BREATHER Plus clinical trial design: A randomised non-inferiority trial evaluating the efficacy, safety and acceptability of short cycle (five days on, two days off) dolutegravir/tenofovir-based triple antiretroviral therapy (ART) compared to daily ART in virologically suppressed adolescents living with HIV aged 12 to <20 years in sub-Saharan Africa

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BACKGROUND: Novel strategies to improve ART adherence, retention in care and quality of life among adolescents living with HIV (ALHIV) are needed. Short-Cycle Therapy (SCT) with 4/5 sequential days on ART, 2/3 days off ART per week has shown non-inferior virological outcomes and high acceptability, but most data are in adults and are very limited for dolutegravir (DTG)-based SCT. METHODS: BREATHER Plus is an ongoing 96-week non-inferiority randomised trial evaluating efficacy, safety and acceptability of SCT (5 sequential days on, 2 days off at the weekend) with DTG/tenofovir (TNV)-based triple ART versus continuous (daily) therapy (CT) in ALHIV. Participants are aged 12 to <20 years in Kenya/South Africa/Uganda/Zimbabwe, virologically suppressed (Viral Load (VL) <50copies/mL) for ≥12 months at enrollment, with no prior treatment failure. Randomisation is 1:1 to SCT versus CT. VL monitoring for clinical management is 6-12 monthly aligning with standard-of-care. The primary outcome is confirmed virological rebound ≥50 copies/mL by 96 weeks. The trial employs the Smooth Away From Expected (SAFE) non-inferiority frontier, where the non-inferiority margin depends on the observed event risk in the CT arm. Secondary outcomes include HIV resistance, toxicities, patient-reported outcomes and cost-effectiveness. Enrolment of 470 participants completed in June 2023. DISCUSSION: BREATHER Plus is the first randomised trial specifically evaluating DTG/TNV-triple based SCT. Rapid roll-out of DTG and a pragmatic approach to VL monitoring mean results will be generalisable to ALHIV across sub-Saharan Africa. If SCT provides non-inferior virological suppression to CT, it may offer choice for ALHIV on how they take their ART.