Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial

Abstract

SummaryBackgroundFor HIV-1-infected young people facing lifelong antiretroviral therapy (ART), short cycle therapy with long-acting drugs offers potential for drug-free weekends, less toxicity, and better quality-of-life. We aimed to compare short cycle therapy (5 days on, 2 days off ART) versus continuous therapy (continuous ART).MethodsIn this open-label, non-inferiority trial (BREATHER), eligible participants were aged 8–24 years, were stable on first-line efavirenz with two nucleoside reverse transcriptase inhibitors, and had HIV-1 RNA viral load less than 50 copies per mL for 12 months or longer. Patients were randomly assigned (1:1) to remain on continuous therapy or change to short cycle therapy according to a computer-generated randomisation list, with permuted blocks of varying size, stratified by age and African versus non-African sites; the list was prepared by the trial statistician and randomisation was done via a web service accessed by site clinician or one of the three coordinating trials units. The primary outcome was the proportion of participants with confirmed viral load 50 copies per mL or higher at any time up to the 48 week assessment, estimated with the Kaplan-Meier method. The trial was powered to exclude a non-inferiority margin of 12%. Analyses were intention to treat. The trial was registered with EudraCT, number 2009-012947-40, ISRCTN, number 97755073, and CTA, number 27505/0005/001-0001.FindingsBetween April 1, 2011, and June 28, 2013, 199 participants from 11 countries worldwide were randomly assigned, 99 to the short cycle therapy and 100 to continuous therapy, and were followed up until the last patient reached 48 weeks. 105 (53%) were men, median age was 14 years (IQR 12–18), and median CD4 cell count was 735 cells per μL (IQR 576–968). Six (6%) patients assigned to the short cycle therapy versus seven (7%) assigned to continuous therapy had confirmed viral load 50 copies per mL or higher (difference −1·2%, 90% CI −7·3 to 4·9, non-inferiority shown). 13 grade 3 or 4 events occurred in the short cycle therapy group and 14 in the continuous therapy group (p=0·89). Two ART-related adverse events (one gynaecomastia and one spontaneous abortion) occurred in the short cycle therapy group compared with 14 (p=0·02) in the continuous therapy group (five lipodystrophy, two gynaecomastia, one suicidal ideation, one dizziness, one headache and syncope, one spontaneous abortion, one neutropenia, and two raised transaminases).InterpretationNon-inferiority of maintaining virological suppression in children, adolescents, and young adults was shown for short cycle therapy versus continous therapy at 48 weeks, with similar resistance and a better safety profile. This short cycle therapy strategy is a viable option for adherent HIV-infected young people who are stable on efavirenz-based ART.FundingUK National Institute for Health Research Health Technology Assessment; UK Medical Research Council; European Commission; PENTA Foundation; INSERM SC10-US19, France.

Non-adherence in non-inferiority trials: pitfalls and recommendations

“…An example might be intolerance to study drug treatments due to mild side effects such as nausea or rash, which cause enough discomfort to affect adherence but not the outcome of the disease 1415. By contrast, non-adherence can be driven by factors that influence the study outcome, such as disease severity 1617. For example, consider an open label study where more severely ill patients are more likely not to adhere to the experimental treatment and these patients cross over to the standard-of-care control arm.…”

Qualitative research on community experiences in large HIV research trials: what have we learned?

“…Working across 11 countries (including one centre in Uganda), this trial compared virological control of short‐cycle therapy (five days on: two days off) with continuous EFV‐based ART in 199 children and young people (aged 8 to 24) (70 from Uganda) living with HIV with viral load <50 c/mL to examine adaptation, acceptability and experience of short‐cycle therapy to inform intervention development 17, 33. The social science component was not fully funded within the trial funding, and a parallel grant from a different funder was secured by the social scientists to support the qualitative research in Uganda.…”

“…These findings informed the way in which the final trial findings were reported and could provide valuable input for further research. It should be noted that while some of the qualitative study findings were integrated into the “main” trial paper the paper 17 detailing the qualitative findings (which was submitted at the same time as the main trial findings paper) was not accepted for publication. The qualitative findings paper was published later in a different journal 34.…”

“…theory building). We share examples of qualitative research studies embedded within two large community‐based trials testing the population‐level effects of universal HIV testing and treatment (UTT) (which aims to extend HIV counselling and testing to an entire population and antiretroviral therapy (ART) to all those person living with HIV) in southern and eastern Africa 16, and of a clinical trial of an intervention to test the adaptation, acceptability and experience of short‐cycle therapy 17 in children and adolescents living with HIV.…”

Qualitative study of the BREATHER trial (Short Cycle antiretroviral therapy): is it acceptable to young people living with HIV?

“…The trial design to test having the weekends off treatment was informed by anecdotal evidence suggesting that managed interruptions can ameliorate the challenges of adhering continuously. 14 The qualitative study aimed to explore the experiences of SCT, and of treatment and care more generally, among a sample of trial participants (aged 10-24). SCT is a behavioural intervention relying on self-administered ART and self-reported adherence.…”