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Management of antiretroviral treatment failure in patients receiving protease inhibitor (PI)-containing regimens is a therapeutic challenge.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.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.Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical Trials Units in the United States.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.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.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.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 (or = 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).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.

To the Editor. —Effective September 1987, the Centers for Disease Control added five diagnoses to the adult AIDS (acquired immunodeficiency syndrome) surveillance definition: (1) human immunodeficiency virus type 1 (HIV-1) encephalopathy; (2) disseminatedMycobacterium tuberculosis; (3) disseminated coccidioidomycosis; (4) wasting syndrome; and (5) recurrentSalmonellasepticemia.1 These additional diagnoses increased reported AIDS incidence and shortened time to AIDS in all risk groups, but particularly in those at risk through intravenous drug use and heterosexual contact.2There were other 1987 AIDS definition changes that eliminated laboratory confirmation for some AIDS-defining diagnoses, but these changes probably did not affect time to AIDS or caseload, since misdiagnosis was unlikely.3 The 1987 change in the AIDS definition could confound AIDS modeling with results based on the pre-1987 definition biased toward longer incubation times and fewer cases. When backcalculation is used to predict HIV-1/AIDS incidence based on historical AIDS diagnosis, adjustments for

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