Antiretroviral therapy that consists of a combination of two nucleoside analog reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor has been shown to suppress viral load in patients with human immunodeficiency virus (HIV) infection. The success of this combination therapy has prompted its endorsement by the International AIDS Society–USA and the U.S. Department of Health and Human Services as the preferred treatment for HIV infection. However, 30 to 66 percent of patients whose therapy includes protease inhibitor–containing antiretroviral regimens fail to maintain viral suppression. A possible explanation is that sequential or simultaneous initiation of the three-drug regimen results in incomplete viral suppression. Gulick and colleagues conducted a multicenter, randomized, double-blind study to compare the antiretroviral effect of a three-drug regimen started simultaneously or sequentially in patients with established HIV infection.

Ninety-seven patients with HIV infection were initially randomized to receive indinavir alone, a combination of zidovudine and lamivudine, or all three drugs for 52 weeks. However, when the three-drug regimen proved to be superior in a preliminary analysis, the study was amended, and all patients were offered the three-drug regimen after 24 weeks. After at least 100 weeks from the time of initial randomization, the effects of the three-drug therapy were compared among the groups. Changes in each patient's HIV RNA level and CD4 cell count were recorded periodically for 100 weeks and compared with baseline characteristics.

The group that originally received the three-drug therapy experienced a median decrease in serum HIV RNA levels of 2.0 log10 after eight weeks, a level that was sustained through the entire 100-week study period. CD4 cell counts at 100 weeks also increased in this group, with a median increase of 0.209 per mm³ (0.209 × 10⁹ per L). Patients who originally received indinavir alone experienced a median decrease in HIV RNA levels of 1.4 log₁₀ and a median increase in CD4 cell count of only 0.163 per mm³ (0.163 × 10⁹ per L). Patients who originally received zidovudine and lamivudine experienced a median decrease in HIV RNA levels of 1.3 log₁₀ at week 100, and a median increase in CD4 cell count of 0.101 per mm³ (0.101 × 10⁹ per L). Seventy-eight percent of the simultaneous-initiation group experienced a reduction in viral load to less than 500 copies per mL, compared with only 30 to 45 percent of patients in the sequential initiation groups.

The authors conclude that their study supports current guidelines recommending simultaneous introduction of at least two or, preferably, three antiretroviral agents, one of which is a protease inhibitor, for the greatest degree of viral suppression in patients with HIV infection. This three-drug regimen is also recommended when changing a failing antiretroviral therapy course. Sequential initiation of the three drugs is much less effective than simultaneous introduction.