Zidovudine - Successful HIV Treatment

Successful HIV Treatment

In May 1984, shortly after the human immunodeficiency virus (HIV) had been unambiguously proved as the cause of AIDS, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan of the United States National Cancer Institute (NCI) initiated a program to develop therapies for HIV/AIDS. Using a CD4+ cell line that they had made, they developed an assay to screen drugs for their ability to protect CD4+ T cells from being killed by HIV. This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells. In order to get drugs into the clinic as soon as possible, they started with compounds that were either in clinical use or for which they could get a pharmaceutical partner. As part of this effort, they initiated a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). Burroughs-Wellcome had expertise in nucleoside analogs and viral diseases, led by researchers including Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts were focused in part on the viral enzyme reverse transcriptase. Reverse transcriptase is an enzyme that retroviruses, including HIV, utilize to replicate themselves. One compound that they were working with (AZT), which they had given the code name "BW A509X", was tested and demonstrated remarkable efficacy against certain mouse viruses. However, the scientists at Burroughs-Wellcome were not working with HIV themselves, and sent 11 compounds to the NCI team for testing against HIV in their newly developed assay. In February 1985, the NCI scientists found that BW A509X, one of these compounds, had potent efficacy in vitro and in rodents. Several months later, Broder, Mitsuya, and Yarchoan started the initial phase 1 clinical trial of AZT at the NCI, in collaboration with the scientists from Burroughs-Wellcome and Duke University. In doing this Phase I trial, they built on their experience in doing an earlier trial, with suramin, another drug that had shown effective anti-HIV activity in the laboratory. This initial trial of AZT proved that the drug could be safely administered to patients with HIV, that it increased their CD4 counts, restored T cell immunity as measured by skin testing, and that it showed strong evidence of clinical effectiveness, such as inducing weight gain in AIDS patients. It also showed that levels of AZT that worked in the test tube could be injected into patients in serum and suppository form, and that the drug penetrated deeply only into infected brains.

A rigorously maintained double-blind, placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome. The study, which was commended by the CDC and the NIH for its standards, proved that AZT safely prolongs the lives of patients with HIV. Burroughs-Wellcome filed for a patent for AZT in 1985. The United States Food and Drug Administration (FDA) approved the drug (via the then-new FDA accelerated approval system) for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-obsolete medical term for pre-AIDS illness) on March 20, 1987. The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months, the shortest period of drug development in recent history.

AZT was subsequently approved unanimously for infants and children in 1990. AZT was initially administered in somewhat higher dosages than today, typically 400 mg every four hours, day and night. The paucity of alternatives for treating HIV/AIDS at that time unambiguously affirmed the health risk/benefit ratio, with inevitable slow, disfiguring, and painful death from HIV outweighing the drug's side-effect such as anemia and malaise.

Current treatment regimens involve relatively lower dosages (e.g., 300 mg) of AZT taken just twice a day, almost always as part of highly active antiretroviral therapy (HAART), in which AZT is combined with other drugs (known affectionately as "the triple cocktail") in order to prevent the mutation of HIV into an AZT-resistant form.