A RANDOMIZED, DOUBLE-BLIND TRIAL COMPARING COMBINATIONS OF NEVIRAPINE, DIDANOSINE, AND ZIDOVUDINE FOR HIV-INFECTED PATIENTS - THE INCAS TRIAL

Context.-Current guidelines recommend that individuals infected with t he human immunodeficiency virus type 1 (HIV-1) be treated using combin ations of antiretroviral agents to achieve sustained suppression of vi ral replication as measured by the plasma HIV-1 RNA assay, in the hope s of achieving prolonged remission of the disease, However, until rece ntly, many drug combinations have not led to sustained suppression of HIV-1 RNA. Objective.-To compare the virologic effects of various comb inations of nevirapine, didanosine, and zidovudine. Design.-Double-bli nd, controlled, randomized trial. Setting.-University-affiliated ambul atory research clinics in Italy, the Netherlands, Canada, and Australi a (INCAS). Patients.-Antiretroviral therapy-naive adults free of the a cquired immunodeficiency syndrome with CD4 cell counts between 0.20 an d 0.60 x 10(9)/L (200-600/mu L). Intervention.-Patients received zidov udine plus nevirapine (plus didanosine placebo), zidovudine plus didan osine (plus nevirapine placebo), or zidovudine plus didanosine plus ne virapine. Main Outcome Measure.-Plasma HIV-1 RNA. Results.-Of the 153 enrolled patients, 151 were evaluable, At week 8, plasma HIV-1 RNA lev els had decreased by log 2.18, 1.55, and 0.90 in the triple drug thera py, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.05). The proportions of patients with plasma HIV-1 R NA levels below 20 copies per milliliter at week 52 were 51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and zidovu dine plus nevirapine groups, respectively (P<.001). Viral amplificatio n was attempted in 59 patients at 6 months. Viral isolation was unsucc essful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients i n the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively. Among patients from whom virus c ould be amplified, resistance to nevirapine was found in all 11 patien ts receiving zidovudine plus nevirapine and in all 5 patients receivin g triple drug therapy, Rates of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51) for the zidovudine plus nevirapin e, zidovudine plus didanosine, and triple drug therapy groups, respect ively (P=.08). Conclusions.-Triple drug therapy with zidovudine, didan osine, and nevirapine led to a substantially greater and sustained dec rease in plasma viral load than the 2-drug regimens studied, Our resul ts also suggest that suppression of viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of quantit ation of the most sensitive test available, may at least forestall the development of resistance.