Once-Weekly Oral Islatravir Plus Lenacapavir Maintains HIV Suppression Through 48 Weeks

Once-weekly oral islatravir (ISL) 2 mg plus lenacapavir (LEN) 300 mg maintained high rates of virologic suppression through 48 weeks in adults with HIV-1 who were already suppressed on daily bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), according to a phase 2, randomized, open-label, active-controlled study conducted across 44 US sites.

The findings point to a potential oral, longer-interval treatment option that may help address adherence challenges associated with daily antiretroviral therapy, such as pill fatigue and treatment fatigue. Confirmation of efficacy and safety in larger, more diverse populations is ongoing in phase 3 trials.

To contextualize the clinical relevance of these data, Contagion spoke with Amy Colson, MD, MPH, medical director of the Zinberg Clinic at Cambridge Health Alliance and research director at Community Resource Initiative.

Contagion: For clinicians reading these data, can you briefly describe the phase 2 study design and the patient population enrolled, and who you think these findings are most applicable to in practice?

Colson: The study was a randomized, open-label, active-controlled trial conducted at 44 sites in the United States. Eligible participants were adults with HIV-1 infection and virologic suppression (HIV-1 RNA < 50 copies/ml) for at least 24 weeks on treatment withbictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).A total of 104 individuals were randomized in a 1:1 ratio to switch to weekly islatravir and lenacapavir or to remain on BIC/FTC/TAF. The primary endpoint of the study was the proportion of participants with an HIV RNAgreater than or equal to 50 copies/ml at week 24.At week 48, all participants were given the opportunity to enter an extension phase and receive the experimental weekly regimen.

She added: These findings are most applicable to adults with HIV-1 infection, virologic suppression, and no history of antiretroviral treatment failure.

Contagion: What are the key efficacy takeaways at weeks 24 and 48, particularly regarding virologic suppression rates and the single participant with detectable viremia at week 24 who later resuppressed?

Colson: ISL+LEN demonstrated high efficacy in this phase 2 trial. At week 24, one participant in the ISL + LEN group and no participants in the BIC/FTC/TAF group had HIV-1 RNA viral load of 50 copies/mL or more.In both the ISL +LEN and BIC/FTC/TAF treatment groups, 94.2% of participants maintained an HIV-1 RNA viral load of less than 50 copies/mL at week 24 . High efficacy was sustained at week 48.No participants in either group had HIV-1 RNA viral load of 50 copies/mL or more at week 48, and viral suppression was maintained by 94.2% in the ISL + LEN group and 92.3% in the BIC/FTC/TAF group

She continued: The participant in the ISL plus LEN group with an HIV RNA > 50 at week 24 actually entered the study with viremia (HIV-1 RNA 251 copies/mL on their day 1 visit after an undetectable measurement at their screening visit) and again demonstrated detectable HIV-1 RNA at week 24 (HIV-1 RNA <100 copies/mL) but resuppressed by week 30 on continued ISL + LEN treatment. Based on self report, pill counts and PK parameters, it appears that this individual took the ISL + LEN correctly

Contagion: Based on this study, what should clinicians know about resistance risk with once-weekly oral islatravir plus lenacapavir, and what was observed in participants who underwent resistance testing?

Colson: Based on the phase 2 data, the risk of treatment-emergent resistance to LEN or ISL appears to be quite low. In fact, no emergent resistance to ISL or LEN has been detected in this study by genotypic or phenotypic analysis, including in the one individual who had low level viremia on ISL+LEN at week 24 and then re-suppressed on this regimen.

Contagion: Can you summarize the main safety findings, including adverse events and CD4+ T-cell or lymphocyte changes, and whether any safety signals stood out through week 48?

Colson: No significant safety concerns emerged during this phase 2 trial. Importantly, there were no treatment-related grade 3, grade 4, or serious adverse events in either group. Adverse events related to ISL+LEN were all grade 1 or grade 2 and occurred in 19% of participants versus 6% in the BIC/FTC/TAF group. It is worth keeping in mind that there is often a higher rate of treatment-related adverse events observed in the experimental arm of an open label switch study. The most common treatment related AE’s in the ISL+ LEN group were diarrhea and dry mouth, each of which occurred in 2 participants.

This phase 2 trial provides reassuring data regarding the impact of ISL on CD4 cells. In prior studies, higher doses of ISL were associated with decreases in CD4+ T-cell and lymphocyte counts. However, in the current study, which used a relatively low ISL dose of 2 mg per week,the CD4 count remained stable in both treatment groups through week 48.Specifically,the mean change from baseline to week 48 in CD4+ T-cell count was –12 (SD, 214.7) cells/µL in the ISL plus LEN group and –29 (SD, 186.1) cells/µL in the BIC/FTC/TAF group. The absence of any observed decline in CD4 count is consistent with modeling predictions for ISL dosed at 2 mg weekly

Contagion: What do you see as the main clinical implications of these results, what key limitations should clinicians keep in mind, and what questions the phase 3 ISLEND studies are designed to answer?

Colson: Key limitations for this study include the small sample size, restriction to US sites only, and the open label design. As in all open label studies, knowledge of treatment assignment could bias the reporting of adverse events.

She added: The results of this phase 2 trial are encouraging for the HIV community. If the robust efficacy and safety data are confirmed in the ongoing phase 3 ISLEND studies, ISL+LEN could become the first once-weekly treatment option for people living with HIV-1 infection.Clinicians who care for people with HIV recognize how daily pill taking can generate adherence-anxiety, raise privacy concerns, and serve as a frequent reminder of HIV status. Addressing these day-to-day stressors could lead to meaningful improvement in quality-of-life which is particularly important when we are dealing with a medical condition which requires lifelong treatment.

The phase 3 studies are larger and will evaluateISL/LEN in a global population, providing robust safety, efficacy and patient-reported-outcomes data from diverse regions making the results more generalizable to the global community of people living with HIV.

Beyond the points addressed in the interview, adherence by pill count was high in both arms, with a median adherence of 100% in the ISL+LEN group and 98.8% in the B/F/TAF group through week 48. The proportion of participants achieving adherence rates of at least 95% was higher with once-weekly ISL+LEN than with daily B/F/TAF. No participants discontinued treatment due to lack of efficacy, and no clinically meaningful differences were observed between groups in weight or body mass index over the study period.

In this phase 2 randomized trial, once-weekly oral islatravir plus lenacapavir maintained virologic suppression comparable to daily B/F/TAF through 48 weeks in virologically suppressed adults with HIV-1, with no treatment-related grade 3 or higher or serious adverse events and no emergent resistance detected. While limited by sample size, open-label design, and US-only enrollment, the findings support continued evaluation of this once-weekly oral regimen in ongoing global phase 3 studies.

Reference

Colson A, Crofoot G, Ruane P, et. al. Once-Weekly Oral Islatravir Plus Lenacapavir Versus Daily Oral Bictegravir, Emtricitabine, and Tenofovir Alafenamide in Persons With HIV-1. Annals of Internal Medicine. https://www.acpjournals.org/doi/10.7326/ANNALS-25-01939