Novel investigational combo a breakthrough in HIV treatment?

Phase II data presented at CROI 2024 demonstrated the ability of an investigational, long-acting, oral once-weekly regimen comprising islatravir, a nucleoside reverse transcriptase translocation inhibitor, and lenacapavir, a first-in-class capsid inhibitor, to maintain viral suppression at week 24 in virologically suppressed people living with HIV (PWH).

“[Our findings show that the] islatravir-lenacapavir combination has the potential to become the first oral weekly complete regimen for the treatment of HIV-1 infection,” said Dr Amy Colson from the Community Resource Initiative, Charlestown, Massachusetts, US, at CROI 2024.

One participant on the combo regimen had a viral load of ≥50 copies/mL per FDA Snapshot algorithm at week 24 but was later suppressed by week 30. No participant was able to achieve the primary outcome in the comparator arm, which comprised patients who continued bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg (B/F/TAF). [CROI 2024, abstract 208]

Week 24 also saw a high rate of viral suppression (HIV-1 RNA <50 copies/mL) with the combo regimen (94.2 percent). This rate mirrored that observed in the B/F/TAF arm.

Safety profile

Grade 1/2 treatment-related adverse events (TRAEs) occurring in ≥2 recipients of the combination regimen included dry mouth and nausea (3.8 percent each). There were no grade 1/2 TRAEs with B/F/TAF.

No grade 3/4 drug-related TRAEs were reported in either arm. Three participants on the combination regimen reported serious AEs; two discontinued the combo owing to AEs unrelated to the regimen.

Five combo recipients had grade 3 laboratory abnormalities, the most common being decreased creatinine clearance and non-fasting hyperglycaemia; one had a grade 4 event (increased creatine kinase). In the B/F/TAF arm, the corresponding numbers were four and 0.

Moreover, no differences were seen between the combo and B/F/TAF arms for changes in CD4+ T cell counts (mean change –4 vs –57 cells/µL; p=0.3477) or absolute lymphocyte counts (mean change –0.04 vs –0.01 x 10³ cells/µL; p=0.6301). None from either arm discontinued their regimens due to reductions in CD4 or absolute lymphocyte count.

May transform HIV treatment landscape

Colson and team randomized 104 virologically suppressed adults on B/F/TAF (median age 40 years) 1:1 to oral islatravir 2 mg + lenacapavir 300 mg QW or to continue daily B/F/TAF. Eighteen percent of the study participants were assigned female at birth.

“HIV treatment is not one-size-fits-all. Developing once-weekly treatment options could help meet the needs of each [patient], aiming toward maximizing long-term outcomes for PWH,” said Dr Jared Baeten, HIV Clinical Development, Gilead Sciences, in another report. [https://www.gilead.com/news-and-press/press-room/press-releases/2024/3/gilead-and-merck-announce-phase-2-data-showing-an-investigational-oral-once-weekly-combination-regimen-of-islatravir-and-lenacapavir-maintained-viral]

“Once-weekly oral antiretrovirals have the potential to address pill fatigue and adherence to challenges related to daily oral treatment for HIV-1 infection,” said Colson. Islatravir and lenacapavir have several mechanisms of action, potent antiretroviral activity at low doses, and long half-lives allowing for weekly dosing. [CROI 2022, abstract 433; AIDS 2022, abstract PESUB23; Clin Trans Sci 2021;14:1935-1944]

“The promising data presented … help bring us one step closer to our goal of providing a wide range of options that may help transform the HIV treatment landscape,” Baeten added.

Dr Elizabeth Rhee, vice president, Global Clinical Development, Merck Research Laboratories, backed Baeten’s sentiments. “Our strategies for managing and treating HIV must evolve with the needs of the HIV community and we are excited to have these promising first data.”

The open-label extension phase (through week 48) is ongoing; findings shall provide longer-term data to validate the efficacy and safety of the islatravir-lenacapavir combination.

Lenacapavir is the first and only approved capsid inhibitor-based, twice-yearly treatment alternative for individuals with multidrug resistant HIV. [https://www.gilead.com/news-and-press/press-room/press-releases/2022/12/sunlenca-lenacapavir-receives-fda-approval-as-a-firstinclass-twiceyearly-treatment-option-for-people-living-with-multidrug-resistant-hiv] Its use for HIV prevention has yet to be established.

Islatravir, alone or in combination with lenacapavir, is investigational and has yet to receive approval from regulatory authorities.