The First HIV Therapy Came About Before HIV

Burroughs Wellcome Chemical Works New York

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 made its way from laboratory archives to become the very first HIV therapy in record time.

The 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).

kaposi's sarcoma lesions skin red
Kaposi’s sarcoma was the most prominent of these, the disease manifesting as widespread purple lesions so famously depicted in Philadelphia.

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 the 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.

Related: The Immune System: Our Personal Security Detail

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.

Beginnings of Antiretroviral 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.

herpes virus structure
AZT was a potential drug candidate against the herpes virus (pictured), but the compound showed little effect in pre-clinical trials and was promptly forgotten.

Fast forward twenty years later and the world was in a state of panic. Treatment was desperately required for HIV, and the responsibility to provide the world its first HIV therapy fell on the shoulders of the U.S. National Cancer Institute (NCI).

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 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)

Related: Process and Costs of Getting a New Drug to Market

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.

AZT azidothymidine label research preclinical chemical
Experimental chemical to record breaker; Azidothymidine (AZT) was developed by Burroughs Wellcome. It was approved as Zidovudine in 1987 as the world’s first antiretroviral medication.

AZT’s Unsung Heroes

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.

HIV structure scanning electron micrograph color budding T cell
HIV (pictured in green) budding from a white blood cell (blue). Reverse transcription is very prone to mutations, enabling retroviruses to grow resistant to medications and vaccines.

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 conservation of reverse transcriptase – 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.

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)

Reference

  1. 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.
  2. 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 Chemistry28(4), 942-944.
  3. Kolata, G. (1987). Imminent marketing of AZT raises problems. Science235, 1462-1464.
  4. Li, J. J. (2006). Laughing gas, Viagra, and Lipitor: the human stories behind the drugs we use. Oxford University Press.

You may also like...

2 Responses

  1. Muay Mios says:

    When are ya’ll going to learn about the biggest scam of all of mankind, known as so-called “HIV/AIDS”. The “HIV tests” are fake, the AIDS drugs murder people and “HIV” was never isolated nor purified.

    • Sean says:

      I am not sure where you get your information, but – respectfully – you’re plain wrong. HIV has in actual fact been isolated multiple times, you will find many papers referencing this (including HIV antigen/antibody tests).

      There are dozens of HIV-specific treatments available today – the company I work for actually manufactures one of these, and the data is solid. These treatments prolong life and restore health (or at least prevent it’s decline), with clinical trial and real-life data citing multiple endpoints met.

      – Sean

Leave a Reply