Medscape Awards in Infectious Diseases: Most Important Antiviral Agent

John G. Bartlett, MD


June 12, 2013

Pivotal AZT Trials

Of the more than 250,000 publications involving HIV infection listed in PubMed, 2 are arguably the most important in launching antiviral therapy in what has now become one of the great medical achievements of the 20th century: the 1987 AZT trial[8] that first demonstrated the potential use of chemotherapy for a retroviral infection, and ACTG 076,[5] the first trial to show that an antiretroviral drug could prevent perinatal HIV transmission.

The AZT trial for FDA approval was a double-blind, placebo-controlled trial of patients with HIV infection who were randomly assigned to receive AZT (250 mg every 4 hours) or placebo. Much of the background work on the drug showing in vitro activity in a CD4 cell model was conducted by the National Cancer Institute's Sam Broder, Mitch Mitsuya, and Robert Yarchoan.[9,10] The study was stopped prematurely at 19 weeks, when interim analysis with 282 participants showed 19 deaths in placebo recipients vs 1 death in an AZT recipient (P<.001) (Table).

Table. Placebo-Controlled Trial of AZT for Patients With AIDS and AIDS-Related Complex: Interim Results[7]

Outcome AZT Placebo
Number of participantsa 145 137
Mean duration (days) 120 127
Deaths 1 19b
Opportunistic infections 24 45
Median CD4 count increase at 12 weeks (cells/mL) +40 -16b,c
Mean weight change at 16 weeks (kg) +2.0 -1.3b
AZT = azidothymidine
a Number who completed 24 weeks, 24; 16 weeks, 152; and 8 weeks, 282.
b P<.001.
c Median CD4 counts decreased in AZT recipients after 12 weeks.

The FDA approved AZT for AIDS and AIDS-related complex after a single trial. Only 152 patients had completed 16 weeks of treatment, and the time from start to finish was a record short 25 months. However, it was not without controversy; in fact, the chairman of the FDA Advisory Committee voted against approval because of concerns about limited data and substantial toxicity.[11] Then came the price tag from the supplier, Burroughs Wellcome: $8000 per year per patient in 1987 dollars (about $16,392 per year per patient in 2013 dollars). The new activist organization, ACT UP, "acted up," and the Health Resources and Services Administration responded by launching a special HIV-drug payment program known as the AIDS Drug Assistance Program (ADAP).

The next banner AZT study that changed HIV forever was ACTG 076, the trial showing that taking AZT during pregnancy prevented perinatal transmission.[5] This was a randomized, double-blind, placebo-controlled study of AZT or placebo given to treatment-naive pregnant women with CD4 counts > 200 cells/mL, plus AZT (2 mg/kg 4 times daily) given to the newborn for 6 weeks. The rate of HIV transmission was 8.3% in 180 AZT recipients vs 40% in 183 in the placebo group (P<.001).

Figure 2. Estimated number of perinatally acquired AIDS cases by year of diagnosis, 1985-2005, United States. Image courtesy of Centers for Disease Control and Prevention.

This was the first drug trial to show effective prevention of HIV transmission, establishing the standard of antiretroviral therapy for all HIV-infected pregnant women as a high priority in virtually all HIV programs in the world, and "076" became one of the most famous trials in medical history. Few antimicrobial trials dramatically change practice, but this one did, and the rate of perinatally transmitted HIV plummeted (Figure 2). Such a rapid alteration in practice based on a therapeutic trial is rare; in this case, it was greatly facilitated by federal legislation in May 1996 requiring a 50% or greater decrease in perinatal HIV infections or HIV testing of at least 95% of pregnant women. The penalty for noncompliance was loss of Title 2 Ryan White funding and mandatory HIV testing of pregnant women.[12]


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