Snapshots of HIV prevention and treatment drugs under development

The landscape of HIV treatment and prevention has been revolutionized by the emergence of long-acting drugs. Since 2021, we have had long-acting injectable anti-retroviral therapy (ART) and pre-exposure prophylaxis (PrEP) agents approved for use by most people living with or vulnerable to HIV, respectively. Cabotegravir/rilpivirine (Cabenuva) for treatment and cabotegravir (Apretude) for PrEP can be administered by intramuscular injection at monthly or bi-monthly intervals. Just as the introduction of single-tablet regimens transformed and challenged our perception of HIV treatment nearly two decades ago, these long-acting agents are doing it again, and it’s only the beginning. Several other medications are working their way through the drug development pipeline with the goal of providing our communities what they have long been asking for—multiple options and modalities that align with our individual needs to promote care engagement for all people impacted by HIV.


Lenacapavir (Sunlenca) belongs to a new class of drugs called capsid inhibitors that work by stopping HIV from replicating at multiple points of its life cycle. It can be administered by subcutaneous injection every six months and is being studied for both HIV treatment and prevention. As it is given subcutaneously (just beneath the skin), lenacapavir has the potential to be self-administered. This, in addition to its twice-yearly dosing, makes it a very exciting option that bypasses many of the constraints noted with Cabenuva and Apretude—mainly their need for patients to attend injection appointments at a clinic or infusion center every two months.

Lenacapavir was approved for use in December 2022 for treatment-experienced adults with multidrug-resistant HIV who are unable to maintain virologic suppression on their current regimen. However, lenacapavir cannot be given on its own for treatment—it needs to be combined with an optimized ART regimen. This would typically require other oral drugs; however, there is a study proposed to the AIDS Clinical Trials Group to examine lenacapavir with long-acting cabotegravir in people with drug resistance. If proven to be successful, this combination of treatment would have a global impact. The World Health Organization (WHO) estimates 10% of people living with HIV worldwide carry resistance to non-nucleoside reverse transcriptase inhibitors including rilpivirine; this is a dealbreaker to the implementation of Cabenuva specifically in sub-Saharan Africa and Asia. However, a treatment combination of lenacapavir and cabotegravir would provide a scalable long-acting ART option for the world.

Lenacapavir for PrEP

After showing promise in early clinical trials, lenacapavir has entered two large Phase 3 trials evaluating its use as PrEP. As a Phase 3 trial, researchers will work to confirm lenacapavir’s effectiveness in preventing HIV, monitoring its side effects compared to commonly used PrEP drugs in large groups of people.

PURPOSE 1 is evaluating the safety and efficacy of lenacapavir compared to oral emtricitabine/tenofovoir (brand name Truvada) in preventing HIV infection in adolescent girls and young women.

PURPOSE 2 is a similar study assessing the safety and efficacy of lenacapavir as PrEP in cisgender men, transgender men, transgender women and nonbinary individuals vulnerable to HIV. Positive data from these trials would support FDA approval for lenacapavir as PrEP.

The availability of a twice-yearly, potentially self-administered option for PrEP would be a game changer for the field of HIV prevention in our ongoing efforts to de-medicalize PrEP and improve its accessibility to people who need it the most.


Islatravir belongs to a new class of drugs called nucleoside reverse transcriptase translocation inhibitors that work by stopping reverse transcription, a key stage in HIV replication. It has been studied in both treatment and prevention through multiple modalities including daily oral pill, weekly oral pill, monthly oral pill and ultra-long-acting drug-eluding implant. Islatravir was undergoing multiple studies as options for both long-acting treatment and long-acting prevention until trials were placed on hold in 2021 due to declining CD4 counts and total lymphocyte counts (TLC) observed in both its treatment and prevention trial participants. After looking at these cases closely, it was determined that this was likely a side effect of using too high a dose of the drug. The lower doses that were also being studied were not associated with this side effect.

A Phase 3 HIV treatment study evaluating a daily oral regimen of islatravir at a lower dose with doravirine (Pifeltro) has resumed in people living with HIV. Regarding its long-acting formulation, an early Phase 2 HIV treatment study has been initiated evaluating the safety and efficacy of islatravir in combination with lenacapavir as a once-weekly oral ART regimen in virologically suppressed people with HIV. If shown to be safe and effective in this smaller trial, once-weekly oral islatravir and lencapavir will proceed to a larger Phase 3 study.

Unfortunately, the future of long-acting oral islatravir for PrEP is much less certain. Many see this option as dead in the water since the study examining monthly oral islatravir as PrEP has been formally discontinued with no future studies looking at lower-dose islatravir for HIV prevention planned.

Islatravir for PrEP

However, an islatravir-eluding subdermal implant has completed a Phase 1 study in which researchers determined its potential as an effective and well-tolerated PrEP modality. Data show that the islatravir implant could provide protection from HIV-1 for longer than a year, comparable to long-acting reversible contraceptives (LARC). A Phase 2 study examining the islatravir-eluding implant for PrEP has been announced. Of note, the islatravir implant is based on the design used for [the LARC] Nexplanon and can be implanted by the same device. This sets up a future in which long-acting PrEP and LARC can be co-administered; prioritizing co-location of PrEP and reproductive services is critical to bridge the PrEP gap in cisgender women and other individuals of childbearing potential.

Broadly neutralizing antibodies (bnAbs)

Broadly neutralizing antibodies (bnAbs) are another newer category of HIV drugs. They are actively being studied for both treatment and prevention. These antibodies target a part of the virus that does not change or mutate very much and should remain effective for most people with HIV. Similar to neutralizing antibody therapy used to treat COVID-19 and RSV, bnAbs bind to the virus to effectively stop HIV replication and its spread.

There is a Phase 2 HIV treatment study examining the safety and efficacy of two bnAbs in addition to lenacapavir dosed every 6 months in virologically suppressed people with HIV. Initial Phase 1 data demonstrated that 90% of participants who transitioned to this regimen of two bnAbs with lenacapavir remained virologically suppressed at six months, showing promise in a twice-yearly ART regimen.

bnAbs for PrEP

Data for bnAbs in HIV prevention are a bit more disappointing. Two large Phase 2 PrEP studies found that use of a single bnAb did not prevent HIV acquisition, but the study data did provide proof-of-concept that bnAb prophylaxis could be effective, and may need to be used in combination with other bnAbs. There are several Phase 1 studies evaluating the safety and tolerability of multiple bnAbs administered together. Pending these results further trials studying combination bnAbs as PrEP may occur.

Future directions and lessons learned

This is an incredibly exciting time for HIV treatment and prevention; in addition to these new drug classes, there are many more long-acting modalities in early stages of development. These include drug-eluding implants for a variety of agents, including dolutegravir, which have the potential to work for a year if not longer.

However, inequities seen in access to existing HIV treatment and prevention options will only be magnified with the approval of these long-acting agents if we don’t have reductions in prescription drug costs. The pricing of the only approved long-acting PrEP drug, Apretude, has been shown not to be a cost-effective option for PrEP. This impacts drug coverage by both private and public payors, ultimately placing it out of the reach of populations most impacted by HIV. We must ensure newer options are made available at scale with consideration of drug pricing and community-informed implementation. Doing so enables long-acting HIV treatment and prevention strategies to reach the people who need them and shortens our distance to ending the HIV epidemic.

Aniruddha Hazra, MD, is an assistant professor at the University of Chicago’s Section of Infectious Diseases and Global Health and serves as a clinical ambassador for the CDC’s Let’s Stop HIV Together campaign.