Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial
Hammer, S.M.; Vaida, F.; Bennett, K.K.; Holohan, M.K.; Sheiner, L.; Eron, J.J.; Wheat, L.Joseph.; Mitsuyasu, R.T.; Gulick, R.M.; Valentine, F.T.; Aberg, J.A.; Rogers, M.D.; Karol, C.N.; Saah, A.J.; Lewis, R.H.; Bessen, L.J.; Brosgart, C.; DeGruttola, V.; Mellors, J.W.
JAMA 288(2): 169-180
2002
ISSN/ISBN: 0098-7484 PMID: 12095381 Document Number: 546771
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<.001). Baseline HIV-1 hypersusceptibility to efavirenz (ltoreq0.4-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). Conclusions: In 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.