Switch to fixed-dose doravirine (100 mg) and islatravir (0.25 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, multicentre, randomised, controlled, double-blind, non-inferiority trial.

Abstract

BACKGROUND: The combination of doravirine and islatravir is under investigation as a fixed-dose, single-tablet regimen for the treatment of HIV-1. We aimed to assess the efficacy and safety of switching to doravirine (100 mg) and islatravir (0·25 mg) from bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV-1.

METHODS: This phase 3, randomised, controlled, double-blind, non-inferiority trial was conducted at 49 research, community, and hospital-based clinics in six countries: Australia, Chile, Israel, Japan, the UK, and the USA. Adults aged 18 years or older with HIV-1, who were virologically suppressed (with a viral load of HIV-1 RNA <50 copies per mL) for at least 3 consecutive months on bictegravir, emtricitabine, and tenofovir alafenamide and had no history of treatment failure or known resistance to doravirine, were eligible for the study. Participants were randomly assigned, in a 2:1 ratio according to a computer-generated randomisation schedule with a block size of three, to switch to oral doravirine (100 mg) and islatravir (0·25 mg) or to continue bictegravir, emtricitabine, and tenofovir alafenamide, once daily. Participants, investigators, study staff, and sponsor personnel were masked to study treatment; sponsor personnel directly involved in this analysis were unmasked at week 48. The primary endpoint, which was assessed in all randomly assigned participants who received at least one dose of study treatment, was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 according to the US Food and Drug Administration snapshot approach; non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%. The trial is registered at ClinicalTrials.gov, NCT05630755, and is ongoing but closed to enrolment.

FINDINGS: Between Feb 17 and Nov 17, 2023, 585 individuals were screened, of whom 514 were randomly assigned and 513 treated: 342 participants were switched to doravirine (100 mg) and islatravir (0·25 mg) and 171 continued bictegravir, emtricitabine, and tenofovir alafenamide. The median age of the 513 participants was 47 years (IQR 37-58), 403 (79%) were assigned male and 110 (21%) were assigned female at birth, 158 (31%) were Black or African American, and 117 (23%) were Hispanic, Latino, or Latina. At week 48, doravirine and islatravir showed non-inferiority to bictegravir, emtricitabine, and tenofovir alafenamide (viral load =50 copies per mL in five [1·5%] of 342 vs one [0·6%] of 171 participants) with a treatment difference of 0·9% (multiplicity-adjusted 95% CI -1·9 to 2·9). The rates of adverse events (74·6% [255 of 342 participants] vs 71·3% [122 of 171 participants]; difference 3·2 [95% CI -4·7 to 11·6]), treatment-related adverse events (10·2% [35] vs 9·4% [16]; 0·9 [-5·1 to 6·0]), serious adverse events (4·4% [15] vs 6·4% [11]; -2·0 [-7·1 to 1·9]), and discontinuations due to adverse events (2·9% [ten] vs 1·8% [three]; 1·2 [-2·3 to 3·9]) were similar in the doravirine and islatravir group and the bictegravir, emtricitabine, and tenofovir alafenamide group, and no deaths were reported.

INTERPRETATION: The combination of doravirine (100 mg) and islatravir (0·25 mg) has similar efficacy and safety profiles to bictegravir, emtricitabine, and tenofovir alafenamide, and could provide a two-drug, once daily, oral single-tablet option without an integrase strand-transfer inhibitor for adults who are virologically suppressed and want to switch to a different ART regimen.

FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.