The Evolution of HIV/AIDS Treatment

Already approved in the US, GSK’s ViiV Healthcare recently received a positive opinion from the EMA’s CHMP committee for a long-acting form of cabotegravir for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1. The drug works by inhibiting an essential step in the HIV replication cycle; in simple terms, viral DNA is prevented from integrating into the genetic material of human immune cells.

PrEP requires high levels of adherence to be effective; however, some at-risk individuals and groups are less likely to adhere to daily medication; it is important then that the new formulation can be administered as little as six times per year. Experts hope that an additional option that requires less frequent administration may increase uptake. In a statement, Kimberly Smith, Head of Research & Development at ViiV Healthcare, said, “The expansion of prevention options is critical if we are to end the HIV epidemic. Long-acting options have the potential to play an important role in reducing challenges such as inconsistent adherence to taking daily pills, and stigma associated with oral PrEP use that can be faced by people who could benefit from PrEP.”

In light of this new advancement in treatment options for the disease, it feels appropriate to revisit the history to appreciate how far research and treatment has come since the first cases were reported in 1981.

The reasons for HIV’s sudden emergence, epidemic spread, and unique pathogenicity have been a subject of intense study. Today, more than 70 million people have been infected with HIV, and about 35 million have died from AIDS since the start of the epidemic.

The beginnings
 

Between the late 1970s and early 1980s, a mysterious virus began to rapidly spread throughout the US. In 1982, the CDC published a case definition naming the condition AIDS – a once unknown oddity that would soon become the number one threat to public health worldwide.

At the time, scientists had no idea how to test for it, how it was transmitted, or how to treat it. It was only understood to be viral, lethal, and contagious – particularly within certain groups declared by the CDC. 

These variables led to considerable public panic, with homosexuals and drug users bearing the brunt of blame and discrimination. Scientists even labeled the group of mystery illnesses as a gay-related immune deficiency or community-acquired immune dysfunction. 

The media had also propagated this fear after profiling HIV as the “4-H disease,” which grouped together homosexual men, people with hemophilia, heroin users, and people of Haitian origin (as many cases of AIDS were reported in Haiti) as the main culprits.

The stigma surrounding HIV/AIDS is widely regarded as a primary reason for the slow healthcare response to the phenomenon. Indeed, it wasn’t until 1985 that President Reagan first mentioned AIDS publicly, suggesting it was a “top priority” in response to a reporter.

Treating the problem
 

Despite widespread efforts, HIV/AIDS proved difficult to treat. In 1983, scientists accepted – in a revolutionary departure from the pathogenic dogma – that HIV/AIDs was a retrovirus. Back then, “the belief that retroviruses were, by definition, not amenable to therapy remained strong” (1). 

It wasn’t until 1987 that scientists unearthed their first major breakthrough: azidothymidine (AZT). Interestingly, AZT wasn’t a new compound scientists developed from scratch – it was a drug developed in the 1960s by a US researcher as a way to thwart cancer. But it didn’t work and was abandoned. Two decades later, researchers conducted massive tests of potential anti-HIV agents, hoping to find anything that might work against this new viral foe. Among the compounds tested was something called Compound S – a re-made version of the original AZT. 

They found that AZT was able to block essential enzymes required for HIV replication, effectively stopping or slowing the virus’s progression. The FDA approved AZT under a fast track program; however, though it could help treat the condition, researchers soon discovered its severe side effects (specifically, liver problems and low blood cell counts) – especially with long-term use.

The limitations of AZT as a standalone treatment prompted scientists to seek out additional therapeutic options, but the virus’ mutations posed a challenge for single-drug therapy. Over the following years, the FDA approved several other drugs with mechanisms similar to AZT – including saquinavir and nevirapine. This then paved the way for combination therapy in 1996, also known as highly active antiretroviral therapy (HAART).

HAART proved to be a powerful tool in managing viral load, and delaying or even preventing the onset of symptoms to AIDS. And though it did considerably reduce mortality rates, there was a notable downside: the extensive medication regimen associated with HAART led many individuals to quit due to its adverse effects on both physical and mental health.

These issues were partly averted with the introduction of Combivir in 1997. This treatment combined two antiretroviral drugs in one, making the medication regimen more manageable. By the mid-1990s, antiretroviral treatments were significantly improving both health and life expectancy.

The most recent major treatment advancement came in 2012 after the FDA approved PrEP. As previously discussed, PrEP is an HIV prevention drug that lowers the risk of contracting the virus, benefiting both HIV-positive individuals, whilst also protecting healthy people from infection. 

Although HIV/AIDS can be managed with treatments, there is still no definitive cure, so research continues. 

Scientists are exploring several avenues, including approaches to eradicate the virus from the body entirely. The “shock and kill” strategy, for instance, is a popular research focus that involves activating latent HIV reservoirs and subsequently targeting them with antiretroviral drugs to eliminate the virus completely. One of the big challenges here, however, is identifying and effectively targeting all viral reservoirs.

Gene therapy is another avenue being explored. CRISPR/Cas9 technology has shown promise in targeting and removing HIV DNA from infected cells. This approach, if successfully refined, could potentially eliminate the need for lifelong antiretroviral therapy.

Finally, the International Maternal Pediatric Adolescent AIDS Clinical Trial Network (IMPAACT) reported on the first case of curing HIV in a woman using dual stem cell transplantation in 2022. The participant stopped antiretroviral therapy at 37 months post-transplant and has had no HIV detected for 14 months. 

Stemcell induced HIV remission has been reported in two other cases. The first, known as the Berlin patient , was reported in 2009. And the second, known as the London patient, was reported more recently. This third case of HIV remission suggests that a dual stem cell transplantation strategy could help people living with HIV who require a stem cell transplant for other diseases. However, the invasive, complex and risky nature of this medical procedure is still not viewed as a feasible strategy to scale up to the millions of people living with HIV globally. 

To showcase the depth of research taking place around HIV/AIDS, here are some example of research published over the last months:

New findings from Emory study offer potential breakthrough in HIV cure research
 

Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques
 

CRISPR editing of CCR5 and HIV-1 facilitates viral elimination in antiretroviral drug-suppressed virus-infected humanized mice
 

Anti-V1/V3-glycan broadly HIV-1 neutralizing antibodies in a post-treatment controller
 

Total Synthesis and Structure Revision of (+)-Lancilactone C