Background <p>In China, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens remain widely utilized as first-line antiretroviral therapy (ART) despite issues of low resistance barriers and significant side effects, leading to frequent treatment interruptions and virologic failures. Timely drug-resistance testing is often inaccessible, complicating subsequent treatment management. This trial aims to fill this critical gap by comparing the efficacy, safety, and tolerability of the single-tablet regimen (STR) of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) with the multi-tablet regimen (MTR) of dolutegravir plus lamivudine plus tenofovir disoproxil fumarate (DTG+3TC+TDF) in people living with HIV (PLWH) experiencing virologic failure.</p> Methods <p>This multicenter, open-label, randomized controlled non-inferiority trial will enroll 374 PLWH experiencing virologic failure of first-line NNRTI-based therapy from 14 clinics across China. Participants will be randomized 1:1 to receive either a once-daily STR of BIC/FTC/TAF or a once-daily MTR of DTG+3TC+TDF. The primary endpoint is the proportion achieving viral suppression (HIV-1 RNA &lt; 50 copies/mL) at week 48. Secondary endpoints include the time to viral suppression, emergence of resistance-associated mutations (RAMs), immunologic markers, treatment adherence, patient-reported outcomes, and safety profiles. Data will be analyzed using intention-to-treat (ITT) and per-protocol (PP) populations, with non-inferiority defined using a margin of 12%.</p> Discussion <p>This trial aims to provide high-quality evidence for a simplified, high-barrier, STR as an optimized second-line strategy in resource-limited settings where drug resistance testing is inaccessible.</p> Trial registration <p>Chinese Clinical Trial Registry (Trial ID: ChiCTR2500108287). Registered on 27 August 2025. Retrospectively registered. <a href="https://www.chictr.org.cn">https://www.chictr.org.cn</a>.</p>