Gilead and Merck report positive Phase 3 ISLEND-1 and ISLEND-2 results showing once-weekly oral islatravir/lenacapavir maintained HIV suppression through 48 weeks.
Written By: Mayuresh Salvi, PharmD
Reviewed By: Pharmacally Editorial Team
Gilead Sciences and Merck have reported positive Week 48 results from the Phase 3 ISLEND-1 and ISLEND-2 trials evaluating the investigational once-weekly oral single-tablet regimen of islatravir 2 mg and lenacapavir 300 mg (ISL/LEN) in adults living with virologically suppressed HIV. The late-breaking data, presented at the 26th International AIDS Conference (AIDS 2026), showed that the regimen maintained high rates of virological suppression with a safety profile generally comparable to current daily oral therapies. The findings will form the basis for global regulatory submissions. ISL/LEN remains investigational and has not been approved for HIV treatment.
Scientific and Clinical Context
Combination antiretroviral therapy has transformed HIV into a chronic, manageable disease, with once-daily single-tablet regimens remaining the standard of care for many people living with HIV. However, lifelong daily treatment can create adherence challenges for some patients. While long-acting injectable therapies have expanded treatment options, a once-weekly oral regimen could provide an alternative that reduces dosing frequency without requiring clinic-administered injections.
The investigational regimen combines islatravir, Merck’s next-generation nucleoside analogue that inhibits HIV replication through multiple mechanisms, including reverse transcriptase translocation inhibition, with Gilead’s first-in-class capsid inhibitor lenacapavir, which disrupts multiple stages of the HIV lifecycle. Their complementary pharmacokinetic properties enable administration as a complete once-weekly oral tablet.
Phase 3 Trials Demonstrate Durable Virological Suppression
The pivotal Phase 3 ISLEND-1 (NCT06630286) and ISLEND-2 (NCT06630299) studies evaluated the efficacy and safety of switching virologically suppressed adults from daily oral antiretroviral therapy to once-weekly ISL/LEN.
ISLEND-1 was a randomized, double-blind study comparing ISL/LEN with continued BIKTARVY® (bictegravir/emtricitabine/tenofovir alafenamide). At Week 48, none of the participants receiving ISL/LEN had HIV-1 RNA levels of at least 50 copies/mL compared with 0.3% of participants who remained on BIKTARVY, meeting the primary endpoint of non-inferiority.
ISLEND-2 was a randomized, open-label study comparing ISL/LEN with standard daily oral antiretroviral regimens. At Week 48, 0.3% of participants receiving ISL/LEN had HIV-1 RNA levels of at least 50 copies/mL compared with 1.3% of participants continuing standard therapy, also demonstrating non-inferiority.
Participants who switched to once-weekly ISL/LEN also reported higher treatment satisfaction and lower treatment burden than those receiving daily oral therapy based on HIV Patient Perspective of Regimen Change assessments.
Safety Profile Remained Comparable to Daily Therapy
The investigational regimen demonstrated a safety profile generally comparable to the comparator treatments, with no new safety concerns identified.
In ISLEND-1, treatment-related adverse events occurred in 13.5% of participants receiving ISL/LEN and 13.2% of those continuing BIKTARVY. Serious adverse events occurred in 5.3% and 4.6% of participants, respectively, while treatment discontinuations due to adverse events remained low at 2.0% and 1.7%.
In ISLEND-2, treatment-related adverse events occurred in 18% of participants receiving ISL/LEN compared with less than 1% among those continuing standard daily therapy. The most frequently reported treatment-related adverse events included headache, nausea, and diarrhea. Discontinuations due to adverse events remained low at 1% in the ISL/LEN group and less than 1% in the comparator group.
Across both studies, CD4+ T-cell counts and lymphocyte counts remained stable through Week 48, with no participant discontinuing treatment because of declines in these measures. Body weight also remained stable, with no clinically meaningful differences between treatment groups.
Expert Perspectives
Jürgen Rockstroh, MD, of the Department of Medicine at University Hospital Bonn, Germany, said that while once-daily single-tablet therapy remains the cornerstone of HIV treatment, the treatment landscape continues to evolve with long-acting options. He noted that the ISLEND-1 findings highlight the potential of ISL/LEN to become the first once-weekly oral single-tablet treatment for people living with HIV.
Amy Colson, MD, Research Director at Community Resource Initiative and Medical Director of the Zinberg Clinic at Cambridge Health Alliance, said that a once-weekly oral regimen could expand treatment choices by addressing individual patient needs and preferences while supporting long-term HIV management.
Future Development
The Week 48 results from ISLEND-1 and ISLEND-2 position ISL/LEN as a promising investigational option for adults with virologically suppressed HIV. Gilead and Merck plan to use these findings to support global regulatory submissions. If approved, ISL/LEN could become the first once-weekly oral single-tablet HIV treatment, offering an additional treatment option for people seeking an alternative to daily oral antiretroviral therapy while maintaining high levels of virological suppression.
What This Means for Patients
For people living with HIV who have achieved virological suppression on daily antiretroviral therapy, a once-weekly oral treatment could offer greater flexibility without compromising effectiveness. In the Phase 3 ISLEND-1 and ISLEND-2 trials, the investigational islatravir/lenacapavir regimen maintained viral suppression through 48 weeks with a safety profile generally comparable to current daily therapies. Participants who switched to the once-weekly regimen also reported higher treatment satisfaction and a lower treatment burden. If approved by regulatory authorities, ISL/LEN could become the first once-weekly oral HIV treatment, providing an additional option for adults who prefer less frequent dosing while maintaining long-term control of HIV. It remains investigational and is not yet available for clinical use.
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About the Writer
Mayuresh Sunil Salvi (Linkedin) is a PharmD professional and healthcare writer with a strong interest in pharmacovigilance, drug safety, and emerging medical research. He is passionate about exploring new drug discoveries, clinical research, and advances in evidence-based medicine. His interests also include ward rounds, prescription audits, and treatment analysis to support rational pharmacotherapy and improved patient care.