ACTG 320: Triple-Drug Combination Antiretroviral Therapy

The Vancouver conference in 1996 had generated conviction based largely on open-label cohort data and viral kinetics. Convincing as those results were to many virologists, they did not constitute a randomized trial. Clinicians who wanted to prescribe triple therapy to every patient with advanced HIV needed controlled evidence, and the ACTG 320 trial was designed to provide it.

AIDS Clinical Trials Group Protocol 320 enrolled 1,156 adults who had taken zidovudine but never lamivudine or a protease inhibitor, all with CD4 counts of 200 cells per cubic millimeter or fewer, a group at high near-term risk of progression. Participants were randomized to zidovudine (or stavudine) and lamivudine with or without indinavir, a protease inhibitor the FDA had approved in March 1996. Patients were stratified by CD4 count, 50 or fewer versus 51 to 200, and the primary endpoint was time to AIDS or death. Scott Hammer was the first author of the report, and Margaret Fischl of the University of Miami was its senior author.

The results appeared in the New England Journal of Medicine on September 11, 1997. In the indinavir arm, 6 percent of patients had reached the primary endpoint versus 11 percent in the two-nucleoside arm, a hazard ratio of 0.50. Mortality was 1.4 percent versus 3.1 percent, a hazard ratio of 0.43. Both differences were statistically significant. The effect was similar in both CD4 strata, and CD4 counts and plasma HIV RNA moved in step with the clinical results.

NIAID describes ACTG 320 as one of the studies that established the efficacy of triple-drug therapy. Adding a drug from a new class to a two-drug backbone lowered the death rate, not only viral load, and the trial showed that patients changing treatment did better when two new drugs were added than when one was.

Treatment advice moved quickly. In June 1997 the International AIDS Society-USA panel, whose members included Hammer and Fischl, wrote that new data gave a stronger rationale for starting more aggressive therapy earlier, and in April 1998 treatment guidelines from a Department of Health and Human Services panel were published in the CDC's MMWR. The CD4 threshold for starting treatment then moved up and down for years; US guidelines dropped it in 2013, and randomized trials settled the question in 2015.