The beginning of treatments for HIV/AIDS

In 1964, Jerome Horwitz developed azidothymidine (AZT) as a potential cancer therapy. It was shown to be ineffective and was subsequently shelved. However, in the 1980s it was included by the National Cancer Institute (NCI) in a screening program to identify potential HIV/AIDS treatments. The National Institute of Health (NIH) tested a range of drugs against an HIV assay targeting reverse transcriptase, which is a HIV enzyme used in the viral replication process.

It was found that AZT, the first drug in the class of Nucleoside Reverse Transcriptase Inhibitors (NRTIs), suppressed HIV replication without damaging normal cells. British pharmaceutical company Burroughs Wellcome initiated a clinical trial to evaluate the use of AZT in people with AIDS. When used as a monotherapy, AZT decreased deaths and any opportunistic infections that occurred because of the disease. Some side effects were observed in the trial that were suspected to be caused by AZT, including unusual bleeding; inflammation of the mouth; and black, tarry stool. In March 1987, the the US Food and Drug Administration (FDA) decided that the benefits outweighed the risks, and AZT became the first drug approved in the US for the treatment of AIDS.

Treating earlier in the infection

The AIDS Clinical Trials Group (ACTG) established in 1987 performed a trial, ACTG 016, to try and establish a lower therapeutic dose of AZT to reduce the side effects. Another study, ACTG 019, established that it was beneficial to put people with HIV on AZT prior to their progression into AIDS. The study showed that AZT effectively delayed the onset of AIDS, which marked the first treatment for HIV, rather than waiting for the disease to progress to AIDS before treating patients.

Improving the benefit-risk profile

AZT was not effective enough on its own, however, as the drug does not completely halt HIV replication, giving the virus an opportunity to mutate and become resistant. Therefore, scientists developed other NRTIs such as didanosine and zalcitabine, both gaining approval by the FDA for the treatment of HIV/AIDS. Combining one of these two drugs with AZT proved to be more effective than AZT monotherapy. The financial cost of these treatments was a major roadblock for many patients. Some estimates of the annual cost of AZT monotherapy in 1987 were as high as $10,000 per person (the equivalent of just under $30,000 (or £23,000) in current money!). This cost meant a lot of patients could not get the regular treatment they needed, especially for people without health insurance in the US. Some subsidies from the US Government helped in October 1987, but the price was still too high.

Newer anti-HIV medicines

The global death toll from HIV/AIDS increased each year, and scientists explored more ways to combat the virus. In 1988, scientists found that the protein snipping facilitated by an enzyme called protease was essential to the life cycle of HIV. This led to several pharmaceutical companies researching and manufacturing protease inhibitors, namely saquinavir, indinavir and ritonavir. The trials for these drugs as a monotherapy did not give the results the researchers were hoping for, as the virus adapted and quickly became resistant to the protease inhibitors.

The birth of HAART

Pharmaceutical company Merck ran another trial, but this time they used a 3-drug combination, indinavir (their protease inhibitor) in combination with two NRTIs, AZT and 3TC. Combination therapy with two different NRTIs had proven successful in the past, but only in patients with no prior exposure to NRTIs.

Merck’s trial was a success, with 90% of patients having no detectable HIV after a few weeks of treatment, and it also worked effectively in patients with previous monotherapy treatment. In November 1995 the FDA approved indinavir for use in combination with AZT and soon after approved saquinavir and ritonavir.

By 1996, doctors were prescribing protease inhibitors with NRTIs, the combination became known as Highly Active Retroviral Therapy (HAART). It immediately began to save lives. One study in 1998 estimated that HAART had reduced the number of AIDS-related deaths in the US by an impressive 70% since 1995.

Stigma

In addition to the financial and health burden that HIV/AIDS causes, people with this infection also have to deal with the stigma.

Merriam-Webster defines stigma as “a set of negative and unfair beliefs that a society or group of people have about something”; or “a mark of shame or discredit”.

In the 1980s there was a significant stigma associated with catching HIV and developing AIDS, in part arising out of ignorance of the condition and its causes. People with HIV/AIDS were discriminated against in the workplace, when trying to raise a loan, and even having an HIV test was seen as a legitimate risk factor that increased the cost of insurance.

Some of these issues have been resolved, and now HIV testing is much more widely accepted, for example it is a routine part of antenatal testing in many countries.

Although lots of effort has been made to break down the stigma behind the disease in the last 30 years, improve public education around this condition and reduce this discrimination,  HIV stigma continues. This can come in various forms, with some people believing only certain groups can get HIV, or feeling that some people deserve to get HIV because of their choices. This stigma can lead people with HIV to develop a negative self-image and feel unnecessary shame or fear. Fear of being judged or discriminated against can inhibit people at risk of HIV from seeking testing or treatment, which leads to worsened outcomes, and increases the risk of transmission.

In order to improve outcomes, we need to encourage people to have testing, educate the public about the condition and the treatments available, and reduce the stigma associated with HIV/AIDS. World AIDS Day is a global initiative to help with this effort.

Is that the end?

HAART was a massive leap forward in the treatment of HIV/AIDS. The main factor in HAART’s effectiveness is that it does not allow the virus to adapt to the drug like many patients experienced with monotherapies, meaning the regimen could achieve consistent viral suppression over an extended period, improving both the quality of life for patients and also extending overall survival.

HAART was not perfect, however. The regimens for taking the combinations were complex, some requiring to be taken with food and some without and some being taken at different times of the day. This meant that some patients found it hard to adhere to the regimens in the long-term.

Look out for our third and final blog on HIV, looking into current and future treatments!

References

ACS. (2024). Discovery of Highly Active Antiretroviral Therapy for HIV. Retrieved from ACS: https://www.acs.org/education/whatischemistry/landmarks/highly-active-antiretroviral-therapy-hiv.html

CDC. (2024, April 16). Stigma and HIV. Retrieved from CDC: https://www.cdc.gov/hiv/health-equity/index.html#:~:text=HIV%20stigma%20is%20negative%20attitudes,testing%2C%20prevention%2C%20and%20care.

Garfield, S. (1993, May 02). The rise and fall of AZT. Retrieved from The Independent: https://www.independent.co.uk/arts-entertainment/the-rise-and-fall-of-azt-it-was-the-drug-that-had-to-work-it-brought-hope-to-people-with-hiv-and-aids-and-millions-for-the-company-that-developed-it-it-had-to-work-there-was-nothing-else-but-for-many-who-us

NIH. (2024, February 5). Antiretroviral Drug Discovery and Development. Retrieved from NIH: https://www.niaid.nih.gov/diseases-conditions/antiretroviral-drug-development#:~:text=Scientists%20funded%20by%20NIH’s%20National,drugs%20to%20treat%20HIV%2FAIDS.

NIH. (2024). The First AIDS Drugs. Retrieved from NIH: https://ccr.cancer.gov/news/landmarks/article/first-aids-drugs

Penslar, R., & Lamm, R. (1989). Who Pays for AZT? Hastings Cent Rep., 30-32.

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