The Evolution of HIV 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). They hope the drug will reduce the risk of sexually acquired HIV-1 by inhibiting an essential step in the replication cycle; one that stops viral DNA from being integrated into the genetic material of human immune cells.

While PrEP requires high levels of adherence to be effective, some at-risk individuals and groups struggle to maintain daily medicine intake. It is important then that the new formulation can be administered as little as six times per year, and 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 advancement, 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 Beginnings

Between the late 1970s and early 1980s, a deadly virus began to spread throughout the US. 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. In 1982, the CDC published a case definition naming the condition AIDS, which was declared to be particularly problematic for certain groups.

These variables led to considerable public panic, with homosexuals and drug users bearing the brunt of blame. Some researchers 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. It wasn’t until 1985 that President Reagan first mentioned AIDS publicly for instance, suggesting it was a “top priority” in response to a reporter. More than 70 million people have been infected with HIV worldwide, and roughly 35 million have died from AIDS since the start of the epidemic.

Treating the problem

HIV can integrate into the DNA of long-lived immune system cells and remain dormant for many years. These infected cells can hide in lymphoid tissue, such as the lymph nodes, liver, and spleen, and are difficult for the immune system to reach. Despite widespread efforts, it had proven difficult to treat for many years. Perhaps the biggest revelation in the virus’ early years came when scientists, in 1983, departed from the pathogenic doma and suggested that HIV/AIDs was a retrovirus. Back then, the belief that retroviruses were, by definition, not amenable to therapy remained strong.

This discovery led to the first major therapeutic breakthrough in 1987, when scientists identified azidothymidine (AZT) – a compound originally developed in the 1960s as a way to thwart cancer. They found it was able to block essential enzymes required for HIV replication and effectively stop or slow the virus’s progression. The FDA then approved AZT under a fast track program, but soon realised that the treatment had severe side effects (such as liver problems and low blood cell counts), especially with long-term use. 

New treatments, with similar mechanisms to AZT, were needed; scientists later discovered saquinavir and nevirapine. These drugs targeted different stages of the virus's life cycle. Saquinavir prevents the maturation of HIV by inhibiting the protease enzyme, whereas nevirapine blocks reverse transcriptase, an enzyme HIV needs to convert its RNA into DNA – both received FDA approval over the following years. In many ways, it was this widespread effort that 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. There was just one problem: it required an extensive medication regimen that 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, which combined two antiretroviral drugs into one.

The most recent 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. This is another treatment that focuses on management; there is still no definitive cure, so research continues.

The Future
 

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. Though one of the big challenges here is identifying and effectively targeting all viral reservoirs.

CRISPR/Cas9 technology has also shown promise in targeting and removing HIV DNA from infected cells, which, if refined, could 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. 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 procedure is still not viewed as a feasible strategy to scale up to the millions of people living with HIV globally.

Advancements in prevention and treatment, from the early struggles in the 1980s to the introduction of combination therapies like HAART, have been significant; an HIV diagnosis no longer defines a patient’s life. The future, as we’ve shown, holds many prospects – hopefully the sort that can offer more effective therapeutics and, potentially, a cure across all stratifications of global society.