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Introduction: Anti-retroviral therapy (ART) simplification strategies are needed for treatment-experienced people with HIV (PWH) and multidrug-resistant viruses. These individuals are commonly treated with boosted ART regimens and are thereby at risk for harmful drug-drug interactions (DDI). In this trial, we aim to assess the efficacy of the combination doravirine, dolutegravir and lamivudine (DOR/DTG/3TC) among people with a history of virological failure who receive boosted ART., Methods and Analysis: B-Free is a multistage, randomised, multicentre, open-label, non-inferiority trial, embedded within the Swiss HIV Cohort Study and conducted in collaboration with cohorts of PWH in the Netherlands and France. Cohort participants with a history of ART change due to virologic failure and who maintain HIV virologic suppression with an ART regimen consisting of a pharmacological booster and at least two drugs from classes other than nucleoside reverse transcriptase inhibitors are included. Patients with major drug resistance mutations against DTG or DOR and individuals with chronic hepatitis B virus infection are not eligible for the study. Individuals are randomised 1:1 to either receiving co-formulated DTG/3TC and DOR once daily or continuing their boosted ART regimen. The primary outcome is the proportion of individuals lacking virologic control (HIV-RNA ≥50 cp/mL) at 48 weeks, according to the Food and Drug Administration snapshot algorithm. Changes in DDI burden (assessed using a DDI score), treatment satisfaction (assessed using the HIV Treatment Satisfaction Questionnaire), quality of life and mental health represent key secondary outcomes. Additional secondary outcomes include the proportion of individuals developing new resistance-associated mutations and changes in quality of life and mental health. In a qualitative substudy, we will conduct semistructured interviews with a subset of participants to assess their expectations and experiences towards HIV treatment and clinical research in general. Enrolling 210 individuals will provide 80% power to demonstrate non-inferiority, defined as less than 8% absolute increase in loss of viral suppression in individuals randomised to DOR/DTG/3TC (one-sided type I error rate of 0.025)., Ethics and Dissemination: The study was approved by the competent ethics committees (reference number BASEC 2023-01060) and the regulatory authority Swissmedic (reference number 701655) in Switzerland before the enrolment of the first participant. Approval by the European Medicines Agency and local ethical committees in the Netherlands and France will be obtained prior to including participants in these countries. Participant's written informed consent is obtained by the investigators before enrolment. The results of all major B-Free study outcomes will be submitted to peer-reviewed journals that enable Open Access publication., Trial Registration Number: Swiss National Clinical Trials Portal (SNCTP000005686, registered on 06 November 2023) and Clinicaltrials.gov (NCT06037564, registered on 07 September 2023)., Competing Interests: Competing interests: BS reports financial support for travel grants from Gilead Sciences and ViiV Healthcare and for advisory boards from Gilead Sciences and MSD, paid to his institution. GW has received research grants from Gilead Sciences and Roche Diagnostics, as well as fees for advisory boards and lectures from ViiV Healthcare, MSD, Roche Diagnostics and Gilead Sciences (all paid to his institution). MC’s institution received research grants and expert opinion fees from Gilead Sciences, MSD and ViiV Healthcare. DLB received money paid to himself outside of the submitted work for advisory boards and lectures from the companies Gilead Sciences, MSD, Pfizer and ViiV Healthcare and money for a research grant from the company ViiV Healthcare. The institution of EB received study grants from Merck and Gilead Sciences; it also received travel grants and fees for EB participation to advisory boards from Gilead Sciences, Merck, ViiV Healthcare, Pfizer AG, Moderna, AstraZeneca, AbbVie and Eli Lilly. DH received fees for consultancies from AstraZeneca, Bavarian Nordic, Gilead Sciences, UCB and ViiV Healthcare, a travel grant from Gilead Sciences, and institutional funding from AstraZeneca, Gilead Sciences, GSK, A. Menarini, MSD and ViiV Healthcare. MvdV has received research grants and fees for participation in advisory boards from Gilead Sciences, MSD and ViiV Healthcare, all paid to his institution. MS reports financial support for travel grants from Gilead Sciences and for advisory boards from Gilead Sciences, MSD and ViiV Healthcare, paid to his institution. AR received research grants from Gilead Sciences, paid to his institution; travel expenses from Gilead Sciences and Pfizer, paid to his institution; and honoraria for advisory board consultations from MSD and Moderna, paid to his institution. PS’s institution has received travel grants, congress and advisory fees from ViiV Healthcare and Gilead Sciences unrelated to this work. All other authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)