Weekend-off ART is non-inferior to continuous ART in young people taking efavirenz-based regimens: results from BREATHER study
Polly Clayden, HIV i-Base
Viral load suppression taking ART five days on and two days off (short cycle therapy) was non-inferior to that achieved with continuous therapy in young people receiving efavirenz-based first line treatment, at 48 weeks. These results from the BREATHER trial were presented as a late breaker at CROI 2015.
Young people have reported difficulties with adherence during weekend, especially when socialising. BREATHER was designed to exploit the pharmacokinetics of long acting drugs such as efavirenz and look at whether a weekend off treatment strategy was feasible in this population.
Karina Butler from Our Lady’s Children’s Hospital, Dublin, Ireland presented the results on behalf of the BREATHER investigators.
BREATHER is a randomised, Phase 2, multicentre, non-inferiority trial conducted in 11 countries. Young people 8 to 24 years of age were eligible if they had a stable viral load <50 copies/mL and no previous virological failure, CD4 > 350 cells/mm3 and were receiving efavirenz plus two NRTIs. They were randomised to continue daily ART or change to short cycle therapy.
Follow up was for a minimum of 48 weeks, with study visits at 0, 4 and 12 weeks, then 12-weekly. The primary outcome was the difference between arms in proportion with viral load >50 copies/mL at 48 weeks, using Kaplan-Meier estimation method adjusted for region and age. The non-inferiority margin was 12%.
A total of 199 young people were randomised: 99 to short cycle and 100 to continuous therapy. They were regionally diverse: 35% Uganda, 18% Thailand, 6% Argentina and 41% Europe and US.
Because of concerns about the trial there was a pilot phase with 32 participants and more intensive monitoring, including viral load testing on Monday mornings, before resuming ART.
The median age of the participants was 14.1 years (IQR: 11.9 – 17.6); 90% were vertically infected; 56% were black, 21% white and 19% Asian. Their median CD4 was 735 cells/mm3 (IQR: 575.5 – 967.5). One fifth of the population was over 18 years of age: 39%, 8 to 13; 40%, 13 to 18; and 21%, 18 to 24.
Median follow up was 85 weeks, with >98% of clinic visits attended up to week 48. Only one participant was lost to follow up by week 48.
Participants reported taking >95% of scheduled drugs in an adherence questionnaire – and this also revealed 27% decreased drug exposure in the short cycle therapy arm. A substudy using MEMs caps in 61 participants (but only 46 by week 48 – MEMs caps were not popluar) showed median weekly cap openings of 5 and 7 in the short cycle and continuous therapy arms, respectively.
At 48 weeks, 6 vs 7 participants in the short cycle and continuous therapy arms had detectable viral load >50 copies/mL. This gave a difference of -1.2% (90% CI, -7.3 to 4.9) in favour of short cycle therapy. The upper bound of difference between Kaplan Meier survival curves of 4.9% was inside the non-inferiority margin of 12%.
There were 4 vs 11 changes in ART regimen in the short cycle vs continuous therapy arms, p=0.1, NS. The changes were: 8 for toxicity, 4 for simplification, 2 for adherence and 1 for viral failure.
There were no differences in clinical, immunologic or virologic parameters, inflammatory markers, or resistance among participants with virologic failure.
Short cycle therapy was popular in a qualitative substudy: 74% of participants said this strategy made things a lot easier and the remainder a little easier. Notably the participants reported fewer side effects at weekends and these had often not previously been disclosed to caregivers.
Pre- and post-trial questionnaires comparing the two strategies showed modest improvement in most things participants found difficult with continuous ART. Only “going out with friends” was statistically significant, p=0.001.
Most participants are continuing follow up for an additional two years.
During the presentation and at the press conference following, it was emphasised that this study was conducted in a carefully selected group of participants. This included a previous history of viral suppression on their first regimen and close to 100% adherence on weekdays. This is not likely to be suitable for everyone.
It is notable that not all the participants were on tenofovir containing regimens – which also has a long half- life. A considerable proportion, particularly in Uganda, received AZT.
Butler KM et al. ART with weekends off is noninferior to continuous ART in young people on EFV+2NRTI. 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle. Oral abstract 38LB.