Once-Weekly Oral Islatravir Plus Lenacapavir Versus Daily Oral Bictegravir, Emtricitabine, and Tenofovir Alafenamide in Persons With HIV-1 : A Phase 2 Randomized Study

Amy E. Colson, Community Resource Initiative, Boston, and Cambridge Health Alliance, Cambridge, Massachusetts (A.E.C.).
Gordon E. Crofoot, The Crofoot Research Center, Houston, Texas (G.E.C.).
Peter J. Ruane, Ruane Clinical Research, Los Angeles, California (P.J.R.).
Moti N. Ramgopal, Midway Immunology & Research Center, Fort Pierce, Florida (M.N.R.).
Alexandra W. Dretler, Metro Infectious Disease Consultants, Decatur, Georgia (A.W.D.).
Ronald G. Nahass, IDCare, Hillsborough, New Jersey (R.G.N.).
Gary I. Sinclair, Prism Health North Texas, Dallas, Texas (G.I.S.).
Mezgebe Berhe, North Texas Infectious Diseases Consultants, Dallas, Texas (M.B.).
Afsoon Roberts, Division of Infectious Diseases, George Washington University School of Medicine and Health Sciences, Washington, DC (A.R.).
Shauna Applin, Community Health Care, Tacoma, Washington (S.A.).
Cynthia Brinson, Central Texas Clinical Research, Austin, Texas (C.B.).
Dushyantha Jayaweera, University of Miami, Miller School of Medicine, Miami, Florida (D.J.).
Kimberly A. Workowski, Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, Georgia (K.A.W.).
Fadi Shihadeh, Gilead Sciences, Foster City, California (F.S., S.-Y.L., S.M., H.D.-S., M.S.R., J.M.B.).
Shan-Yu Liu, Gilead Sciences, Foster City, California (F.S., S.-Y.L., S.M., H.D.-S., M.S.R., J.M.B.).
Stephanie Klopfer, Merck & Co., Rahway, New Jersey (S.K., C.L., E.G.R.).
Cyril Llamoso, Merck & Co., Rahway, New Jersey (S.K., C.L., E.G.R.).
Sharline Madera, Gilead Sciences, Foster City, California (F.S., S.-Y.L., S.M., H.D.-S., M.S.R., J.M.B.).
Hadas Dvory-Sobol, Gilead Sciences, Foster City, California (F.S., S.-Y.L., S.M., H.D.-S., M.S.R., J.M.B.).
Martin S. Rhee, Gilead Sciences, Foster City, California (F.S., S.-Y.L., S.M., H.D.-S., M.S.R., J.M.B.).
Elizabeth G. Rhee, Merck & Co., Rahway, New Jersey (S.K., C.L., E.G.R.).
Jared M. Baeten, Gilead Sciences, Foster City, California (F.S., S.-Y.L., S.M., H.D.-S., M.S.R., J.M.B.).
Joseph J. Eron, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.J.E.).

Document Type

Journal Article

Publication Date

12-23-2025

Journal

Annals of internal medicine

DOI

10.7326/ANNALS-25-01939

Abstract

BACKGROUND: Once-weekly oral islatravir plus lenacapavir (ISL+LEN) has the potential to address adherence challenges with daily HIV-1 treatment. OBJECTIVE: To evaluate efficacy and safety of once-weekly ISL+LEN. DESIGN: Phase 2, randomized, open-label, active-controlled study. (ClinialTrials.gov: NCT05052996). SETTING: 44 U.S. sites. PARTICIPANTS: Adults with HIV-1 RNA viral load of less than 50 copies/mL receiving daily bictegravir, emtricitabine, and tenofovir alafenamide combination (B/F/TAF) for 24 weeks or more. INTERVENTION: Once-weekly oral ISL, 2 mg, plus LEN, 300 mg, or daily oral B/F/TAF. MEASUREMENTS: Proportion with HIV-1 RNA viral load of 50 copies/mL or more at week 24 (primary end point; U.S. Food and Drug Administration Snapshot Algorithm). Secondary end points: proportion of participants with HIV-1 RNA viral load of 50 copies/mL or more (weeks 12 and 48) and HIV-1 RNA viral load of less than 50 copies/mL (weeks 12, 24. and 48), safety, and CD4 T-cell and lymphocyte count changes (weeks 12, 24, and 48). RESULTS: A total of 104 participants were randomly assigned and treated (n = 52 per group). At week 24, one ISL+LEN participant and no B/F/TAF participants had HIV-1 RNA viral load of 50 copies/mL or more (difference, 1.9% [95% CI, -5.2% to 10.5%]); 94.2% of participants in both groups had HIV-1 RNA viral load of less than 50 copies/mL (difference, 0% [CI, -10.9% to 10.9%]). At week 48, 94.2% and 92.3% of ISL+LEN and B/F/TAF participants, respectively, had HIV-1 RNA viral load of less than 50 copies/mL (difference, 1.9% [CI, -9.3% to 13.6%]); no participant had HIV-1 RNA viral load of 50 copies/mL or more. Two ISL+LEN participants discontinued treatment (before week 24) due to adverse events (AEs) unrelated to the study drug. No AEs that were grade 3 or greater or serious were related to treatment in either group. Changes in CD4 T-cell and lymphocyte counts from baseline to week 48 were similar between groups, with no discontinuations of study drug treatment due to decreased CD4 T cells or lymphocytes. LIMITATION: Open-label, modest sample size, and only U.S.-based participants. CONCLUSION: Once-weekly oral ISL+LEN maintained high rates of virologic suppression through week 48 and was not associated with any treatment-related grade 3 or greater or serious AEs. PRIMARY FUNDING SOURCE: Gilead Sciences, Inc.

Department

Medicine

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