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

Background: For 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).

Methods: In 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.

Findings: Between 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).

Interpretation: Non-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.

Funding: UK National Institute for Health Research Health Technology Assessment; UK Medical Research Council; European Commission; PENTA Foundation; INSERM SC10-US19, France.

Copyright © 2016 The BREATHER (PENTA 16) Trial Group. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile *One participant was unable to attend the randomisation visit due to a traffic accident and another participant was excluded because of unreliable attendance.

Figure 2

Time to viral rebound (A) Kaplan-Meier graph adjusted for stratification factors—time from randomisation to viral rebound (confirmed viral load ≥50 copies per mL). (B) Estimated difference in proportion of participants with viral rebound (two-sided 90% CI) between short cycle therapy and continuous therapy at week 48 for different analyses. *Difference in estimated probability of viral rebound, Kaplan-Meier methods, with adjustment for study stratification factors. †Difference in estimated probability of viral rebound, Kaplan-Meier methods. ‡With exact confidence intervals. §Kaplan-Meier methods, censoring individuals who violated the profile at that time, with adjustment for study stratification factors.

Figure 3

Proportion of days MEMS caps were opened Data for 31 participants in the short cycle therapy group and 30 participants in the continuous treatment group (including 23 in each group with data to 48 weeks). MEMS=Medication Event Monitoring System.