Infectious Disease · 1997
ACTG 320: Triple-Drug Combination Antiretroviral Therapy
AIDS Clinical Trials Group Protocol 320
The Vancouver conference in July 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 patients at multiple centers across the United States, selecting for CD4 counts below 200 cells per cubic millimeter to ensure a population at high near-term risk of progression. Participants were randomized to zidovudine and lamivudine with or without indinavir, a protease inhibitor that had received accelerated approval from the FDA the previous year. The study was double-blind and placebo-controlled, with a primary endpoint of time to AIDS-defining illness or death. Roy Gulick led the trial; John Mellors contributed the viral load methodology that allowed investigators to track HIV RNA as a secondary measure.
The data safety monitoring board stopped the trial after a median of 38 weeks. In the indinavir arm, 6 percent of patients had reached the primary endpoint versus 11 percent in the two-nucleoside arm. Mortality was 1.4 percent versus 3.1 percent. Both differences were statistically significant. The viral load data showed that the three-drug regimen was also substantially more likely to suppress HIV RNA below the limit of detection, a finding that would later become central to treatment guidelines as suppression became the explicit therapeutic target.
The trial's design established a template. Showing that adding one new active drug class to an existing backbone produced a measurable survival benefit validated the concept of combination therapy and set the standard for how subsequent antiretroviral regimens would be evaluated: each new drug or class had to demonstrate added benefit over the current best available regimen, not just over placebo.
ACTG 320 also accelerated the regulatory and clinical response. The FDA used the data in reviewing additional protease inhibitors and, later, other drug classes. Guidelines from the Department of Health and Human Services and the International AIDS Society updated within the year to recommend triple therapy as the standard of care for patients meeting the trial's enrollment criteria. Within five years, that recommendation had expanded to cover virtually all treatment-naive patients regardless of CD4 count.
Key People
- Roy Gulick — Principal investigator, ACTG 320
- John Mellors — Co-investigator; contributed viral load methodology to the trial
- Michael Fischl — Miami HIV clinician, senior ACTG investigator and co-author
- Douglas Richman — UCSD virologist who contributed resistance analysis to the trial
N Engl J Med. 1997;337(11):725-733
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