Efficacy and Safety of Islatravir and Ulonivirine Once Weekly versus Bictegravir, Emtricitabine, and Tenofovir Alafenamide Once Daily in Treatment-Naïve Adults with HIV-1

The primary objective of this Phase 2/3 study is to evaluate the antiretroviral activity (5) and safety (4) of islatravir and ulonivirine administered once weekly compared to bictegravir, emtricitabine, and tenofovir alafenamide administered once daily in treatment-naïve adults living with HIV-1. Clinical efficacy is assessed by the proportion of participants achieving <50 copies/mL of HIV-1 RNA at Week 24 in Phase 2 and at Week 48 in Phase 3. Additionally, tolerability (4) is evaluated through the review of accumulated safety data at the conclusion of each phase.

Secondary objectives include:

• Evaluation of additional antiretroviral activity (5) levels, specifically the percentage of participants with HIV-1 RNA <50 copies/mL and <200 copies/mL at various time points up to Week 96.
• Assessment of the immunologic effect (3) via the mean change from baseline in CD4+ T-cell count at Weeks 24, 48, and 96.
• Monitoring for the development of viral drug resistance.
• Evaluation of the effect on body weight through mean change from baseline at Weeks 48 and 96.

This clinical trial involves a total of 450 patients. The study population includes both males and females within the age ranges corresponding to codes 3 and 4. Participants are diagnosed with human immunodeficiency virus type 1 (HIV-1) and are naïve to antiretroviral therapy, meaning no prior treatment with any antiretroviral agent has been administered following diagnosis. For the Phase 2 portion of the study, inclusion requires a plasma HIV-1 ribonucleic acid (RNA) level between 500 and 100,000 copies/mL and a cluster of differentiation 4-positive (CD4+) T-cell count of at least 200 cells/mm³. In the Phase 3 stage, the requirement for plasma HIV-1 RNA is a level of at least 500 copies/mL.

This Phase 2/3 clinical trial is a randomized study designed to evaluate the antiretroviral activity, safety, and tolerability of islatravir and ulonivirine administered once weekly compared to bictegravir/emtricitabine/tenofovir alafenamide administered once daily. The study utilizes an open-label design for Phase 2 and a double-blind design for Phase 3. The research is conducted in treatment-naïve adults living with HIV-1. The trial includes a screening period to confirm eligibility based on plasma HIV-1 RNA levels and CD4+ T-cell count. Participants receive the study intervention for a duration of up to 96 weeks, with primary efficacy assessments occurring at Week 24 for Phase 2 and Week 48 for Phase 3. Follow-up assessments monitor adverse events, viral drug resistance-associated substitutions, and changes in body weight. Early termination from the study may occur due to the occurrence of an adverse event leading to discontinuation of the study intervention.

The experimental treatment consists of MK-8591B, which is a film-coated tablet containing a combination of islatravir and ulonivirine. The total dose is 202 mg administered via the oral route.

The study also evaluates islatravir administered as a 2 mg capsule for oral use, and ulonivirine administered as a 200 mg tablet for oral use.

The comparator therapy is a combination of emtricitabine, tenofovir alafenamide, and bictegravir provided in a 275 mg oral pharmaceutical form.

To maintain the double-blind design in the Phase 3 portion, placebo formulations are utilized, specifically a placebo to BIC/FTC/TAF and a placebo to 8591B.

The antiretroviral activity of the investigational combination will be assessed through the evaluation of HIV-1 RNA levels. In Phase 2, the primary efficacy endpoint is the percentage of participants with <50 copies/mL of human immunodeficiency virus type 1 ribonucleic acid at Week 24. Secondary assessments include the percentage of participants with <50 copies/mL or <200 copies/mL at Week 48 and Week 96. In Phase 3, the primary efficacy endpoint is the percentage of participants with <50 copies/mL of HIV-1 RNA at Week 48, with secondary assessments measuring the same parameter at Week 96 and the percentage of participants with <200 copies/mL at Week 48 and Week 96.

Additional efficacy parameters include the mean change from baseline in CD4+ T-cell count at Week 24, Week 48, and Week 96. The number of participants with evidence of viral drug resistance-associated substitutions will be monitored at various timepoints, including Week 24, Week 48, and Week 96. In Phase 3, the mean change from baseline in body weight will also be evaluated at Week 48 and Week 96.