AZT Treats People with AIDS

Because of promising findings, the U.S. Food and Drug Administration ended a clinical trial of AZT early and released the experimental drug so that it could be prescribed to people with AIDS.

Date September, 1986

Locale Washington, D.C.

Key Figures

• Janet Rideout organic chemist and codiscoverer of AZT’s effectiveness in fighting HIV
• Samuel Broder research scientist, National Cancer Institute, who helped find AZT’s role in fighting HIV
• Hiroaki Mitsuya (b. 1950), research scientist, National Cancer Institute, who helped find AZT’s role in fighting HIV
• Robert Yarchoan (b. 1950), research scientist, National Cancer Institute, who helped find AZT’s role in fighting HIV
• Larry Kramer (b. 1935), playwright, novelist, and gay rights activist

Summary of Event

Azidothymidine, or AZT (now called zidovudine), was developed first during the 1960’s by scientists in the United States using National Cancer Institute (NCI) funding, and when many scientists thought that human cancers were caused by infectious agents (retroviruses). Consistent findings dispelled these beliefs, so research on AZT was stopped.

In 1985, NCI scientist Hiroaki Mitsuya published the first report of AZT’s successful effects against AIDS in humans. Mitsuya and colleagues Samuel Broder, Robert Yarchoan, and Burroughs-Wellcome chemist Janet Rideout, showed that AZT interferes with the functioning of the virus’s reverse transcriptase enzyme, an enzyme the virus needs if it is to insert its RNA into the DNA of the host cell. Scientists found that AZT does not destroy the AIDS virus per se. Rather, the drug incapacitates the virus’s reproductive capabilities, thus delaying disease progression. This was the first documented instance of the effectiveness of an antiretroviral medication in humans. Based on these data, and at Mitsuya’s urging, AZT was selected over other potential medication for continued study by NCI.

The early clinical trials of AZT for use against AIDS were sponsored jointly by NCI and the pharmaceutical company Burroughs-Wellcome (now GlaxoSmithKline). Initial, promising findings led to a larger, multisite, placebo-controlled trial of AZT in 282 patients who had either recently had pneumocystis carinii pneumonia or were diagnosed with AIDS-related complex (that is, had a compromised immune system and a history of multiple AIDS-defining illnesses). This study was to follow participants, each receiving either AZT or placebo, for twenty-four weeks, but to the pleasant surprise of scientists and people living with AIDS, the study was terminated several months ahead of schedule, in September of 1986.

An interim analysis of the data performed by an independent scientific advisory board showed promising but preliminary effects of AZT on mortality, with significantly greater short-term survival rates in the HIV-infected patients receiving AZT compared to placebo. Institutional ethics boards that oversee medical and behavioral research generally take the drastic step of stopping a trial early only when the trial shows unequivocal benefit or unacceptable toxicity. In this study, only one patient who received AZT had died, but there were nineteen deaths among patients receiving the placebo. Still, this step was particularly surprising since only 10 percent of the patients (27 of 282) had been observed for the full duration of the study. These strong results marked the first major success in the fight against AIDS.

One week later, the U.S. Food and Drug Administration (FDA) approved a plan to offer AZT to the study participants who had been receiving the placebo pills. Soon after the clinical trial was stopped, Burroughs-Wellcome purchased the AZT formula and filed for a patent in the United States. In January, 1987, more than three thousand HIV-infected individuals began receiving AZT.

With the recommendation of FDA scientists, as well as the support of the FDA’s independent Anti-Infective Drugs Advisory Committee, the agency officially approved AZT for use against AIDS in March, 1987, and then as a preventive treatment (for example, for hospital employees accidentally stuck by syringes containing HIV-infected blood) in 1990. In 1994, AZT was approved for use in HIV-infected pregnant women and in newborn babies of HIV-infected mothers.

Significance

Burroughs-Wellcome was granted a patent for AZT, giving the company a monopoly in the U.S. market and allowing the company to sell the drug for more than twelve times its production cost. Consumers and advocates were incensed. Generally, high drug prices reflect a pharmaceutical company’s attempt to recoup the cost of developing and testing a drug, but in this case, those initial costs were covered by taxpayers through NCI funding. Lawsuits that garnered heavy press coverage ensued, claiming that the AZT patent was invalid, but a U.S. federal appeals court in 1994 ruled in favor of the drug company.

In response to apathy from the U.S. government and from drug companies, gay activist Larry Kramer founded the AIDS Coalition to Unleash Power (ACT UP), which boasted tens of thousands of members, organized into 140 chapters worldwide at the organization’s peak in the late 1980’s. With the slogans “Silence = Death” and “Knowledge = Power,” ACT UP used extreme and radical measures to gain visibility and, in particular, to convince Burroughs-Wellcome to increase the availability of AZT and make it less expensive. Early tactics included a large protest at the New York Stock Exchange and a “die in” (where protesters sat in a city street during rush hour), which brought lower Manhattan traffic to a near standstill.

Despite the success of the initial study, later studies showed that AZT was having no positive effect against AIDS progression. A heated international debate ensued about whether AZT was helpful or a waste of time and money and whether it was causing more health problems than it prevents. With the rise of other antiretroviral medications, that controversy diminished, but not before it gave birth to the AIDS “rethinker” movement, which claims, in spite of overwhelming scientific evidence, that HIV does not cause AIDS. Led by biologist Peter Duesberg, AIDS “denialists” gained currency especially in the 1990’s in Africa, as government leaders used this movement to justify their positions to downplay the seriousness of the widespread AIDS epidemic in their countries.

AZT’s intense side effects and a complicated dosing schedule (for example, every four hours) meant that it was difficult to adhere to the drug regimen. Those taking the drug would end up developing a resistance to it, which would weaken the drug’s effectiveness over time. Eventually, virtually all persons with AIDS who were treated long term with AZT alone (called AZT monotherapy) developed an increased resistance to AZT through viral mutations. Using knowledge gained from the biological mechanism of AZT, however, scientists subsequently developed other drugs, and combination therapy would prove most effective at controlling, at least to some degree, the disease’s effects.

Bibliography

Barnes, D. M. “Promising Results Halt Trial of Anti-AIDS Drug.” Science 234 (1986): 15-16.

Duesberg, Peter H. Inventing the AIDS Virus. Washington, D.C.: Regnery, 1996.

Ezzell, Carol. “Hope in a Vial: Will There Be an AIDS Vaccine Anytime Soon?” Scientific American 186 (June, 2002): 38-45.

Fischl, M. A., D. D. Richman, M. H. Grieco, et al. “The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex: A Double-Blind, Placebo-Controlled Trial.” New England Journal of Medicine 317, no. 4 (1987): 185-191.

Kramer, Larry. Reports from the Holocaust: The Making of An AIDS Activist. New York: St. Martin’s Press, 1989.

Roleff, Tamara L., ed. AIDS: Opposing Viewpoints. San Diego, Calif.: Greenhaven Press, 2003.