hiv drug class review - utah department of health medicaid revie… · hiv/aids disease staging...

1

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 University of Utah College of Pharmacy Copyright © 2015 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved.

2

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

3

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

4

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.

5

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.

6

Table 1. Comparison of the HIV Protease Inhibitor Agents2,3 Product Route of

Administration Available Doses Dosing Generic

Available

Single Agents

Atazanavir (REYATAZ®)

Oral capsule 150 mg, 200 mg, 300 mg

Adult dosing (treatment naïve):

300 mg daily w/ritonavir 100 mg daily; 400 mg daily alone Adult dosing (treatment experienced):

300 mg daily w/ritonavir 100 mg daily 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

No

Oral powder (packet)

50 mg per packet

Darunavir (PREZISTA®)

Oral tablet 75 mg, 150 mg, 400mg, 600mg, 800 mg

Adult dosing (treatment naïve):

800 mg daily w/ritonavir 100 mg daily Adult dosing (treatment experienced; w/o darunavir resistance substitution):

800 mg daily w/ritonavir 100 mg daily 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

No

Oral suspension 100 mg/mL

7

Product Route of Administration

Available Doses Dosing Generic 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 (LEXIVA®)

Oral tablet 700 mg Adult dosing (treatment naïve):

1400 mg twice daily

Alternate: 1400 mg daily w/ritonavir 100‐200 mg

Alternate: 700 mg twice daily w/ritonavir 100 mg twice daily 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

No

Oral suspension 50 mg/mL

8



▬ 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):

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

800 mg every 8 hours Pediatric dosing:

Limited experience, no current recommendation

No

Nelfinavir (VIRACEPT®)

Oral tablet 250 mg, 625 mg Adult dosing (treatment naïve):

1250 mg twice daily or 750 mg three times daily Adult dosing (treatment experienced):

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

No

Oral powder 50 mg/g

Ritonavir (NORVIR®) Oral capsule 100 mg Adult dosing:

600 mg twice daily

Not preferred as primary PI

Start at 300 mg twice daily and titrate up Pediatric dosing:

No

Oral tablet 100 mg

9



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 (INVIRASE®)

Oral capsule 200 mg Adult dosing (treatment naïve):

1000 mg twice daily w/ritonavir 100 mg twice daily Adult dosing (treatment experienced):

1000 mg twice daily w/ritonavir 100 mg twice daily Pediatric dosing:

>16 yo; 1000 mg twice daily w/ritonavir 100 mg twice daily

No

Oral tablet 500 mg

Tipranavir (APTIVUS®)

Oral capsule 250 mg Adult dosing (treatment naive):

500 mg twice daily w/ritonavir 200 mg twice daily Adult dosing (treatment experienced):

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

No

Oral solution 100 mg/mL

Dual Protease Inhibitor

Lopinavir and Ritonavir (KALETRA®)

Oral tablet 100mg/25mg; 200mg/50mg

Adult dosing (treatment naïve or experienced; w/o efavirenz, nelfinavir, or nevirapine):

400 mg/100 mg twice daily Adult dosing (treatment naïve or experienced; if given w/efavirenz, nelfinavir, or nevirapine; or w/lopinavir resistance substitutions):

Tablet: 500 mg/125 mg twice daily

Suspension: 533 mg/133 mg twice daily Pediatric dosing (w/o efavirenz, nelfinavir, or nevirapine):

No

Oral suspension 80mg/20mg per mL

10



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 Cobicistat (EVOTAZ®)

Oral tablet 300 mg/150 mg Adult dosing (treatment naïve):

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

300 mg/150 mg daily Pediatric dosing:

Not currently recommended in pediatric patients

No

Darunavir and Cobicistat (PREXCOBIX®)

Oral tablet 800 mg/150 mg Adult dosing (treatment naïve):

800 mg/150 mg daily Adult dosing (treatment experienced w/o darunavir resistance substitution):

800 mg/150 mg daily Pediatric dosing:

Not currently recommended in pediatric patients

No

11

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

12

Table 2. Summary of HIV Treatments2,3 Drug Class Agents in the class Indications & Use Manufacturer &

Approval date Safety

Nucleoside Reverse Transcriptase Inhibitors (NRTI) Black Box: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs in combination with other antiretrovirals.

Combivir®: lamivudine and zidovudine

Treatment of HIV infectionOral: one tablet twice daily Not recommended in patients requiring dosage reduction including pediatric patients <30 kg, renally‐impaired patients with a creatinine clearance <50 mL/minute, patients with hepatic impairment

GlaxoSmithKline, 9/27/97; Generic Available

Black Box: Associated with hematologic toxicity, including neutropenia and anemia, particularly in patients with advanced HIV‐1 disease; Prolonged use of 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

Emtriva®: emtricitabin (FTC)

Treatment of HIV infection in combination with at least two other antiretroviral agents Oral: Capsule‐ 200 mg once daily; Solution‐ 240 mg once daily

Gilead Sciences, 7/2/2003

Black Box: Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued emtricitabine.

Epivir®: lamivudine (3TC)

HIV: Treatment of HIV infection in combination with other antiretroviral agents Oral: 150 mg twice daily or 300 mg once daily HBV: Treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation


Black Box: 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

Epzicom®: abacavir and lamivudine

Treatment of HIV infections in combination with other antiretroviral agents Oral: One tablet (abacavir 600 mg and lamivudine 300 mg) once daily

GlaxoSmithKline, 8/2/2004

Black Box: Serious and sometimes fatal hypersensitivity reactions 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

13

Drug Class Agents in the class Indications & Use Manufacturer & Approval date

Safety

Hivid®: zalcitabine, dideoxycytidine (ddC) *no longer marketed

Treatment of HIV infection in conjunction with other antiretrovirals Oral: 0.75 mg every 8 hours

Hoffmann‐La Roche, 6/19/1992

Black Box: Severe peripheral neuropathy reported; Pancreatitis reported rarely; Hepatic failure and death reported rarely

Retrovir®: zidovudine (ZDV, azidothymidine, AZT)

Treatment of HIV‐1 infection in combination with at least two other antiretroviral agents; Prevention of perinatal HIV‐1 transmission Oral: 300 mg twice daily, IV: 1 mg/kg/dose administered every 4 hours around‐the‐clock

GlaxoSmithKline, 3/19/1987; May be generic depending on product

Black Box: Zidovudine has been associated with hematologic toxicity, including neutropenia and severe anemia; Prolonged use of zidovudine has been associated with symptomatic myopathy

Trizivir®: abacavir, zidovudine, and lamivudine

Treatment of HIV‐1 infection in combination with other antiretroviral agents or alone in patients weighing more than 40 kg Oral: One tablet twice daily


Black Box: Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir; Zidovudine has been associated with hematologic toxicity; Prolonged use of 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 disoproxil fumarate and emtricitabine

Treatment of HIV‐1 infection in combination with other antiretroviral 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


Black Box: Risk of drug resistance with use for preexposure prophylaxis

14


Safety

Videx®: didanosine (ddI)

Treatment of HIV‐1 infection in combination with other antiretroviral agents Oral: <60 kg: 125 mg twice daily (preferred) or 250 mg once daily, ≥60 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

Bristol Myers‐Squibb; 10/9/1991, enteric coated 10/31/2000; May be generic depending on product

Black Box: Fatal and nonfatal pancreatitis have occurred during therapy with didanosine used alone or in combination regimens

Viread®: tenofovir disoproxil fumarate (TDF)

Treatment of HIV‐1 infection in combination with other antiretroviral 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 (d4T)

Treatment of HIV infection in combination with other antiretroviral agents Oral: <60 kg: 30 mg every 12 hours ≥60 kg: 40 mg every 12 hours

Bristol Myers‐Squibb, 6/24/1994; Generic Available

Black Box: Fatal and nonfatal pancreatitis has occurred during therapy when stavudine was part of a combination regimen that included didanosine

Ziagen®: abacavir sulfate (ABC)

Treatment of HIV‐1 infection in combination with other antiretroviral agents Oral: 300 mg twice daily or 600 mg once daily

GlaxoSmithKline, 12/17/1998; May be generic depending on product

Black Box: Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir therapy

15


Safety

Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Edurant®: rilpivirine Treatment of HIV‐1 infection in combination with other agents Oral: 25 mg once daily

Tibotec Therapeutics, 5/20/2011

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


Rescriptor®: delavirdine (DLV)

Treatment of HIV‐1 infection in combination with at least two additional antiretroviral agents Oral: 400 mg 3 times/day

Pfizer, 4/4/1997

Sustiva®: efavirenz (EFV)

Treatment of HIV‐1 infection in combination with other antiretroviral agents in adults and pediatric patients at least 3 months old and weighing at least 3.5 kg Oral: 600 mg once daily

Bristol Myers‐Squibb, 9/17/1998

Viramune®: nevirapine (NVP)

Treatment of HIV‐1 infection in combination with additional antiretroviral agents Oral: Immediate release: 200 mg twice daily; Extended release: 400 mg once daily

Boehringer Ingelheim; 6/21/1996, XR 3/25/2011; Generic Available

Black Box: Severe, life‐threatening, and, in some cases, fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine; Severe, life‐threatening skin reactions, including fatal cases, have occurred in 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

16


Safety

Protease Inhibitors (PI) Agenerase®: amprenavir (APV) *no longer marketed

Treatment of HIV Infection Oral: 1.2 g once to twice daily


Black Box: The oral solution is contraindicated in infants and children <4 years of age, pregnant 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 (TPV)

Treatment of HIV‐1 infection in combination with ritonavir and other antiretroviral agents; limited to treatment‐experienced or multiprotease inhibitor resistance. Oral: 500 mg twice daily

Boehringer Ingelheim, 6/22/2005

Black Box: Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported; Both fatal and nonfatal intracranial hemorrhage have been reported.

Crixivan®: indinavir (IDV)

Treatment of HIV infection; should always be used as part of a multidrug regimen (at least 3 antiretroviral agents)Oral: 800 mg two to three times daily

Merck, 3/13/1996

Evotaz®: atazanavir and cobicistat

Treatment of HIV‐1 infection in adults in combination with other antiretroviral agents Oral: One tablet (atazanavir 300 mg/cobicistat 150 mg) once daily

Bristol‐Myers Squibb, 1/29/2015

Invirase®: saquinavir mesylate (SQV; previously Fortovase®)

Treatment of HIV infection; used in combination with ritonavir and other antiretroviral agents Oral: 1000 mg twice daily

Hoffmann‐La Roche, 12/6/1995

17


Safety

Kaletra®: lopinavir and ritonavir (LPV/RTV)

Treatment of HIV‐1 infection in combination with other antiretroviral agents Oral: Lopinavir 400 mg/ritonavir 100 mg twice daily

Abbott Laboratories, 9/15/2000

Lexiva®: fosamprenavir calcium (FOS‐APV)

Treatment of HIV infections in combination with at least two other antiretroviral agents Oral: 700‐1,400 mg once to twice daily


Norvir®: ritonavir (RTV)

Treatment of HIV infection; should always be used as part of a multidrug regimen Oral: 600 mg twice daily

Abbott Laboratories, 3/1/1996

Black Box: Coadministration with sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life‐threatening adverse reactions due to possible effects of ritonavir on the hepatic metabolism of certain drugs

Prezcobix®: darunavir and cobicistat

Treatment of HIV‐1 infection, coadministered with other antiretroviral 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

Janssen Therapeutics, 1/29/2015

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


18


Safety

Reyataz®: atazanavir sulfate (ATV)

Treatment of HIV‐1 infections in combination with other antiretroviral agents in patients ≥3 months weighing ≥10 kg Oral: 300‐400 mg once daily


Viracept®: nelfinavirmesylate (NFV)

Treatment of HIV infection in combination with other antiretroviral therapies Oral: 750 mg 3 times daily or 1250 mg twice daily

Agouron Pharmaceuticals, 3/14/1997

Entry Inhibitors Selzentry®: maraviroc Treatment of only CCR5‐tropic HIV‐1 infection, in combination with other antiretroviral agents Oral: 300 mg twice daily

Pfizer, 8/6/2007 Black Box: Hepatotoxicity has been reported with maraviroc use

Fusion Inhibitors Fuzeon®: enfuvirtide (T‐20)

Treatment of HIV‐1 infection in combination with other antiretroviral agents in treatment‐experienced patients with evidence of HIV‐1 replication despite ongoing antiretroviral therapy SubQ: 90 mg twice daily

Hoffmann‐La Roche & Trimeris, 3/13/2003

Integrase Inhibitors Isentress®: raltegravir Treatment of HIV‐1 infection in combination with other antiretroviral 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

Merck & Co.: 10/21/2007

19


Safety

Tivicay®: dolutegravir Treatment of HIV‐1 infection in combination with other antiretroviral 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 combination with other antiretroviral agents Oral: 85‐150 mg once daily


Multi‐Class Combination Agents

Atripla®: efavirenz, emtricitabine, tenofovir disoproxil fumarate

Treatment of HIV‐1 infectionOral: One tablet once daily Recommended as an initial regimen for antiretroviral‐naive patients (HHS [adult], 2014)


Moderate‐to‐severe renal OR hepatic impairment: Use not recommended

Complera®: emtricitabine, rilpivirine, tenofovir disoproxil fumarate

Treatment of HIV‐1 infection Oral: One tablet once daily Recommended as a complete regimen 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


Dosage adjustment required for concomitant therapy with rifabutin

Stribild®: elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate

Treatment of HIV‐1 infection Oral: One tablet once daily Recommended in adults who are antiretroviral treatment‐naïve and in certain virologically suppressed (HIV‐1 RNA <50 copies/mL) adult patients


CrCl <70 mL/minute: Use not recommended

20


Safety

Triumeq®: Abacavir, Dolutegravir, Lamivudine

Treatment of HIV‐1 infection Oral: One tablet daily

ViiV Healthcare, 8/22/2014

Black Box: Serious and sometimes fatal hypersensitivity reactions, with multiple organ 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

21

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 Control and Prevention (CDC)

CD4+ T Cell Count Category A (Asymptomatic)

Category B (Symptomatic) Category C (AIDS‐indicator symptoms)

>500/µL A1 B1 C1

200‐499/ µL A2 B2 C2

<200/ µL A3 B3 C3

World Health Organization (WHO) Clinical Staging and Disease Classification System

Stage Symptoms

Primary HIV Infection Asymptomatic, Acute retroviral syndrome

Stage 1 Asymptomatic, Persistent generalized lymphadenopathy

Stage 2 Moderate unexplained weight loss, Recurrent respiratory infections, Herpes zoster, Angular 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

22

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 Antiretroviral Agents in HIV‐1‐Infected Adults and Adolescents (US Department of Health and Human Services; 2015) 15

Treatment naïve patients, recommended regimens:

INSTI‐based regimens: ▬ DTG/ABC/(3TC or FTC) only for patients who are HLA‐B*5701 negative ▬ DTG plus TDF/(3TC OR FTC) ▬ AVG/c/TDF/(3TC OR FTC) only for patient with pre‐treatment estimated CrCl ≥70

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

23

▬ 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 Antiretroviral Agents in Pediatric HIV Infection (National Institutes of Health Office of AIDS Research Advisory Council; 2015)16

Pediatric initial therapy recommendations:

2‐NRTI backbone: ▬ <3 months: AZT plus (3TC or FTC) ▬ ≥3 months: ABC plus (3TC or FTC) OR AZT plus (3TC or FTC); ABC only if HLA‐B*5701

negative ▬ ≥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

24

Recommendations for Use of Antiretroviral Drugs in Pregnant HIV‐1‐Infected Women for Maternal health and Interventions to Reduce Perinatal HIV Transmission in the United States (National Institutes of Health Office of AIDS Research Advisory Council; 2014)17

Generally, the same regimens used in non‐pregnant adults are used in pregnant women unless there are known risks to the fetus or mother during pregnancy

Avoid EFV containing regimens until after 8 weeks gestation (may be continued if started if woman present in first trimester and it is achieving virologic suppression)

Avoid combination of d4T and ddI

PI‐based regimens present a small risk of preterm birth

Antiretroviral therapy for HIV infection in infants and children: towards universal access (World Health Organization; 2010)18

Infants, first‐line treatment:

No prior exposure to ARVs: ▬ NVP + 2 NRTIs

Prior exposure to NVP or other NNRTIs: ▬ 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 Care (Health Resource and Services Administration (HRSA); 2011)19

Treatment naïve patients, preferred regimens:

INSTI‐based regimens: ▬ RAL + TDF/(FTC or 3TC) ▬ 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

25

<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 prevention, diagnosis, treatment and care for key populations (World Health Organization (WHO); 2014)20

Adults (including pregnant/breastfeeding women and adults with TB or HBV coinfection), first‐line regimens:

▬ TDF + 3TC (or FTC) + EFV ▬ Alternate: AZT + 3TC + EFV ▬ 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

26

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

27

Table 5. Pharmacokinetic Properties of the HIV Protease Inhibitor Agents2,3,22 Agent Half‐life

(h) Bioavailability (%)

Effect of meals on AUC

Protein binding (%)

Renal Excretion of parent drug (%)

Metabolism Autoinduction of metabolism

Inhibition of CYP3A4

Atazanavir 6.5‐7.9 low ↑70% (light meal)

86 7 CYP3A4 No ++

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% (Moderate fat)

98‐99 <3 CYP3A4 Yes +++

Nelfinavir 3.5‐5 20‐80 (food and formulation dependent)

↑100‐200% >98 1‐2 CYP2C19 > CYP3A4

Yes ++

Ritonavir 3‐5 >60 ↑13% (capsule)

98‐99 3.5 CYP3A4 > CYP2D6

Yes +++

Saquinavir 1‐2 13 ↑570% (high fat)

98 <3 CYP3A4 No +

Tipranavir 4.8‐6.0 NA ↔ 99.9 0.5 CYP3A4 Yes +++ Key: NA = not available

28

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

29

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

30

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).

31

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)

32

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.

33

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

34

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

35

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

36

Table 6. Adverse Events Reported with the HIV Protease Inhibitor Agents2,3 Product Frequency Cardiovascular Central Nervous

System Endocrine & Metabolic Gastrointestinal Hepatic Neuromuscular/Skeletal Other

Atazanavir (REYATAZ®)

>10% ↑ amylase↑ serum cholesterol

nausea

jaundice ↑ serum bilirubin

↑ CPK

coughfever skin rash

2‐10% AV block (first or second degree) peripheral edema P‐R interval prolongation

depressiondizziness headache insomnia neuropathy peripheral

hyperglycemiahypoglycemia lipodystrophy ↑ serum triglycerides

abdominal pain diarrhea vomiting ↑ serum lipase

↑ serum ALT↑ serum AST

limb pain myalgia

neutropenia↓ hemoglobin nasal congestion oropharyngeal pain rhinorrhea thrombocytopenia wheezing

Atazanavir and Cobicistat (EVOTAZ®)

>10% abnormal bilirubin levels jaundice

scleral icterus

1‐10% AV block (first or second degree) cardiac conduction disturbances P‐R interval prolongation

abnormal dreamsdepression fatigue headache insomnia

↑ cholesterolcushingoid appearance Fanconi’s syndrome glycosuria ↑ GGT buffalo hump ↑ serum triglycerides truncal obesity

diarrhea nausea ↑ serum amylase ↑ serum lipase upper abdominal pain vomiting

hepatotoxicity (pts w/hepatitis) ↑ serum ALT ↑ serum AST

amyotrophy↑ CPK lipoatrophy rhabdomyolysis

acute renal failurebreast hypertrophy ↓ crea nine clearance hematuria hemorrhage immune reconstitution syndrome nephrolithiasis renal insufficiency ↑ serum creatinine skin rash Stevens‐Johnson syndrome

Darunavir (PREZISTA®)

>10% hypercholesterolemiahyperglycemia ↑ LDL cholesterol

diarrhea nausea vomiting

skin rash

2‐10% fatigue headache

↑ amylase diabetes mellitus lipodystrophy ↑ serum triglycerides

abdominal distention abdominal pain anorexia decreased appetite dyspepsia ↑ serum lipase

↑ serum ALT↑ serum AST

weakness increased bleeding (pts w/hemophilia) pruritus

Darunavir and Cobicistat (PREXCOBIX®)

1‐10% headache abdominal pain diarrhea flatulence nausea vomiting

↑ liver enzymes drug‐induced hypersensitivity immune reconstitution syndrome

37

skin rash

Fosamprenavir (LEXIVA®)

>10% hypertriglyceridemia diarrhea rash

1‐10% fatigue headache

hyperglycemia abdominal pain nausea ↑ serum lipase vomiting

↑ transaminases neutropenia pruritus

Indinavir (CRIXIVAN®)

>10% abdominal pain nausea

hyperbilirubinemia nephrolithiasisurolithiasis

1‐10% dizzinessdrowsiness fatigue headache malaise

fat redistribution hypercholesterolemia hyperglycemia hyperlipidemia

anorexia↑ appe te diarrhea dysgeusia dyspepsia gastroesophageal reflux disease ↑ serum amylase taste perversion vomiting

jaundice ↑ serum transaminases

back painweakness

anemiacough dysuria fever hydronephrosis neutropenia pruritus skin rash

Lopinavir and Ritonavir (KALETRA®)

>10% ↑ GGThypercholesterolemia ↑ serum triglycerides

abdominal pain diarrhea dysgeusia nausea vomiting

↑ serum ALT

skin rashupper respiratory tract infection

>2‐10% vasodilation anxietyfatigue headache insomnia

alteration in sodiumfat redistribution hyperglycemia hypertriglyceridemia hyperuricemia weight loss

dyspepsiaflatulence gastroenteritis ↑ serum amylase ↑ serum lipase

hepatitis↑ serum AST ↑ serum bilirubin

circumoral & peripheral asthenia paresthesia musculoskeletal pain weakness

hypersensitivitylower respiratory tract infection neutropenia skin infection thrombocytopenia

Nelfinavir (VIRACEPT®)

>10% diarrhea

2‐10% fat redistributionhyperglycemia hyperlipidemia hypercholesterolemia

flatulence nausea

↓ lymphocytes↓ neutrophils rash

Ritonavir (NORVIR®)

>10% flushing

dizzinessfatigue paresthesia

↑ GGT hypercholesterolemia ↑ serum triglycerides

abdominal pain diarrhea dysgeusia dyspepsia nausea vomiting

↑ CPK musculoskeletal pain weakness

oropharyngeal painpruritus skin rash

2‐10% edema hypertension syncope vasodilation

anxietyattention disturbance confusion

fat redistributionhyperglycemia lipodystrophy ↑ uric acid

anorexiaflatulence gastrointestinal hemorrhage

hepatitis↑ serum ALT ↑ serum AST

astheniamyalgia

acne vulgarisanemia blurred vision cough

38

depressiondrowsiness headache insomnia malaise peripheral neuropathy

↑ serum amylase taste perversion throat irritation

diaphoresisfever hypersensitivity neutropenia pharyngitis polyuria thrombocytopenia

Saquinavir (INVIRASE®)

>10% nausea

1‐10% chest pain

anxietydepression fatigue fever headache insomnia pain

fat redistribution hyperglycemia hypoglycemia hyperkalemia libido disorder lipodystrophy ↑ serum amylase

abdominal discomfort abdominal pain ↓ appe te buccal mucosa ulceration constipation diarrhea dyspepsia flatulence taste alteration vomiting

↑ bilirubinhepatic decompensation (pts w/hepatitis) ↑ serum ALT ↑ serum AST

back pain↑ CPK paresthesia weakness

bronchitis↑ crea nine kinase dry lips/skin eczema influenza pneumonia pruritus rash sinusitis verruca

Tipranavir (APTIVUS®)

>10%

hypercholesterolemia hypertriglyceridemia

diarrhea

↑ transaminases

↑ CPK

skin rash

2‐10% fatigueheadache

dehydrationfat redistribution

abdominal pain ↑ amylase diarrhea nausea vomiting weight loss

↑ serum ALT↑ serum AST ↑ GGT

myalgia anemiableeding ↑ bleeding me cough dyspnea epistaxis fever intracranial hemorrhage neutropenia ↓ WBC

39

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.

40

References

1. Fauci AS. Human Immunodificiency Virus Disease: AIDS and Related Disorders. Harrison's Principles of

Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015. 2. Lexi-Comp I, ed Drug Information Handbook. 21st ed. Hudson, OH: Lexi-Comp; 2015. 3. McEvoy GK, Snow EK, Kester L, Litvak K, Miller J, Welsh OH, eds. AHFS 2015 Drug Information.

Bethesda, MD: American Society of Health-System Pharmacists; 2015. 4. CDC. HIV in the United States: At a Glance. 2015; http://www.cdc.gov/hiv/statistics/basics/ataglance.html.

Accessed April 5, 2015, 2015. 5. Lansky A, Brooks JT, DiNenno E, Heffelfinger J, Hall HI, Mermin J. Epidemiology of HIV in the United

States. Journal of acquired immune deficiency syndromes (1999). Dec 2010;55 Suppl 2:S64-68. 6. AIDSVu. Utah Highlights. 2012; http://aidsvu.org/state/utah/. Accessed 7/15/15. 7. Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of

opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. Apr 10 2009;58(Rr-4):1-207; quiz CE201-204.

8. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK, Panel on Clinical Practices for the Treatment of HIV. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. May 17 2002;51(RR-7):1-55.

9. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK, Panel on Clinical Practices for Treatment of HIV. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Annals of internal medicine. Sep 3 2002;137(5 Pt 2):381-433.

10. Mofenson LM, Brady MT, Danner SP, et al. Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. Sep 4 2009;58(RR-11):1-166.

11. Rathbun RC, Lockhart SM, Stephens JR. Current HIV treatment guidelines--an overview. Current pharmaceutical design. 2006;12(9):1045-1063.

12. From the Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. JAMA : the journal of the American Medical Association. Feb 10 1993;269(6):729-730.

13. World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-Related Disease in Adults and Children. 2007.

14. Guidelines for national human immunodeficiency virus case surveillance, including monitoring for human immunodeficiency virus infection and acquired immunodeficiency syndrome. Centers for Disease Control and Prevention. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. Dec 10 1999;48(RR-13):1-27, 29-31.

15. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.: Department of Health and Human Services.

16. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. National Institutes of Health Office of AIDS Research Advisory Council. 2015.

17. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal health and Interventions to Reduce Perinatal HIV Transmission in the United States. National Institutes of Health Office of AIDS Research Advisory Council. 2014.

18. . Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access: Recommendations for a Public Health Approach: 2010 Revision. Geneva2010.

19. Guide for HIV/AIDS Clinical Care. Health Resource and Services Administration (HRSA),. 2011. 20. . Consolidated Guidelines on HIV Prevention, Diagnosis, Treatment and Care for Key Populations.

Geneva2014.

41

21. Flexner C. HIV-protease inhibitors. The New England journal of medicine. Apr 30 1998;338(18):1281-1292.

22. Flexner C. Antiretroviral Agents and the Treatment of HIV Infection. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. Ney York, NY: McGraw-Hill; 2011.

23. W.L. Antiviral Drugs. Review of Medical Microbilogy and Immunology. 13th ed. New York, NY: McGraw-Hill; 2014.

24. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. The New England journal of medicine. Mar 29 2001;344(13):984-996.

25. Hammer SM, Vaida F, Bennett KK, et al. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA : the journal of the American Medical Association. Jul 10 2002;288(2):169-180.

26. Florence E, Dreezen C, Desmet P, et al. Ritonavir/saquinavir plus one nucleoside reverse transcriptase inhibitor (NRTI) versus indinavir plus two NRTIs in protease inhibitor-naive HIV-1-infected adults (IRIS study). Antiviral therapy. Dec 2001;6(4):255-262.

27. Wensing AM, Reedijk M, Richter C, Boucher CA, Borleffs JC. Replacing ritonavir by nelfinavir or nelfinavir/saquinavir as part of highly active antiretroviral therapy leads to an improvement of triglyceride levels. AIDS (London, England). Nov 9 2001;15(16):2191-2193.

28. Hellinger JA, Cohen CJ, Stein AJ, Gallant JE, Gathe J, Keiser P. Efficacy of nelfinavir in patients switched from ritonavir/saquinavir combination antiretroviral therapy. HIV clinical trials. Sep-Oct 2000;1(2):25-28.

29. Moyle G, Pozniak A, Opravil M, et al. The SPICE study: 48-week activity of combinations of saquinavir soft gelatin and nelfinavir with and without nucleoside analogues. Study of Protease Inhibitor Combinations in Europe. Journal of acquired immune deficiency syndromes (1999). Feb 1 2000;23(2):128-137.

30. Hall CS, Raines CP, Barnett SH, Moore RD, Gallant JE. Efficacy of salvage therapy containing ritonavir and saquinavir after failure of single protease inhibitor-containing regimens. AIDS (London, England). Jul 9 1999;13(10):1207-1212.

31. Kirk O, Katzenstein TL, Gerstoft J, et al. Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. AIDS (London, England). Jan 14 1999;13(1):F9-16.

32. Bierman WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS (London, England). Jan 28 2009;23(3):279-291.

33. van Rossum AM, Geelen SP, Hartwig NG, et al. Results of 2 years of treatment with protease-inhibitor--containing antiretroviral therapy in dutch children infected with human immunodeficiency virus type 1. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Apr 1 2002;34(7):1008-1016.

34. Mocroft A, Phillips AN, Miller V, et al. The use of and response to second-line protease inhibitor regimens: results from the EuroSIDA study. AIDS (London, England). Jan 26 2001;15(2):201-209.

35. Reijers MH, Weverling GJ, Jurriaans S, et al. The ADAM study continued: maintenance therapy after 50 weeks of induction therapy. AIDS (London, England). Jan 5 2001;15(1):129-131.

36. Salzberger B, Rockstroh J, Wieland U, et al. Clinical efficacy of protease inhibitor based antiretroviral combination therapy--a prospective cohort study. European journal of medical research. Nov 22 1999;4(11):449-455.

37. Rockstroh JK, Altfeld M, Kupfer B, et al. Failure of double protease inhibitor therapy as a salvage therapy for HIV-infected patients resistant to conventional triple therapy. European journal of medical research. Jul 28 1999;4(7):271-274.

38. Deeks SG, Hellmann NS, Grant RM, et al. Novel four-drug salvage treatment regimens after failure of a human immunodeficiency virus type 1 protease inhibitor-containing regimen: antiviral activity and correlation of baseline phenotypic drug susceptibility with virologic outcome. The Journal of infectious diseases. Jun 1999;179(6):1375-1381.

39. Lawrence J, Schapiro J, Winters M, et al. Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor-experienced persons. The Journal of infectious diseases. Jun 1999;179(6):1356-1364.

40. Reiser M, Salzberger B, Stiepel A, Hoetelmans R, Diehl V, Fatkenheuer G. Virological efficacy and plasma drug concentrations of nelfinavir plus saquinavir as salvage therapy in HIV-infected patients refractory to standard triple therapy. European journal of medical research. Feb 25 1999;4(2):54-58.

42

41. Ruiz L, Nijhuis M, Boucher C, et al. Efficacy of adding indinavir to previous reverse transcriptase nucleoside analogues in relation to genotypic and phenotypic resistance development in advanced HIV-1-infected patients. Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association. Sep 1 1998;19(1):19-28.

42. Shey MS, Kongnyuy EJ, Alobwede SM, Wiysonge CS. Co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection and AIDS. Cochrane Database Syst Rev. 2013;3:Cd005481.

43. Manosuthi W, Sungkanuparph S, Ruxrungtham K, et al. Plasma levels, safety, and 60-week efficacy of a once-daily double-boosted protease inhibitor regimen of atazanavir, saquinavir, and ritonavir. Journal of acquired immune deficiency syndromes (1999). Jan 1 2008;47(1):127-129.

44. Cruciani M, Mengoli C, Serpelloni G, Parisi SG, Malena M, Bosco O. Abacavir-based triple nucleoside regimens for maintenance therapy in patients with HIV. Cochrane Database Syst Rev. 2013;6:CD008270.

45. Ross LL, Weinberg WG, DeJesus E, et al. Impact of low abundance HIV variants on response to ritonavir-boosted atazanavir or fosamprenavir given once daily with tenofovir/emtricitabine in antiretroviral-naive HIV-infected patients. AIDS research and human retroviruses. Apr 2010;26(4):407-417.

46. Saah AJ, Haas DW, DiNubile MJ, et al. Treatment with indinavir, efavirenz, and adefovir after failure of nelfinavir therapy. The Journal of infectious diseases. Apr 1 2003;187(7):1157-1162.

47. Mocroft A, Ruiz L, Reiss P, et al. Virological rebound after suppression on highly active antiretroviral therapy. AIDS (London, England). Aug 15 2003;17(12):1741-1751.

48. Rizzardi GP, De Boer RJ, Hoover S, et al. Predicting the duration of antiviral treatment needed to suppress plasma HIV-1 RNA. The Journal of clinical investigation. Mar 2000;105(6):777-782.

49. Adje-Toure CA, Cheingsong R, Garcia-Lerma JG, et al. Antiretroviral therapy in HIV-2-infected patients: changes in plasma viral load, CD4+ cell counts, and drug resistance profiles of patients treated in Abidjan, Cote d'Ivoire. AIDS (London, England). Jul 2003;17 Suppl 3:S49-54.

50. Ghosh AK, Schiltz GE, Rusere LN, et al. Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1-P2 ligands. Organic & biomolecular chemistry. Sep 21 2014;12(35):6842-6854.

51. Smith D, Hales G, Roth N, et al. A randomized trial of nelfinavir, ritonavir, or delavirdine in combination with saquinavir-SGC and stavudine in treatment-experienced HIV-1-infected patients. HIV clinical trials. Mar-Apr 2001;2(2):97-107.

52. Mocroft A, Kirk O, Reiss P, et al. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS (London, England). Jul 17 2010;24(11):1667-1678.

53. Condra JH, Petropoulos CJ, Ziermann R, Schleif WA, Shivaprakash M, Emini EA. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. The Journal of infectious diseases. Sep 2000;182(3):758-765.

54. Langmann P, Zilly M, Weissbrich B, et al. Therapeutic drug monitoring of saquinavir in patients during protease inhibitor therapy with saquinavir alone or in combination with ritonavir or nelfinavir. European journal of medical research. Feb 28 2000;5(2):59-62.

55. Fletcher CV, Jiang H, Brundage RC, et al. Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group Study 359. The Journal of infectious diseases. Apr 1 2004;189(7):1176-1184.

56. Le Moing V, Peytavin G, Journot V, et al. Plasma levels of indinavir and nelfinavir at time of virologic response may have a different impact on the risk of further virologic failure in HIV-infected patients. Journal of acquired immune deficiency syndromes (1999). Dec 15 2003;34(5):497-499.

57. Urban AW, Bean P, Aziz D, Graziano FM, Neudeck BL. Protease inhibitor drug levels in the management of human immunodeficiency virus-1 antiretroviral therapy. International journal of STD & AIDS. Feb 2003;14(2):103-108.

58. Duan J, Freeling JP, Koehn J, Shu C, Ho RJ. Evaluation of atazanavir and darunavir interactions with lipids for developing pH-responsive anti-HIV drug combination nanoparticles. Journal of pharmaceutical sciences. Aug 2014;103(8):2520-2529.

59. Podany AT, Winchester LC, Robbins BL, Fletcher CV. Quantification of cell-associated atazanavir, darunavir, lopinavir, ritonavir, and efavirenz concentrations in human mononuclear cell extracts. Antimicrob Agents Chemother. May 2014;58(5):2866-2870.

60. Mishra T, Shrivastav PS. Validation of simultaneous quantitative method of HIV protease inhibitors atazanavir, darunavir and ritonavir in human plasma by UPLC-MS/MS. TheScientificWorldJournal. 2014;2014:482693.

43

61. Richmond SR, Carper MJ, Lei X, Zhang S, Yarasheski KE, Ramanadham S. HIV-protease inhibitors suppress skeletal muscle fatty acid oxidation by reducing CD36 and CPT1 fatty acid transporters. Biochimica et biophysica acta. May 2010;1801(5):559-566.

62. Davis DA, Soule EE, Davidoff KS, Daniels SI, Naiman NE, Yarchoan R. Activity of human immunodeficiency virus type 1 protease inhibitors against the initial autocleavage in Gag-Pol polyprotein processing. Antimicrob Agents Chemother. Jul 2012;56(7):3620-3628.

63. Martinez-Cajas JL, Wainberg MA, Oliveira M, et al. The role of polymorphisms at position 89 in the HIV-1 protease gene in the development of drug resistance to HIV-1 protease inhibitors. The Journal of antimicrobial chemotherapy. Apr 2012;67(4):988-994.

64. Capel E, Auclair M, Caron-Debarle M, Capeau J. Effects of ritonavir-boosted darunavir, atazanavir and lopinavir on adipose functions and insulin sensitivity in murine and human adipocytes. Antiviral therapy. 2012;17(3):549-556.

65. Balkundi S, Nowacek AS, Veerubhotla RS, et al. Comparative manufacture and cell-based delivery of antiretroviral nanoformulations. International journal of nanomedicine. 2011;6:3393-3404.

66. Ye ZW, Van Pelt J, Camus S, Snoeys J, Augustijns P, Annaert P. Species-specific interaction of HIV protease inhibitors with accumulation of cholyl-glycylamido-fluorescein (CGamF) in sandwich-cultured hepatocytes. Journal of pharmaceutical sciences. Jun 2010;99(6):2886-2898.

67. Wang Y, Liu Z, Brunzelle JS, et al. The higher barrier of darunavir and tipranavir resistance for HIV-1 protease. Biochemical and biophysical research communications. Sep 9 2011;412(4):737-742.

68. Lan X, Kiyota T, Hanamsagar R, et al. The effect of HIV protease inhibitors on amyloid-beta peptide degradation and synthesis in human cells and Alzheimer's disease animal model. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. Jun 2012;7(2):412-423.

69. Huang J, Gautam N, Bathena SP, et al. UPLC-MS/MS quantification of nanoformulated ritonavir, indinavir, atazanavir, and efavirenz in mouse serum and tissues. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. Aug 1 2011;879(23):2332-2338.

70. Berginc K, Kristl A. Transwell-grown HepG2 cell monolayers as in vitro permeability model to study drug-drug or drug-food interactions. Journal of medicinal food. Jan-Feb 2011;14(1-2):135-139.

71. Gu J, Soldin SJ. Modification of tandem mass spectrometric method to permit simultaneous quantification of 17 anti-HIV drugs which include atazanavir and tipranavir. Clinica chimica acta; international journal of clinical chemistry. Mar 2007;378(1-2):222-224.

72. Berginc K, Milisav I, Kristl A. Garlic flavonoids and organosulfur compounds: impact on the hepatic pharmacokinetics of saquinavir and darunavir. Drug metabolism and pharmacokinetics. 2010;25(6):521-530.

73. Konig SK, Herzog M, Theile D, Zembruski N, Haefeli WE, Weiss J. Impact of drug transporters on cellular resistance towards saquinavir and darunavir. The Journal of antimicrobial chemotherapy. Nov 2010;65(11):2319-2328.

74. Bandaranayake RM, Kolli M, King NM, et al. The effect of clade-specific sequence polymorphisms on HIV-1 protease activity and inhibitor resistance pathways. Journal of virology. Oct 2010;84(19):9995-10003.

75. Berginc K, Trdan T, Trontelj J, Kristl A. HIV protease inhibitors: garlic supplements and first-pass intestinal metabolism impact on the therapeutic efficacy. Biopharmaceutics & drug disposition. Nov 2010;31(8-9):495-505.

76. Berginc K, Trontelj J, Kristl A. The influence of aged garlic extract on the uptake of saquinavir and darunavir into HepG2 cells and rat liver slices. Drug metabolism and pharmacokinetics. 2010;25(3):307-313.

77. Lisovsky I, Schader SM, Martinez-Cajas JL, Oliveira M, Moisi D, Wainberg MA. HIV-1 protease codon 36 polymorphisms and differential development of resistance to nelfinavir, lopinavir, and atazanavir in different HIV-1 subtypes. Antimicrob Agents Chemother. Jul 2010;54(7):2878-2885.

78. Elens L, Veriter S, Di Fazio V, et al. Quantification of 8 HIV-protease inhibitors and 2 nonnucleoside reverse transcriptase inhibitors by ultra-performance liquid chromatography with diode array detection. Clinical chemistry. Jan 2009;55(1):170-174.

79. Sayer JM, Louis JM. Interactions of different inhibitors with active-site aspartyl residues of HIV-1 protease and possible relevance to pepsin. Proteins. May 15 2009;75(3):556-568.

80. Pyrko P, Kardosh A, Wang W, Xiong W, Schonthal AH, Chen TC. HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress. Cancer research. Nov 15 2007;67(22):10920-10928.

44

81. Koh Y, Matsumi S, Das D, et al. Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. The Journal of biological chemistry. Sep 28 2007;282(39):28709-28720.

82. Chinn LW, Gow JM, Tse MM, Becker SL, Kroetz DL. Interindividual variability in the effect of atazanavir and saquinavir on the expression of lymphocyte P-glycoprotein. The Journal of antimicrobial chemotherapy. Jul 2007;60(1):61-67.

83. Reijers MH, Weigel HM, Hart AA, et al. Toxicity and drug exposure in a quadruple drug regimen in HIV-1 infected patients participating in the ADAM study. AIDS (London, England). Jan 7 2000;14(1):59-67.

84. Bini T, Testa L, Chiesa E, et al. Outcome of a second-line protease inhibitor-containing regimen in patients failing or intolerant of a first highly active antiretroviral therapy. Journal of acquired immune deficiency syndromes (1999). Jun 1 2000;24(2):115-122.

85. Mehling M, Drechsler H, Kuhle J, et al. Adaptation of antiretroviral therapy in human immunodeficiency virus infection with central nervous system involvement. Journal of neurovirology. Jan 2008;14(1):78-84.

86. Lopez Galera RM, Ribera Pascuet E, Esteban Mur JI, Montoro Ronsano JB, Juarez Gimenez JC. Interaction between cat's claw and protease inhibitors atazanavir, ritonavir and saquinavir. European journal of clinical pharmacology. Dec 2008;64(12):1235-1236.

87. Bongiovanni M, Pisacreta M, Ortu M, et al. Pseudoaneurysm of the femoral artery in a HIV-infected man. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. Oct 2004;28(4):451-453.

88. Ibrahim F, Naftalin C, Cheserem E, et al. Immunodeficiency and renal impairment are risk factors for HIV-associated acute renal failure. AIDS (London, England). Sep 10 2010;24(14):2239-2244.

89. Kirk O, Gerstoft J, Pedersen C, et al. Low body weight and type of protease inhibitor predict discontinuation and treatment-limiting adverse drug reactions among HIV-infected patients starting a protease inhibitor regimen: consistent results from a randomized trial and an observational cohort. HIV medicine. Jan 2001;2(1):43-51.

90. Schrooten W, Colebunders R, Youle M, et al. Sexual dysfunction associated with protease inhibitor containing highly active antiretroviral treatment. AIDS (London, England). May 25 2001;15(8):1019-1023.

91. van Rossum AM, Bergshoeff AS, Fraaij PL, et al. Therapeutic drug monitoring of indinavir and nelfinavir to assess adherence to therapy in human immunodeficiency virus-infected children. The Pediatric infectious disease journal. Aug 2002;21(8):743-747.

92. Shuter J, Sarlo JA, Rode RA, Zingman BS. Occurrence of selective ritonavir nonadherence and dose-staggering in recipients of boosted HIV-1 protease inhibitor therapy. HIV clinical trials. May-Jun 2009;10(3):135-142.

93. Gianotti N, Galli L, Bocchiola B, et al. Number of daily pills, dosing schedule, self-reported adherence and health status in 2010: a large cross-sectional study of HIV-infected patients on antiretroviral therapy. HIV medicine. Mar 2013;14(3):153-160.

94. Nieuwkerk PT, Sprangers MA, Burger DM, et al. Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study. Arch Intern Med. Sep 10 2001;161(16):1962-1968.

95. d'Arminio Monforte A, Lepri AC, Rezza G, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS (London, England). Mar 31 2000;14(5):499-507.

96. Nelson RL, Kelsey P, Leeman H, et al. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev. 2011(9):CD004610.

97. Carosi G, Castelli F, Suter F, et al. Antiviral potency of HAART regimens and clinical success are not strictly coupled in real life conditions: evidence from the MASTER-1 study. HIV clinical trials. Sep-Oct 2001;2(5):399-407.

98. Karmochkine M, Si Mohamed A, Piketty C, et al. The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients. Antiviral research. Sep 2000;47(3):179-188.

99. Grabar S, Pradier C, Le Corfec E, et al. Factors associated with clinical and virological failure in patients receiving a triple therapy including a protease inhibitor. AIDS (London, England). Jan 28 2000;14(2):141-149.

45

100. Vrouenraets SM, Wit FW, Fernandez Garcia E, et al. Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naive HIV-1-infected patients. HIV medicine. Nov 2011;12(10):620-631.

101. Belperio PS, Mole LA, Boothroyd DB, Backus LI. Trends in uptake of recently approved antiretrovirals within a national healthcare system. HIV medicine. Mar 2010;11(3):209-215.

102. Winston A, Puls R, Kerr SJ, et al. Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: a randomized, controlled study. HIV medicine. Apr 2012;13(4):245-251.

103. Kort JJ, Aslanyan S, Scherer J, Sabo JP, Kohlbrenner V, Robinson P. Effects of tipranavir, darunavir, and ritonavir on platelet function, coagulation, and fibrinolysis in healthy volunteers. Current HIV research. Jun 2011;9(4):237-246.

104. Tomaka F, Lefebvre E, Sekar V, et al. Effects of ritonavir-boosted darunavir vs. ritonavir-boosted atazanavir on lipid and glucose parameters in HIV-negative, healthy volunteers. HIV medicine. May 2009;10(5):318-327.

105. Sekar VJ, Lefebvre E, De Marez T, et al. Pharmacokinetics of darunavir (TMC114) and atazanavir during coadministration in HIV-negative, healthy volunteers. Drugs in R&D. 2007;8(4):241-248.

106. Sekar VJ, Lefebvre E, Marien K, De Pauw M, Vangeneugden T, Hoetelmans RM. Pharmacokinetic interaction between darunavir and saquinavir in HIV-negative volunteers. Therapeutic drug monitoring. Dec 2007;29(6):795-801.

107. King JR, Kakuda TN, Paul S, Tse MM, Acosta EP, Becker SL. Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers. Journal of clinical pharmacology. Feb 2007;47(2):201-208.

108. Murphy RL. Reviving protease inhibitors: new data and more options. Journal of acquired immune deficiency syndromes (1999). Jun 1 2003;33 Suppl 1:S43-52; quiz S53, S55-46.

109. Murphy RL, Sanne I, Cahn P, et al. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS (London, England). Dec 5 2003;17(18):2603-2614.

110. Sanne I, Piliero P, Squires K, Thiry A, Schnittman S. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. Journal of acquired immune deficiency syndromes (1999). Jan 1 2003;32(1):18-29.

111. Greenberg RN, Feinberg J, Goodrich J, Pilson RS, Siemon-Hryczyk P. Long-term efficacy and safety of twice-daily saquinavir soft gelatin capsules (SGC), with or without nelfinavir, and three times daily saquinavir-SGC, in triple combination therapy for HIV infection: 100-week follow-up. Antiviral therapy. Feb 2003;8(1):37-42.

112. Elgadi MM, Piliero PJ. Boosted tipranavir versus darunavir in treatment-experienced patients: observational data from the randomized POTENT trial. Drugs in R&D. Dec 1 2011;11(4):295-302.

113. Lowe SH, Wensing AM, Hassink EA, et al. Comparison of two once-daily regimens with a regimen consisting of nelfinavir, didanosine, and stavudine in antiretroviral therapy-naive adults: 48-week results from the Antiretroviral Regimen Evaluation Study (ARES). HIV clinical trials. Sep-Oct 2005;6(5):235-245.

114. Berhan A, Berhan Y. Virologic response to tipranavir-ritonavir or darunavir-ritonavir based regimens in antiretroviral therapy experienced HIV-1 patients: a meta-analysis and meta-regression of randomized controlled clinical trials. PloS one. 2013;8(4):e60814.

115. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Annals of internal medicine. Oct 7 2014;161(7):461-471.

116. Aberg JA, Tebas P, Overton ET, et al. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks. AIDS research and human retroviruses. Oct 2012;28(10):1184-1195.

117. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. Aug 23 2008;372(9639):646-655.

46

118. Smith KY, Weinberg WG, Dejesus E, et al. Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT. AIDS research and therapy. 2008;5:5.

119. Landman R, Capitant C, Descamps D, et al. Efficacy and safety of ritonavir-boosted dual protease inhibitor therapy in antiretroviral-naive HIV-1-infected patients: the 2IP ANRS 127 study. The Journal of antimicrobial chemotherapy. Jul 2009;64(1):118-125.

120. Gathe JC, Jr., Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir /ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS (London, England). Jul 23 2004;18(11):1529-1537.

121. Kirk O, Lundgren JD, Pedersen C, et al. A randomized trial comparing initial HAART regimens of nelfinavir/nevirapine and ritonavir/saquinavir in combination with two nucleoside reverse transcriptase inhibitors. Antiviral therapy. Dec 2003;8(6):595-602.

122. Gulick RM, Hu XJ, Fiscus SA, et al. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. The Journal of infectious diseases. Nov 2000;182(5):1375-1384.

123. Kirk O, Mocroft A, Pradier C, et al. Clinical outcome among HIV-infected patients starting saquinavir hard gel compared to ritonavir or indinavir. AIDS (London, England). May 25 2001;15(8):999-1008.

124. Katzenstein TL, Kirk O, Pedersen C, et al. The danish protease inhibitor study: a randomized study comparing the virological efficacy of 3 protease inhibitor-containing regimens for the treatment of human immunodeficiency virus type 1 infection. The Journal of infectious diseases. Sep 2000;182(3):744-750.

125. Dragsted UB, Gerstoft J, Pedersen C, et al. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 Trial. The Journal of infectious diseases. Sep 1 2003;188(5):635-642.

126. Cohen Stuart JW, Schuurman R, Burger DM, et al. Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as part of triple therapy (CHEESE study). AIDS (London, England). May 7 1999;13(7):F53-58.

127. Antoniou T, Raboud JM, Diong C, et al. Virologic and immunologic effectiveness of tipranavir/ritonavir (TPV/r)- versus darunavir/ritonavir (DRV/r)-based regimens in clinical practice. Journal of the International Association of Physicians in AIDS Care (Chicago, Ill. : 2002). Nov-Dec 2010;9(6):382-389.

128. Johnson M, Grinsztejn B, Rodriguez C, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS (London, England). Apr 29 2005;19(7):685-694.

129. Haas DW, Zala C, Schrader S, et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS (London, England). Jun 13 2003;17(9):1339-1349.

130. Roca B, Gomez CJ, Arnedo A. A randomized, comparative study of lamivudine plus stavudine, with indinavir or nelfinavir, in treatment-experienced HIV-infected patients. AIDS (London, England). Jan 28 2000;14(2):157-161.

131. Chavanet P, Piroth L, Grappin M, et al. Randomized salvage therapy with saquinavir-ritonavir versus saquinavir-nelfinavir for highly protease inhibitor-experienced HIV-infected patients. HIV clinical trials. Sep-Oct 2001;2(5):408-412.

132. Para MF, Glidden DV, Coombs RW, et al. Baseline human immunodeficiency virus type 1 phenotype, genotype, and RNA response after switching from long-term hard-capsule saquinavir to indinavir or soft-gel-capsule saquinavir in AIDS clinical trials group protocol 333. The Journal of infectious diseases. Sep 2000;182(3):733-743.

133. Rusconi S, Giacomet V, Mameli C, et al. Efficacy and safety of a dual boosted protease inhibitor-based regimen, atazanavir and fosamprenavir/ritonavir, against HIV: experience in a pediatric population. BMC infectious diseases. 2012;12:179.

134. Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. Journal of acquired immune deficiency syndromes (1999). Jan 1 2004;35(1):22-32.

135. Croom KF, Dhillon S, Keam SJ. Atazanavir: a review of its use in the management of HIV-1 infection. Drugs. May 29 2009;69(8):1107-1140.

47

136. Plosker GL, Noble S. Indinavir: a review of its use in the management of HIV infection. Drugs. Dec 1999;58(6):1165-1203.

137. Rufo PA, Lin PW, Andrade A, et al. Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling. American journal of physiology. Cell physiology. May 2004;286(5):C998-C1008.

138. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS (London, England). Jul 31 2008;22(12):1389-1397.

139. Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS (London, England). Aug 24 2009;23(13):1679-1688.

140. Fischl MA, Ribaudo HJ, Collier AC, et al. A randomized trial of 2 different 4-drug antiretroviral regimens versus a 3-drug regimen, in advanced human immunodeficiency virus disease. The Journal of infectious diseases. Sep 1 2003;188(5):625-634.

141. Johnson M, Grinsztejn B, Rodriguez C, et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS (London, England). Mar 21 2006;20(5):711-718.

142. Atzori C, Villani P, Regazzi M, et al. Detection of HIV protease inhibitors in alveolar epithelial lining fluid: relevance for modulation of pneumocystis infection in the course of HAART. The Journal of eukaryotic microbiology. 2006;53 Suppl 1:S140-141.

143. Ntemgwa M, Brenner BG, Oliveira M, Moisi D, Wainberg MA. Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors. Antimicrob Agents Chemother. Feb 2007;51(2):604-610.

144. Weller DR, Brundage RC, Balfour HH, Jr., Vezina HE. An isocratic liquid chromatography method for determining HIV non-nucleoside reverse transcriptase inhibitor and protease inhibitor concentrations in human plasma. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. Apr 1 2007;848(2):369-373.

145. Verbesselt R, Van Wijngaerden E, de Hoon J. 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. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. Jan 1 2007;845(1):51-60.

146. Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG. In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug metabolism and disposition: the biological fate of chemicals. Nov 2005;33(11):1729-1739.

147. Delille CA, Pruett ST, Marconi VC, et al. Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations. Journal of clinical pharmacology. Sep 2014;54(9):1063-1071.

148. Crommentuyn KM, Rosing H, Hillebrand MJ, Huitema AD, Beijnen JH. 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. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. May 25 2004;804(2):359-367.

149. Taylor S, Back DJ, Drake SM, et al. Antiretroviral drug concentrations in semen of HIV-infected men: differential penetration of indinavir, ritonavir and saquinavir. The Journal of antimicrobial chemotherapy. Sep 2001;48(3):351-354.

150. Hazenberg MD, Stuart JW, Otto SA, et al. 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). Blood. Jan 1 2000;95(1):249-255.

151. Dierynck I, De Meyer S, Lathouwers E, et al. In vitro susceptibility and virological outcome to darunavir and lopinavir are independent of HIV type-1 subtype in treatment-naive patients. Antiviral therapy. 2010;15(8):1161-1169.

152. Rabi SA, Laird GM, Durand CM, et al. Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. The Journal of clinical investigation. Sep 2013;123(9):3848-3860.

48

153. Chang JH, Plise E, Cheong J, Ho Q, Lin M. Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia. Molecular pharmaceutics. Aug 5 2013;10(8):3067-3075.

154. Mittal S, Bandaranayake RM, King NM, et al. Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50. Journal of virology. Apr 2013;87(8):4176-4184.

155. Dam E, Lebel-Binay S, Rochas S, et al. Synergistic inhibition of protease-inhibitor-resistant HIV type 1 by saquinavir in combination with atazanavir or lopinavir. Antiviral therapy. 2007;12(3):371-380.

156. Yadav M, Trivedi V, Upadhyay V, et al. Comparison of extraction procedures for assessment of matrix effect for selective and reliable determination of atazanavir in human plasma by LC-ESI-MS/MS. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. Feb 15 2012;885-886:138-149.

157. Rhoades JA, Peterson YK, Zhu HJ, Appel DI, Peloquin CA, Markowitz JS. Prediction and in vitro evaluation of selected protease inhibitor antiviral drugs as inhibitors of carboxylesterase 1: a potential source of drug-drug interactions. Pharmaceutical research. Apr 2012;29(4):972-982.

158. Bethell R, Scherer J, Witvrouw M, Paquet A, Coakley E, Hall D. 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. AIDS research and human retroviruses. Sep 2012;28(9):1019-1024.

159. Poirier JM, Robidou P, Jaillon P. 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. Therapeutic drug monitoring. Apr 2005;27(2):186-192.

160. Nowacek AS, Balkundi S, McMillan J, et al. Analyses of nanoformulated antiretroviral drug charge, size, shape and content for uptake, drug release and antiviral activities in human monocyte-derived macrophages. Journal of controlled release : official journal of the Controlled Release Society. Mar 10 2011;150(2):204-211.

161. Leroyer S, Vatier C, Kadiri S, et al. Glyceroneogenesis is inhibited through HIV protease inhibitor-induced inflammation in human subcutaneous but not visceral adipose tissue. Journal of lipid research. Feb 2011;52(2):207-220.

162. Choi SO, Rezk NL, Kashuba AD. High-performance liquid chromatography assay for the determination of the HIV-protease inhibitor tipranavir in human plasma in combination with nine other antiretroviral medications. Journal of pharmaceutical and biomedical analysis. Mar 12 2007;43(4):1562-1567.

163. Hulskotte EG, Feng HP, Xuan F, et al. Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, darunavir, and lopinavir. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Mar 2013;56(5):718-726.

164. Piscitelli S, Kim J, Gould E, et al. Drug interaction profile for GSK2248761, a next generation non-nucleoside reverse transcriptase inhibitor. Br J Clin Pharmacol. Aug 2012;74(2):336-345.

165. Kuznetsov NA, Kozyr AV, Dronina MA, et al. Pre-steady-state kinetics of interaction of wild-type and multiple drug-resistant HIV protease with first and second generation inhibitory drugs. Doklady. Biochemistry and biophysics. Sep-Oct 2011;440:239-243.

166. Boffito M, Jackson A, Amara A, et al. Pharmacokinetics of once-daily darunavir-ritonavir and atazanavir-ritonavir over 72 hours following drug cessation. Antimicrob Agents Chemother. Sep 2011;55(9):4218-4223.

167. Goldwirt L, Braun J, de Castro N, et al. Switch from enfuvirtide to raltegravir lowers plasma concentrations of darunavir and tipranavir: a pharmacokinetic substudy of the EASIER-ANRS 138 trial. Antimicrob Agents Chemother. Jul 2011;55(7):3613-3615.

168. Sekar V, Lefebvre E, De Marez T, et al. Pharmacokinetic interaction between indinavir and darunavir with low-dose ritonavir in healthy volunteers. Intervirology. 2010;53(3):176-182.

169. McRae M, Clay PG, Anderson PL, Glaros AG. Pharmacokinetics of concurrent administration of fosamprenavir and atazanavir without ritonavir in human immunodeficiency virus-negative subjects. Pharmacotherapy. Aug 2009;29(8):937-942.

170. von Hentig N, Lotsch J. 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. Antimicrob Agents Chemother. Aug 2009;53(8):3524-3527.

49

171. Mathias AA, Hinkle J, Shen G, et al. Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir. Journal of acquired immune deficiency syndromes (1999). Oct 1 2008;49(2):156-162.

172. Pawinski T, Pulik P, Gralak B, Horban A. Pharmacokinetic monitoring of HIV-1 protease inhibitors in the antiretroviral therapy. Acta poloniae pharmaceutica. Jan-Feb 2008;65(1):93-100.

173. Busti AJ, Bain AM, Hall RG, 2nd, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. Journal of cardiovascular pharmacology. Jun 2008;51(6):605-610.

174. Abel S, Russell D, Taylor-Worth RJ, Ridgway CE, Muirhead GJ. Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers. Br J Clin Pharmacol. Apr 2008;65 Suppl 1:27-37.

175. Ofotokun I, Acosta EP, Lennox JL, Pan Y, Easley KA. Pharmacokinetics of an indinavir-ritonavir-fosamprenavir regimen in patients with human immunodeficiency virus. Pharmacotherapy. Jan 2008;28(1):74-81.

176. Justesen US, Fox Z, Pedersen C, et al. 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. Basic & clinical pharmacology & toxicology. Nov 2007;101(5):339-344.

177. Luber AD, Brower R, Kim D, Silverman R, Peloquin CA, Frank I. Steady-state pharmacokinetics of once-daily fosamprenavir/ritonavir and atazanavir/ritonavir alone and in combination with 20 mg omeprazole in healthy volunteers. HIV medicine. Oct 2007;8(7):457-464.

178. Panhard X, Legrand M, Taburet AM, Diquet B, Goujard C, Mentre F. Population pharmacokinetic analysis of lamivudine, stavudine and zidovudine in controlled HIV-infected patients on HAART. European journal of clinical pharmacology. Nov 2007;63(11):1019-1029.

179. von Hentig N, Muller A, Rottmann C, et al. Pharmacokinetics of saquinavir, atazanavir, and ritonavir in a twice-daily boosted double-protease inhibitor regimen. Antimicrob Agents Chemother. Apr 2007;51(4):1431-1439.

180. Ford J, Boffito M, Maitland D, et al. 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. The Journal of antimicrobial chemotherapy. Nov 2006;58(5):1009-1016.

181. Boffito M, Maitland D, Dickinson L, et al. Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1-infected individuals administered different atazanavir doses. AIDS research and human retroviruses. Aug 2006;22(8):749-756.

182. Robertson SM, Formentini E, Alfaro RM, Falloon J, Penzak SR. Lack of in vivo correlation between indinavir and saquinavir exposure and cytochrome P450 3A phenotype as assessed with oral midazolam as a phenotype probe. Pharmacotherapy. Aug 2006;26(8):1051-1059.

183. Kiser JJ, Lichtenstein KA, Anderson PL, Fletcher CV. Effects of esomeprazole on the pharmacokinetics of atazanavir and fosamprenavir in a patient with human immunodeficiency virus infection. Pharmacotherapy. Apr 2006;26(4):511-514.

184. Goujard C, Legrand M, Panhard X, et al. High variability of indinavir and nelfinavir pharmacokinetics in HIV-infected patients with a sustained virological response on highly active antiretroviral therapy. Clinical pharmacokinetics. 2005;44(12):1267-1278.

185. Tie Y, Boross PI, Wang YF, et al. 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. The FEBS journal. Oct 2005;272(20):5265-5277.

186. Seminari E, Guffanti M, Villani P, et al. Steady-state pharmacokinetics of atazanavir given alone or in combination with saquinavir hard-gel capsules or amprenavir in HIV-1-infected patients. European journal of clinical pharmacology. Aug 2005;61(7):545-549.

187. Pea F, Tavio M, Pavan F, et al. Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients. Antiviral therapy. 2008;13(5):739-742.

188. Boffito M, Dickinson L, Hill A, et al. Steady-State pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients. Journal of acquired immune deficiency syndromes (1999). Nov 1 2004;37(3):1376-1384.

189. Boffito M, Kurowski M, Kruse G, et al. Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen. AIDS (London, England). Jun 18 2004;18(9):1291-1297.

190. DiCenzo R, Forrest A, Fischl MA, et al. Pharmacokinetics of indinavir and nelfinavir in treatment-naive, human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. Mar 2004;48(3):918-923.

50

191. Washington CB, Flexner C, Sheiner LB, et al. Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors. Clinical pharmacology and therapeutics. May 2003;73(5):406-416.

192. Bratt G, Stahle L. Sildenafil does not alter nelfinavir pharmacokinetics. Therapeutic drug monitoring. Apr 2003;25(2):240-242.

193. Pfister M, Labbe L, Hammer SM, et al. Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398. Antimicrob Agents Chemother. Jan 2003;47(1):130-137.

194. Justesen US, Pedersen C. Diurnal variation of plasma protease inhibitor concentrations. AIDS (London, England). Dec 6 2002;16(18):2487-2489.

195. Lu JF, Blaschke TF, Flexner C, Rosenkranz SL, Sheiner LB. Model-based analysis of the pharmacokinetic interactions between ritonavir, nelfinavir, and saquinavir after simultaneous and staggered oral administration. Drug metabolism and disposition: the biological fate of chemicals. Dec 2002;30(12):1455-1461.

196. Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother. Dec 2001;45(12):3663-3668.

197. Fleury S, Rizzardi GP, Chapuis A, et al. Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. Proceedings of the National Academy of Sciences of the United States of America. May 9 2000;97(10):5393-5398.

198. Fletcher CV, Acosta EP, Cheng H, et al. Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV- infected subjects: ACTG 884. AIDS (London, England). Nov 10 2000;14(16):2495-2501.

199. St Clair MH, Millard J, Rooney J, et al. In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. Antiviral research. Jan 1996;29(1):53-56.

200. Kosel BW, Aweeka FT, Benowitz NL, et al. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS (London, England). Mar 8 2002;16(4):543-550.

201. Slain D, Pakyz A, Israel DS, Monroe S, Polk RE. Variability in activity of hepatic CYP3A4 in patients infected with HIV. Pharmacotherapy. Aug 2000;20(8):898-907.

202. Hoetelmans RM, Reijers MH, Weverling GJ, et al. The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy. AIDS (London, England). Jul 30 1998;12(11):F111-115.

203. Pfister M, Labbe L, Lu JF, et al. Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir. Clinical pharmacology and therapeutics. Aug 2002;72(2):133-141.

204. Mata-Munguia C, Escoto-Delgadillo M, Torres-Mendoza B, et al. Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis. BMC bioinformatics. 2014;15:72.

205. Codoner FM, Pou C, Thielen A, et al. Added value of deep sequencing relative to population sequencing in heavily pre-treated HIV-1-infected subjects. PloS one. 2011;6(5):e19461.

206. Munerato P, Sucupira MC, Oliveros MP, et al. HIV type 1 antiretroviral resistance mutations in subtypes B, C, and F in the City of Sao Paulo, Brazil. AIDS research and human retroviruses. Mar 2010;26(3):265-273.

207. Demeter LM, Ribaudo HJ, Erice A, et al. 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. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Aug 15 2004;39(4):552-558.

208. Tartaglia A, Saracino A, Monno L, Tinelli C, Angarano G. Both a protective and a deleterious role for the L76V mutation. Antimicrob Agents Chemother. Apr 2009;53(4):1724-1725.

209. Delaugerre C, Pavie J, Palmer P, et al. Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir-containing regimen. AIDS (London, England). Sep 12 2008;22(14):1809-1813.

210. Young TP, Parkin NT, Stawiski E, et al. Prevalence, mutation patterns, and effects on protease inhibitor susceptibility of the L76V mutation in HIV-1 protease. Antimicrob Agents Chemother. Nov 2010;54(11):4903-4906.

211. Poveda E, Anta L, Blanco JL, et al. Drug resistance mutations in HIV-infected patients in the Spanish drug resistance database failing tipranavir and darunavir therapy. Antimicrob Agents Chemother. Jul 2010;54(7):3018-3020.

51

212. Mo H, Parkin N, Stewart KD, et al. 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. Antimicrob Agents Chemother. Feb 2007;51(2):732-735.

213. Poveda E, de Mendoza C, Parkin N, et al. Evidence for different susceptibility to tipranavir and darunavir in patients infected with distinct HIV-1 subtypes. AIDS (London, England). Mar 12 2008;22(5):611-616.

214. Desbois D, Roquebert B, Peytavin G, et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother. Apr 2008;52(4):1545-1548.

215. Abecasis AB, Deforche K, Bacheler LT, et al. Investigation of baseline susceptibility to protease inhibitors in HIV-1 subtypes C, F, G and CRF02_AG. Antiviral therapy. 2006;11(5):581-589.

216. Hsieh SM, Chang SY, Hung CC, Sheng WH, Chen MY, Chang SC. Emerging HIV-1 resistance to tipranavir and darunavir in patients with virological failure to first-generation protease inhibitors in Taiwan. International journal of STD & AIDS. Nov 2011;22(11):617-620.

217. Hsieh SM, Chang SY, Hung CC, Sheng WH, Chen MY, Chang SC. Impact of first-line protease inhibitors on predicted resistance to tipranavir in HIV-1-infected patients with virological failure. BMC infectious diseases. 2009;9:154.

218. Spagnuolo V, Gianotti N, Seminari E, et al. Changes in darunavir/r resistance score after previous failure to tipranavir/r in HIV-1-infected multidrug-resistant patients. Journal of acquired immune deficiency syndromes (1999). Feb 1 2009;50(2):192-195.

219. Rusconi S, La Seta Catamancio S, Citterio P, et al. Susceptibility to PNU-140690 (Tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrob Agents Chemother. May 2000;44(5):1328-1332.

220. Schapiro JM, Winters MA, Lawrence J, Merigan TC. Clinical cross-resistance between the HIV-1 protease inhibitors saquinavir and indinavir and correlations with genotypic mutations. AIDS (London, England). Feb 25 1999;13(3):359-365.

221. Deeks ED. Cobicistat: a review of its use as a pharmacokinetic enhancer of atazanavir and darunavir in patients with HIV-1 infection. Drugs. Feb 2014;74(2):195-206.

222. Guaraldi G, Stentarelli C, Zona S, Santoro A. HIV-associated lipodystrophy: impact of antiretroviral therapy. Drugs. Sep 2013;73(13):1431-1450.

223. Arribas JR. Drugs in traditional drug classes (nucleoside reverse transcriptase inhibitor/nonnucleoside reverse transcriptase inhibitor/protease inhibitors) with activity against drug-resistant virus (tipranavir, darunavir, etravirine). Current opinion in HIV and AIDS. Nov 2009;4(6):507-512.

224. Hughes A, Barber T, Nelson M. New treatment options for HIV salvage patients: an overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists. The Journal of infection. Jul 2008;57(1):1-10.

225. Fernandez-Montero JV, Barreiro P, Soriano V. HIV protease inhibitors: recent clinical trials and recommendations on use. Expert opinion on pharmacotherapy. Jul 2009;10(10):1615-1629.

226. Clotet B. Strategies for overcoming resistance in HIV-1 infected patients receiving HAART. AIDS reviews. Jul-Sep 2004;6(3):123-130.

227. Turner D, Schapiro JM, Brenner BG, Wainberg MA. The influence of protease inhibitor resistance profiles on selection of HIV therapy in treatment-naive patients. Antiviral therapy. Jun 2004;9(3):301-314.

228. Randolph JT, DeGoey DA. Peptidomimetic inhibitors of HIV protease. Current topics in medicinal chemistry. 2004;4(10):1079-1095.

229. Tejerina F, Bernaldo de Quiros JC. Protease inhibitors as preferred initial regimen for antiretroviral-naive HIV patients. AIDS reviews. Oct-Dec 2011;13(4):227-233.

230. Cooper RD, Tonelli M. Renal disease associated with antiretroviral therapy in the treatment of HIV. Nephron. Clinical practice. 2011;118(3):c262-268.

231. Piacenti FJ. An update and review of antiretroviral therapy. Pharmacotherapy. Aug 2006;26(8):1111-1133. 232. Waters L, Nelson MR. New drugs. HIV medicine. Jul 2005;6(4):225-231. 233. Harris M, Montaner JS. Management of HIV-infected patients with multidrug-resistant virus. Current

HIV/AIDS reports. Sep 2004;1(3):116-121. 234. Musial BL, Chojnacki JK, Coleman CI. Atazanavir: a new protease inhibitor to treat HIV infection.

American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. Jul 1 2004;61(13):1365-1374.

235. Sension M. Initial therapy for human immunodeficiency virus: broadening the options. HIV clinical trials. Mar-Apr 2004;5(2):99-111.

52

236. Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Mar 1 2004;38 Suppl 2:S90-97.

237. Tomasselli AG, Heinrikson RL. Targeting the HIV-protease in AIDS therapy: a current clinical perspective. Biochimica et biophysica acta. Mar 7 2000;1477(1-2):189-214.

238. Johnston SS, Juday T, Esker S, et al. Comparative incidence and health care costs of medically attended adverse effects among U.S. Medicaid HIV patients on atazanavir- or darunavir-based antiretroviral therapy. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. Mar-Apr 2013;16(2):418-425.

239. Siccardi M, Marzolini C, Seden K, et al. Prediction of drug-drug interactions between various antidepressants and efavirenz or boosted protease inhibitors using a physiologically based pharmacokinetic modelling approach. Clinical pharmacokinetics. Jul 2013;52(7):583-592.

240. Talbot A, Grant P, Taylor J, et al. 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. Antimicrob Agents Chemother. Jun 2010;54(6):2473-2479.

241. Jayakanthan M, Chandrasekar S, Muthukumaran J, Mathur PP. Analysis of CYP3A4-HIV-1 protease drugs interactions by computational methods for Highly Active Antiretroviral Therapy in HIV/AIDS. Journal of molecular graphics & modelling. Jan 2010;28(5):455-463.

242. Hyland R, Dickins M, Collins C, Jones H, Jones B. Maraviroc: in vitro assessment of drug-drug interaction potential. Br J Clin Pharmacol. Oct 2008;66(4):498-507.

243. Lucia MB, Anu R, Handley M, et al. Exposure to HIV-protease inhibitors selects for increased expression of P-glycoprotein (ABCB1) in Kaposi's sarcoma cells. British journal of cancer. Aug 9 2011;105(4):513-522.

244. Peatey CL, Andrews KT, Eickel N, et al. Antimalarial asexual stage-specific and gametocytocidal activities of HIV protease inhibitors. Antimicrob Agents Chemother. Mar 2010;54(3):1334-1337.

245. He Z, Qin L, Chen L, Peng N, You J, Chen X. Synergy of human immunodeficiency virus protease inhibitors with chloroquine against Plasmodium falciparum in vitro and Plasmodium chabaudi in vivo. Antimicrob Agents Chemother. Jul 2008;52(7):2653-2656.

246. Fumagalli L, Zucchetti M, Parisi I, et al. The pharmacokinetics of liposomal encapsulated daunorubicin are not modified by HAART in patients with HIV-associated Kaposi's sarcoma. Cancer chemotherapy and pharmacology. 2000;45(6):495-501.

247. Rutschmann OT, Negro F, Hirschel B, Hadengue A, Anwar D, Perrin LH. Impact of treatment with human immunodeficiency virus (HIV) protease inhibitors on hepatitis C viremia in patients coinfected with HIV. The Journal of infectious diseases. Mar 1998;177(3):783-785.

248. Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL. Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clinical pharmacology and therapeutics. Aug 2007;82(2):197-203.

249. Lowe SH, Hassink EA, van Eck-Smit BL, Borleffs JC, Lange JM, Reiss P. Stavudine but not didanosine as part of HAART contributes to peripheral lipoatrophy: a substudy from the Antiretroviral Regimen Evaluation Study (ARES). HIV clinical trials. Sep-Oct 2007;8(5):337-344.

250. Wood R, Phanuphak P, Cahn P, et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. Journal of acquired immune deficiency syndromes (1999). Jun 1 2004;36(2):684-692.

251. Casado JL, Moreno S, Hertogs K, et al. Plasma drug levels, genotypic resistance, and virological response to a nelfinavir plus saquinavir-containing regimen. AIDS (London, England). Jan 4 2002;16(1):47-52.

252. Riddler SA, Havlir D, Squires KE, et al. Coadministration of indinavir and nelfinavir in human immunodeficiency virus type 1-infected adults: safety, pharmacokinetics, and antiretroviral activity. Antimicrob Agents Chemother. Dec 2002;46(12):3877-3882.

253. Linde R, Funk MB, Schuster T, et al. Low incidence of genotypic and phenotypic resistance in paediatric HIV-infected patients on long-term first-line antiretroviral triple therapy. AIDS (London, England). May 25 2001;15(8):1077-1079.

254. Ucciferri C, Falasca K, Vignale F, Di Nicola M, Pizzigallo E, Vecchiet J. Improved metabolic profile after switch to darunavir/ritonavir in HIV positive patients previously on protease inhibitor therapy. Journal of medical virology. May 2013;85(5):755-759.

53

255. Turatti L, Sprinz E, Lazzaretti RK, et al. Short communication: UGT1A1*28 variant allele is a predictor of severe hyperbilirubinemia in HIV-infected patients on HAART in southern Brazil. AIDS research and human retroviruses. Sep 2012;28(9):1015-1018.

256. Worm D, Kirk O, Andersen O, et al. Clinical lipoatrophy in HIV-1 patients on HAART is not associated with increased abdominal girth, hyperlipidaemia or glucose intolerance. HIV medicine. Oct 2002;3(4):239-246.

257. Casado JL, Dronda F, Hertogs K, et al. Efficacy, tolerance, and pharmacokinetics of the combination of stavudine, nevirapine, nelfinavir, and saquinavir as salvage regimen after ritonavir or indinavir failure. AIDS research and human retroviruses. Jan 20 2001;17(2):93-98.

258. Jacobson MA, Zegans M, Pavan PR, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet. May 17 1997;349(9063):1443-1445.

259. Labetoulle M, Goujard C, Frau E, et al. Cytomegalovirus retinitis in advanced HIV-infected patients treated with protease inhibitors: incidence and outcome over 2 years. Journal of acquired immune deficiency syndromes (1999). Nov 1 1999;22(3):228-234.

260. Tebas P, Patick AK, Kane EM, et al. Virologic responses to a ritonavir--saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS (London, England). Feb 4 1999;13(2):F23-28.

261. Silva M, Skolnik PR, Gorbach SL, et al. The effect of protease inhibitors on weight and body composition in HIV-infected patients. AIDS (London, England). Sep 10 1998;12(13):1645-1651.

262. Martinez E, Gonzalez-Cordon A, Ferrer E, et al. Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir. HIV medicine. Jul 2014;15(6):330-338.

263. Grover SA, Coupal L, Gilmore N, Mukherjee J. Impact of dyslipidemia associated with Highly Active Antiretroviral Therapy (HAART) on cardiovascular risk and life expectancy. The American journal of cardiology. Mar 1 2005;95(5):586-591.

264. Roge BT, Katzenstein TL, Gerstoft J. Comparison of P-triglyceride levels among patients with human immunodeficiency virus on randomized treatment with ritonavir, indinavir or ritonavir/saquinavir. Scand J Infect Dis. 2001;33(4):306-311.

265. Gyalrong-Steur M, Bogner JR, Seybold U. Changes in lipid profiles after switching to a protease inhibitor-containing cART--unfavourable effect of fosamprenavir in obese patients. European journal of medical research. Feb 24 2011;16(2):85-92.

266. Crane HM, Van Rompaey SE, Kitahata MM. Antiretroviral medications associated with elevated blood pressure among patients receiving highly active antiretroviral therapy. AIDS (London, England). Apr 24 2006;20(7):1019-1026.

267. Nishijima T, Hamada Y, Watanabe K, et al. Ritonavir-boosted darunavir is rarely associated with nephrolithiasis compared with ritonavir-boosted atazanavir in HIV-infected patients. PloS one. 2013;8(10):e77268.

268. de Lastours V, Ferrari Rafael De Silva E, Daudon M, et al. High levels of atazanavir and darunavir in urine and crystalluria in asymptomatic patients. The Journal of antimicrobial chemotherapy. Aug 2013;68(8):1850-1856.

269. Rockwood N, Mandalia S, Bower M, Gazzard B, Nelson M. Ritonavir-boosted atazanavir exposure is associated with an increased rate of renal stones compared with efavirenz, ritonavir-boosted lopinavir and ritonavir-boosted darunavir. AIDS (London, England). Aug 24 2011;25(13):1671-1673.

270. Raffi F, Battegay M, Rusconi S, et al. Combined tipranavir and enfuvirtide use associated with higher plasma tipranavir concentrations but not with increased hepatotoxicity: sub-analysis from RESIST. AIDS (London, England). Sep 12 2007;21(14):1977-1980.

271. Bruno R, Sacchi P, Maiocchi L, Zocchetti C, Filice G. Hepatotoxicity and nelfinavir: a meta-analysis. Clin Gastroenterol Hepatol. May 2005;3(5):482-488.

272. Vispo E, Fernandez-Montero JV, Labarga P, Barreiro P, Soriano V. Low risk of liver toxicity using the most recently approved antiretroviral agents but still increased in HIV-hepatitis C virus coinfected patients. AIDS (London, England). Apr 24 2013;27(7):1187-1188.

273. Bonfanti P, Valsecchi L, Parazzini F, et al. Incidence of adverse reactions in HIV patients treated with protease inhibitors: a cohort study. Coordinamento Italiano Studio Allergia e Infezione da HIV (CISAI) Group. Journal of acquired immune deficiency syndromes (1999). Mar 1 2000;23(3):236-245.

274. Casado JL, de Los Santos I, Del Palacio M, et al. Lipid-lowering effect and efficacy after switching to etravirine in HIV-infected patients with intolerance to suppressive HAART. HIV clinical trials. Jan-Feb 2013;14(1):1-9.

54

275. Gruber VA, Rainey PM, Moody DE, et al. Interactions between buprenorphine and the protease inhibitors darunavir-ritonavir and fosamprenavir-ritonavir. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. Feb 1 2012;54(3):414-423.

276. Tavel JA, Babiker A, Fox L, et al. Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: the STALWART study. PloS one. 2010;5(2):e9334.

277. Losso MH, Belloso WH, Emery S, et al. 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. The Journal of infectious diseases. May 2000;181(5):1614-1621.

278. Zolopa AR, Berger DS, Lampiris H, et al. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV Type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. The Journal of infectious diseases. Mar 15 2010;201(6):814-822.

279. Sension MG, Bellos NC, Johnson J, et al. Lamivudine 300 mg QD versus continued lamivudine 150 mg BID with stavudine and a protease inhibitor in suppressed patients. HIV clinical trials. Sep-Oct 2002;3(5):361-370.

280. Gerstoft J, Kirk O, Obel N, et al. Low efficacy and high frequency of adverse events in a randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine. AIDS (London, England). Sep 26 2003;17(14):2045-2052.

281. Salcedo Gomez PM, Amano M, Yashchuk S, et al. 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. Antimicrob Agents Chemother. Dec 2013;57(12):6110-6121.

282. Amano M, Tojo Y, Salcedo-Gomez PM, et al. 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. Antimicrob Agents Chemother. May 2013;57(5):2036-2046.

283. Lascar M, Cartledge JD. New protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Journal of HIV therapy. Jun 2008;13(2):40-44.

284. Trial of tipranavir versus darunavir in treatment-experienced patients enrolling. AIDS patient care and STDs. Aug 2007;21(8):6-3.

285. Pierone G, Jr., Urban T, Martin A, Mieras J, Kantor C. Successful use of a tipranavir/ritonavir-based antiretroviral regimen following development of viral resistance to darunavir. HIV clinical trials. Mar-Apr 2008;9(2):140-141.

286. Coleman CI, White CM. A comparison of different protease inhibitors on coronary heart disease risk. Connecticut medicine. Jan 2007;71(1):15-17.

287. Sax PE. Meeting report. Report from ICAAC. AIDS clinical care. Dec 2006;18(12):111-112. 288. Anti-HIV agents. Atazanavir and saquinavir. TreatmentUpdate. Apr-May 2004;16(3):9-10. 289. Dauer B. Protease inhibitors: the current status. Journal of HIV therapy. Dec 2005;10(4):72-74. 290. Huff B. A lame duck, a dark horse, and a goat. GMHC treatment issues : the Gay Men's Health Crisis

newsletter of experimental AIDS therapies. May-Jun 2005;19(5-6):4-5. 291. Atazanavir affects saquinavir. AIDS patient care and STDs. Apr 2005;19(4):273-274. 292. Boyle BA. The continuing evolution of HIV therapy. The AIDS reader. Dec 2003;13(12):576-578, 582. 293. Moyle GJ. Boosted PIs: competition hots up. The AIDS reader. Sep 2003;13(9):425-429. 294. Gallant JE. New antiretroviral agents. The Hopkins HIV report : a bimonthly newsletter for healthcare

providers / Johns Hopkins University AIDS Service. Mar 2001;13(2):2, 16. 295. Hoffman CJ, Gallant JE. When and how to use tipranavir and darunavir. The AIDS reader. Apr

2007;17(4):194-198, 201. 296. Anti-HIV agents. Saquinavir with fosamprenavir. TreatmentUpdate. Apr-May 2004;16(3):9. 297. Sax PE. Report from the 2008 joint ICAAC/IDSA meeting. Darunavir and atazanavir: 96-week data from

ARTEMIS and CASTLE. AIDS clinical care. Dec 2008;20(12):98. 298. Bartlett JG. Report on new drugs. The Hopkins HIV report : a bimonthly newsletter for healthcare

providers / Johns Hopkins University AIDS Service. Mar 2000;12(2):11. 299. Lehmann C, Jung N, Hofmann A, et al. Nucleoside-free boosted double PI regimen: significant CD4+ T-

cell recovery in patients with poor immunologic response despite virologic suppression. Current HIV research. Nov 2008;6(6):555-559.

55

300. de Mendoza C, Valer L, Ribera E, et al. Performance of six different ritonavir-boosted protease inhibitor-based regimens in heavily antiretroviral-experienced HIV-infected patients. HIV clinical trials. Jul-Aug 2006;7(4):163-171.

301. Hammer SM, Bassett R, Squires KE, et al. A randomized trial of nelfinavir and abacavir in combination with efavirenz and adefovir dipivoxil in HIV-1-infected persons with virological failure receiving indinavir. Antiviral therapy. Dec 2003;8(6):507-518.

302. Portilla J, Boix V, Garcia-Henarejos JA, et al. 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. International journal of STD & AIDS. Dec 2005;16(12):807-810.

Appendix: Evidence Tables

Evidence Table 1. Systematic Reviews Evaluating the HIV Protease Inhibitors Reference/ Study Design

N Patient Population Treatment Interventions Results Safety

Berhan et al, 2013114 Meta‐analysis of 14 randomized, controlled trials

6,301 ART experienced patients with plasma viral load above 1,000 copies HIV RNA/ml

The treatments evaluated were:

TPV/r 500/200 mg or DRV/r 600/100 mg twice daily based regimens o Outcome 1 N = 3,163 o Outcome 2 N = 2,189 o Outcome 3 N = 2,861

Investigator selected boosted comparator PIs (CPIs) o Outcome 1 N = 3,138 o Outcome 2 N = 2,156 o Outcome 3 N = 2,821

Conducted: No date range mentioned in the methodology

Outcome 1: Viral load reduction by ≥1 log10 copies HIV‐RNA/ml from baseline

TPV/r vs CPIs o OR 2.96 (95% CI 2.60–3.38)

DRV/r vs CPIs o OR 6.66 (95% CI 2.89–15.36)

TPV/r or DRV/r vs CPIs o OR 4.21 (95% CI 3.07–5.79)

Outcome 2: Patients who achieved HIV1‐RNA < 400 copies/ml




Outcome 3: Patients who achieved HIV1‐RNA < 50 copies/ml




Not assessed in the meta‐analysis.

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/ Study Design

N Patient Selection Treatment Interventions Results Safety

Treatment naïve patients Lennox et al, 2014115 Phase 3, open‐label, randomized, non‐inferiority trial

1,809 Treatment naïve patients aged ≥18 years with HIV1‐RNA > 1,000 copies/mL and no resistance to NRTI or PIs Setting: 57 sites in the US and Puerto Rico

The following three in combination with tenofovir 300mg and emtricitabine 200mg daily:

ATV/r 300/100 mg daily o N = 605

RAL 400 mg twice daily o N = 603

DRV/r 800/100 mg daily o N = 601

Follow‐up: at least 96 weeks Conducted: May ‘09 – June ‘11

Primary Endpoint: Incidence of virologic failure by 96 weeks with a margin of equivalence defined as ‐10% to 10%:

ATV/r vs RAL o 3.4% (97.5% CI ‐0.7–7.4%)

DRV/r vs RAL o 5.6% (97.5% CI 1.3–9.9%)

ATV/r vs DRV/r o ‐2.2% (97.5% CI ‐6.7–2.3%)

Adverse event discontinuation rate:

ATV/r v. RAL: 12.7% (97.5% CI 9.4%‐16.1%)

ATV/r v. DRV/r: 9.2% (97.5% CI 5.5%‐12.9%)

Most common adverse events cited for discontinuation

ATV/r: hyperbilirubinemia

DRV/r: Diarrhea, nausea, and vomiting

RAL: headache Aberg et al, 2012116 Phase 4, multi‐center, open‐label, randomized trial

65 Treatment naïve patients aged ≥18 years with HIV1‐RNA ≥ 1,000 copies/mL and not resistant to DRV, ATV, TDF, and FTC Setting: centers across the US

The following two in combination with tenofovir 300mg and emtricitabine 200mg daily:


DRV/r 800/100 mg daily o N = 34

Follow‐Up: 48 weeks Conducted: Not specified

Primary Endpoint: To evaluate the change in triglyceride levels from baseline to week 12 Efficacy data for both arms was provided (although no statistical analyses were carried out to accompany them). At week 48, the following percentage of patients achieved virologic response:

ATV/r = 71.0% DRV/r = 76.5%

Rates of adverse events were comparable between the two arms. The only exception was grade 2‐4 hyperbilirubinemia, which was observed more in the ATV/r arm.

58

Reference/ Study Design


Landman et al, 2009119 prospective open‐label randomized pilot trial

61 Treatment‐naïve patients

Fosamprenavir/atazanavir/ritonavir (n = 30) Saquinavir/atazanavir/ritonavir (n = 31)

Primary endpoint: early virologic success, defined as plasma viral load <50 copies/mL at week 16

Fosamprenavir/atazanavir/ritonavir: 12/30 (40%)

Saquinavir/atazanavir/ritonavir: 13/31 patients (42%)

“Ritonavir‐boosted dual protease inhibitor regimens targeting only one step of viral replication were insufficient to rapidly suppress plasma HIV RNA to <50 copies/mL in antiretroviral‐naive patients with high viral load at baseline.”

Gastrointestinal adverse events:

Fosamprenavir/ atazanavir/ritonavir: 30%

Saquinavir/ atazanavir/ritonavir: 16%

Hyperbilirubinemia:

Fosamprenavir/ atazanavir/ritonavir: 10%

Saquinavir/ atazanavir/ritonavir: 23%

59



Ortiz et al, 2008 138 & Mills et al, 2009 139 & Orkin et al, 2012 Phase 3, open‐label, multi‐center, randomized non‐inferiority trial

689 Treatment naïve patients aged ≥18 years with HIV1‐RNA ≥ 5,000 copies/mL Setting: centers across 26 countries, including the US

The following two arms in combination with tenofovir 300mg and emtricitabine 200mg daily:

DRV/r 800/100 mg daily (n = 343)

LPV/r 800/200 mg total daily dose (1‐2 times daily; n = 346)

Follow‐Up: 192 weeks Conducted: September ‘05 – all patients reached 192 weeks (specific date not mentioned)

Primary Endpoint: Non‐inferiority with respect to the proportion of patients who achieved virologic response (HAV1‐RNA < 50 copies/mL) Week 48

DRV/r = 84% LPV/r = 78%

o Difference DRV/r vs LPV/r = 5.6%95% CI ‐0.1–11%

o Considered non‐inferior Week 96

DRV/r = 79% LPV/r = 71% Difference DRV/r vs LPV/r = 8.4%

o 95% CI 1.9–14.8%, P < 0.001 o Considered non‐inferior

Secondary Endpoint: Durability and statistical superiority of virologic response over 96 and 192 weeks of DRV/r to LPV/r Week 96

Difference DRV/r vs LPV/r = 8.3% o 95% CI 1.8–14.7%, P = 0.012 o Superiority of DRV/r shown

Week 192

DRV/r = 68.8% LPV/r = 57.2% Difference DRV/r vs LPV/r = 11.6%

o 95% CI 4.4–18.8% o Superiority of DRV/r shown

Week 48: Permanent discontinuation due to adverse events (including pregnancies):

DRV/r = 3% LPV/r = 7% Week 96: Discontinuation

of treatment due to

adverse events:

DRV/r = 4% LPV/r = 9% Incidence of grade 2‐4

adverse events:

DRV/r = 23% LPV/r = 34% Week 192: Permanent discontinuation due to adverse events (including pregnancies):

DRV/r = 7.6% LPV/r = 14.5%

o P = 0.005 Most common adverse events: diarrhea, nausea, and rash.

60



Molina et al, 2008 117 & Molina et al, 2010 Open‐label, multi‐center, randomized non‐inferiority trial

883 Treatment naïve patients aged ≥18 years with HIV1‐RNA ≥ 5,000 copies/mL Setting: 134 sites in 29 countries, including the US



LPV/r 400/100 mg twice daily o N = 443

Follow‐Up: 96 weeks Conducted: November ‘05 – June ‘06

Primary Endpoint: Non‐inferiority with respect to the proportion of patients who achieved virologic response (HIV1‐RNA < 50 copies/mL) at week 48

ATV/r = 78% LPV/r = 76%

o 95% CI ‐3.8–7.1%; non‐inferior Secondary Endpoint: The proportion of patients who maintained virologic response (HIV1‐RNA < 50 copies/mL) at week 96

ATV/r = 74% LPV/r = 68%

o 95% CI 0.3–12%, p < 0.05

Week 48: Serious adverse events occurred in the following percentage of patients:

ATV/r = 12% LPV/r = 10% Week 96: Serious adverse events occurred in the following percentage of patients:

ATV/r = 14% LPV/r = 11% Most common adverse events were diarrhea and nausea.

Smith et al, 2008 118 Multi‐center, open‐label, randomized trial

106 Treatment naïve patients aged >18 years Setting: 16 outpatient sites in the US



FPV/r 1400/100 mg daily o N = 53

Follow‐Up: 48 weeks Conducted: April ’05 – September ‘06

Primary Endpoint: Comparison of the proportion of patients with HIV1‐RNA < 50 copies/mL at week 48

ATV/r = 83% FPV/r = 75%, p = NS

Diarrhea and nausea were reported more frequently in the FPV/r arm compared to the ATV/r arm. Hyperbilirubinemia, fatigue, and jaundice were reported more frequently in the ATV/r arm compared to the FPV/r arm.

61



Dragsted et al, 2003125 Phase 4, open‐label, multi‐center, randomized trial

306 Treatment naïve and experienced patients aged ≥ 18 years Setting: 28 sites in 13 countries, including the US

The following two in combination with at least 2 NRTIs and/or NNRTIs (as selected by the treating physician):

IDV/r 800/100 mg twice daily o N = 158

SQV/r 1000/100 mg twice daily o N = 148

Follow‐Up: 48 weeks Conducted: September ‘00 – March ‘01

Primary Endpoint: Difference in the rate of virologic failure between both arms (defined based on the patient’s viral load upon inclusion)

IDV/r vs SQV/r = 2.2% (95% CI ‐2.8–7.2%), p = NS

Grade 3‐4 adverse events were experienced by the following percentage of patients in each arm:

IDV/r = 41% SQV/r = 24%

o P = 0.001 Patients in the IDV/r arm experienced more renal, dermatological, and gastrointestinal severe adverse effects than those in the SQV/r arm.

Kirk et al, 2003121 Randomized, controlled, open‐label trial

233 PI‐ and NNRTI‐naïve patients about to initiate their first HAART regimen Setting: Denmark

The following two in combination two NRTIs:

SQV/r 400/400 mg twice daily o N = 115

NFV/NVP 1250/200 mg twice daily o N = 118

Follow‐Up: 48 weeks Conducted: January 1998 – January 2001

Primary Endpoint: Comparison of the proportion of patients with HIV1‐RNA ≤ 20 copies/mL at week 48

SQV/r = 56% NFV/NVP = 69%

o P = 0.037

The following percentage of patients switched therapy based on adverse events:

SQV/r = 73% NFV/NVP = 80%

o P = 0.99 The most limiting adverse event in both groups was gastrointestinal events. Skin reactions and allergy were significantly more common in the NFV/NVP arm.

62



Fischl et al, 2003140 Randomized, open‐label study

517 Persons with advanced human immunodeficiency virus (HIV) disease and little to no experience with ART

Subjects received lamivudine (150 mg) and zidovudine (300 mg) twice daily along with

Indinavir (IDV) 800 mg three times daily (n = 168)

efavirenz 600 mg once daily plus indinavir 1000 mg three times daily (EFV/IDV, n = 173)

nelfinavir 1250 mg twice daily plus indinavir 1000 mg twice daily (NFV/IDV, n = 176)

Follow‐up: 2.1 years

Virologic failure

EFV/IDV < IDV, p = 0.04 NFV/IDV > IDV, p = 0.006

Adverse event rate

EFV/IDV = NFV/IDV = IDV

The most frequent grade 3 or 4 signs or symptoms reported were aches or pains, fatigue, or gastrointestinal complaints (nausea, vomiting, and diarrhea)

Gathe et al, 2002120 Phase III, open‐label, multi‐center, randomized, non‐inferiority study

649 Treatment naïve patients aged ≥18 years with HIV1‐RNA ≥ 1,000 copies/mL Setting: 101 centers in North America, Europe, South Africa, and Australia

The following two in combination with abacavir and lamivudine twice daily:

FPV/r 1400/200 mg daily o N = 322

NFV 1250 mg twice daily o N = 327

Follow‐Up: 48 weeks

Primary Endpoint: Comparison of the magnitude and durability of virologic response over 48 weeks HIV1‐RNA < 400 copies/mL

FPV/r = 69% NFV = 68%

o 1% (95% CI ‐6–8%) o Considered non‐inferior

HAV1‐RNA < 50 copies/mL

FPV/r = 55% NFV = 53%

Grade 2‐4 adverse events were experienced by the following percentage of patients in each arm:

FPV/r = 41% NFV = 39% Diarrhea was significantly more common in the NFV arm.

Kirk et al, 200189 Prospective, observational, multicenter cohort study

2708 HIV‐infected patients older than 16 years

HAART with > 3 drugs including:

Indinavir (n = 1342) Ritonavir (n = 556) Saquinavir (n = 810) Median follow‐up: 30 months

Proportion of patients who had experienced clinical progression at 12 months

Indinavir: 9.2% Ritonavir: 11.9% 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

Not reported

63



Gulick et al, 2000122 Prospective, randomized, 2x3 factorial, multicenter study

277 NNRTI treatment naïve patients

Delavirdine and/or Adefovir in combination with

SQV/r (n = 139) SQV/NFV (n = 138) Duration: 16 weeks

Virologic Response (<500 HIV RNA copies/mL)

SQV/r: 28% SVQV/NFV: 33%, p = NS

Adverse event rate

SQV/r = SQV/NLV, p = 0.07

Katzenstein et al, 1999124 Randomized, open‐label, multicenter comparative study

318 Patients ⩾ 18 years old with documented HIV infection and 0–13 days prior use of PIs

Two NRTIs in combination with:

Indinavir 800 mg three times daily (n = 107)

Ritonavir 600 mg twice daily (n = 107)

Saquinavir/r 400/600 mg twice daily (n = 104)

Follow‐up: up to 72 weeks

⩽20 HIV RNA copies/mL at 72 weeks

Indinavir: 51% Ritonavir: 41% Saquinavir/r: 58% Saquinavir/r > Ritonavir, p < 0.05 Virus loads of ⩽20 copies/mL at 72 weeks

Indinavir: 63% Ritonavir: 55% Saquinavir/r: 77%, p = NS Treatment success rate

Indinavir: 52% Ritonavir: 41% Saquinavir/r: 58%, p = NS

Adverse‐event discontinuation rate:

Indinavir: 27% Ritonavir: 68% Saquinavir/r: 33%, p < 0.001

Renal adverse reactions were most common among patients receiving indinavir, whereas gastrointestinal and neurologic adverse reactions were more often experienced by patients receiving ritonavir.

Cohen Stuart et al, 1999126 Randomized, open label, multicenter study

70 Patients who were antiretroviral‐naive and who had a CD4 cell count < 500 x 10(6)/I and/or > 10000 HIV RNA copies/ml plasma and/or HIV‐related symptoms

ART with zidovudine 200 mg three times per day plus lamivudine 150 mg twice per day plus either

Indinavir 800 mg three times daily (n = 35)

Saquinavir 1200 mg three times daily (n = 35)

Follow‐up 24 weeks

Decrease in HIV RNA

Indinavir = Saquinavir Increase in CD4 cell counts

Indinavir < Saquinavir, p = 0.01

Overall adverse event rate:

Indinavir = Saquinavir Discontinuation rate:

Indinavir = Saquinavir

Treatment experienced patients

64



Antoniou et al, 2010127 Multicenter, retrospective cohort study

85 Patients with multidrug resistant HIV

Tipranavir/ritonavir (TPV/r; n = 38) Darunavir/ritonavir (DRV/r; n = 47)

Virologic Response (viral load < 50 copies/mL)

TPV/r: 82% DRV/r: 79%, p = NS Sustained virologic suppression (2 or more sequential viral load results below 50 copies/mL)

TPV/r: 74% DRV/r: 72%, p = NS

Adverse event rate

TPV/r = DRV/r

Johnson et al, 2005 128 & Johnson et al, 2006 141 Multi‐center, open‐label, randomized non‐inferiority trial

358 Treatment experienced patients aged ≥16‐18 years (legal minimum age as locally required) that had failed ≥ 2 HAART regimens that included one or more NRTI and PI and had previously responded to at least 1 HAART regimen with a 1 log10 copies/mL viral load reduction or a viral load decline to < 400 copies/mL Setting: Europe and North and South America

The following in combination with tenofovir 300mg daily and one NRTI:


ATV/SQV 400/1200 mg daily o N = 115

LPV/r 400/100 mg twice daily o N = 123

Follow‐Up: 48 weeks Conducted: April ’05 – September ‘06

Primary Endpoint: Comparison of the magnitude and durability of viral load reduction from baseline based on the timed average difference through week 48 and 96 Week 48

ATV/r vs LPV/r = 0.13 log10 copies/mL (97.5% CI ‐0.12–0.39); non‐inferior

ATV/SQV vs LPV/r = 0.33 log10 copies/mL (97.5% CI 0.07–0.60); inferior

Week 96

ATV/r vs LPV/r = 0.14 log10 copies/mL (97.5% CI ‐0.13–0.41), non‐inferior

Secondary Endpoint: Mean change of HIV1‐RNA from baseline to week 48 and 96 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

Grade 2‐4 adverse events Week 48:

ATV/r = 29% ATV/SQV = 26% LPV/r = 25% Week 96:

ATV/r = 13% LPV/r = 11%

65



Haas et al, 2003129 Randomized, multinational pilot trial

85 Treatment experienced patients having at least 1000 HIV‐1 RNA copies/ml, 100 x 106 CD4 cells/l (75 x 106 cells/l without AIDS diagnosis) and virologic response to a prior regimen

Two NRTIs in combination with:

ATV/SQV 400/1200 mg once daily (n = 34)

ATV/SQV 600/1200 mg once daily (n = 28)

r/SQV 400 mg/400 mg twice daily (n = 23)

Duration: 48 weeks

Primary Endpoint: Assess safety and tolerability Secondary Endpoints: Mean change in HIV1‐RNA, viral load and CD4+ T cell count Virologic response (> 1.0 log(10) decrease HIV‐1 RNA or HIV‐1 RNA < 400 copies/ml):

ATV 400 mg = 41%

ATV 600 mg = 29%

r = 35%; p = NS

Adverse‐event discontinuation rate:

ATV 400 mg = 9%

ATV 600 mg = 11%

r = 30%; p = NS Mean change in low‐density cholesterol

ATV 400 mg = ‐0.6%

ATV 600 mg = ‐6.7%

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, 2001131 Prospective, multicenter, randomized open trial

31 Patients age > 18 with HIV and previous PI exposure > 6 months, unchanged HAART > 3 months, and viral load > 3 log

NRTIs in combination with:

r/SQV 200/600 mg twice daily (n = 16)

NFV/SQV 1000/600 mg twice daily (n = 15)

Duration: 3 months

Plasma viral load stabilization or decrease >/= 0.5 log

r/SQV: 10 NFV/SQV: 8

Not reported

Para et al, 2000132 Multicenter, randomized, phase II, open‐label trial

89 Patients age > 18 with HIV‐1 infection

ARV therapy including

SQV 1200 mg every 8 hours (n = 59)

IDV 800 mg every 8 hours (n = 30) Follow‐up: 24 weeks

Achieved viral RNA level of <500 copies/mL

SQV: 4‐8% IDV: 49%; p < 0.001

Not reported

66



Roca et al, 2000130 Randomized, open‐label, prospective study.

112 Patients with HIV and CD4 cell count below 500 × 106/l or HIV RNA plasma level > 5000 copies/ml

Art with stavudine 40 mg (30 mg if weight < 60 kg) twice daily and lamivudine 150 mg twice daily with

IDV 800 mg three times daily (n = 56)

NFV 750 mg three times daily (n = 56)

Median duration of follow‐up: 9 months

CD4+ Call increase > 100/mL

IDV: 42% NFV: 35%, p = NS HIV RNA level below limit of detection

IDV: 46% NFV: 47%, p = NS

Frequency of treatment‐related side effects

IDV: 54% NFV: 46%, p = NS Treatment‐related discontinuation rate

IDV: 60% NFV: 38%, p < 0.05

Pediatric patients Rodriguez‐French et al, 2004134 Multi‐center, open‐label, randomized study

249

Treatment naïve patients aged ≥13‐18 years (legal minimum age as locally required) with HIV1‐RNA ≥ 5,000 copies/mL Setting: US, Puerto Rico, Panama, and South Africa

The following two in combination with abacavir 300mg and lamivudine 150mg twice daily:

FPV 1400 mg twice daily o N = 166

NFV 1250 mg twice daily o N = 83

Follow‐Up: 48 weeks Conducted: November ‘00 – July ‘01

Primary Endpoint: Comparison of the efficacy and durability of the antiviral response (HIV1‐RNA < 400 copies/mL) at 48 weeks

FPV = 66% NFV = 51%

Adverse events of at least grade 2 in severity were experienced by the following percentage of patients:

FPV = 30% NFV = 34% Diarrhea was more common in the NFV arm. 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}

68

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}

69

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}

70

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}

71

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}

72

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}

hiv drug class review - utah department of health medicaid revie… · hiv/aids disease staging...

Documents