Background: For HIV-1 infected young people (YP) facing lifelong ART, short cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity and better adherence, as well as cost savings.
Methods: BREATHER is a randomised, non-inferiority trial in Europe, Thailand, Uganda, Argentina & US. YP (>8, ≤24 yrs) on efavirenz (EFV)+2NRTIs and HIV-RNA (VL)<50c/ml for >12 months were randomised to continue daily ART (CT) or change to SCT (5 days on; 2 days off ART). Followup was for minimum 48 weeks, with 0, 4, 12, then 12 weekly visits. The primary outcome was the difference between arms in proportion with VL>50c/ml (confirmed) by 48 weeks, estimated using Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age.
Results: 199 YP (11 countries) were randomised; 99 SCT, 100 CT and followed for median 86 weeks: 53% male, median age 14yrs (21% ≥18yrs); 35% Uganda site; 56% black, 19% Asian; 21% Caucasian; median CD4% 34%; CD4 count 793 cells/mm3. By week 48, only one YP on CT was lost to followup. The SCT arm had 27% decreased drug exposure as measured by adherence questionnaire and a MEMs substudy showing median cap openings/week of 5 SCT vs 7 CT. By 48 weeks, 6 SCT vs 7 CT had confirmed VL>50c/ml; difference (90% CI) -1.2% (-7.3, 4.9); 2 SCT vs 4 CT had confirmed VL>400c/ml; difference 2% (-6, 2.0). All 6 SCT with VL>50c/ml resumed daily ART; 5/6 resuppressed, 3 on same regimen, 2 with switch; 2 others on SCT resumed daily ART for other reasons. Overall, 4 SCT vs 11 CT (p=0.1) changed ART regimen: 8 for toxicity, 4 simplification, 2 compliance and 1 VL failure. 7 YP (2 SCT, 5 CT) had major NNRTI mutations at VL failure; 2 (1 SCT, 1 CT) had M184V. 2 YP had new CDC B events (1 SCT, 1 CT). There were no significant differences in toxicity between SCT and CT: grade 3/4 AEs (8 vs 12), ART-related AEs (2 vs 8), SAEs (7 vs 6). At week 48, there was no evidence that SCT led to increased inflammation using an extensive panel of markers. YP expressed preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires, particularly as it enabled weekend time with friends. 98% YP are in a 2-year followup extension of the trial.
Conclusions: Non-inferiority of VL suppression in YP on EFV-based firstline ART with VL<50c/ml was demonstrated for SCT vs CT, with similar resistance, safety and inflammatory marker profiles. Detailed evaluation of the immunological and virological impact of SCT is planned.