Once-weekly combination of islatravir and lenacapavir safe and effective in 48-week study
Keith Alcorn, reporting from HIV Glasgow, 12 November 2024
A once-weekly oral combination of two investigational antiretrovirals, islatravir and lenacapavir, maintained high rates of viral suppression 48 weeks after a switch from daily treatment, HIV Drug Therapy Glasgow 2024 heard this week.
Islatravir is the first nucleoside reverse transcriptase translocation inhibitor (NRTtI). Early studies of the drug found that the doses used in those trials caused suppression of total lymphocyte counts and CD4 cell reductions, so Merck has continued development of the drug at lower doses. Its long half-life in the body means that islatravir can be dosed once a week.
Pharmacokinetic modelling indicates that lymphocyte suppression is not expected at the 2mg dose used in this study. Lenacapavir is the first capsid inhibitor. Developed by Gilead Sciences, lenacapavir can be injected subcutaneously, allowing for six-monthly dosing in the form of Sunlenca (approved in 2022). Lenacapavir is approved in Europe and the United States for treatment of highly treatment-experienced people with HIV who cannot construct a viable antiretroviral regimen otherwise. It is also being investigated as treatment for virologically suppressed or previously untreated people with HIV, in combination with other antiretrovirals, and as pre-exposure prophylaxis (PrEP). Gilead and Merck are collaborating to develop lenacapavir and islatravir as the first once-a-week oral HIV treatment.
At HIV Glasgow 2024, Dr Amy Colson of Community Research Initiative, Boston, presented results of a phase 2b trial that randomised 104 virologically suppressed adults on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) to switch to once-weekly lenacapavir (300mg) and islatravir (2mg) tablets or to continue taking B/F/TAF. People with HIV were eligible to join the study if they had viral load below 50 copies/ml on B/F/TAF for at least 24 weeks prior to study entry, no history of virological failure, a CD4 count above 350 cells/mm3 and a total lymphocyte count of at least 900 cells/mm3. The study excluded people with active hepatitis B infection and people with documented resistance to nucleoside or non-nucleoside reverse transcriptase inhibitors. Nineteen of 104 study participants were female, 50% were White, 35% Black, 28% Latino and 7% were Asian, Native American or Pacific Islander. The median age of participants was 40 years.
After 48 weeks of follow-up, virological data were available for 49 participants in the isltatravir / lenacapavir arm and 48 in the B/F/TAF arm (due to six discontinuations and one person with missing virological data at week 48). By intent-to-treat analysis, 94% assigned to isltatravir / lenacapavir and 92% assigned to B/F/TAF had viral load below 50 copies/ml at week 48. All participants on study treatment at week 48 had viral load below 50 copies/ml.
Two treatment discontinuations due to non-drug-related adverse events occurred during the study, one due to a perforated bowel and the other to acute infection with hepatitis B. No participant discontinued treatment due to drug-related adverse events. Changes in CD4 cell counts or total lymphocyte counts did not differ significantly between the two groups. Treatment-related adverse events were more common in the isltatravir / lenacapavir group (19.2% vs 5.8%) but all reported adverse events were graded mild to moderate (grade 1 or 2). The only events reported by at least two people in the isltatravir / lenacapavir group were dry mouth and nausea. There was no significant difference between study arms in changes in body weight or body mass index; in both cases, changes were negligible. There was no significant difference between study arms in changes in CD4 count or total lymphocyte count – both counts remained stable in both study arms over 48 weeks of follow-up. No participants discontinued treatment due to declines in CD4 count or total lymphocyte count.
The case of hepatitis B acquisition during the study highlights the need for immunisation against hepatitis B for participants in clinical trials of regimens that do not include tenofovir, a panel discussion after the presentation agreed.
Two phase 3 studies of the combination are now recruiting. ISLEND-1 will compare isltatravir / lenacapavir with B/F/TAF in virologically suppressed people; ISLEND-2 will compare isltatravir / lenacapavir with participants’ existing guideline-recommended two- or three-drug regimens in virologically suppressed people.
Reference
AE Colson. Once-weekly islatravir plus lenacapavir in virologically suppressed PWH: week 48 safety, efficacy and metabolic changes. HIV Glasgow 2024, abstract O1.
Reporting from HIV Glasgow 2024 by Keith Alcorn, Gus Cairns and Roger Pebody has been financially supported by the Congress. The writers are editorially independent of the Congress and the presenting speakers.
Photo credit: Alan Donaldson Photography