ObjectiveTo assess the efficacy and tolerability of a triple nucleoside reverse transcriptase inhibitor combination of zidovudine, lamivudine, and didanosine therapy.DesignA randomized open-label trial.PatientsAntiretroviral-naive HIV-infected patients with CD4+cell counts of 100 to 500 cells/&mgr;l.MethodsA total of 106 patients were randomly assigned to 300 mg of zidovudine (200 mg for body weight <60 kg) twice daily plus 150 mg of lamivudine twice daily plus 200 mg of didanosine (125 mg for body weight <60 kg) twice daily (n= 53) or to zidovudine plus lamivudine (n= 53) for 48 weeks.Main Outcome MeasuresDegree and duration of reduction of HIV-1 RNA load and increase in CD4+cell counts from baseline and development of drug-related toxicities.ResultsAt 48 weeks, triple drug therapy showed greater declines in plasma HIV-RNA levels from the beginning of treatment than double drug therapy (1.86 vs. 1.15 log10copies/ml, respectively;p< .001). The proportions of patients with HIV-RNA <50 copies/ml in an intention-to-treat analysis were 54.7% (29 of 53 patients) and 11.3% (6 of 53 patients) in the triple and double drug therapy, respectively (p= .001). There was no significant difference in increase of CD4 count.ConclusionTriple drug therapy with zidovudine, lamivudine, and didanosine was significantly more effective in inducing sustained immunologic and virologic responses than the double combination of zidovudine and lamivudine.