1987: AZT: First Antiretroviral Drug for HIV/AIDS (1987)

The AIDS epidemic, first recognised in 1981, progressed with terrifying speed. By 1987, AIDS had
killed over 40,000 Americans and tens of thousands more globally, with no effective treatment.
The causative agent—HIV—was identified in 1983–1984 by Françoise Barré-Sinoussi and Luc Montagnier
at the Institut Pasteur and Robert Gallo's group at the NCI.

Zidovudine (AZT, azidothymidine) was originally synthesised by Jerome Horwitz in 1964 as a
potential anticancer agent but was never developed. Burroughs Wellcome chemist Janet Rideout and
colleagues tested AZT against HIV in early 1985 and found potent in vitro inhibition of reverse
transcriptase—the viral enzyme essential for retroviral replication. AZT is a thymidine analogue
that, after intracellular phosphorylation, is incorporated into viral DNA and terminates chain
elongation due to the absence of a 3'-OH group.

The Phase II clinical trial, placebo-controlled, was terminated early after 16 weeks when
interim analysis showed significant mortality benefit in the AZT group. FDA approved AZT on
20 March 1987—just 25 months after the first human trial, a record that reflected the urgency
of the epidemic. It was the first drug to demonstrate survival benefit in AIDS.

AZT's limitations—toxicity (bone marrow suppression), and rapid emergence of resistance with
monotherapy—drove the development of additional antiretrovirals and ultimately highly active
antiretroviral therapy (HAART) from 1996 onwards. The AZT story also transformed the FDA's
approach to drug approvals for life-threatening conditions, leading to accelerated approval
pathways and compassionate use programmes that persist today.