Dual vs Single Protease Inhibitor Therapy Following Antiretroviral Treatment Failure: A Randomized Trial

• Published in: JAMA : the journal of the American Medical Association 2002-07, Vol.288 (2), p.169-180
• Main Authors: Hammer, Scott M, Vaida, Florin, Bennett, Kara K, Holohan, Mary K, Sheiner, Lewis, Eron, Joseph J, Wheat, Lawrence Joseph, Mitsuyasu, Ronald T, Gulick, Roy M, Valentine, Fred T, Aberg, Judith A, Rogers, Michael D, Karol, Cheryl N, Saah, Alfred J, Lewis, Ronald H, Bessen, Laura J, Brosgart, Carol, DeGruttola, Victor, Mellors, John W, for the AIDS Clinical Trials Group 398 Study Team
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacokinetics; Adenine - therapeutic use; Adult; Anti-HIV Agents - adverse effects; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral Therapy, Highly Active; Antiviral agents; Benzoxazines; Biological and medical sciences; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides - pharmacokinetics; Dideoxynucleosides - therapeutic use; Disease Progression; Double-Blind Method; Drug Resistance, Viral; Drug therapy; Female; HIV; HIV Infections - drug therapy; HIV Infections - immunology; HIV Protease Inhibitors - adverse effects; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - therapeutic use; Human immunodeficiency virus; Humans; Indinavir - pharmacokinetics; Indinavir - therapeutic use; Male; Medical research; Medical sciences; Nelfinavir - pharmacokinetics; Nelfinavir - therapeutic use; Organophosphonates; Oxazines - pharmacokinetics; Oxazines - therapeutic use; Pharmacology. Drug treatments; Proportional Hazards Models; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - pharmacokinetics; Reverse Transcriptase Inhibitors - therapeutic use; Saquinavir - pharmacokinetics; Saquinavir - therapeutic use; Sulfonamides - pharmacokinetics; Sulfonamides - therapeutic use; Treatment Failure; Viral Load
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.288.2.169

CONTEXT Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)–containing regimens is a therapeutic challenge. OBJECTIVE To assess whether adding a second PI improves antiviral efficacy of a 4-drug combination in patients with virologic failure while taking a PI-containing regimen. DESIGN Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled for second PI, conducted between October 1998 and April 2000, for which there was a 24-week primary analysis with extension to 48 weeks. SETTING Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States. PARTICIPANTS A total of 481 human immunodeficiency virus (HIV)–infected persons with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL. INTERVENTION Selectively randomized assignment (per prior PI exposure) to saquinavir (n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxil. MAIN OUTCOME MEASURES Primary efficacy analysis involved the proportion with viral load below 200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4 cell count from baseline, adverse events, and HIV drug susceptibility. RESULTS Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week 24. The proportions of patients with a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36% (25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35% [112/324] vs 23% [36/157], respectively; P = .002). Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor (NNRTI)–naive patients had a viral load below 200 copies/mL compared with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P