TREATMENT OF HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION WITH SAQUINAVIR, ZIDOVUDINE, AND ZALCITABINE

Background. In patients with human immunodeficiency virus (HIV) infect ion, combined treatment with several agents may increase the effective ness of antiviral therapy. We studied the safety and efficacy of saqui navir, an HIV-protease inhibitor, given with one or two nucleoside ant iretroviral agents, as compared with the safety and efficacy of a comb ination of two nucleosides alone. Methods. 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 c ells per cubic millimeter and had previously received zidovudine for a median of 27 months. The study lasted 24 weeks, with an optional doub le-blind extension period of an additional 12 to 32 weeks. Results. Ni nety-six percent of the patients completed the 24-week study. In all t hree treatment groups, CD4+ cell counts rose at first and then fell gr adually. The normalized area under the curve for the CD4+ cell count w as greater with the three-drug combination than with either saquinavir and zidovudine (P=0.017) or zalcitabine and zidovudine (P<0.001). The re were significantly greater reductions in plasma HIV with the three- drug combination than with the other regimens when peripheral-blood mo nonuclear cells were cultured for HIV and HIV RNA was assessed, and th ere were greater decreases in serum neopterin and beta(2)-microglobuli n levels. There were no major differences in toxic effects among the t hree treatments. Conclusions. Treatment with saquinavir, zalcitabine, and zidovudine was well tolerated. This drug combination reduced HIV-1 replication, increased CD4+ cell counts, and decreased levels of acti vation markers in serum more than did treatment with zidovudine and ei ther saquinavir or zalcitabine. Studies are warranted to evaluate whet her the three-drug combination will reduce morbidity and mortality.