Study Evaluating the Safety and Efficacy of Islatravir in Combination With Lenacapavir in Virologically Suppressed People With HIV

A Phase 2 Randomized, Open-Label, Active-Controlled Study Evaluating the Safety and Efficacy of an Oral Weekly Regimen of Islatravir in Combination With Lenacapavir in Virologically Suppressed People With HIV

The primary objective of this study is to evaluate the efficacy of oral weekly islatravir (ISL) in combination with lenacapavir (LEN) in virologically suppressed people with HIV (PWH) at Week 24.

Study Overview

• Status: Active, not recruiting
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: ISL; Drug: LEN; Drug: B/F/TAF; Drug: ISL/LEN FDC

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Pacific Oaks Medical Group
    • Los Angeles, California, United States, 90069
      • Mills Clinical Research
    • Los Angeles, California, United States, 90036
      • Ruane Clinical Research Group, Inc
    • Newport Beach, California, United States, 92663
      • Hoag Medical Group - Newport Beach
    • Palm Springs, California, United States, 92262
      • BIOS Clinical Research
    • San Francisco, California, United States, 94102
      • Optimus Medical Group
  • Colorado
    • Denver, Colorado, United States, 80204
      • Public Health Institute at Denver Health
    • Denver, Colorado, United States, 80246
      • Vivent Health
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20017
      • Washington Health Institute
    • Washington D.C., District of Columbia, United States, 20037
      • The George Washington University Medical Faculty Associates Inc.
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • CAN Community Health Care, Inc.
    • Ft. Pierce, Florida, United States, 34982
      • Midway Immunology and Research Center
    • Lake Worth, Florida, United States, 33462
      • JEM Research Institute
    • Miami, Florida, United States, 33136
      • Schiff Center for Liver Diseases/University of Miami
    • Miami Lakes, Florida, United States, 33016
      • Floridian Clinical Research
    • Orlando, Florida, United States, 32803
      • Orlando Immunology Center
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Atlanta ID Group, PC
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown Infectious Disease Clinic
    • Decatur, Georgia, United States, 30033
      • Metro Infectious Disease Consultants
    • Savannah, Georgia, United States, 31401
      • Chatham County Health Department
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • John A. Burns School of Medicine, University of Hawaii Clinics at Kaka'ako
  • Illinois
    • Chicago, Illinois, United States, 60613
      • Howard Brown Health Center
    • Chicago, Illinois, United States, 60657
      • Northstar Healthcare
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana CTSI Clinical Research Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02129
      • AccessHealth MA
  • Michigan
    • Berkley, Michigan, United States, 48072
      • Be Well Medical Center
  • Minnesota
    • New Brighton, Minnesota, United States, 55112
      • Hennepin Healthcare HCMC
  • Missouri
    • St Louis, Missouri, United States, 63139
      • Southampton Healthcare, Inc.
  • Nevada
    • Las Vegas, Nevada, United States, 89104
      • Huntridge Family Clinic
  • New Jersey
    • Hillsborough, New Jersey, United States, 08844
      • ID Care
  • New Mexico
    • Santa Fe, New Mexico, United States, 87505
      • Axces Research Group
  • New York
    • Flushing, New York, United States, 11355
      • New York-Presbyterian Queens
    • The Bronx, New York, United States, 10461
      • Jacobi Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • NC TraCS Institute - CTRC: University of North Carolina at Chapel Hill
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Philadelphia FIGHT Community Health Centers
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Medicine: Perelman Center for Advanced Medicine at the Hospital of the University of Pennsylvania
  • Texas
    • Austin, Texas, United States, 78705
      • Central Texas Clinical Research, LLC
    • Dallas, Texas, United States, 75246
      • North Texas Infectious Diseases Consultants, P.A.
    • Dallas, Texas, United States, 75208
      • AIDS Arms Inc
    • Houston, Texas, United States, 77098
      • The Crofoot Research Center, INC
  • Washington
    • Seattle, Washington, United States, 98104
      • Peter Shalit, M.D.
    • Spokane, Washington, United States, 99202
      • MultiCare Rockwood Main Clinic
    • Tacoma, Washington, United States, 98405
      • Community Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Received bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for ≥ 24 weeks at screening.
• Documented plasma human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) < 50 copies/mL (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) for ≥ 24 weeks before and at screening.
• Plasma HIV-1 RNA < 50 copies/mL at screening.

Key Exclusion Criteria:

• History of prior virologic failure while receiving treatment for HIV-1.
• Prior use of, or exposure to, islatravir (ISL) or lenacapavir (LEN).
• Active, serious infections requiring parenteral therapy < 30 days before randomization.
• Active or occult hepatitis B virus (HBV) coinfection, defined as hepatitis B core antibody (HBcAb) positive, hepatitis B surface antigen (HBsAg) positive, or HBV deoxyribonucleic acid (DNA) positive as determined by the central laboratory.
• Active hepatitis C virus (HCV) coinfection, defined as detectable HCV RNA.

• Any of the following laboratory values at screening:

  • Creatinine clearance (CLcr) ≤ 30 mL/min according to the Cockcroft-Gault formula
• CD4+ T-cells < 200 cells/mm^3 (Cohort 1); CD4+ T-cells < 350 cells/mm^3 (cohort 2).
• Absolute lymphocyte count < 900 cells/mm^3 (cohort 2).
• Individuals of childbearing potential (as defined in protocol) who have a positive serum pregnancy test at screening or positive urine and serum pregnancy tests at Day 1 prior to study drug administration.
• Individuals who plan to continue breastfeeding during the study.
• Documented historical or screening resistance reports showing nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) or non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs) resistance mutations in reverse transcriptase, including M184V/I (Cohort 2).

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (ISL+LEN); Participants will receive the following for at least 48 weeks: Day 1 and Day 2: ISL 40 and LEN 600 mg; Day 8 and weekly thereafter (ie, every 7 days): ISL 20 mg and LEN 300 mg	Drug: ISL; Capsules administered orally without regard to food; Drug: LEN; Tablets administered orally without regard to food; Other Names: GS-6207
Experimental: Cohort 1 (B/F/TAF to ISL+LEN); Participants will receive bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) 50/200/25 mg once daily for at least 48 weeks After 48 weeks, participants will switch from B/F/TAF to ISL+LEN; ISL 40 and LEN 600 mg on Day 1 and Day 2; ISL 20 mg and LEN 300 mg weekly Participants who do not switch from B/F/TAF to ISL+LEN at Week 48 will be discontinued from the study.	Drug: ISL; Capsules administered orally without regard to food; Drug: LEN; Tablets administered orally without regard to food; Other Names: GS-6207; Drug: B/F/TAF; Tablets administered orally without regard to food; Other Names: Biktarvy®
Experimental: Cohort 2 (ISL+LEN); Participants will receive the following for at least 48 weeks; Day 1: LEN oral 600 mg (2 x 300 mg) and ISL 2 mg (2 x 1 mg); Day 2: LEN only oral 600 mg (2 x 300 mg); Day 8 and weekly thereafter (ie, every 7 days): LEN oral 300 mg (1 x 300 mg) and ISL 2 mg	Drug: ISL; Capsules administered orally without regard to food; Drug: LEN; Tablets administered orally without regard to food; Other Names: GS-6207
Experimental: Cohort 2 (B/F/TAF to ISL+LEN); Participants will receive B/F/TAF 50/200/25 mg once daily for at least 48 weeks.	Drug: ISL; Capsules administered orally without regard to food; Drug: LEN; Tablets administered orally without regard to food; Other Names: GS-6207; Drug: B/F/TAF; Tablets administered orally without regard to food; Other Names: Biktarvy®
Experimental: Extension Phase Cohort 2 of ISL/LEN Fixed Dose Combination (FDC); After 48 Weeks of randomized treatment, all participants will be given an option to participate in an Extension Phase to receive ISL+LEN or ISL/LEN FDC tablet (when available) until ISL/LEN becomes available or until the sponsor elects to discontinue the study, whichever occurs first. Participants receiving ISL+LEN during the randomized phase will continue to take ISL + LEN weekly. Participants receiving B/F/TAF during the randomized phase will switch to ISL+LEN: Day 1: LEN oral 600 mg (2 x 300 mg) and ISL 2 mg (2 x 1 mg); Day 2: LEN only oral 600 mg (2 x 300 mg); Day 8 and weekly thereafter (ie, every 7 days): LEN oral 300 mg (1 x 300 mg) and ISL 2 mg Participants who do not switch from B/F/TAF to ISL+LEN at Week 48 will be discontinued from the study. All participants in the extension phase will be transitioned to weekly ISL/LEN FDC (Dose A) tablet when it becomes available.	Drug: ISL/LEN FDC; Tablets administered orally without regard to food

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 24 as Determined by the US Food and Drug Administration (FDA)-Defined Snapshot Algorithm	The percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with the applicable study drug discontinuation status. Week 24 window was between Day 148 and 189 (inclusive). Percentages were rounded off.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 12 as Determined by the US FDA-defined Snapshot Algorithm	The percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 12 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with the applicable study drug discontinuation status. Week 12 window was between Day 71 and 105 (inclusive). Percentages were rounded off.	Week 12
Percentage of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 48 as Determined by the US FDA-defined Snapshot Algorithm	The percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with the applicable study drug discontinuation status. Week 48 window was between Day 316 and 378 (inclusive). Percentages were rounded off.	Week 48
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 as Determined by the US FDA-defined Snapshot Algorithm	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with the applicable study drug discontinuation status. Week 12 window was between Day 71 and 105 (inclusive). Percentages were rounded off.	Week 12
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 as Determined by the US FDA-defined Snapshot Algorithm	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with the applicable study drug discontinuation status. Week 24 window was between Day 148 and 189 (inclusive). Percentages were rounded off.	Week 24
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Determined by the US FDA-defined Snapshot Algorithm	The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with the applicable study drug discontinuation status. Week 48 window was between Day 316 and 378 (inclusive). Percentages were rounded off.	Week 48
Change From Baseline in Clusters of Differentiation 4 (CD4)+ Cell Count at Week 12		Baseline and Week 12
Change From Baseline in CD4+ Cell Count at Week 24		Baseline and Week 24
Change From Baseline in CD4+ Cell Count at Week 48		Baseline and Week 48
Percentage of Participants Experiencing Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation	TEAEs were defined as 1 or both of any AEs leading to premature discontinuation of study drug, or any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. Percentages were rounded off.	Up to 5 years
Cohort 1: Plasma Concentrations for ISL		Anytime postdose at Week 4
Cohort 2: Pharmacokinetic (PK) Parameter: Cmax of Islatravir (ISL)	Cmax was defined as the maximum observed concentration of drug.	Anytime post dose on Day 1 and at either Week 12 or Week 18
Cohort 2: PK Parameter: Tmax of ISL	Tmax was defined as the time (observed time point) of Cmax.	Anytime post dose on Day 1 and at either Week 12 or Week 18
Cohort 2: PK Parameter: Ctau of ISL	Ctau was defined as the observed drug concentration at the end of the dosing interval.	Anytime post dose at either Week 12 or Week 18
Cohort 2: PK Parameter: AUCtau of ISL	AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	Anytime post dose at either Week 12 or Week 18
Plasma Concentrations for LEN		Anytime postdose at Week 4
Cohort 2: Pharmacokinetic (PK) Parameter: Cmax of LEN	Cmax was defined as the maximum observed concentration of drug.	Anytime post dose on Day 1, Day 2 and at either Week 12 or 18
Cohort 2: PK Parameter: Tmax of LEN	Tmax is defined as the time (observed time point) of Cmax.	Anytime post dose on Day 1, Day 2 and at either Week 12 or Week 18
Cohort 2: PK Parameter: Ctau of LEN	Ctau was defined as the observed drug concentration at the end of the dosing interval.	Anytime post dose at either Week 12 or Week 18
Cohort 2: PK Parameter: AUCtau of LEN	AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	Anytime post dose at either Week 12 or Week 18

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Gilead Study Director, Gilead Sciences

Publications and helpful links

General Publications

• Colson AE, Crofoot GE, Ruane PJ, Ramgopal MN, Dretler AW, Nahass RG, Sinclair GI, Berhe M, Roberts A, Applin S, Brinson C, Jayaweera D, Workowski KA, Shihadeh F, Liu SY, Klopfer S, Llamoso C, Madera S, Dvory-Sobol H, Rhee MS, Rhee EG, Baeten JM, Eron JJ. 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. Online ahead of print.

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2021
• Primary Completion (Actual): December 19, 2023
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: September 13, 2021
• First Submitted That Met QC Criteria: September 13, 2021
• First Posted (Actual): September 22, 2021

Study Record Updates

• Last Update Posted (Actual): February 4, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: lenacapavir; bictegravir, emtricitabine, tenofovir alafenamide, drug combination
• Other Study ID Numbers: GS-US-563-6041

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No