Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial.

Background: Doravirine and islatravir is an investigational, once-daily regimen with high antiviral potency, favourable safety and tolerability, and a low propensity for resistance. We investigated a switch from bictegravir, emtricitabine, and tenofovir alafenamide to doravirine (100 mg) and islatravir (0·75 mg) in virologically suppressed adults with HIV-1.
Methods: We conducted a phase 3, multicentre, randomised, active-controlled, double-blind, double-dummy, non-inferiority trial at 89 research, community, and hospital-based clinics in 11 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL for at least 3 months on bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation allocation schedule, with block randomisation based on a block size of four, to switch to doravirine (100 mg) and islatravir (0·75 mg) or continue bictegravir, emtricitabine, and tenofovir alafenamide orally once daily, with matching placebos taken by all participants. Participants, investigators, study staff, and sponsor personnel involved in study drug administration or clinical evaluation of participants were masked to treatment assignment until week 48. Participants were instructed at each visit to take one tablet from each of the two bottles received, one of study drug and one of placebo, once daily, and participants were assessed at baseline and weeks 4, 12, 24, 36, and 48. The primary endpoint was the proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug; US Food and Drug Administration snapshot; prespecified non-inferiority margin 4%). The study is ongoing, with all remaining participants in post-treatment follow-up, and is registered with ClinicalTrials.gov, NCT04223791.
Findings: We screened 726 individuals for eligibility between Feb 18 and Sept 3, 2020, of whom 643 (88·6%) participants were randomly assigned to a treatment group (183 [28·5%] women and 460 [71·5%] men). 322 participants were switched to doravirine (100 mg) and islatravir (0·75 mg) and 321 continued bictegravir, emtricitabine, and tenofovir alafenamide (two participants [one with a protocol deviation and one who withdrew] assigned to bictegravir, emtricitabine, and tenofovir alafenamide did not receive treatment). The last follow-up visit for the week 48 analysis occurred on Aug 26, 2021. At week 48, two (0·6%) of 322 participants in the doravirine and islatravir group compared with one (0·3%) of 319 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group had greater than or equal to 50 HIV-1 RNA copies per mL (difference 0·3%, 95% CI -1·2 to 2·0). The per-protocol analysis showed consistent results. 25 (7·8%) participants in the doravirine and islatravir group had headache compared with 23 [7·2%] participants in the bictegravir, emtricitabine, and tenofovir alafenamide group; 101 (31·4%) compared with 98 (30·7%) had infections; and eight (2·5%) participants in each group discontinued therapy due to adverse events. 32 (9·9%) participants had treatment-related adverse events in the islatravir and doravirine group comapred with 38 (11·9%) in the bictegravir, emtricitabine, and tenofovir alafenamide group. In the islatravir and doravirine group, CD4 cell counts (mean change -19·7 cells per μL) and total lymphocyte counts (mean change -0·20 × 10 ⁹ /L) were decreased at 48 weeks.
Interpretation: Switching to daily doravirine (100 mg) and islatravir (0·75 mg) was non-inferior to bictegravir, emtricitabine, and tenofovir alafenamide at week 48. However, decreases in CD4 cell and total lymphocyte counts do not support the further development of once-daily doravirine (100 mg) and islatravir (0·75 mg).
Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.
Competing Interests: Declaration of interests F-HS, SOK, KE, RMP, TC (former), and MCF are or were employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, who might own stock, hold stock options, or both in the company. AMM has received research funding from AbbVie, Gilead Sciences, Merck, Taimed, GSK, and ViiV Healthcare; honoraria from Gilead Sciences, ViiV Healthcare, and EMD Serono; and served on advisory boards for Gilead Sciences and ViiV Healthcare. GR has received honoraria from MSD, Gilead Sciences, GSK, and ViiV Healthcare and meeting or travel support from Gilead Sciences. MNR has received consulting fees from Gilead Sciences, Merck, and ViiV Healthcare and honoraria from AbbVie, Gilead Sciences, Janssen, and ViiV Healthcare. OOO has received honoraria from Gilead Sciences and ViiV Healthcare. JRB has received consulting fees from Gilead Sciences, MSD, Pfizer, and ViiV Healthcare and honoraria from AbbVie, Gilead Sciences, MSD, Pfizer, AstraZeneca, GSK, Janssen, ViiV Healthcare, and NovoNordisk. DPH has received research funding from Gilead Sciences, MSD, ViiV Healthcare, GSK, Janssen; honoraria for speakers bureau from Gilead Sciences and ViiV Healthcare; meeting or travel support from Gilead Sciences, ViiV Healthcare, GSK, and MSD; and served on advisory boards for and received consulting fees from Gilead Sciences, ViiV Healthcare, and Janssen. RP has served on advisory boards for and received consulting fees from Pfizer, MSD, Gilead Sciences, ViiV Healthcare, GSK, Roche, Atea, and Lilly and has received research funds (awarded to institution) from MSD, Gilead Sciences, and ViiV Healthcare. JR has received honoraria from MSD, Gilead Sciences, ViiV Healthcare, and Theratechnologies, outside the submitted work; meeting or travel support from Gilead Sciences; and has served on advisory boards for MSD, Gilead Sciences, and ViiV Healthcare. JKR has received consulting fees from AbbVie, Boehringer, Gilead Sciences, Merck, and ViiV Healthcare; honoraria from Gilead, Merck, Janssen, and ViiV; has served on advisory board for Abivax; and is a member of the governing board of the European AIDS Clinical Society. AC has received research funding from MSD and ViiV Healthcare; lecture and travel sponsorships from Gilead Sciences and ViiV Healthcare; and has served on advisory boards for Gilead Sciences, MSD, and ViiV Healthcare.
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