It’s the end of the road for monthly oral islatravir as HIV PrEP

While there is continued excitement about the promise of injectable products to prevent HIV, there have also been questions about the possibility of other long-acting agents, including oral options.

While long-acting oral HIV prevention medications remain a focus of research, at the 5^th Conference on HIV Research for Prevention (HIVR4P 2024) in Lima, Peru, this month, the door closed on one investigational agent: islatravir, a once-promising candidate with high efficacy whose development has been short-circuited by safety concerns.

Islatravir is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) that has an exceptionally long half-life in the body (192 hours), which made it a potentially ideal long-acting drug for both the treatment and prevention of HIV.

However, there have long been concerns about total lymphocyte and CD4 cell declines seen among study participants receiving islatravir. The U.S. Food and Drug Administration (FDA) placed a clinical hold on research involving the drug in late 2021, which included pausing enrollment on two Phase 3 pre-exposure prophylaxis (PrEP) studies, IMPOWER 22 and IMPOWER 24. This was later extended by the FDA to a full clinical hold, which stopped any provision of islatravir to trial participants.

However, investigators continued to monitor CD4 cells and total lymphocyte counts to check for signs of recovery. The full safety and efficacy data for both studies were presented at HIVR4P 2024 this month.

IMPOWER 22 and 24 Results

IMPOWER 22 and IMPOWER 24 both investigated the efficacy of islatravir as once-monthly oral PrEP: the former in cisgender women, the latter in cisgender men and transgender women. In both instances, islatravir was compared to an existing effective form of oral PrEP, daily FTC/TDF.

Renee Heffron, Ph.D., M.P.H., from the University of Alabama at Birmingham presented results from IMPOWER 22 at HIVR4P 2024.

As women and girls account for approximately 62% of all new HIV cases in sub-Saharan Africa, IMPOWER 22 recruited participants in four sites within that region: Eswatini, Kenya, Malawi, and South Africa. In the double-blind phase, the trial originally intended to recruit a total of 4,500 participants who were between ages 16 and 45, did not have HIV, were sexually active, and were deemed to have an increased chance of contracting HIV. However, as the blinded phase and enrollment were stopped early, only 727 participants were recruited and randomized, 362 to the islatravir arm and 365 to the FTC/TDF arm. The median age of participants was 25, with the majority being Black (92%) and from South Africa (90%), and most were PrEP-naïve, with only 4% having used any PrEP before.

In the double-blind phase, no participants in either arm acquired HIV. This protection was maintained for 42 days after discontinuation of islatravir, which represents five half-life cycles of the drug.

Once enrollment was stopped due to CD4 concerns, participants who had been on islatravir were offered FTC/TDF for the remainder of the trial. In this open-label phase, 23 out of 727 participants who continued in the study acquired HIV, or around 3%. Seventeen of these participants were initially assigned to take islatravir and six were assigned to take FTC/TDF. Among the islatravir-assigned participants, HIV was detected 142 to 473 days after the last dose of the drug.

Heffron’s presentation also included full safety data. In the islatravir group, from baseline to the third month of the blinded phase, there was a 21% decline in the total lymphocyte count. Comparatively, for this period, there was only a 9% decline for participants taking daily FTC/TDF.

Fortunately, lymphocytes appeared to recover after discontinuation: By month 12, after most participants had stopped taking islatravir, an approximately 6% decrease was seen from baseline in those originally assigned to take islatravir, versus a 5% decrease in those originally assigned to take FTC/TDF. Additionally, for those taking islatravir, the CD4 count did not fall below 200 cells/mm³ nor did the total lymphocyte count drop below 500 cells/mm³ at any point.

Adverse events involving infections were common. They were lower in the islatravir group than the FTC/TDF group (22% vs. 41%) during the double-blind phase of the study, but evened out once the open-label phase was included (83% vs. 86%). Bacterial vaginosis, vulvovaginal candidiasis, upper respiratory tract infections, and chlamydia were each experienced by more than 15% of participants across all study phases.

Raphael Landovitz, M.D., M.Sc., from the University of California, Los Angeles, shared the IMPOWER 24 results at HIVR4P 2024. This study was conducted across eight global sites (Brazil, France, Japan, Kenya, Peru, South Africa, Thailand, and the U.S.). Most aspects of the two trials were similar, though IMPOWER 24 aimed to recruit and randomize 1,500 cisgender men and transgender women who have sex with men and were deemed to have an increased chance of contracting HIV. Ultimately, 494 people were enrolled before recruitment was paused.

Participants were randomized to take islatravir (328 people) or FTC/TDF (166 people) prior to the blinded phase being stopped; this study used a 2:1 ratio, unlike IMPOWER 22. The median age was 27, most participants were cisgender males (92%), 42% were white, and a quarter were Black. Over half of the participants were from the U.S. (56%) and had used PrEP before (56%).

As with IMPOWER 22, no HIV acquisitions occurred during the double-blinded phase or 42 days after. In the open-label phase, seven of 460 participants who remained in the trial acquired HIV, five of whom had initially been in the islatravir arm. In these instances, HIV was detected 99 to 329 days after the last dose of islatravir.

As with IMPOWER 22, there were decreases in total lymphocyte count from baseline: Reductions after three months averaged approximately 7% in the islatravir group and 3% in the FTC/TDF group. However, recovery was seen by month 10, after most participants stopped taking islatravir, with a slight increase seen from baseline lymphocyte count in the original islatravir group (+0.9%) and a minor decrease in the FTC/TDF group (-0.4%).

In those assigned to take islatravir, two participants had total lymphocytes drop below 500 cells/mm3, but these were not considered serious adverse events; no participants had CD4 counts drop below 200 cells/mm3 at any point.

The Way Forward for Islatravir and Long-Acting Oral PrEP

While islatravir was generally well-tolerated, and no HIV acquisitions were noted in either study while on the drug, it is not being further developed as oral or implantable PrEP due to concerns about total lymphocyte decreases. However, it is still being investigated at lower doses as part of a treatment regimen for people living with HIV, along with other drugs such as lenacapavir.

However, another NRTTI agent, MK-8527, is being developed as a monthly oral PrEP option and is currently undergoing a Phase 2 trial. When Mitchell Warren of AVAC asked, during Landovtiz’s presentation, if the same issues with lymphocyte decreases could be expected to impact MK-8527, Landovitz stated that the mechanism of the lymphocyte toxicity does not appear to be applicable to the new product. Additionally, the dose is likely to be multiple factors lower, Heffron added, enhancing its safety. However, this will need to be confirmed by the results of the safety trial.

By Krishen Samuel, Ph.D., M.S.P.H.