HIV: handling a killer condition

The first AIDS-related deaths began to surface almost 40 years ago in 1981. At that time, we had no effective medication and AIDS was a certain death sentence. At its peak, the AIDS crisis was killing 2 million people each year – people from all corners of society and across the globe.

Thanks to the development of antiretroviral medication, we can now completely prevent HIV transmission. Deaths from AIDS are less than half of what they once were[a] and are decreasing steadily – more and more patients are enjoying near-normal life expectancies and quality of life. Of course, these benefits are only possible if patients have access, and adhere, to treatments – something which is much more difficult in low-income countries. This article illustrates the progress that has been made and the challenges that still lie ahead.

Discovery and diagnosis

In early 80s America, concerning reports of increased incidents of certain rare diseases began to surface. Strangely, they were being observed in young gay men, despite normally only being associated with elderly and immuno-comprised patients. None of those men survived and the mysterious diagnoses kept on coming.[b]

After a few years, the mysterious outbreaks were given the name AIDS – Acquired Immune Deficiency Syndrome. As time progressed, it became apparent that AIDS was caused by infection with a previously unknown virus – Human Immunodeficiency Virus, or HIV. HIV was found to cause severe damage to the body’s ability to defend itself against infection, allowing all manner of diseases to take hold.

Early treatment

Clinical trials were initiated to investigate potential treatments. The central hypothesis was that protecting uninfected cells by blocking viral infection would permit meaningful recovery and restoration of immune function, or at least prevent further loss of immunity.[c]

Azidothymidine (AZT) was previously investigated as a cancer therapeutic in 1964, however, in the context of HIV it acted as a nucleoside reverse transcriptase inhibitor, which opened the doorway to its use as an antiretroviral medication. Researchers at the National Cancer Institute found that AZT could suppress HIV replication in February 1985.[d]

By 1987, a clinical trial involving 282 patients had been completed, showing that AZT was able to prolong the lives of AIDS patients and reduce the likelihood of lethal infections taking hold.[e]   The FDA approved AZT as the first HIV therapy on 19 March 1987[f] – a difference of 25 months, one of the shortest periods of drug development in recent history. Since then, the FDA has implemented various regulatory changes, which contributed to the rapid development of new HIV drugs.[g]  As an aside, this illustrates how drug repurposing can be a faster route into the clinic and onto the market.

The discovery of AZT was a long-awaited step forward, but by no means a cure. AZT treatment only held off disease progression for a matter of months, until HIV became resistant. Several long years followed the approval of AZT, with no new treatment in sight. At the end of the 1980s the FDA was able to approve several new monotherapies, but in reality these were not much better than those already on offer.[h]  The toxicity and unpleasant side effects resulting from the treatment coupled with large numbers of pills meant that patient compliance was not optimal.

Combination treatment

In the early 1990s a new strategy began to emerge: combination therapy – different drugs in a single treatment. In 1992, the FDA approved the combination of Zalcitabine and AZT based upon data that demonstrated an improvement in disease progression and death compared to AZT monotherapy. But this small yet significant advance had little impact on global deaths from AIDS, which had escalated to over 500,000 per year.[i]

The tide turns

A hugely significant breakthrough was made at the end of 1995[j]: the arrival of Highly Active Anti-Retroviral Therapy, or HAART.

Before HAART, all known drugs had been nucleoside reverse transcriptase inhibitors (NRTIs). However, even when different types of NRTIs were combined, HIV was quick to adapt and evade the treatment strategy.

HAART was different because it used a cocktail of drugs from different classes, not just one. HAART was enabled by the discovery of protease inhibitors (PIs), such as saquinavir – a completely new type of HIV drug. This combined regimen allowed doctors to employ several weapons against HIV at the same time. This made it much more difficult for HIV to adapt and become resistant to treatment.

Life expectancies suddenly and dramatically increased, and in a period of approximately ten years, the death rate from HIV disease was reduced by up to 80%.[k] Side effects were still a problem.

The next decade saw the discovery of further novel HIV drug classes: the first non-nucleoside reverse transcriptase inhibitor (NNRTI) was approved in 1996. Other drug classes followed, such as post-attachment inhibitors and integrase inhibitors. At the same time, scientists were developing new drugs within existing classes. Side effects were gradually reduced and treatment became both more tolerable and effective.

Treatment as prevention

The 2010s ushered in the era of “Treatment as Prevention”: it was discovered that treatment of heterosexual HIV-positive individuals could be used to reduce the risk of transmission by 96%, because antiretroviral drugs reduce their viral load so much that it becomes very difficult to pass on the virus. [l] In 2011 this was hailed “breakthrough of the year” by the journal Science.[m]

This has been corroborated by various other studies. In 2014, the PARTNER study was conducted with 1166 couples, one partner being HIV positive and one HIV negative.[n]  The study found not a single incident of HIV transmission when the HIV-positive partner was using suppressive antiretroviral therapy.

The PARTNER study was largely carried out with heterosexual couples. Further studies have confirmed the above findings in other patient populations. In June 2019, research published in The Lancet confirmed that the risk of HIV transmission for homosexual couples is effectively zero where a HIV-positive partner is receiving effective antiretroviral therapy.[o]

Studies like these form the basis of the mantra now adopted by many national health services: “Undetectable = Untransmittable”. This means that for a person on antiretroviral medication maintaining an undetectable viral load[p], they “can’t pass the virus on through sex”.[q] [r]

Not only can we prevent transmission of the virus – we can also dramatically reduce the risk of contracting the virus. The 2010s saw the arrival of pre-exposure prophylaxis (PrEP, marketed as Truvada). This is a daily course of antiretroviral drugs taken orally, which can reduce the risk of a HIV-negative person contracting HIV to near zero.[s]

Future Challenges

While new and improved antiretrovirals remain an area of intensive research, focus has expanded to other types of treatment as well as modes of administration.

Ever since the discovery of HIV, all have hoped there might one day be a vaccine. This still eludes researchers, but we are seeing promising trial data. For example, in the RV144 clinical trial in Thailand, the vaccinated population demonstrated a 31% reduction in instances of HIV infection.[t]  Vaccine trials in different populations have begun and the results will hopefully be available in the coming months and years, with studies investigating antibody-based vaccines also being planned.[u]

Progression in HIV management has led to new challenges in the form of increased rates of “comorbidities” in an ageing HIV-positive population. Although short-term side effects of modern HIV therapeutics are hugely improved, long-term effects are varied and are now beginning to arise in aging patients who have been taking medication for a long time. They may include, for example, increased rates of cardiovascular disease.[v]  This challenge of caring for a population with increased rates of these comorbidities is likely to be keenly felt in developing countries with less mature healthcare systems.

Relevant to this is the provision of affordable and effective treatment, especially in less developed countries. Treatment cost and availability for national health providers is largely affected by patents on HIV therapeutics and the ability of authorities to negotiate with patent owners. A particular concern is striking the right balance between remuneration for pharmaceutical companies through patent exclusivity, and affordable treatment for patients and healthcare providers. Access to treatment on a patient level (especially for newer second- and third-line treatments) may also be influenced by social or economic aspects – stigma surrounding HIV, or the cost of travelling to obtain treatment, for example.

Various initiatives have been and are being set up to improve overall access to treatment. One example is an organisation called The Medicines Patent Pool, a United Nations-backed public health organisation working to increase access to, and facilitate the development of, life-saving medicines for low- and middle-income countries.[w]  This organisation negotiates public-health driven licences with patent holders, and sub-licenses to generic manufacturers to encourage the sale of lower-cost generic versions of medicines in over a hundred developing countries.

Compulsory licences are another option, which are rights granted by a government to produce or supply a patented drug without the consent of the patent holder, effectively overruling the patent. The patent holder may still receive a fair or negotiated royalty, depending on national law. This option has been used relatively frequently for HIV therapeutics in developing countries. Between 2001 and 2016, 137 out of 176 (77.8%) instances of compulsory licences concerned HIV/AIDS or related diseases.[x]

We have made fantastic progress in learning to manage HIV, but more work needs to be done on getting treatment to those who need it: in 2017 an estimated 15.2 million were not receiving treatment out of a total of 36.9 million people living with HIV.[y]

[a] https://www.unaids.org/en/resources/fact-sheet
[b] https://www.hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline
[c] The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res. 2010;85(1):1–18.
[d] The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res. 2010;85(1):1–18.
[e] The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex, N Engl J Med. 1987;23;317(4):185-91.
[f] https://www.fda.gov/patients/hiv-timeline-and-history-approvals/hivaids-historical-time-line-1981-1990
[g] Naeger LK, Struble KA, Murray JS, Birnkrant DB. Running a tightrope: regulatory challenges in the development of antiretrovirals. Antiviral Res. 2010 this issue.
[h] The history of antiretroviral therapy and of its implementation in resource-limited areas of the world, AIDS: June 19th, 2012 – Volume 26 – Issue 10 – p 1231–1241
[i] https://ourworldindata.org/hiv-aids
[j] https://www.fda.gov/patients/hiv-timeline-and-history-approvals/hivaids-historical-time-line-1995-1999
[k] History of HAART – the true story of how effective multi-drug therapy was developed for treatment of HIV disease. Retrovirology. 2006; 3(Suppl 1): S6.
[l] Prevention of HIV-1 Infection with Early Antiretroviral Therapy. N Engl J Med 2011; 365:493-505
[m] Breakthrough of the year. HIV treatment as prevention. Science. 2011; 334: 1628
[n] Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. JAMA; 2016; 12;316(2):171-81
[o] Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet, 2019; 393 (10189):2428-2438.
[p] Viral load is a measure of the amount of HIV in the blood.
[q] https://www.nhs.uk/conditions/hiv-and-aids/
[r] Evidence of HIV Treatment and Viral Suppression in Preventing the Sexual Transmission of HIV https://www.cdc.gov/hiv/pdf/risk/art/cdc-hiv-art-viral-suppression.pdf
[s] https://www.avert.org/professionals/hiv-programming/prevention/pre-exposure-prophylaxis
[t] Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009; 361 (23):2209–2220.
[u] https://www.nih.gov/news-events/news-releases/hiv-vaccine-awareness-day-2019-may-18-2019
[v] The Aging Population with HIV Infection. Trans Am Clin Climatol Assoc. 2017; 128:131–144.
[w] https://medicinespatentpool.org/
[x] Medicine procurement and the use of flexibilities in the Agreement on Trade-Related Aspects of Intellectual Property Rights, 2001-2016. Bull World Health Organ. 2018;96(3):185–193
[y] https://www.unaids.org/en/resources/fact-sheet

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