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. These viruses usually target and infect people with weakened immune systems, such as the elderly, pregnant women, patients under chemotherapy, etc. However, these individuals didn’t seem to fit these criteria. Rather, it was drug users and homosexual men that made up the majority of these cases, fueling suspicion and stigma historically associated with the disease1. The umbrella term for the disease 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. HIV hijacks our cell’s machinery, feeding them the instructions for the production of proteins for new viruses.
HIV primarily infects helper T cells, a key part of our immune system. When many copies of the virus have been produced inside the cell, they burst forth, kidding our T cell in the process. The reduction of T cell numbers severely impacts our immune response, paving the way for opportunistic infections and the diagnosis of AIDS. The wide spectrum of serious infectious diseases in AIDS patients meant that they did not live for long after diagnosis. Thus sparked a race to uncover the first HIV therapy.
Almost 20 years prior to the discovery of AIDS, 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. After preclinical trials in mice models showed no tangible anticancer activity, the development of the drug candidate was shelved indefinitely.
Fast forward to 1983 and the
Dozens of pharmaceutical companies and research institutes offered up numerous compounds, one of which was a 20-year-old failed lead compound 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. It slowed the spread of the virus, improving the immune system of patients and substantially prolonging their lives in the process. 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.
Mechanism of Action
HIV – being a retrovirus – possess reverse transcriptase enzymes that are able to convert RNA to DNA. Since human cells operate using DNA, it is crucial for the virus to be able to perform this process. Inhibiting this enzyme would mean that the virus would have a much harder time replicating. This was already known, as the enzyme had been isolated and studied by biochemists Baltimore and Termin as early as 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 for activity against the actual HIV virus. However, because they knew that retroviruses had similar life cycles and machinery, mouse cells infected with a different retrovirus could be used as an alternative.
They proved to be correct. AZT showed potent activity against the substitute retrovirus and was predicted to inhibit HIV as well. It was quickly included in the list of compounds sent to the NCI by Janet Rideout of Burroughs Wellcome. It was only later that they discovered that AZT’s success was attributed to its inhibition of the reverse transcriptase enzyme, common in all retroviruses.
AZT turned out to be the perfect answer to the first HIV therapy the world desperately needed. Safe and effective, AZT performed well on all clinical trial endpoints (T cell counts, weight gain), and was able to be administered easily vis serum or suppository4. 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 quickly.
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.
However, AZT did not cure the virus completely. In fact, although at the time of writing there exists multiple treatments for HIV, none of them are considered full cures. Though the drugs slow the rapid lifecycle of the virus, an extremely high mutation rate characteristic of HIV means that drug resistance develops quickly. But we must be optimistic that a cure can be found. Already, we have seen in the ebolavirus that previously incurable diseases can indeed be cured. Now, the race is on to discover a drug that will eradicate the human immunodeficiency virus 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.