Once-weekly HIV treatment with the islatravir (ISL) and lenacapavir (LEN) combination shows strong potential to simplify care. Moreover, this oral regimen could significantly improve medication adherence for people living with HIV-1. New results from a Phase 2, randomized, active-controlled study (NCT05052996) demonstrate that once-weekly oral ISL (2 mg) plus LEN (300 mg) effectively maintains high rates of viral suppression comparable to the current daily standard-of-care, bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF).
Adherence remains a critical barrier to long-term success in antiretroviral therapy (ART). Daily regimens pose challenges, especially in settings where patients face travel expenses or fear of social stigma, as documented in India. Therefore, less frequent dosing schedules offer a patient-centred approach to overcome these issues.
Study Design and Key Efficacy Findings for Once-weekly HIV Treatment
The open-label Phase 2 trial enrolled 104 adults already maintaining virologic suppression (HIV-1 RNA viral load <50 copies/mL) on daily B/F/TAF for at least 24 weeks. Participants were randomly assigned to either switch to the once-weekly ISL+LEN regimen or continue daily B/F/TAF. Researchers evaluated virologic outcomes at weeks 24 and 48 using the U.S. FDA Snapshot Algorithm.
At the 24-week primary endpoint, 94.2% of participants in both the ISL+LEN group and the B/F/TAF group maintained HIV-1 RNA viral loads of less than 50 copies/mL. This represents a zero percent difference between the groups (95% CI, -10.9% to 10.9%). Furthermore, the efficacy remained robust through the 48-week mark. At week 48, 94.2% of ISL+LEN participants still showed viral suppression, while the B/F/TAF group maintained 92.3%. Consequently, no participants in either group experienced virologic failure (HIV-1 RNA ≥50 copies/mL) at week 48. These findings strongly support the once-weekly oral regimen as a potent alternative to daily therapy.
Safety and Tolerability Profile
The safety profile of the once-weekly ISL+LEN regimen appears favourable. Importantly, no Grade 3 or greater adverse events (AEs) or serious AEs were reported as treatment-related in either study group. However, two participants in the ISL+LEN arm discontinued treatment before week 24 due to AEs that were determined to be unrelated to the study drug. Changes in CD4 T-cell and lymphocyte counts from baseline to week 48 were similar between the two treatment groups. Additionally, researchers reported no discontinuations of study drug treatment due to decreases in CD4 T cells or lymphocytes, addressing a past concern with higher ISL doses.
Frequently Asked Questions
Q1: What is the main benefit of the once-weekly ISL+LEN regimen?
The main benefit is the potential for overcoming adherence challenges and reducing the burden of daily medication, which could significantly improve the quality of life and long-term treatment success for people with HIV-1.
Q2: What are Islatravir and Lenacapavir, and how do they work?
Islatravir is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI). Lenacapavir is a first-in-class HIV-1 capsid inhibitor. Both drugs possess potent anti-HIV-1 activity and pharmacokinetic profiles that support less frequent, once-weekly oral dosing.
Q3: Is the once-weekly ISL+LEN combination currently approved for use?
No, the combination of islatravir and lenacapavir is still investigational and has not yet been approved by regulatory bodies globally. The promising Phase 2 results support its advancement into ongoing Phase 3 clinical trials.
References
- Colson AE et al. Once-Weekly Oral Islatravir Plus Lenacapavir Versus Daily Oral Bictegravir, Emtricitabine, and Tenofovir Alafenamide in Persons With HIV-1 : A Phase 2 Randomized Study. Ann Intern Med. 2025 Dec 23. doi: 10.7326/ANNALS-25-01939. PMID: 41429026.
- Abstract: Week 48 Results of a Phase 2 Study Evaluating Once-weekly Oral Islatravir Plus Lenacapavir. NIH. (2025-01-29).
- Novel Once-Weekly HIV Treatment with Islatravir and Lenacapavir Shows Promising 94% Viral Suppression at 48 Weeks. Applied Clinical Trials Online. (2024-10-21).
- Adherence to anti-retroviral therapy among HIV patients in Bangalore, India. PMC.