Efficacy and safety of short-cycle, dolutegravir-based antiretroviral therapy in adolescents living with HIV (BREATHER Plus): a multicentre, open-label, randomised, parallel, two-arm, non-inferiority trial

BACKGROUND: Short-cycle antiretroviral therapy (ART), comprising 5 days on and 2 days off treatment, offers the potential for ART-free weekends, reduced toxicity, and improved quality of life for adolescents living with HIV, who typically have worse treatment outcomes than other age groups. We aimed to compare the efficacy and safety of short-cycle ART containing tenofovir disoproxil fumarate-lamivudine-dolutegravir with continuous ART in adolescents living with HIV in Africa. METHODS: We conducted an open-label, randomised, parallel, two-arm, non-inferiority trial (BREATHER Plus) in five clinical research centres across Kenya, South Africa, Uganda, and Zimbabwe. Adolescents (aged ≥12 years to <20 years) with an HIV-1 viral load of less than 50 copies per mL over the previous 12 months and no documented history of treatment failure were eligible for inclusion. Participants were randomly assigned (1:1) by use of permuted blocks to either short-cycle ART or continuous ART, stratified by clinical centre and mode of HIV acquisition (vertical vs horizontal or other). Participants received a daily oral fixed-dose combination of tenofovir disoproxil fumarate (300 mg), lamivudine (300 mg), and dolutegravir (50 mg); those assigned to short-cycle ART could choose their two consecutive days off (ie, Friday and Saturday or Saturday and Sunday). The primary outcome was confirmed viral rebound (the first of two consecutive viral load measurements ≥50 copies per mL) by week 96, analysed by intention to treat in all participants with viral load data after baseline assessment by use of adjusted Kaplan-Meier estimated proportions. The non-inferiority margin and confidence level depended on the event rate in the continuous ART group (an 8% margin with 99% CI for a 5% event rate). This trial is registered with ISRCTN (85058577), and follow-up is complete. FINDINGS: Between June 29, 2022, and May 10, 2023, 470 adolescents living with HIV were randomly assigned to either short-cycle ART (239 [51%]) or continuous ART (231 [49%]). 263 (56%) participants were female and 207 (44%) were male. Median follow-up was 117 weeks (IQR 108-120). 23 participants in the short-cycle ART group and 11 in the continuous ART group had confirmed viral rebound by 96 weeks, with an estimated probability of confirmed HIV-1 RNA of at least 50 copies per mL of 9·9% (95% CI 6·4-14·3) in the short-cycle ART group versus 4·8% (2·6-7·8) in the continuous ART group. With an estimated difference of 5·1% (99% CI -0·8 to 11·5; bootstrap p=0·034), an 8% higher rate of confirmed virological rebound in the short-cycle ART group was not rejected, and the rate of confirmed virological rebound was significantly higher in the short-cycle ART group than in the continuous ART group. By the end of follow-up, 16 serious adverse events in 15 participants were reported in the short-cycle ART group (including one death unrelated to HIV or ART) and 22 serious adverse events in 16 participants in the continuous ART group. INTERPRETATION: BREATHER Plus findings demonstrate that short-cycle ART with tenofovir disoproxil fumarate-lamivudine-dolutegravir should not be recommended for adolescents living with HIV receiving standard-of-care, routine viral load monitoring every 6-12 months. FUNDING: European and Developing Countries Clinical Trials Partnership, and UK Medical Research Council.