Clinical trials of HIV antiretroviral therapy: Protease inhibitors
- Paul E Sax, MD
Paul E Sax, MD
- Clinical Director, Division of Infectious Diseases
- Brigham and Women's Hospital
- Professor of Medicine
- Harvard Medical School
The widespread use of combination antiretroviral therapy using nucleoside reverse transcriptase inhibitors (NRTIs) and a protease inhibitor (PI) dramatically improved the prognosis for people living with HIV . With the potent PIs ritonavir and indinavir, clinical trials demonstrated survival advantages for use of these drugs compared with regimens that consisted only of NRTIs [2,3]. Since the FDA approval in 1995 of saquinavir, many additional protease inhibitors have been developed with varying efficacy and adverse event profiles.
This topic will review the major clinical trials comparing protease inhibitors currently in common use: saquinavir, nelfinavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and darunavir. As neither indinavir nor full dose ritonavir are presently preferred options for therapy in any clinical setting, studies evaluating their efficacy, safety, and tolerability will not be reviewed further here.
A discussion of the relative advantages and disadvantages of the different drugs and the clinical context where they may be best utilized is presented elsewhere. (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient" and "Overview of antiretroviral agents used to treat HIV".)
Details about pharmacology, dosing and side effect profiles, as well as "pharmacokinetic boosting" with ritonavir are discussed elsewhere (see "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'). Clinical trial information regarding other classes of HIV drugs is addressed within their respective topics.
Antiretroviral therapy (ART) generally consists of at least three active antiretroviral medications. In treatment-naïve patients, this consists of two NRTIs (sometimes referred to as the "backbone") and a third drug, either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. The selection of specific antiretroviral regimens is discussed elsewhere. (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient".)
- Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853.
- Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998; 351:543.
- Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337:725.
- Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002; 346:2039.
- Kempf DJ, King MS, Bernstein B, et al. Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J Infect Dis 2004; 189:51.
- 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 2004; 18:1529.
- Eron J Jr, Yeni P, Gathe J Jr, et al. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet 2006; 368:476.
- Smith K, Weinberg W, DeJesus E, et al. Once-daily ritonavir (100 mg) boosting of fosamprenavir (FPV/r) or atazanavir (ATZ/r) with tenofovir (TDF)/emtricitabine (FTC) in antiretroviral-naïve HIV-infected patients: 48-week safet/efficacy results from COL103952 (ALERT) [Abstract WEPEB023]. Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, 2007.
- 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 2008; 372:646.
- Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr 2010; 53:323.
- 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 2008; 22:1389.
- 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 2009; 23:1679.
- Raffi F, Ward D, Ruxrungtham K, et al. Saquinavir/ritonavir BID vs lopinavir/ritonavir BID plus emtricitabine/tenofovir QD as initial therapy in HIV-1-infected patients: the Gemini Study 24-week interim analysis. Presented at the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia abstract # WePeB027.
- Walmsley S, Ruxrungham K, Slim J, et al. Saquinavir (QV/r) BID versus lopinavir (LPV/r) TWICE DAILY, plus emtricitabine/tenofovir (FTC/TDF) qD as initial therapy in HIV-infected patients; the GEMINI study (Abstract PS/4). 11th European AIDS Conference, Madrid, 2007.
- Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008; 358:2095.
- Johnson M, Grinsztejn B, Rodriguez C, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 2005; 19:685.
- Gathe J, Cooper DA, Farthing C, et al. Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial. Clin Infect Dis 2006; 43:1337.
- Cahn P, Villacian J, Lazzarin A, et al. Ritonavir-boosted tipranavir demonstrates superior efficacy to ritonavir-boosted protease inhibitors in treatment-experienced HIV-infected patients: 24-week results of the RESIST-2 trial. Clin Infect Dis 2006; 43:1347.
- Naeger LK, Struble KA. Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. AIDS 2007; 21:179.
- Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 2007; 21:395.
- Haubrich R, Berger D, Chiliade P, et al. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS 2007; 21:F11.
- De Meyer S, Hill A, De Baere I, et al. Effect of baseline susceptibility and on-treatment mutations of TMC114 and control PI efficacy: preliminary analysis of data from PI-experienced patients form POWER 1 and POWER 2. Presented at the 13th annual Conference on Retroviruses and Opportunistic Infections, Denver, CO, February 5-8th, 2006; abstract #157.
- Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 2007; 369:1169.
- Molina JM, Cohen C, Katlama C, et al. Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients: 24-week results of POWER 3. J Acquir Immune Defic Syndr 2007; 46:24.
- Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 2007; 370:49.
- De Meyer S, Lathouwers E, Dierynck I, et al. Characterization of virologic failure patients on darunavir/ritonavir in treatment-experienced patients. AIDS 2009; 23:1829.
- De Meyer SM, Spinosa-Guzman S, Vangeneugden TJ, et al. Efficacy of once-daily darunavir/ritonavir 800/100 mg in HIV-infected, treatment-experienced patients with no baseline resistance-associated mutations to darunavir. J Acquir Immune Defic Syndr 2008; 49:179.
- GENERAL PRINCIPLES
- Abbreviations used
- TREATMENT-NAIVE PATIENTS
- Lopinavir versus nelfinavir
- Fosamprenavir versus nelfinavir (SOLO study)
- Fosamprenavir versus lopinavir (KLEAN study)
- Fosamprenavir versus atazanavir (ALERT trial)
- Atazanavir versus lopinavir (CASTLE)
- Darunavir versus lopinavir (ARTEMIS)
- Saquinavir versus lopinavir (GEMINI study)
- Summary of selection of PIs in the treatment-naive patient
- TREATMENT-EXPERIENCED PATIENTS
- Atazanavir/r versus atazanavir/saquinavir versus lopinavir/r
- Tipranavir versus optimized regimen (RESIST-1 and RESIST-2)
- Darunavir versus optimized therapy (POWER trials)
- Darunavir versus lopinavir (TITAN)
- SUMMARY AND RECOMMENDATIONS
- Treatment-naive patients
- Treatment-experienced patients