercholesterolemia and hypertriglyceridemia need close follow-up in this patient population. 133 Rodriguez-French et al (2004)134 reported similar rates of safety and efficacy for fosamprenavir and nelfinavir in treatment-naïve pediatric patients with HIV infection. Of note, diarrhea occurred more frequently in the nelfinavir treatment group and rash occurred more frequently in the fosamprenavir treatment group. In addition, there are a number of observational and noncomparative trials which evaluate the protease inhibitors in the pediatric population. Overall, the protease inhibitors demonstrate safety and efficacy in pediatric patients but may require additional monitoring.

32 Safety

The HIV protease inhibitors are preferred agents in antiretroviral combination therapy regimens as they are associated with potent anti-HIV activity and have relatively favorable resistance patterns.1,22,23 However, the protease inhibitor agents are also associated with both short- and long-term toxicities, which may limit use. Table 6 provides a list of the adverse events reported with protease inhibitor use. The most common adverse events reported with protease inhibitor therapy vary between the agents and include gastrointestinal irritation, skin reactions and metabolic disturbances.2,3 The metabolic disturbances may include hyperlipidemia, lipodystrophy and impaired glucose tolerance. Some of the protease inhibitors are also indicated in the development of hyperbilirubinemia. Clinicians should monitor patients receiving protease inhibitors carefully for adverse events, especially those involving altered lipid and glucose metabolism.14-16,18,20 In addition, adverse events may occur more frequently in pediatric patients and older adults (age > 50 years) and careful monitoring of bone, kidney, metabolic, cardiovascular and liver health of older patients receiving ART is recommended. The HIV protease inhibitors also have pharmacokinetic interactions due to cytochrome P450 metabolism. For example, the agents have a significant interaction with oral contraceptives and additional or alternative contraceptive methods are recommended in women of childbearing age to prevent unintended pregnancy. Some of the antiretroviral therapies may also be associated with teratogenic effects and careful selection of combination therapies in pregnant women is warranted.17

Atazanavir: Adverse effects reported with atazanavir therapy include diarrhea and nausea, which may disappear after the first few weeks of therapy.2,3 The most common laboratory abnormality associated with atazanavir therapy includes unconjugated hyperbilirubinemia, although this is not associated with hepatotoxicity. “Approximately 40% of subjects receiving 400 mg atazanavir once daily in initial clinical trials developed a significant increase in total bilirubin, although only 5% developed jaundice. Postmarketing reports include hepatic adverse reactions of cholecystitis, cholelithiasis, cholestasis, and other hepatic function abnormalities135 Because atazanavir is metabolized by CYP3A4, concomitant administration of agents that induce this enzyme (e.g., rifampin) is contraindicated.

Darunavir: Adverse effects most frequently reported with darunavir therapy are gastrointestinal (GI) irritation.2,3 Darunavir is associated with increases in plasma triglycerides and cholesterol and, like fosamprenavir, contains a sulfa moiety, and rash has been reported in up to 10% of recipients. Darunavir therapy has also been associated with episodes of hepatotoxicity and is metabolized by CYP3A4. Concomitant administration of agents that induce CYP3A4 (e.g., rifampin) is contraindicated. The drug interaction profile of darunavir/ritonavir is dominated by those expected with ritonavir.

Fosamprenavir: Adverse effects most frequently reported with fosamprenavir therapy include GI irritation (diarrhea, nausea, vomiting), hyperglycemia, fatigue, paresthesias and headache.2,3 Fosamprenavir therapy is associated with rash and severe rash has been reported in up to 8% of patients. The onset of skin rash is usually within 2 weeks of beginning therapy. Fosamprenavir

33 does not have effects on plasma lipid profiles and is not generally associated with drug- interactions.

Indinavir: “A unique and common adverse effect of indinavir is crystalluria and nephrolithiasis. This stems from the poor solubility of the drug, which is lower at pH 7.4 than at pH 3.5. Precipitation of indinavir and its metabolites in urine can cause renal colic, and nephrolithiasis occurs in ~3% of patients.”136Patients receiving indinavir treatment should drink plenty fluids to prevent renal complications. Similar to atazanavir, indinavir causes asymptomatic hyperbilirubinemia which is not generally associated with serious long-term sequelae.2,3 Long- term administration of indinavir is associated with the HIV lipodystrophy syndrome, fat accumulation and hyperglycemia. Dermatologic complications have been reported with indinavir therapy and may include loss, dry skin, dry/cracked lips and ingrown toenails.

Lopinavir: GI adverse effects reported with lopinavir therapy are generally mild compared to other PI agents and may include loose stools, diarrhea, nausea and vomiting.2,3 The most common laboratory abnormalities associated with lopinavir therapy include elevated total cholesterol and triglycerides. Lopinavir metabolism is highly dependent on CYP3A4 and concomitant administration of agents that induce CYP3A4 (i.e. rifampin, St. John's wort) should be avoided. The liquid formulation of lopinavir contains 42% ethanol and should not be administered with disulfiram or metronidazole.

Nelfinavir: Nelfinavir is generally well tolerated. The most important side effect of nelfinavir is diarrhea, which resolves in most patients within the first 4 weeks of therapy. “Up to 20% of patients report chronic occasional diarrhea lasting >3 months, although <2% of patients discontinue the drug because of diarrhea. Nelfinavir augments intestinal calcium-dependent chloride channel secretory responses in vitro, and electrolyte analysis of stool is most consistent with a secretory diarrhea.”137Nelfinavir may also be associated with glucose intolerance, elevated cholesterol levels and elevated triglycerides. Because nelfinavir is metabolized by CYPs 2C19 and 3A4, concomitant administration of agents that induce these enzymes may be contraindicated.2,3

Ritonavir: Adverse effects most frequently reported with ritonavir therapy are gastrointestinal (GI) irritation, including nausea, vomiting, diarrhea, anorexia, abdominal pain and taste perversion.2,3 The GI toxicities may be dose-dependent and can be reduced if taken with food. Peripheral paresthesias have been reported with ritonavir therapy but generally disappear within a few weeks of initiating therapy. Long-term ritonavir therapy may cause dose-dependent elevations in serum cholesterol. “Ritonavir is one of the most potent known inhibitors of CYP3A4, markedly increasing the plasma concentrations and prolonging the elimination of many drugs. Ritonavir should be used with caution in combination with any CYP3A4 substrate and should not be combined with drugs that have a narrow therapeutic index such as midazolam, triazolam, fentanyl, and ergot derivatives.”21

Saquinavir: Adverse effects reported with saquinavir therapy are generally mild and short lived and most are gastrointestinal in nature (nausea, vomiting, diarrhea, and abdominal discomfort).2,3 Long-term use of saquinavir may be associated with lipodystrophy. “Saquinavir clearance is increased with CYP3A4 induction; thus, co-administration of inducers of CYP3A4 such as

34 rifampin, phenytoin, or carbamazepine lowers saquinavir concentrations and should be avoided.”21

Tipranavir: Tipranavir is associated with rare but serious adverse events, including fatal hepatotoxicity. “Through 48 weeks of treatment, grade 3 or 4 elevation of hepatic transaminases occurred in 20% of treatment-naive and 10% of treatment-experienced patients. Tipranavir use has been associated with rare intracranial hemorrhage (including fatalities) and bleeding episodes in patients with hemophilia. The drug has anticoagulant properties in vitro and in animal models, and these effects are potentiated by vitamin E.”21,22Elevation in lipids and triglycerides are frequently reported with tipranavir use and transient rash may occur as tipranavir contains a sulfa moiety.2,3

35 Table 6. Adverse Events Reported with the HIV Protease Inhibitor Agents2,3 Product Frequency Cardiovascular Central Nervous Endocrine & Metabolic Gastrointestinal Hepatic Neuromuscular/Skeletal Other System Atazanavir >10% ↑ amylase nausea jaundice ↑ CPK cough (REYATAZ®) ↑ serum cholesterol ↑ serum bilirubin fever skin rash 2‐10% AV block (first or depression hyperglycemia abdominal pain ↑ serum ALT limb pain myalgia neutropenia second degree) dizziness headache hypoglycemia diarrhea ↑ serum AST ↓ hemoglobin peripheral edema insomnia lipodystrophy vomiting nasal congestion P‐R interval neuropathy ↑ serum triglycerides ↑ serum lipase oropharyngeal pain prolongation peripheral rhinorrhea thrombocytopenia wheezing

Atazanavir and >10% abnormal bilirubin scleral icterus Cobicistat levels (EVOTAZ®) jaundice

1‐10% AV block (first or abnormal dreams ↑ cholesterol diarrhea hepatotoxicity (pts amyotrophy acute renal failure second degree) depression cushingoid appearance nausea w/hepatitis) ↑ CPK breast hypertrophy cardiac conduction fatigue Fanconi’s syndrome ↑ serum amylase ↑ serum ALT lipoatrophy ↓ creanine disturbances headache glycosuria ↑ serum lipase ↑ serum AST rhabdomyolysis clearance P‐R interval insomnia ↑ GGT upper abdominal hematuria prolongation buffalo hump pain hemorrhage ↑ serum triglycerides vomiting immune truncal obesity reconstitution syndrome nephrolithiasis renal insufficiency ↑ serum creatinine skin rash Stevens‐Johnson syndrome Darunavir >10% hypercholesterolemia diarrhea skin rash (PREZISTA®) hyperglycemia nausea ↑ LDL cholesterol vomiting 2‐10% fatigue ↑ amylase abdominal ↑ serum ALT weakness increased bleeding headache diabetes mellitus distention ↑ serum AST (pts w/hemophilia) lipodystrophy abdominal pain pruritus ↑ serum triglycerides anorexia decreased appetite dyspepsia ↑ serum lipase Darunavir and 1‐10% headache abdominal pain ↑ liver enzymes drug‐induced Cobicistat diarrhea hypersensitivity (PREXCOBIX®) flatulence nausea immune vomiting reconstitution syndrome

36 skin rash

Fosamprenavir >10% hypertriglyceridemia diarrhea rash (LEXIVA®) 1‐10% fatigue hyperglycemia abdominal pain ↑ transaminases neutropenia headache nausea pruritus ↑ serum lipase vomiting Indinavir >10% abdominal pain hyperbilirubinemia nephrolithiasis (CRIXIVAN®) nausea urolithiasis 1‐10% dizziness fat redistribution anorexia jaundice back pain anemia drowsiness hypercholesterolemia ↑ appete ↑ serum weakness cough fatigue hyperglycemia diarrhea transaminases dysuria headache hyperlipidemia dysgeusia fever malaise dyspepsia hydronephrosis gastroesophageal neutropenia reflux disease pruritus ↑ serum amylase skin rash taste perversion vomiting Lopinavir and >10% ↑ GGT abdominal pain ↑ serum ALT skin rash Ritonavir hypercholesterolemia diarrhea upper respiratory (KALETRA®) ↑ serum triglycerides dysgeusia tract infection nausea vomiting >2‐10% vasodilation anxiety alteration in sodium dyspepsia hepatitis circumoral & peripheral hypersensitivity fatigue fat redistribution flatulence ↑ serum AST asthenia paresthesia lower respiratory headache hyperglycemia gastroenteritis ↑ serum bilirubin musculoskeletal pain tract infection insomnia hypertriglyceridemia ↑ serum amylase weakness neutropenia hyperuricemia ↑ serum lipase skin infection weight loss thrombocytopenia

Nelfinavir >10% diarrhea (VIRACEPT®) 2‐10% fat redistribution flatulence ↓ lymphocytes hyperglycemia nausea ↓ neutrophils hyperlipidemia rash hypercholesterolemia Ritonavir >10% flushing dizziness ↑ GGT abdominal pain ↑ CPK oropharyngeal pain (NORVIR®) fatigue hypercholesterolemia diarrhea musculoskeletal pain pruritus paresthesia ↑ serum triglycerides dysgeusia weakness skin rash dyspepsia nausea vomiting 2‐10% edema anxiety fat redistribution anorexia hepatitis asthenia acne vulgaris hypertension attention hyperglycemia flatulence ↑ serum ALT myalgia anemia syncope disturbance lipodystrophy gastrointestinal ↑ serum AST blurred vision vasodilation confusion ↑ uric acid hemorrhage cough

37 depression ↑ serum amylase diaphoresis drowsiness taste perversion fever headache throat irritation hypersensitivity insomnia neutropenia malaise pharyngitis peripheral polyuria neuropathy thrombocytopenia Saquinavir >10% nausea (INVIRASE®)

1‐10% chest pain anxiety fat redistribution abdominal ↑ bilirubin back pain bronchitis depression hyperglycemia discomfort hepatic ↑ CPK ↑ creanine kinase fatigue hypoglycemia abdominal pain decompensation paresthesia dry lips/skin fever hyperkalemia ↓ appete (pts w/hepatitis) weakness eczema headache libido disorder buccal mucosa ↑ serum ALT influenza insomnia lipodystrophy ulceration ↑ serum AST pneumonia pain ↑ serum amylase constipation pruritus diarrhea rash dyspepsia sinusitis flatulence verruca taste alteration vomiting Tipranavir >10% hypercholesterolemia diarrhea ↑ transaminases ↑ CPK skin rash (APTIVUS®) hypertriglyceridemia

2‐10% fatigue dehydration abdominal pain ↑ serum ALT myalgia anemia headache fat redistribution ↑ amylase ↑ serum AST bleeding diarrhea ↑ GGT ↑ bleeding me nausea cough vomiting dyspnea weight loss epistaxis fever intracranial hemorrhage neutropenia ↓ WBC

38 Summary

HIV, the virus that causes acquired immune deficiency syndrome (AIDS), is a worldwide health challenge and is the world’s leading cause of death from infection. The virus causes a chronic infection with a gradual onset of clinical symptoms starting with general malaise and illness, progressing to the development of opportunistic diseases and ultimately death. All patients with HIV should receive Antiretroviral Therapy (ART) to reduce the risk of disease progression and to prevent transmission. The goal of HIV therapy is to decrease viral load, increase CD4+ T cell count and prevent opportunistic infections. The biggest challenge with HIV/AIDS treatment is the development of resistance to drug therapy. Before initiation of ART, genotypic drug-resistance testing is recommended to help guide therapy decisions. In addition, all patients should receive education outlining the benefits and risks of therapy and the importance of adherence before initiation of therapy.

The HIV protease inhibitors are recommended for use in the treatment of HIV/AIDS as part of a comprehensive combination therapy regimen. Clinical evidence suggests, when used in combination regimens, the protease inhibitors all demonstrate efficacy in the treatment of HIV-1. In general, standard combination therapy consists of two nucleoside reverse transcriptase inhibitors (NRTI) combined with a third antiretroviral agent from one of the other direct-acting antiviral drug classes, such as a protease inhibitor. The US Department of Health and Human Services recommends darunavir/ritonavir in combination with tenofavir and lamivudine or emtricitabine as their preferred PI-based regimen. There are a number of additional protease inhibitor-based therapies, as well as integrase inhibitor-based and NNRTI-based regimens, outlined in the guideline documents and therapy should be guided by both current guideline recommendations and genotype testing in addition to individual patient characteristics (medical history, concurrent medication therapies, etc.)

The protease inhibitors are associated with short- and long-term toxicities, which may limit use. The most common adverse events reported with protease inhibitor therapy vary between the agents and may include gastrointestinal irritation, skin reactions and metabolic disturbances. The metabolic disturbances reported with PI use include hyperlipidemia, lipodystrophy and impaired glucose tolerance. Clinicians should monitor patients receiving protease inhibitors carefully for adverse events, especially pediatric patients, older adults and those at risk for altered lipid and glucose metabolism.

39 References

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Appendix: Evidence Tables

Evidence Table 1. Systematic Reviews Evaluating the HIV Protease Inhibitors Reference/ N Patient Population Treatment Interventions Results Safety Study Design Berhan et al, 6,301 ART experienced The treatments evaluated Outcome 1: Viral load reduction by Not assessed in the meta‐ 114 2013 patients with plasma were: ≥1 log10 copies HIV‐RNA/ml from analysis. viral load above 1,000  TPV/r 500/200 mg or baseline Meta‐analysis of copies HIV RNA/ml DRV/r 600/100 mg twice  TPV/r vs CPIs 14 randomized, daily based regimens o OR 2.96 (95% CI 2.60–3.38) controlled trials o Outcome 1 N = 3,163  DRV/r vs CPIs o Outcome 2 N = 2,189 o OR 6.66 (95% CI 2.89–15.36) o Outcome 3 N = 2,861  TPV/r or DRV/r vs CPIs  Investigator selected o OR 4.21 (95% CI 3.07–5.79) boosted comparator PIs Outcome 2: Patients who achieved (CPIs) HIV1‐RNA < 400 copies/ml o Outcome 1 N = 3,138  TPV/r vs CPIs o Outcome 2 N = 2,156 o OR 2.77 (95% CI 2.34–3.29) o Outcome 3 N = 2,821  DRV/r vs CPIs o OR 3.48 (95% CI 1.56–7.77) Conducted: No date range  TPV/r or DRV/r vs CPIs mentioned in the o OR 2.94 (95% CI 2.15–4.11) methodology Outcome 3: Patients who achieved HIV1‐RNA < 50 copies/ml  TPV/r vs CPIs o OR 2.89 (95% CI 2.40–3.49)  DRV/r vs CPIs o OR 4.65 (95% CI 2.74–7.91)  TPV/r or DRV/r vs CPIs o OR 3.73 (95% CI 2.79–4.98) Key: ART = antiretroviral therapy, TPV = tipranavir; DRV = darunavir; r = ritonavir; PI = protease inhibitor; OR = odds ratio; 95% CI = 95% confidence interval; ATV = atazanavir

Evidence Table 2. Clinical Trials Evaluating the HIV Protease Inhibitors Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Treatment naïve patients Lennox et al, 1,809 Treatment naïve The following three in combination Primary Endpoint: Incidence of virologic Adverse event 2014115 patients aged ≥18 years with tenofovir 300mg and failure by 96 weeks with a margin of discontinuation rate: with HIV1‐RNA > 1,000 emtricitabine 200mg daily: equivalence defined as ‐10% to 10%:  ATV/r v. RAL: 12.7% Phase 3, open‐ copies/mL and no  ATV/r 300/100 mg daily  ATV/r vs RAL (97.5% CI 9.4%‐16.1%) label, randomized, resistance to NRTI or PIs o N = 605 o 3.4% (97.5% CI ‐0.7–7.4%)  ATV/r v. DRV/r: 9.2% non‐inferiority trial  RAL 400 mg twice daily  DRV/r vs RAL (97.5% CI 5.5%‐12.9%) Setting: 57 sites in the o N = 603 o 5.6% (97.5% CI 1.3–9.9%) US and Puerto Rico  DRV/r 800/100 mg daily  ATV/r vs DRV/r Most common adverse o N = 601 o ‐2.2% (97.5% CI ‐6.7–2.3%) events cited for discontinuation Follow‐up: at least 96 weeks  ATV/r: Conducted: May ‘09 – June ‘11 hyperbilirubinemia  DRV/r: Diarrhea, nausea, and vomiting  RAL: headache Aberg et al, 2012116 65 Treatment naïve The following two in combination with Primary Endpoint: To evaluate the change in Rates of adverse events patients aged ≥18 years tenofovir 300mg and emtricitabine triglyceride levels from baseline to week 12 were comparable between Phase 4, multi‐ with HIV1‐RNA ≥ 1,000 200mg daily: the two arms. The only center, open‐label, copies/mL and not  ATV/r 300/100 mg daily Efficacy data for both arms was provided exception was grade 2‐4 randomized trial resistant to DRV, ATV, o N = 31 (although no statistical analyses were hyperbilirubinemia, which TDF, and FTC  DRV/r 800/100 mg daily carried out to accompany them). At week was observed more in the o N = 34 48, the following percentage of patients ATV/r arm. Setting: centers across achieved virologic response: the US Follow‐Up: 48 weeks Conducted: Not  ATV/r = 71.0% specified  DRV/r = 76.5% Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Landman et al, 61 Treatment‐naïve Fosamprenavir/atazanavir/ritonavir (n Primary endpoint: early virologic success, Gastrointestinal adverse 2009119 patients = 30) defined as plasma viral load <50 copies/mL events: at week 16  Fosamprenavir/ prospective open‐ Saquinavir/atazanavir/ritonavir (n = 31)  Fosamprenavir/atazanavir/ritonavir: atazanavir/ritonavir: label randomized 12/30 (40%) 30% pilot trial  Saquinavir/atazanavir/ritonavir: 13/31  Saquinavir/ patients (42%) atazanavir/ritonavir: 16% “Ritonavir‐boosted dual protease inhibitor regimens targeting only one step of viral Hyperbilirubinemia: replication were insufficient to rapidly  Fosamprenavir/ suppress plasma HIV RNA to <50 copies/mL atazanavir/ritonavir: in antiretroviral‐naive patients with high 10% viral load at baseline.”  Saquinavir/ atazanavir/ritonavir: 23%

58 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Ortiz et al, 2008 138 689 Treatment naïve The following two arms in combination Primary Endpoint: Non‐inferiority with Week 48: Permanent & patients aged ≥18 years with tenofovir 300mg and respect to the proportion of patients who discontinuation due to Mills et al, 2009 139 with HIV1‐RNA ≥ 5,000 emtricitabine 200mg daily: achieved virologic response (HAV1‐RNA < 50 adverse events (including & copies/mL  DRV/r 800/100 mg daily (n = 343) copies/mL) pregnancies): Orkin et al, 2012  LPV/r 800/200 mg total daily dose Week 48  DRV/r = 3% Setting: centers across (1‐2 times daily; n = 346)  DRV/r = 84%  LPV/r = 7% Phase 3, open‐ 26 countries, including  LPV/r = 78% label, multi‐center, the US Follow‐Up: 192 weeks o Difference DRV/r vs LPV/r = 5.6%95% Week 96: Discontinuation randomized non‐ Conducted: September ‘05 – all CI ‐0.1–11% of treatment due to inferiority trial patients reached 192 weeks (specific o Considered non‐inferior adverse events: date not mentioned) Week 96  DRV/r = 4%  DRV/r = 79%  LPV/r = 9%  LPV/r = 71% Incidence of grade 2‐4  Difference DRV/r vs LPV/r = 8.4% adverse events: o 95% CI 1.9–14.8%, P < 0.001  DRV/r = 23% o Considered non‐inferior  LPV/r = 34%

Secondary Endpoint: Durability and Week 192: Permanent statistical superiority of virologic response discontinuation due to over 96 and 192 weeks of DRV/r to LPV/r adverse events (including Week 96 pregnancies):  Difference DRV/r vs LPV/r = 8.3%  DRV/r = 7.6% o 95% CI 1.8–14.7%, P = 0.012  LPV/r = 14.5% P = 0.005 o Superiority of DRV/r shown o

Week 192 Most common adverse  DRV/r = 68.8% events: diarrhea, nausea,  LPV/r = 57.2% and rash.  Difference DRV/r vs LPV/r = 11.6% o 95% CI 4.4–18.8% o Superiority of DRV/r shown

59 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Molina et al, 2008 883 Treatment naïve The following two in combination with Primary Endpoint: Non‐inferiority with Week 48: Serious adverse 117 patients aged ≥18 years tenofovir 300mg and emtricitabine respect to the proportion of patients who events occurred in the & with HIV1‐RNA ≥ 5,000 200mg daily: achieved virologic response (HIV1‐RNA < 50 following percentage of Molina et al, 2010 copies/mL  ATV/r 300/100 mg daily copies/mL) at week 48 patients: o N = 440  ATV/r = 78%  ATV/r = 12% Open‐label, multi‐ Setting: 134 sites in 29  LPV/r 400/100 mg twice daily  LPV/r = 76%  LPV/r = 10% center, randomized countries, including the o N = 443 o 95% CI ‐3.8–7.1%; non‐inferior non‐inferiority trial US Week 96: Serious adverse Follow‐Up: 96 weeks Secondary Endpoint: The proportion of events occurred in the Conducted: November ‘05 – June ‘06 patients who maintained virologic response following percentage of (HIV1‐RNA < 50 copies/mL) at week 96 patients:  ATV/r = 74%  ATV/r = 14%  LPV/r = 68%  LPV/r = 11% o 95% CI 0.3–12%, p < 0.05 Most common adverse events were diarrhea and nausea. Smith et al, 2008 106 Treatment naïve The following two in combination with Primary Endpoint: Comparison of the Diarrhea and nausea were 118 patients aged >18 years tenofovir 300mg and emtricitabine proportion of patients with HIV1‐RNA < 50 reported more frequently 200mg daily: copies/mL at week 48 in the FPV/r arm compared Multi‐center, Setting: 16 outpatient  ATV/r 300/100 mg daily  ATV/r = 83% to the ATV/r arm. open‐label, sites in the US o N = 53  FPV/r = 75%, p = NS Hyperbilirubinemia, randomized trial  FPV/r 1400/100 mg daily fatigue, and jaundice were o N = 53 reported more frequently in the ATV/r arm Follow‐Up: 48 weeks Conducted: April compared to the FPV/r ’05 – September ‘06 arm.

60 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Dragsted et al, 306 Treatment naïve and The following two in combination with Primary Endpoint: Difference in the rate of Grade 3‐4 adverse events 2003125 experienced patients at least 2 NRTIs and/or NNRTIs (as virologic failure between both arms (defined were experienced by the aged ≥ 18 years selected by the treating physician): based on the patient’s viral load upon following percentage of Phase 4, open‐  IDV/r 800/100 mg twice daily inclusion) patients in each arm: label, multi‐center, Setting: 28 sites in 13 o N = 158  IDV/r vs SQV/r = 2.2% (95% CI ‐2.8–  IDV/r = 41% randomized trial countries, including the  SQV/r 1000/100 mg twice daily 7.2%), p = NS  SQV/r = 24% US o N = 148 o P = 0.001 Patients in the IDV/r arm Follow‐Up: 48 weeks Conducted: experienced more renal, September ‘00 – March ‘01 dermatological, and gastrointestinal severe adverse effects than those in the SQV/r arm. Kirk et al, 2003121 233 PI‐ and NNRTI‐naïve The following two in combination two Primary Endpoint: Comparison of the The following percentage patients about to NRTIs: proportion of patients with HIV1‐RNA ≤ 20 of patients switched Randomized, initiate their first HAART  SQV/r 400/400 mg twice daily copies/mL at week 48 therapy based on adverse controlled, open‐ regimen o N = 115  SQV/r = 56% events: label trial  NFV/NVP 1250/200 mg twice daily  NFV/NVP = 69%  SQV/r = 73% Setting: Denmark o N = 118 o P = 0.037  NFV/NVP = 80% o P = 0.99 Follow‐Up: 48 weeks Conducted: January 1998 – January 2001 The most limiting adverse event in both groups was gastrointestinal events. Skin reactions and allergy were significantly more common in the NFV/NVP arm.

61 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Fischl et al, 2003140 517 Persons with advanced Subjects received lamivudine (150 mg) Virologic failure Adverse event rate human and zidovudine (300 mg) twice daily  EFV/IDV < IDV, p = 0.04  EFV/IDV = NFV/IDV = Randomized, open‐ immunodeficiency virus along with  NFV/IDV > IDV, p = 0.006 IDV label study (HIV) disease and little  Indinavir (IDV) 800 mg three times to no experience with daily (n = 168) The most frequent grade 3 ART  efavirenz 600 mg once daily plus or 4 signs or symptoms indinavir 1000 mg three times daily reported were aches or (EFV/IDV, n = 173) pains, fatigue, or  nelfinavir 1250 mg twice daily plus gastrointestinal complaints indinavir 1000 mg twice daily (nausea, vomiting, and (NFV/IDV, n = 176) diarrhea)

Follow‐up: 2.1 years Gathe et al, 2002120 649 Treatment naïve The following two in combination with Primary Endpoint: Comparison of the Grade 2‐4 adverse events patients aged ≥18 years abacavir and lamivudine twice daily: magnitude and durability of virologic were experienced by the Phase III, open‐ with HIV1‐RNA ≥ 1,000  FPV/r 1400/200 mg daily response over 48 weeks following percentage of label, multi‐center, copies/mL o N = 322 HIV1‐RNA < 400 copies/mL patients in each arm: randomized, non‐  NFV 1250 mg twice daily  FPV/r = 69%  FPV/r = 41% inferiority study Setting: 101 centers in o N = 327  NFV = 68%  NFV = 39% North America, Europe, o 1% (95% CI ‐6–8%) South Africa, and Follow‐Up: 48 weeks o Considered non‐inferior Diarrhea was significantly Australia HAV1‐RNA < 50 copies/mL more common in the NFV  FPV/r = 55% arm.  NFV = 53% Kirk et al, 200189 2708 HIV‐infected patients HAART with > 3 drugs including: Proportion of patients who had Not reported older than 16 years  Indinavir (n = 1342) experienced clinical progression at 12 Prospective,  Ritonavir (n = 556) months observational,  Saquinavir (n = 810)  Indinavir: 9.2% multicenter cohort  Ritonavir: 11.9% study Median follow‐up: 30 months  Saquinavir: 11.9%

Relative Risk for Clinical Progression  Indinavir vs. Saquinavir: 0.77 (0.6‐0.99), p = 0.043  Ritonavir vs. Saquinavir: 0.83 (0.62– 1.11);p = NS

62 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Gulick et al, 2000122 277 NNRTI treatment naïve Delavirdine and/or Adefovir in Virologic Response (<500 HIV RNA Adverse event rate patients combination with copies/mL)  SQV/r = SQV/NLV, Prospective,  SQV/r (n = 139)  SQV/r: 28% p = 0.07 randomized, 2x3  SQV/NFV (n = 138)  SVQV/NFV: 33%, p = NS factorial, multicenter study Duration: 16 weeks Katzenstein et al, 318 Patients ⩾ 18 years old Two NRTIs in combination with: ⩽20 HIV RNA copies/mL at 72 weeks Adverse‐event 1999124 with documented HIV  Indinavir 800 mg three times daily (n  Indinavir: 51% discontinuation rate: infection and 0–13 days = 107)  Ritonavir: 41%  Indinavir: 27% Randomized, open‐ prior use of PIs  Ritonavir 600 mg twice daily (n =  Saquinavir/r: 58%  Ritonavir: 68% label, multicenter 107)  Saquinavir/r > Ritonavir, p < 0.05  Saquinavir/r: 33%, p < comparative study  Saquinavir/r 400/600 mg twice daily 0.001 (n = 104) Virus loads of ⩽20 copies/mL at 72 weeks  Indinavir: 63% Renal adverse reactions Follow‐up: up to 72 weeks  Ritonavir: 55% were most common  Saquinavir/r: 77%, p = NS among patients receiving indinavir, whereas Treatment success rate gastrointestinal and  Indinavir: 52% neurologic adverse  Ritonavir: 41% reactions were more often  Saquinavir/r: 58%, p = NS experienced by patients receiving ritonavir. Cohen Stuart et al, 70 Patients who were ART with zidovudine 200 mg three Decrease in HIV RNA Overall adverse event rate: 1999126 antiretroviral‐naive and times per day plus lamivudine 150 mg  Indinavir = Saquinavir  Indinavir = Saquinavir who had a CD4 cell twice per day plus either Discontinuation rate: Randomized, open count < 500 x 10(6)/I  Indinavir 800 mg three times daily (n Increase in CD4 cell counts  Indinavir = Saquinavir label, multicenter and/or > 10000 HIV RNA = 35)  Indinavir < Saquinavir, p = 0.01 study copies/ml plasma  Saquinavir 1200 mg three times and/or HIV‐related daily (n = 35) symptoms Follow‐up 24 weeks Treatment experienced patients

63 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Antoniou et al, 85 Patients with multidrug Tipranavir/ritonavir (TPV/r; n = 38) Virologic Response (viral load < 50 Adverse event rate 2010127 resistant HIV copies/mL)  TPV/r = DRV/r Darunavir/ritonavir (DRV/r; n = 47)  TPV/r: 82% Multicenter,  DRV/r: 79%, p = NS retrospective cohort study Sustained virologic suppression (2 or more sequential viral load results below 50 copies/mL)  TPV/r: 74%  DRV/r: 72%, p = NS Johnson et al, 2005 358 Treatment experienced The following in combination with Primary Endpoint: Comparison of the Grade 2‐4 adverse events 128 patients aged ≥16‐18 tenofovir 300mg daily and one NRTI: magnitude and durability of viral load Week 48: & years (legal minimum  ATV/r 300/100 mg daily reduction from baseline based on the timed  ATV/r = 29% Johnson et al, 2006 age as locally required) o N = 120 average difference through week 48 and 96  ATV/SQV = 26% 141 that had failed ≥ 2  ATV/SQV 400/1200 mg daily  LPV/r = 25% HAART regimens that o N = 115 Week 48 Multi‐center, included one or more  LPV/r 400/100 mg twice daily  ATV/r vs LPV/r = 0.13 log10 copies/mL Week 96: open‐label, NRTI and PI and had o N = 123 (97.5% CI ‐0.12–0.39); non‐inferior  ATV/r = 13% randomized non‐ previously responded to  ATV/SQV vs LPV/r = 0.33 log10 copies/mL  LPV/r = 11% inferiority trial at least 1 HAART Follow‐Up: 48 weeks Conducted: April (97.5% CI 0.07–0.60); inferior regimen with a 1 log10 ’05 – September ‘06 copies/mL viral load Week 96

reduction or a viral load  ATV/r vs LPV/r = 0.14 log10 copies/mL decline to < 400 (97.5% CI ‐0.13–0.41), non‐inferior copies/mL Secondary Endpoint: Mean change of HIV1‐ Setting: Europe and RNA from baseline to week 48 and 96 North and South America Week 48

 ATV/r = 1.93 log10 copies/mL  ATV/SQV = 1.55 log10 copies/mL  LPV/r = 1.87 log10 copies/mL Week 96

 ATV/r = ‐2.29 log10 copies/mL  LPV/r = ‐2.08 log10 copies/mL

64 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Haas et al, 2003129 85 Treatment experienced Two NRTIs in combination with: Primary Endpoint: Assess safety and Adverse‐event patients having at least  ATV/SQV 400/1200 mg once daily (n tolerability discontinuation rate: Randomized, 1000 HIV‐1 RNA = 34)  ATV 400 mg = 9% multinational pilot copies/ml, 100 x 106  ATV/SQV 600/1200 mg once daily (n Secondary Endpoints: Mean change in HIV1‐  ATV 600 mg = 11% trial CD4 cells/l (75 x 106 = 28) RNA, viral load and CD4+ T cell count  r = 30%; p = NS cells/l without AIDS  r/SQV 400 mg/400 mg twice daily (n diagnosis) and virologic = 23) Virologic response (> 1.0 log(10) decrease Mean change in low‐ response to a prior HIV‐1 RNA or HIV‐1 RNA < 400 copies/ml): density cholesterol regimen Duration: 48 weeks  ATV 400 mg = 41%  ATV 400 mg = ‐0.6%  ATV 600 mg = 29%  ATV 600 mg = ‐6.7%  r = 35%; p = NS  r = 23.2%; p < 0.05

Mean change in triglyceride  ATV 400 mg = ‐4.8%  ATV 600 mg = ‐27.1%  r = 93%; p < 0.001 Chavanet et al, 31 Patients age > 18 with NRTIs in combination with: Plasma viral load stabilization or decrease Not reported 2001131 HIV and previous PI  r/SQV 200/600 mg twice daily (n = >/= 0.5 log exposure > 6 months, 16)  r/SQV: 10 Prospective, unchanged HAART > 3  NFV/SQV 1000/600 mg twice daily  NFV/SQV: 8 multicenter, months, and viral load > (n = 15) randomized open 3 log trial Duration: 3 months Para et al, 2000132 89 Patients age > 18 with ARV therapy including Achieved viral RNA level of <500 copies/mL Not reported HIV‐1 infection  SQV 1200 mg every 8 hours (n = 59)  SQV: 4‐8% Multicenter,  IDV 800 mg every 8 hours (n = 30)  IDV: 49%; p < 0.001 randomized, phase II, open‐label trial Follow‐up: 24 weeks

65 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Roca et al, 2000130 112 Patients with HIV and Art with stavudine 40 mg (30 mg if CD4+ Call increase > 100/mL Frequency of treatment‐ CD4 cell count below weight < 60 kg) twice daily and  IDV: 42% related side effects Randomized, open‐ 500 × 106/l or HIV RNA lamivudine 150 mg twice daily with  NFV: 35%, p = NS  IDV: 54% label, prospective plasma level > 5000  IDV 800 mg three times daily (n =  NFV: 46%, p = NS study. copies/ml 56) HIV RNA level below limit of detection  NFV 750 mg three times daily (n =  IDV: 46% Treatment‐related 56)  NFV: 47%, p = NS discontinuation rate  IDV: 60% Median duration of follow‐up: 9  NFV: 38%, p < 0.05 months Pediatric patients Rodriguez‐French 249 Treatment naïve The following two in combination with Primary Endpoint: Comparison of the Adverse events of at least et al, 2004134 patients aged ≥13‐18 abacavir 300mg and lamivudine 150mg efficacy and durability of the antiviral grade 2 in severity were years (legal minimum twice daily: response (HIV1‐RNA < 400 copies/mL) at 48 experienced by the Multi‐center, age as locally required)  FPV 1400 mg twice daily weeks following percentage of open‐label, with HIV1‐RNA ≥ 5,000 o N = 166  FPV = 66% patients: randomized study copies/mL  NFV 1250 mg twice daily  NFV = 51%  FPV = 30% o N = 83  NFV = 34%

Setting: US, Puerto Rico, Follow‐Up: 48 weeks Conducted: Diarrhea was more Panama, and South November ‘00 – July ‘01 common in the NFV arm. Africa Rash was more common in the FPV arm. Key: NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; ATV = atazanavir; RAL = raltegravir; DRV = darunavir; r = ritonavir; 97.5% or 95% CI = 97.5% or 95% confidence interval; LPV = lopinavir; TDF = tenofovir; FTC = emtricitabine; FPV = fosamprenavir; SQV = saquinavir; NFV = nelfinavir; HAART = highly active antiretroviral therapy

Evidence Table 3. Excluded Clinical Trials Bench Science Studies (synthesis, delivery systems, drug concentration quant, cell culture/animal studies, T‐cell proliferation, etc.) PubMed ID {Reference} 1. 17169034 {Atzori, 2006, Detection of HIV protease inhibitors in alveolar epithelial lining fluid: relevance for modulation of pneumocystis infection in the course of HAART} 2. 17116674 {Ntemgwa, 2007, Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors} 3. 17081812 {Weller, 2007, An isocratic liquid chromatography method for determining HIV non‐nucleoside reverse transcriptase inhibitor and protease inhibitor concentrations in human plasma} 4. 16997640 {Verbesselt, 2007, Simultaneous determination of 8 HIV protease inhibitors in human plasma by isocratic high‐performance liquid chromatography with combined use of UV and fluorescence detection: amprenavir`, indinavir`, atazanavir`, ritonavir`, lopinavir`, saquinavir`, nelfinavir and M8‐nelfinavir metabolite} 5. 16118329 {Zhang, 2005, In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation} 6. 24691856 {Delille, 2014, Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations} 7. 15081931 {Crommentuyn, 2004, Simultaneous quantification of the new HIV protease inhibitors atazanavir and tipranavir in human plasma by high‐performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry} 8. 11532998 {Taylor, 2001, Antiretroviral drug concentrations in semen of HIV‐infected men: differential penetration of indinavir`, ritonavir and saquinavir} 9. 10607709 {Hazenberg, 2000, T‐cell division in human immunodeficiency virus (HIV)‐1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART)} 10. 21149923 {Dierynck, 2010, In vitro susceptibility and virological outcome to darunavir and lopinavir are independent of HIV type‐1 subtype in treatment‐naive patients} 11. 23979165 {Rabi, 2013, Multi‐step inhibition explains HIV‐1 protease inhibitor pharmacodynamics and resistance} 12. 23750830 {Chang, 2013, Evaluating the in vitro inhibition of UGT1A1`, OATP1B1`, OATP1B3`, MRP2`, and BSEP in predicting drug‐induced hyperbilirubinemia} 13. 23365446 {Mittal, 2013, Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV‐1 protease with mutations at residue 50} 14. 17591027 {Dam, 2007, Synergistic inhibition of protease‐inhibitor‐resistant HIV type 1 by saquinavir in combination with atazanavir or lopinavir} 15. 22265353 {Yadav, 2012, Comparison of extraction procedures for assessment of matrix effect for selective and reliable determination of atazanavir in human plasma by LC‐ESI‐MS/MS} 16. 22161308 {Rhoades, 2012, Prediction and in vitro evaluation of selected protease inhibitor antiviral drugs as inhibitors of carboxylesterase 1: a potential source of drug‐drug interactions} 17. 22098079 {Bethell, 2012, Short communication: Phenotypic protease inhibitor resistance and cross‐resistance in the clinic from 2006 to 2008 and mutational prevalences in HIV from patients with discordant tipranavir and darunavir susceptibility phenotypes} 18. 15795650 {Poirier, 2005, Simple and simultaneous determination of the hiv‐protease inhibitors amprenavir`, atazanavir`, indinavir`, lopinavir`, nelfinavir`, ritonavir and saquinavir plus M8 nelfinavir metabolite and the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine in human plasma by reversed‐phase liquid chromatography} 19. 21108978 {Nowacek, 2011, Analyses of nanoformulated antiretroviral drug charge`, size`, shape and content for uptake`, drug release and antiviral activities in human monocyte‐derived macrophages} 20. 21104925 {Berginc, 2010, HIV protease inhibitors: garlic supplements and first‐pass intestinal metabolism impact on the therapeutic efficacy} 21. 21068005 {Leroyer, 2011, Glyceroneogenesis is inhibited through HIV protease inhibitor‐induced inflammation in human subcutaneous but not visceral adipose tissue} 22. 17236737 {Choi, 2007, High‐performance liquid chromatography assay for the determination of the HIV‐protease inhibitor tipranavir in human plasma in combination with nine other antiretroviral medications} PK (ADME) or Kinetics Studies 23. 23155151 {Hulskotte, 2013, Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir‐boosted HIV‐1 protease inhibitors atazanavir`, darunavir`, and lopinavir} 24. 22288567 {Piscitelli, 2012, Drug interaction profile for GSK2248761`, a next generation non‐nucleoside reverse transcriptase inhibitor} 25. 22095129 {Kuznetsov, 2011, Pre‐steady‐state kinetics of interaction of wild‐type and multiple drug‐resistant HIV protease with first and second generation inhibitory drugs} 26. 21709075 {Boffito, 2011, Pharmacokinetics of once‐daily darunavir‐ritonavir and atazanavir‐ritonavir over 72 hours following drug cessation} 27. 24951533 {Kakuda, 2014, Pharmacokinetics and pharmacodynamics of boosted once‐daily darunavir} 28. 21576452 {Goldwirt, 2011, Switch from enfuvirtide to raltegravir lowers plasma concentrations of darunavir and tipranavir: a pharmacokinetic substudy of the EASIER‐ANRS 138 trial} 29. 20197684 {Sekar, 2010, Pharmacokinetic interaction between indinavir and darunavir with low‐dose ritonavir in healthy volunteers} 30. 19637947 {McRae, 2009, Pharmacokinetics of concurrent administration of fosamprenavir and atazanavir without ritonavir in human immunodeficiency virus‐negative subjects} 31. 19528289 {von Hentig, 2009, Cytochrome P450 3A inhibition by atazanavir and ritonavir`, but not demography or drug formulation`, influences saquinavir population pharmacokinetics in human immunodeficiency virus type 1‐infected adults} 32. 19203907 {Boffito, 2008, Pharmacokinetics`, efficacy`, and safety of darunavir/ritonavir 800/100 mg once‐daily in treatment‐naïve and ‐experienced patients} 33. 18769354 {Mathias, 2008, Effect of ritonavir‐boosted tipranavir or darunavir on the steady‐state pharmacokinetics of elvitegravir} 34. 18536180 {Pawinski, 2008, Pharmacokinetic monitoring of HIV‐1 protease inhibitors in the antiretroviral therapy} 35. 18520949 {Busti, 2008, Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin} 36. 18333863 {Abel, 2008, Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers} 37. 18154477 {Ofotokun, 2008, Pharmacokinetics of an indinavir‐ritonavir‐fosamprenavir regimen in patients with human immunodeficiency virus} 38. 18043478 {Sekar, 2007, Pharmacokinetic interaction between darunavir and saquinavir in HIV‐negative volunteers} 39. 17910618 {Justesen, 2007, Pharmacokinetics of two randomized trials evaluating the safety and efficacy of indinavir`, saquinavir and lopinavir in combination with low‐dose ritonavir: the MaxCmin1 and 2 trials} 40. 17760738 {Luber, 2007, Steady‐state pharmacokinetics of once‐daily fosamprenavir/ritonavir and atazanavir/ritonavir alone and in combination with 20 mg omeprazole in healthy volunteers} 41. 17694300 {Panhard, 2007, Population pharmacokinetic analysis of lamivudine`, stavudine and zidovudine in controlled HIV‐infected patients on HAART} 42. 17296738 {von Hentig, 2007, Pharmacokinetics of saquinavir`, atazanavir`, and ritonavir in a twice‐daily boosted double‐protease inhibitor regimen} 43. 16984898 {Ford, 2006, Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV‐infected patients} 44. 16910830 {Boffito, 2006, Pharmacokinetics of saquinavir hard‐gel/ritonavir and atazanavir when combined once daily in HIV Type 1‐infected individuals administered different atazanavir doses} 45. 16863481 {Robertson, 2006, Lack of in vivo correlation between indinavir and saquinavir exposure and cytochrome P450 3A phenotype as assessed with oral midazolam as a phenotype probe} 46. 16553510 {Kiser, 2006, Effects of esomeprazole on the pharmacokinetics of atazanavir and fosamprenavir in a patient with human immunodeficiency virus infection} 47. 16372824 {Goujard, 2005, High variability of indinavir and nelfinavir pharmacokinetics in HIV‐infected patients with a sustained virological response on highly active antiretroviral therapy} 48. 16218957 {Tie, 2005, Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 angstroms resolution crystal structures of HIV‐1 protease mutants with substrate analogs} 49. 16041598 {Seminari, 2005, Steady‐state pharmacokinetics of atazanavir given alone or in combination with saquinavir hard‐gel capsules or amprenavir in HIV‐1‐infected patients} 50. 18771060 {Pea, 2008, Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV‐infected liver transplant patients} 51. 15483467 {Boffito, 2004, Steady‐State pharmacokinetics of saquinavir hard‐gel/ritonavir/fosamprenavir in HIV‐1‐infected patients} 52. 15362661 {Boffito, 2004, Atazanavir enhances saquinavir hard‐gel concentrations in a ritonavir‐boosted once‐daily regimen} 53. 14982784 {DiCenzo, 2004, Pharmacokinetics of indinavir and nelfinavir in treatment‐naive`, human immunodeficiency virus‐infected subjects} 54. 12732841 {Washington, 2003, Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors} 55. 12657921 {Bratt, 2003, Sildenafil does not alter nelfinavir pharmacokinetics} 56. 12499180 {Pfister, 2003, Population pharmacokinetics and pharmacodynamics of efavirenz`, nelfinavir`, and indinavir: Adult AIDS Clinical Trial Group Study 398} 57. 12461428 {Justesen, 2002, Diurnal variation of plasma protease inhibitor concentrations} 58. 12433819 {Lu, 2002, Model‐based analysis of the pharmacokinetic interactions between ritonavir`, nelfinavir`, and saquinavir after simultaneous and staggered oral administration} 59. 11709366 {Sadler, 2001, Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir} 60. 10805798 {Fleury, 2000, Long‐term kinetics of T cell production in HIV‐infected subjects treated with highly active antiretroviral therapy} 61. 11101060 {Fletcher, 2000, Competing drug‐drug interactions among multidrug antiretroviral regimens used in the treatment of HIV‐ infected subjects: ACTG 884} 62. 8721545 {St Clair, 1996, In vitro antiviral activity of 141W94 (VX‐478) in combination with other antiretroviral agents} 63. 11872997 {Kosel, 2002, The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir} 64. 22121190 {Zhu, 2012, Pharmacokinetics and inhibitory quotient of atazanavir/ritonavir versus lopinavir/ritonavir in HIV‐infected`, treatment‐naive patients who participated in the CASTLE Study} 65. 10939550 {Slain, 2000, Variability in activity of hepatic CYP3A4 in patients infected with HIV} 66. 9708400 {Hoetelmans, 1998, The effect of plasma drug concentrations on HIV‐1 clearance rate during quadruple drug therapy} 67. 12189360 {Pfister, 2002, Effect of coadministration of nelfinavir`, indinavir`, and saquinavir on the pharmacokinetics of amprenavir} HIV mutations or sequencing studies 68. 24629078 {Mata‐Munguia, 2014, Natural polymorphisms and unusual mutations in HIV‐1 protease with potential antiretroviral resistance: a bioinformatic analysis}

68 69. 21602929 {Codoner, 2011, Added value of deep sequencing relative to population sequencing in heavily pre‐treated HIV‐1‐infected subjects} 70. 20210652 {Munerato, 2010, HIV type 1 antiretroviral resistance mutations in subtypes B`, C`, and F in the City of Sao Paulo`, Brazil} 71. 15356820 {Demeter, 2004, HIV‐1 drug resistance in subjects with advanced HIV‐1 infection in whom antiretroviral combination therapy is failing: a substudy of AIDS Clinical Trials Group Protocol 388} 72. 19299521 {Tartaglia, 2009, Both a protective and a deleterious role for the L76V mutation} 73. 18690163 {Delaugerre, 2008, Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir‐containing regimen} 74. 20805393 {Young, 2010, Prevalence`, mutation patterns`, and effects on protease inhibitor susceptibility of the L76V mutation in HIV‐1 protease} 75. 20479204 {Poveda, 2010, Drug resistance mutations in HIV‐infected patients in the Spanish drug resistance database failing tipranavir and darunavir therapy} 76. 21311113 {Lathouwers, 2011, Virological characterization of patients failing darunavir/ritonavir or lopinavir/ritonavir treatment in the ARTEMIS study: 96‐week analysis} 77. 17101675 {Mo, 2007, Identification and structural characterization of I84C and I84A mutations that are associated with high‐level resistance to human immunodeficiency virus protease inhibitors and impair viral replication} Drug resistance/susceptibility/cross‐resistance studies 78. 18317002 {Poveda, 2008, Evidence for different susceptibility to tipranavir and darunavir in patients infected with distinct HIV‐1 subtypes} 79. 18227188 {Desbois, 2008, In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors} 80. 16964826 {Abecasis, 2006, Investigation of baseline susceptibility to protease inhibitors in HIV‐1 subtypes C`, F`, G and CRF02_AG} 81. 22096044 {Hsieh, 2011, Emerging HIV‐1 resistance to tipranavir and darunavir in patients with virological failure to first‐generation protease inhibitors in Taiwan} 82. 19751502 {Hsieh, 2009, Impact of first‐line protease inhibitors on predicted resistance to tipranavir in HIV‐1‐infected patients with virological failure} 83. 19131889 {Spagnuolo, 2009, Changes in darunavir/r resistance score after previous failure to tipranavir/r in HIV‐1‐infected multidrug‐resistant patients} 84. 10770770 {Rusconi, 2000, Susceptibility to PNU‐140690 (Tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors} 85. 10199226 {Schapiro, 1999, Clinical cross‐resistance between the HIV‐1 protease inhibitors saquinavir and indinavir and correlations with genotypic mutations} Noncomparative studies 86. 24343782 {Deeks, 2014, Cobicistat: a review of its use as a pharmacokinetic enhancer of atazanavir and darunavir in patients with HIV‐1 infection} 87. 24002702 {Guaraldi, 2013, HIV‐associated lipodystrophy: impact of antiretroviral therapy} 88. 19323590 {McKeage, 2009, Darunavir: a review of its use in the management of HIV infection in adults} 89. 20048718 {Arribas, 2009, Drugs in traditional drug classes (nucleoside reverse transcriptase inhibitor/nonnucleoside reverse transcriptase inhibitor/protease inhibitors) with activity against drug‐resistant virus (tipranavir`, darunavir`, etravirine)} 90. 18556070 {Hughes, 2008, New treatment options for HIV salvage patients: an overview of second generation PIs`, NNRTIs`, integrase inhibitors and CCR5 antagonists} 91. 19195460 {García Deltoro, 2008, [Resistance to darunavir]} 92. 19527188 {Fernandez‐Montero, 2009, HIV protease inhibitors: recent clinical trials and recommendations on use} 93. 15595429 {Clotet, 2004, Strategies for overcoming resistance in HIV‐1 infected patients receiving HAART} 94. 19195457 {Antela López, 2008, [Safety and tolerability of darunavir]} 95. 15259893 {Turner, 2004, The influence of protease inhibitor resistance profiles on selection of HIV therapy in treatment‐naive patients} 96. 15193140 {Randolph, 2004, Peptidomimetic inhibitors of HIV protease} 97. 19195454 {Estrada, 2008, [Darunavir in treatment‐naïve patients. The ARTEMIS study]} 98. 21975358 {Tejerina, 2011, Protease inhibitors as preferred initial regimen for antiretroviral‐naive HIV patients} 99. 21212689 {Cooper, 2011, Renal disease associated with antiretroviral therapy in the treatment of HIV} 100. 19436623 {Rivas, 2009, Role of atazanavir in the treatment of HIV infection} 101. 16863488 {Piacenti, 2006, An update and review of antiretroviral therapy} 102. 16011526 {Waters, 2005, New drugs} 103. 16091231 {Harris, 2004, Management of HIV‐infected patients with multidrug‐resistant virus} 104. 15287232 {Musial, 2004, Atazanavir: a new protease inhibitor to treat HIV infection} 105. 15116286 {Sension, 2004, Initial therapy for human immunodeficiency virus: broadening the options} 106. 14986280 {Sulkowski, 2004, Drug‐induced liver injury associated with antiretroviral therapy that includes HIV‐1 protease inhibitors} 107. 12946064 {Murphy, 2003, Reviving protease inhibitors: new data and more options}

69 108. 19735222 {Chetchotisakd, 2009, The CASTLE study: atazanavir/r versus lopinavir/r in antiretroviral‐naive patients} 109. 10708858 {Tomasselli, 2000, Targeting the HIV‐protease in AIDS therapy: a current clinical perspective} 110. 26035169 {Curran, 2015, Rezolsta® (Darunavir/Cobicistat): First Boosted Protease Inhibitor Co‐formulated with Cobicistat} Cost‐analysis studies 111. 23538194 {Johnston, 2013, Comparative incidence and health care costs of medically attended adverse effects among U.S. Medicaid HIV patients on atazanavir‐ or darunavir‐based antiretroviral therapy} 112. 22563716 {Simpson, 2012, Economic and health‐related quality‐of‐life (HRQoL) comparison of lopinavir/ritonavir (LPV/r) and atazanavir plus ritonavir (ATV+RTV) based regimens for antiretroviral therapy (ART)‐naïve and ‐experienced United Kingdom patients in 2011} 113. 21288058 {Broder, 2011, Cost effectiveness of atazanavir‐ritonavir versus lopinavir‐ritonavir in treatment‐naïve human immunodeficiency virus‐infected patients in the United States} 114. 24906477 {Brogan, 2014, Cost effectiveness of darunavir/ritonavir combination antiretroviral therapy for treatment‐naive adults with HIV‐1 infection in Canada} 115. 21231811 {Thuresson, 2011, Cost‐effectiveness of atazanavir/ritonavir compared with lopinavir/ritonavir in treatment‐naïve human immunodeficiency virus‐1 patients in Sweden} 116. 23620210 {Simpson, 2013, Lopinavir/ritonavir versus darunavir plus ritonavir for HIV infection: a cost‐effectiveness analysis for the United States} Computer simulation/model studies 117. 23479398 {Siccardi, 2013, Prediction of drug‐drug interactions between various antidepressants and efavirenz or boosted protease inhibitors using a physiologically based pharmacokinetic modelling approach} 118. 20368406 {Talbot, 2010, Predicting tipranavir and darunavir resistance using genotypic`, phenotypic`, and virtual phenotypic resistance patterns: an independent cohort analysis of clinical isolates highly resistant to all other protease inhibitors} 119. 19931478 {Jayakanthan, 2010, Analysis of CYP3A4‐HIV‐1 protease drugs interactions by computational methods for Highly Active Antiretroviral Therapy in HIV/AIDS} 120. 18647303 {Hyland, 2008, Maraviroc: in vitro assessment of drug‐drug interaction potential} Studies focusing on other disease states (e.g. Karposi’s sarcoma, malaria, HCV) 121. 21829205 {Lucia, 2011, Exposure to HIV‐protease inhibitors selects for increased expression of P‐glycoprotein (ABCB1) in Kaposi's sarcoma cells} 122. 20028821 {Peatey, 2010, Antimalarial asexual stage‐specific and gametocytocidal activities of HIV protease inhibitors} 123. 18443126 {He, 2008, Synergy of human immunodeficiency virus protease inhibitors with chloroquine against Plasmodium falciparum in vitro and Plasmodium chabaudi in vivo} 124. 10854138 {Fumagalli, 2000, The pharmacokinetics of liposomal encapsulated daunorubicin are not modified by HAART in patients with HIV‐associated Kaposi's sarcoma} 125. 9498464 {Rutschmann, 1998, Impact of treatment with human immunodeficiency virus (HIV) protease inhibitors on hepatitis C viremia in patients coinfected with HIV} 126. 17361129 {Parikh, 2007, Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa} No Direct Comparison between agents 127. 17956835 {Lowe, 2007, Stavudine but not didanosine as part of HAART contributes to peripheral lipoatrophy: a substudy from the Antiretroviral Regimen Evaluation Study (ARES)} 128. 15167287 {Wood, 2004, Long‐term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir} 129. 11741162 {Casado, 2002, Plasma drug levels`, genotypic resistance`, and virological response to a nelfinavir plus saquinavir‐containing regimen} 130. 12435691 {Riddler, 2002, Coadministration of indinavir and nelfinavir in human immunodeficiency virus type 1‐infected adults: safety`, pharmacokinetics`, and antiretroviral activity} 131. 11399999 {Linde, 2001, Low incidence of genotypic and phenotypic resistance in paediatric HIV‐infected patients on long‐term first‐line antiretroviral triple therapy} 132. 10714568 {Reijers, 2000, Toxicity and drug exposure in a quadruple drug regimen in HIV‐1 infected patients participating in the ADAM study} 133. 23508901 {Ucciferri, 2013, Improved metabolic profile after switch to darunavir/ritonavir in HIV positive patients previously on protease inhibitor therapy} 134. 22050734 {Turatti, 2012, Short communication: UGT1A1*28 variant allele is a predictor of severe hyperbilirubinemia in HIV‐infected patients on HAART in southern Brazil} 135. 12444941 {Worm, 2002, Clinical lipoatrophy in HIV‐1 patients on HAART is not associated with increased abdominal girth`, hyperlipidaemia or glucose intolerance} 136. 11177388 {Casado, 2001, Efficacy`, tolerance`, and pharmacokinetics of the combination of stavudine`, nevirapine`, nelfinavir`, and saquinavir as salvage regimen after ritonavir or indinavir failure} 137. 9164318 {Jacobson, 1997, Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy} 138. 10770342 {Labetoulle, 1999, Cytomegalovirus retinitis in advanced HIV‐infected patients treated with protease inhibitors: incidence and outcome over 2 years} 139. 10202820 {Tebas, 1999, Virologic responses to a ritonavir‐‐saquinavir‐containing regimen in patients who had previously failed nelfinavir} 140. 9764784 {Silva, 1998, The effect of protease inhibitors on weight and body composition in HIV‐infected patients} Evaluating drug side effects/safety compared to another PI‐containing regimen Lipids and Cholesterol: 141. 24417772 {Martinez, 2014, Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir}

70 142. 15721096 {Grover, 2005, Impact of dyslipidemia associated with Highly Active Antiretroviral Therapy (HAART) on cardiovascular risk and life expectancy} 143. 11345223 {Roge, 2001, Comparison of P‐triglyceride levels among patients with human immunodeficiency virus on randomized treatment with ritonavir`, indinavir or ritonavir/saquinavir} 144. 21463988 {Gyalrong‐Steur, 2011, Changes in lipid profiles after switching to a protease inhibitor‐containing cART‐‐unfavourable effect of fosamprenavir in obese patients} 145. 23440570 {Arathoon, 2013, Effects of once‐daily darunavir/ritonavir versus lopinavir/ritonavir on metabolic parameters in treatment‐naive HIV‐1‐infected patients at week 96: ARTEMIS} 146. 20035166 {Nelson, 2010, Friedewald equation underestimates low‐denisty lipoprotein elevations for patients with high triglyceride levels in the ARTEMIS and TITAN trials} Hypertension 147. 16603854 {Crane, 2006, Antiretroviral medications associated with elevated blood pressure among patients receiving highly active antiretroviral therapy} Weight: 148. 24557728 {Moyle, 2014, Comparison of body composition changes between atazanavir/ritonavir and lopinavir/ritonavir each in combination with tenofovir/emtricitabine in antiretroviral‐ naïve patients with HIV‐1 infection} Renal‐related: 149. 20523203 {Mocroft, 2010, Estimated glomerular filtration rate`, chronic kidney disease and antiretroviral drug use in HIV‐positive patients} 150. 24130871 {Nishijima, 2013, Ritonavir‐boosted darunavir is rarely associated with nephrolithiasis compared with ritonavir‐boosted atazanavir in HIV‐infected patients} 151. 23599359 {de Lastours, 2013, High levels of atazanavir and darunavir in urine and crystalluria in asymptomatic patients} 152. 21716074 {Rockwood, 2011, Ritonavir‐boosted atazanavir exposure is associated with an increased rate of renal stones compared with efavirenz`, ritonavir‐boosted lopinavir and ritonavir‐ boosted darunavir} Hepatic‐related: 153. 17721109 {Raffi, 2007, Combined tipranavir and enfuvirtide use associated with higher plasma tipranavir concentrations but not with increased hepatotoxicity: sub‐analysis from RESIST} 154. 15880318 {Bruno, 2005, Hepatotoxicity and nelfinavir: a meta‐analysis} 155. 23739226 {Vispo, 2013, Low risk of liver toxicity using the most recently approved antiretroviral agents but still increased in HIV‐hepatitis C virus coinfected patients} 156. 22404426 {McDonald, 2012, Clinical significance of hyperbilirubinemia among HIV‐1‐infected patients treated with atazanavir/ritonavir through 96 weeks in the CASTLE study} Quality of Life Studies 157. 10839659 {Bonfanti, 2000, Incidence of adverse reactions in HIV patients treated with protease inhibitors: a cohort study. Coordinamento Italiano Studio Allergia e Infezione da HIV (CISAI) Group} 158. 20467943 {Malan, 2010, Gastrointestinal tolerability and quality of life in antiretroviral‐naive HIV‐1‐infected patients: data from the CASTLE study} Comparison to another drug or drug class (e.g. NNRTI, IL2, buprenorphine, elvitegravir, lamivudine, NRTI) 162. 23372109 {Casado, 2013, Lipid‐lowering effect and efficacy after switching to etravirine in HIV‐infected patients with intolerance to suppressive HAART} 163. 22100576 {Gruber, 2012, Interactions between buprenorphine and the protease inhibitors darunavir‐ritonavir and fosamprenavir‐ritonavir} 164. 20186278 {Tavel, 2010, Effects of intermittent IL‐2 alone or with peri‐cycle antiretroviral therapy in early HIV infection: the STALWART study} 165. 10823761 {Losso, 2000, A randomized`, controlled`, phase II trial comparing escalating doses of subcutaneous interleukin‐2 plus antiretrovirals versus antiretrovirals alone in human immunodeficiency virus‐infected patients with CD4+ cell counts >/=350/mm3} 166. 20146631 {Zolopa, 2010, Activity of elvitegravir`, a once‐daily integrase inhibitor`, against resistant HIV Type 1: results of a phase 2`, randomized`, controlled`, dose‐ranging clinical trial} 167. 12407485 {Sension, 2002, Lamivudine 300 mg QD versus continued lamivudine 150 mg BID with stavudine and a protease inhibitor in suppressed patients} 168. 14502007 {Gerstoft, 2003, Low efficacy and high frequency of adverse events in a randomized trial of the triple nucleoside regimen abacavir`, stavudine and didanosine} New, unapproved PIs 169. 24080647 {Salcedo Gomez, 2013, GRL‐04810 and GRL‐05010`, difluoride‐containing nonpeptidic HIV‐1 protease inhibitors (PIs) that inhibit the replication of multi‐PI‐resistant HIV‐1 in vitro and possess favorable lipophilicity that may allow blood‐brain barrier penetration} 170. 23403426 {Amano, 2013, GRL‐0519`, a novel oxatricyclic ligand‐containing nonpeptidic HIV‐1 protease inhibitor (PI)`, potently suppresses replication of a wide spectrum of multi‐PI‐resistant HIV‐1 variants in vitro} No access to abstract or article to assess adequacy for inclusion in table 187. 18953273 {Lascar, 2008, New protease inhibitors and non‐nucleoside reverse transcriptase inhibitors} 188. 17902242 {, 2007, Trial of tipranavir versus darunavir in treatment‐experienced patients enrolling} 189. 18474499 {Pierone, 2008, Successful use of a tipranavir/ritonavir‐based antiretroviral regimen following development of viral resistance to darunavir} 190. 17288101 {Coleman, 2007, A comparison of different protease inhibitors on coronary heart disease risk} 191. 17228446 {Sax, 2006, Meeting report. Report from ICAAC}

71 192. 17219610 {, 2004, Anti‐HIV agents. Atazanavir and saquinavir} 193. 16519246 {Dauer, 2005, Protease inhibitors: the current status} 194. 16193576 {Huff, 2005, A lame duck`, a dark horse`, and a goat} 195. 19043840 {, 2008, 96‐week CASTLE data show similar efficacy results} 196. 15918234 {, 2005, Atazanavir affects saquinavir} 197. 19230058 {, 2008, 96‐week data from CASTLE study presented} 198. 18661646 {, 2008, Anti‐HIV agents. The Castle study: lopinavir vs. atazanavir} 199. 14959692 {Boyle, 2003, The continuing evolution of HIV therapy} 200. 14598789 {Moyle, 2003, Boosted PIs: competition hots up} 201. 12184261 {Gallant, 2001, New antiretroviral agents} 202. 17479503 {Hoffman, 2007, When and how to use tipranavir and darunavir} 203. 17219609 {, 2004, Anti‐HIV agents. Saquinavir with fosamprenavir} 204. 19271333 {Sax, 2008, Report from the 2008 joint ICAAC/IDSA meeting. Darunavir and atazanavir: 96‐week data from ARTEMIS and CASTLE} 205. 12184224 {Bartlett, 2000, Report on new drugs} 206. 18348342 {, 2008, CASTLE study showed similar efficacy} 207. 18802980 {, 2008, CASTLE data show no gender differences} 208. 18991621 {Lehmann, 2008, Nucleoside‐free boosted double PI regimen: significant CD4+ T‐cell recovery in patients with poor immunologic response despite virologic suppression} 209. 17065028 {de Mendoza, 2006, Performance of six different ritonavir‐boosted protease inhibitor‐based regimens in heavily antiretroviral‐experienced HIV‐infected patients} 210. 14760884 {Hammer, 2003, A randomized trial of nelfinavir and abacavir in combination with efavirenz and adefovir dipivoxil in HIV‐1‐infected persons with virological failure receiving indinavir} 211. 16336763 {Portilla, 2005, Quadruple‐2 protease inhibitors (PI)‐therapy does not accelerate viral decay and suppression in PI‐naive HIV‐1 infected patients with severe immunosuppression and high viral load as compared with standard triple therapy}