Milestones and Recent Advances in HIV Research

In 1981, reports emerged of strange illnesses afflicting otherwise young and healthy gay men in the United States such as pneumocystis pneumonia and Kaposi’s sarcoma, a rare cancer usually found in much older adults [3, 4]. Given the prevalence of these illnesses in the gay community, this disease was originally coined as gay-related immune deficiency (GRID). However, in 1982, the condition was renamed as AIDS after evidence revealed that the syndrome was not exclusive to the gay community [4].

In 1983, scientists determined that a then-novel retrovirus is the cause of AIDS [3, 5]. HIV is a retrovirus that attacks CD4+ T cells, which play a central role in helping the immune system to recognize pathogens and mount an appropriate defense. HIV replicates within these cells with the aid of three virally encoded enzymes: reverse transcriptase, integrase, and protease [1, 6]. Reverse transcriptase is used to produce DNA from the virus’ RNA genome, which is integrated into the host cell’s DNA with the help of the integrase enzyme. Protease cleaves protein precursors to build new, complete viral particles, which assemble at the cell surface and are released to infect other CD4+ T cells in the body. As the population of T cells is depleted, the immune system slowly loses its ability to effectively protect itself. If left untreated, HIV infection will usually progress to AIDS. While HIV/AIDS is not itself fatal, the resulting susceptibility to opportunistic infection and cancer is deadly [1].

Following early research efforts to characterize HIV/AIDS, the first anti-HIV medication, a drug called azidothymidine (AZT), was found to be effective and was made available in 1987 [4]. Researchers had discovered that AZT, an ineffective drug from the 1960s originally developed to treat cancer, could reduce mortality and the number of opportunistic infections in individuals with AIDS [7]. AZT works by inhibiting HIV’s reverse transcriptase enzyme and thus belongs to a class of drugs called nucleoside reverse transcriptase inhibitors (NRTIs). One of the limitations of single-treatment drugs such as AZT, however, is that viruses mutate quickly and can evolve, rendering treatments ineffective.

While more NRTIs became available, researchers also focused on different mechanisms of action to target HIV. As a result, the first protease inhibitor (PI) was approved by the Food and Drug Administration (FDA) in 1995 [8]. Similar to NRTIs, PIs have been shown to reduce viral loads in patients with HIV, but target the protease enzyme to prevent virus maturation. Further developments in anti-HIV therapy include the approval of the first non-nucleoside reverse transcriptase inhibitor (NNRTI) in 1996, the first entry inhibitor in 2003, and the first integrase strand transfer inhibitor (INSTI) in 2008 [9].

The standard of care for HIV patients was revolutionized in the late 1990s when physicians began prescribing combination therapies, which are known as highly active ART (HAART) or combination ART (cART) [4, 10]. HAART greatly improved the life expectancy of people with AIDS, but required multiple pills daily, resulting in decreased adherence to prescribed treatment protocols. A combination pill containing two anti-HIV medications was approved in 1997 to address this problem [11].

More recently, long-acting ART (LA-ART) has further revolutionized anti-HIV therapy. In 2021, the first combination long-acting injectable ART (LAI-ART), cabotegravir and rilpivirine, was approved by the FDA [12]. Cabotegravir is an INSTI with a high barrier to resistance and a high antiviral potency [13], while rilpivirine is a potent NNRTI that is active against NNRTI-resistant HIV [14]. It’s an effective combination: together, the drugs are highly potent and last a long time due to their strong antiretroviral activity and long half-life [15]. When formulated into a suspension, pure nanosized drug crystals are produced, which is suitable for intramuscular depot injection [13 – 15].

LAI-ART like cabotegravir and rilpivirine is convenient in that the daily pill burden of traditional ART is decreased to only six or twelve intramuscular injections per year [15]. Furthermore, these drugs are administered under direct medical supervision, thereby overcoming treatment adherence problems associated with traditional ART. In addition to convenience, LAI-ART also reduces the social stigma associated with the daily oral intake of anti-HIV treatments, which can provide tremendous emotional benefits to people living with HIV.

Researchers are also developing long-lasting implants as therapy as well as antibody-based strategies. Islatravir is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) that is intended to be formulated as an implant with a dosing interval of one year or greater [16]. NRTTIs act as a reverse transcriptase chain terminator and prevent DNA translocation. The drug lenacaptavir is also currently being evaluated in combination with islatravir and is a first-in-class capsid inhibitor which interferes with multiple capsid-dependent functions required for viral replication [15]. Notable antibody-based strategies for LAI-ART include ibalizumab and leronlimab, which are humanized IgG4 antibodies directed towards CD4 and CCR5, respectively [17]. Ibalizumab is injected every two weeks intravenously, while leronlimab is injected subcutaneously every week, both of which follow a more frequent dosing regimen compared to other LAI-ARTs [15].

LA-ART is not without its limitations, however. Currently available LA-ARTs are administered at fixed standard doses which do not take into account a patient’s weight or host factors that influence their systemic disposition [15]. Although patients receiving LAI-ART appreciate its convenience, many patients report immense pain and discomfort at the injection site [18]. Current and future formulation efforts are intended to alleviate injection-induced pain by extending injection intervals or by using microneedle patches.

Globally, approximately 37.7 million people were living with HIV in 2020, with approximately 1.5 million people newly infected [2]. Both HIV infection rates and AIDS-related mortality have decreased dramatically with the advent of ART. In 2020, 680,000 people died of an AIDS-related illness, a figure that has decreased by nearly 50% since 2010 [2].

Unsurprisingly, people living with HIV experience more severe outcomes from COVID-19 and higher comorbidities than the general population. Recent studies have reported that HIV infection increases the likelihood of hospitalization and mortality due to COVID-19. [19, 20]. As recently as mid-2021, most people living with HIV have not had access to COVID-19 vaccines, particularly in sub-Saharan Africa [2].

COVID-19 lockdowns and other restrictions have also disrupted HIV testing, diagnosis, and referrals for treatment. In 32 African and Asian countries, HIV testing has declined by 41% since the first COVID-19 lockdown compared to the same time period in 2019 [2]. Referrals for diagnosis and treatment have also declined by 37% during this period [2].

The U=U campaign was developed to spread awareness of the high efficacy of current HIV medications [21]. An individual living with HIV cannot sexually transmit the virus to others if the viral load is suppressed by effective treatment to the point where it is undetectable in the blood (< 200 copies/mL) [22]. An undetectable viral load does not mean that an individual is cured of HIV, but it does protect their immune system and can alleviate the anxiety of passing HIV onto a partner.

While there is still no cure for HIV, those with access to anti-HIV therapy now have a near-normal life expectancy. Researchers hope that the advent of LA-ART will improve the quality of life for individuals with HIV and lower the stress of traditional ART adherence. Importantly, advances in anti-HIV therapy over the past few decades have turned a deadly disease into a manageable chronic condition.