Dual vs Single Protease Inhibitor Therapy Following Antiretroviral Treatment FailureA Randomized Trial

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Abstract
Research from JAMA — Dual vs Single Protease Inhibitor Therapy Following Antiretroviral Treatment Failure — A Randomized Trial — ContextManagement of antiretroviral treatment failure in patients receiving protease inhibitor (PI)–containing regimens is a therapeutic challenge.ObjectiveTo 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.DesignMulticenter, 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.SettingThirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States.ParticipantsA 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.InterventionSelectively 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 MeasuresPrimary 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.ResultsOf 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<.001). Baseline HIV-1 hypersusceptibility to efavirenz (≤0.4-fold difference in susceptibility compared with reference virus) was associated with suppression of viral load at 24 weeks to below 200 copies/mL (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P = .001), and more than 10-fold reduction in efavirenz susceptibility, with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P = .03).ConclusionsIn this study of antiretroviral-experienced patients with advanced immunodeficiency, viral load suppression to below 200 copies/mL was achieved in 31% of patients with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs, and baseline hypersusceptibility to efavirenz were associated with a favorable outcome.