Weekends off ART: a strategy to maintain adherence in children and adolescents?

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.

The BREATHER (PENTA 16) Trial Group. Lancet HIV. 2016 Sep;3(9):e421-30. doi: 10.1016/S2352-3018(16)30054-6. Epub 2016 Jun 20.

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 percent (6%) patients assigned to the short cycle therapy versus seven percent (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 continuous 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.

Abstract [1]  Full-text [free] access  [2]

Editor’s notes: Increasing number of children born with HIV infection, who would otherwise have died in infancy, are now reaching adolescence because of the scale-up of antiretroviral therapy (ART). Adherence to treatment for chronic illnesses often drops as children approach adolescence, and unfortunately HIV is no exception.  

BREATHER is an open-label, non-inferiority trial comparing continuous daily ART (CT) with short cycle treatment (SCT) enabling two days off treatment every week. The participants were aged 8 to 24 years and had to have been virally suppressed for at least one year prior to enrolment on an ART regimen containing efavirenz. At 48 weeks, 6.1% of children in the SCT arm versus 7.3% in the CT arm had virologic rebound (defined as an HIV viral load > 50 copies/ml), demonstrating that SCT is non-inferior to CT. There was no statistical difference between arms in the proportion who developed major resistance mutations or in proportion of adverse events.

This is the first trial to demonstrate that controlled interruption appears to be safe in terms of maintaining viral suppression and lack of emergence of drug resistance mutations. Notably, the trial was conducted in geographically diverse settings (11 countries) and achieved an impressive retention rate with only one participant being lost to follow-up. In addition, the strategy was highly acceptable to participants, particularly as it provided a legitimate way of missing doses. Children are expected to take ART for 20 years longer on average than adults and strategies that enable time off ART may be an effective way to reduce treatment fatigue. In addition, reduced ART usage may provide potential cost savings. 

A concern, however, is that such a strategy may give out the detrimental message that missing doses is acceptable and may not affect the viral load. Therefore, appropriate counselling is important to ensure that people understand that there is a maximum break in treatment of two designated days per week. It is also important to note that the findings of this study are only generalisable to people who are stable on ART, who have not experienced treatment failure and who are taking efavirenz-based regimens. The trial was carried out with intensive viral load monitoring and further research is required to work out how such a strategy could be safely implemented in settings where routine viral load monitoring may not be available.

Viral suppression is the ultimate goal to improve health outcomes and reduce HIV transmission. Consistent adherence to ART is critical to ensure sustained virologic suppression. Children and adolescents face multiple challenges to adhere to treatment and a number of different approaches to address this are required- this trial now provides an innovative and promising option to offer to children.

Africa [7], Asia [8], Europe [9], Latin America [10], Northern America [11]
Argentina [12], Belgium [13], Denmark [14], Germany [15], Ireland [16], Spain [17], Thailand [18], Uganda [19], Ukraine [20], United Kingdom [21], United States of America [22]
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