HIV: Inside 36 years of treatment access

For the approximately 38.4 million people around the world living with HIV, access to medication is vital. The virus targets the immune system, specifically the CD4 T-cells and, if left to its own devices, can cause so much damage to these cells that the body becomes vulnerable to various opportunistic infections. Once a patient has fewer than 200 CD4 cells per cubic millimetre of blood, they are classified as having acquired immunodeficiency syndrome (AIDS).

Thankfully, in the last few decades the number and efficacy of treatments to help patients manage their symptoms and live rich, full lives has skyrocketed. But getting to this point has not been easy. While HIV and AIDS were prevalent in developing countries throughout the 20th century, it was not until the 1970s that they began to emerge as an epidemic in developed countries, particularly the United States; a development that uprooted the status quo of drug development and laid the foundation for approvals and access today.

Here, we take a look back at some of the most important steps in the journey towards developing today’s HIV treatments.

1980s – Early efforts to combat HIV

Faced with a swift and burgeoning number of patients displaying unfamiliar symptoms, it is understandable that in the early confusion of HIV in the 1980s researchers focused efforts on understanding the hows and whys behind the rapid spread of the virus, rather than on treating symptoms and preventing deterioration in existing patients.

Credit: Two enlarged images of T-cells one infected with HIV by the Frederick Cancer Research and Development Center. Colour lithograph by Nancy Burson and Kunio Nagashima, 1991.

However, towards the end of the decade, the tide appeared to turn when it came to treatment options. Interestingly, the first real treatment breakthrough did not emerge from a new discovery, but from a ‘failed’ cancer drug developed in the 1960s: zidovudine, otherwise known as azidothymidine (AZT).

AZT is a form of antiretroviral therapy (ART) called a nucleoside reverse transcriptase inhibitor (NRTIs), which prevents HIV from using the reverse transcriptase enzyme to build HIV DNA and therefore stops the virus from infecting more cells.

Two decades after its initial development, AZT, or Compound S as it was known at this point, became part of Burroughs Wellcomes’ push to identify potential anti-HIV agents. During testing, researchers discovered that AZT appeared to block the virus from replicating itself. With no other treatment options available, this was a huge development. Recognising the importance of this, the team at Burroughs Wellcome quickly sent samples to both the FDA and National Cancer Institute.

But the discovery alone was not nearly enough. To ensure that the drug could actually help those patients in dire need of treatment, researchers had to prove that the compound was both safe and effective. At the time, this process could take upward of ten years.

But patients didn’t have ten years.

1987 – ACT UP for AZT

The FDA officially gave AZT the green light in 1987. Sold under the brand name Retrovir, the regulator fast-tracked the process, with an FDA advisory committee voting ten to one to recommend its approval only 25 months after the first demonstration of efficacy.

Attribution: The U.S. Food and Drug Administration, Public domain, via Wikimedia Commons

Unfortunately, it also happened to be the most expensive prescription drug in history, with a one-year price tag of $17,000 in today’s dollars.

With one drug now on the market, but unaffordable for the majority of patients, attention turned to finding alternative solutions. As a monotherapy, AZT had one big problem – the virus adapted. While the drug may be effective early on in treatment, it would soon be outmatched by its opponent.

Looking back at the progress made in HIV treatment, one thing that simply cannot be overlooked is the role that patients and activists played in driving developments.

One of the most influential groups, and proudly sharp thorn in the side of regulatory bureaucracy, was AIDS Coalition to Unleash Power – ACT UP. Comprised of those living with HIV, loved ones, even scientists, the group’s members put enormous pressure on regulators to fast-track access to medications. It was a feat unheard of in the pharmaceutical world, as hundreds of ACT-UP activists converged on the FDA’s headquarters to demand the regulatory body meet to discuss what would later be deemed ‘the right to try’.

While highly controversial (and in no way encouraged), the group’s efforts proved to be instrumental in changing medicines access. Faced with enormous public pressure, the FDA relented, agreeing to meet with the activists. Only a few short months later, officials created a new fast-track approval process for HIV/AIDS treatments, which opened the door for multiple drug approvals either slowing the progression of the disease or treating associated conditions.

1990s – The ART of combatting drug resistance

Amid mounting concerns over the waning efficacy of single-drug treatments, in the early 90s researchers began to turn their attention to the potential of combination therapies.

Credit: Seth Pincus, Elizabeth Fischer and Austin Athman, National Institute of Allergy and Infectious Diseases/NIH

In 1995, Roche’s saquinavir became the first protease inhibitor (PI) approved for HIV/AIDS patients through the FDA’s accelerated programme. While not a cure for HIV, the treatment proved to be highly effective at preventing the virus from maturing and infecting additional cells. However, as with AZT, drug resistance remained a pressing issue.

However, protease inhibitors are particularly effective when used in combination with other drugs. Consequently, in an effort to limit HIV’s drug resistance, the FDA authorised saquinavir to be used in conjunction with other NRTIs, such as AZT, only a few months after granting market approval. The next year, Roche was also given the green light for saquinavir to be prescribed with AbbVie’s ritonavir, another PI, which gained market approval in 1996.

That same year, Boehringer Ingelheim’s nevirapine, the first non-nucleoside reverse transcriptase inhibitor (NNRTI), gained FDA approval. Like NRTIs, NNRTIs inhibit the reverse transcriptase. However, because NNRTIs stop the virus from copying itself at a different stage during the infection, this helped to strengthen NRTI-PI combinations against ongoing continuing drug resistance.

The multi-drug approach dramatically altered the way that HIV/AIDS was treated. And, with the subsequent rise of Highly Active Antiretroviral Therapy (HAART), the dawn of a new era of treatment had begun.

According to the US Centers for Disease Control and Prevention (CDC), the introduction of HAART resulted in a 63% decrease in AIDS-related deaths between 1995 and 1998, from 50,628 to 18,851. This reduction in mortality rates has been attributed to the availability of combined HAART treatment, which was a key commitment of the reauthorised CARE Act.

2000s – Improving access to ARTs

While significant progress had been made in improving HIV treatment access in the developed world, in developing nations, notably where the virus was most prevalent, patients faced a significant hurdle – the cost.

Credit: By U.S. Government – Extracted from PDF version of World AIDS Day 2007: The Power of Partnerships: December 2007 Results (direct PDF URL [1])., Public Domain, https://commons.wikimedia.org/w/index.php?curid=3248784

To address this access inequality, the United Nations’ Programme on HIV/AIDS (UNAIDS) partnered with the World Health Organization (WHO) to urge pharmaceutical companies to cut the price of their ARTs in developing countries. According to the International Centre for Trade and Sustainable Development, this joint initiative led to Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Glaxo-Wellcome, and Merck agreeing to cut the costs of HIV/AIDS drugs by up to 80% in May 2000.

To support this effort, former-US President Bill Clinton issued an executive order to assist developing countries in importing and producing generic versions of ARTs and, in 2003, newly-elected US President George W Bush expanded on this initiative by establishing the President’s Emergency Plan for AIDS Relief (PEPFAR).

Only two years later, in 2005, the WHO and UNAIDS confirmed that approximately 700,000 more people had access to ARTs due to these efforts. Through PEPFAR, the FDA had authorised 100 drugs to combat HIV/AIDS outside the US by 2009, including 29 new drugs and 71 generics.

In the 20 years since PEPFAR’s inception, the US Government has invested over $100 billion in the global HIV/AIDS response, and as of September 2021, has supported life-saving antiretroviral treatment (ART) for nearly 19 million people.

2007 – The Berlin Patient

Even with the progress made in treating HIV, in 2007 there was still no known cure available. So, the news that a US-born HIV patient had been seemingly ‘cured’ following a bone marrow transplant sent shockwaves through the medical world.

Credit: Griffin Boyce, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons

At 41, Timothy Ray Brown – aka The Berlin Patient – had been living with HIV since his initial diagnosis in 1995. Born in the US, Brown was living in Germany, where he received his first diagnosis and was prescribed ART, which helped to prolong his life. However, in 2006, Brown received yet another life-threatening diagnosis: acute myeloid leukaemia. After some hesitation, he agreed to undergo a radical stem cell transplant therapy.

Brown’s doctors in Berlin selected a donor who tested positive for a rare homozygous CCR5-delta32 mutation, which made them naturally resistant to HIV, since most HIV strains cannot enter cells without a functional CCR5 gene.

After transplant, Brown stopped taking his ART treatment. Three months later, his HIV levels plummeted to undetectable levels, and his CD4 T-cell count increased. Additionally, his genotype changed from heterozygous and homozygous with regards to the CCR6-delta32 allele. This was a ground-breaking result since discontinuing ART typically leads to a rapid rebound of HIV load within weeks.

Brown remained HIV-free until his death in September 2020. His case inspired researchers to investigate the possibility of using stem cell transplants as a potential cure for HIV, although this remains a complex and challenging process that is not a feasible option for most people with HIV.

2012 – Enter the PrEP era

As multiple treatments emerged for HIV treatment, another approach was rapidly gaining traction in the labs of drugmakers – prevention.

Credit: NIAID, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons

Pre-exposure prophylaxis, or PrEP, was developed based on scientific research that showed that antiretroviral drugs, which are used to treat people with HIV, could also be used to prevent HIV transmission.

The first studies on PrEP were conducted in the early 2000s, with the aim of testing the effectiveness of antiretroviral drugs for preventing HIV transmission in people at high risk of infection, such as men who have sex with men and serodiscordant couples (where one partner has HIV and the other does not).

In 2010, a large-scale clinical trial called the iPrEx study was conducted, which demonstrated that taking a daily oral dose of the antiretroviral drug Truvada reduced the risk of HIV infection among men who have sex with men and transgender women by up to 92%. This was followed by several other studies that confirmed the effectiveness of PrEP in reducing HIV transmission.

Based on these studies, the US FDA approved Gilead’s Truvada for use as PrEP in 2012. Since then, other antiretroviral drugs, such as Descovy and Tivicay, have also been approved for use as PrEP. The development of PrEP has been a major breakthrough in the field of HIV prevention, providing a highly effective tool for reducing the risk of HIV transmission in people at high risk of infection.

2014 – 90-90-90

As part of ongoing efforts to combat HIV/AIDs, in 2014 UNAIDS launched the 90-90-90 target, which aimed to ensure that by 2020, 90% of all people living with HIV know their status, 90% of those diagnosed with HIV are receiving ART, and 90% of those receiving ART have viral suppression.

Image: Original source here

2019 – The London Patient

While the unusual case of Timothy Ray Brown provided some hope of a future without HIV, he remained something of an anomaly in the world of HIV treatment. That was, of course, until March 2019, when University College London (UCL) and Imperial College London announced that another HIV-positive individual– dubbed the London Patient – had been functionally cured of HIV following a bone marrow transplant in 2016.

Attribution: Truthbetold71, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

Similar to Brown, the London Patient – who has now come forward as being Adam Castillejo – received a bone marrow transplant from a donor with a rare genetic mutation that made him resistant to HIV.

The donor, like the donor in the previous Berlin patient case, had two copies of the CCR5-delta32 genetic mutation. After stopping ART 16 months following the transplant, Castillejo’s blood viral load remained undetectable 18 months later.

According to University of Cambridge Professor Ravindra Gupta, who led the study while working at UCL, “by successfully achieving remission in a second patient using a similar approach, [it was] demonstrated that the Berlin patient was not an exception, and that the treatment methods were effective in eradicating HIV in both individuals.”

2020-2021 – COVID-19 enters the fray

For those who lived through the HIV/AIDS epidemic, the sudden arrival of the COVID-19 pandemic was a stark reminder of the challenges patients, policy makers, and pharma companies face during a health crisis.

Credit: “2020_06_020100 – a human cell attacked by Covid-19” by Gwydion M. Williams is licensed under CC BY 2.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/2.0/?ref=openverse.

As drugmakers fought to produce an effective treatment to address a new target, those in need of HIV treatments faced disruptions to treatment and access, with many HIV clinics closing or reducing services, and disruptions to global supply chains for HIV medication and supplies.

Despite the challenges of the COVID-19 pandemic, progress was made toward the 90-90-90 target. In 2021, UNAIDS reported that of all people living with HIV in 2021, 85% knew their status, 75% were accessing treatment, and 68% were virally suppressed.

Efforts also continued to expand access to HIV prevention, treatment, and care, particularly in low- and middle-income countries.

2022/23 – Mixed-results for injectables

Efforts to produce an effective HIV vaccine have been in the works for years, with varying levels of success. At present, no candidate has been able to reach the finish line, yet, with each new development there have been notable signs that researchers are inching ever closer to a success.

Credit: “Syringe and Vaccine” by NIAID is licensed under CC BY 2.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/2.0/?ref=openverse.

Given the complexity of combating HIV, traditional approaches to vaccine development that led to many of the licensed vaccines in use today are either impractical or have so far failed to result in effective vaccines.

Although recent examples, such as the Phase 3 Mosaico study of Janssen’s investigational HIV vaccine regimen, have fallen at the last hurdle, the HIV research community appears to be setting its sights on vaccines based on new approaches, such as messenger RNA (mRNA)-based vaccines or those using human cytomegalovirus (HCMV) vectors.

With results of several key trials set for 2023, there is much anticipation ahead for the future of vaccines in HIV treatment.

Nonetheless, although a cure that can be widely used remains out of sight for now, what can be assured is that the fight to find better treatments will continue.

Eloise McLennan is the editor for pharmaphorum’s Deep Dive magazine. She has been a journalist and editor in the healthcare field for more than five years and has worked at several leading publications in the UK.

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