Abstract:
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 out-
comes 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.
