Dual vs single protease inhibitor therapy following antiretroviral treatment failure - A randomized trial

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 saquina.. vir (n=116); indinavir (n=69); nelfinavir (n=139); or placebo twice per day (n=157); in combination with amprenavir, abacavir, efavirenz, and adefovir dipivoxii,., 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% [116/270] 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% Cl, 0.09-0.87; P=.03). Conclusions In this study of anti retroviral-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.