Is a four-drug regimen any more effective than the current three-drug standard? Not according to a recent study reviewed at the XVI International AIDS Conference in Toronto.

“We saw no differences over three years between a four-drug regimen and a three-drug regimen in terms of decreasing viral load, increasing CD4 cells (T cells), or side effects,” said Roy Gulick, MD, MPH, of Weill Cornell Medical College in New York.

“These findings suggest that current triple-drug therapies continue to perform remarkably well for the large majority of patients,” according to Dr. Gulick. “For these patients, adding a fourth drug provided no added benefit.”

The findings, based on an AIDS Clinical Trials Group study involving 765 HIV-positive people, were recently published in the Journal of the American Medical Association (JAMA) and were reviewed by Dr. Gulick at a press briefing sponsored by the American Medical Association on Sunday in Toronto.

Dr. Gulick explained the rationale for conducting this study. “Researchers initially discovered that two drugs together worked better than one, and then that three-drug regimens worked better than two-drug regimens,” he said. “With each additional medication, we saw decreased progression to AIDS and decreased deaths. However, an open question was whether four drugs would work better than three.”

In this randomized, double-blind, placebo-controlled study, approximately half of the patients – all of whom were starting therapy for the first time – received a triple-drug regimen consisting of Sustiva® (efavirenz) plus the two-drug combination tablet Combivir® (containing zidovudine and lamivudine). The other half of the patients took a four-drug regimen consisting of Sustiva plus the three-drug combination tablet Trizivir® (containing zidovudine, lamivudine, and abacavir). “Whether you got the three- or four-drug regimen, you still took the same number of pills per day. That means the four-drug regimen was no more complicated than standard triple therapy.”

Dr. Gulick and his colleagues looked at three important parameters during the three-year study period: time to virologic failure (i.e., a rebound in viral load), changes in CD4 counts, and serious side effects.

As reviewed by Dr. Gulick, 26% of participants on the three-drug combo reached virologic failure, compared to 25% of those on the four-drug combo. The average time to virologic failure was also similar between the two groups.

After three years of treatment, approximately 85% of patients in the three-drug group had viral loads below 50, compared to 88% of those in the four-drug group.

There was also no significant difference between the two treatment arms in terms of CD4 counts or the incidence of side effects.

Why doesn’t adding a fourth drug seem to matter? According to Dr. Gulick, “it seems that our current triple-drug therapies are already so effective that it’s just hard to improve on that. In that sense, we’re doing incredibly well.” However, he explained that there are many exceptions to the rule. “Some patients with HIV do take a fourth medication,” he said. “Even five- or six-drug regimens are not unheard of in patients with past treatment experience.”

Gulick RM, Ribaudo HJ, Shikuma CM, et al. Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection. JAMA 296(7):769-81, 2006.