In patients with human immunodeficiency virus (HIV) infection, combined treatment with several agents may increase the effectiveness of antiviral therapy. We studied the safety and efficacy of saquinavir, an HIV-protease inhibitor, given with one or two nucleoside antiretroviral agents, as compared with the safety and efficacy of a combination of two nucleosides alone.

In this double-blind trial, patients with HIV infection were randomly assigned to receive either saquinavir (1800 mg per day) plus both zidovudine (600 mg per day) and zalcitabine (2.25 mg per day) or zidovudine plus either saquinavir or zalcitabine. The 302 patients enrolled had CD4+ counts of 50 to 300 cells per cubic millimeter and had previously received zidovudine for a median of 27 months. The study lasted 24 weeks, with an optional double-blind extension period of an additional 12 to 32 weeks.

Ninety-six percent of the patients completed the 24-week study. In all three treatment groups, CD4+ cell counts rose at first and then fell gradually. The normalized area under the curve for the CD4+ cell count was greater with the three-drug combination than with either saquinavir and zidovudine (P = 0.017) or zalcitabine and zidovudine (P<0.001). There were significantly greater reductions in plasma HIV with the three-drug combination than with the other regimens when peripheral-blood mononuclear cells were cultured for HIV and HIV RNA was assessed, and there were greater decreases in serum neopterin and beta₂-microglobulin levels. There were no major differences in toxic effects among the three treatments.

Treatment with saquinavir, zalcitabine, and zidovudine was well tolerated. This drug combination reduced HIV-1 replication, increased CD4+ cell counts, and decreased levels of activation markers in serum more than did treatment with zidovudine and either saquinavir or zalcitabine. Studies are warranted to evaluate whether the three-drug combination will reduce morbidity and mortality.