The First HIV Therapy Came About Before HIV
Drugs are designed to combat existing diseases; it makes little sense to invest time and money into developing a cure otherwise! Sometimes though, a previously discarded drug candidate can resurface years later to make an instant impact. Shelved for years, Zidovudine (azidothymidine) made its way from laboratory archives to become the very first HIV therapy in record time.
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Recent Origins Of HIV/AIDS
In 1981, reports arose of individuals being diagnosed with extremely rare opportunistic infections. Drug users and homosexual men made up the majority of these cases, fueling the suspicion and stigma historically associated with the patients1.
Opportunistic infections affect individuals with weakened immune systems, for which the umbrella term was coined Acquired Immune Deficiency Syndrome (AIDS).
After two years of intense medical research, the root cause of the disease was identified concurrently by rival researchers Gallo and Montagnier. They attributed the diseases to a specific retrovirus, which eventually gave rise to the term Human Immunodeficiency Virus (HIV).
Retroviruses work by converting their single-stranded RNA into double-stranded DNA, which can then be incorporated into the DNA of our own cells. This genetic material provides instructions for the production of new viruses.
HIV primarily infects helper T cells, causing their deaths as they emerge from the cell. T cells are a key part of our immune system, the reduction of their numbers paves the way for opportunistic infections and the diagnosis of AIDS.
The wide spectrum of cancers and diseases in AIDS meant that its patients did not live for long after diagnosis. Thus sparked a race to uncover the first HIV therapy.
In 1964, chemist Jerome Horwitz published the synthesis and possible activity of an anticancer agent named azidothymidine (AZT), with the rights to the compound handed over to research foundation Burroughs Wellcome2.
Fast forward twenty years later and the
Dozens of pharmaceutical companies offered up potential compounds for screening, one of which was a 20-year-old drug candidate named AZT. The NCI systematically set up assays measuring the activity of these compounds, and in February 1985 AZT was discovered to be active against HIV in vitro.
AZT in Clinical Trials
AZT was quickly pushed through to clinical trials in June 1985, showing remarkable efficacy in patients. (As an aside, Phase I clinical trials for AIDS and cancer drugs are almost always performed on patients rather than the usual healthy volunteers)
Burroughs Wellcome rapidly completed the process of filing the drug, and in March 1987 AZT was approved by the FDA as an antiviral treatment against HIV. The 25 months between the discovery that AZT was active against HIV and regulatory approval is one of the shortest periods of drug development in history3.
The success of AZT arose not only because of its efficacy but also its lightning-quick transition from discovery to market. But the actual journey of this drug had started much earlier, starting from its synthesis in 1964.
HIV – being a retrovirus – possess reverse transcriptase enzymes that help to convert its RNA to DNA. Inhibiting this enzyme meant that it had a much harder time replicating. This was already known, as the enzyme had been isolated by biochemists Baltimore and Termin in 1970.
Their research proved critical in the development of retroviral assays. Burroughs Wellcome, who had the rights to AZT, did not have a viable technique to screen for compounds that had activity against HIV. However, mouse cells infected with another retrovirus was used as the alternative.
AZT showed potent activity against the substitute retrovirus and – due to the
Another factor that accelerated the development of AZT was that it boasted a solid safety profile. Prior preclinical trials in rats showed low toxicities even at high doses, allowing human trials to proceed.
AZT turned out to be the perfect answer to the first HIV therapy the world desperately needed. Safe and effective, doing well on all endpoints (T cell counts, weight gain), as well as able to be administered as a serum or suppository4.
The health benefits that AZT brought to patients suffering from HIV/AIDS was many times more effective than any other alternative treatments at the time. Such was its success that FDA approval for its use in adults with HIV was quickly followed up by an indication for infants and children.
Suddenly, patients facing a slow but inevitable, disfiguring and painful death from HIV had hope. Now, the race is on to discover a vaccine to eradicate this disease once and for all.
Feature photo: Burroughs Wellcome Chemical and Galenical Works, New York (Source)
- Hymes, K., Greene, J., Marcus, A., William, D., Cheung, T., Prose, N., … & Laubenstein, L. (1981). Kaposi’s sarcoma in homosexual men—a report of eight cases. The Lancet, 318(8247), 598-600.
- Horwitz, J. P., Chua, J., Urbanski, J. A., & Noel, M. (1963). Nucleosides. III. 1-(2′-Deoxy-3′, 5′-epoxy-β-D-threo-pentofuranosyl) thymine1, 2. The Journal of Organic Chemistry, 28(4), 942-944.
- Kolata, G. (1987). Imminent marketing of AZT raises problems. Science, 235, 1462-1464.
- Li, J. J. (2006). Laughing gas, Viagra, and Lipitor: the human stories behind the drugs we use. Oxford University Press.