Short-cycle ART not inferior with adolescents

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Short-cycle ART, which entails taking it for 5 days then a break for 2 days, was non-inferior to continuous therapy for adolescents, reports Healio.

“The findings of this trial, supported by previous adult studies, show that a short cycle therapy strategy with 5 days on and 2 days off efavirenz-based ART with a standard dose of efavirenz is a viable option for virologically suppressed children, adolescents and young adults with 29% reduction in the cost of drugs,” Dr Karina M Butler, clinical professor of paediatrics at University College Dublin, and colleagues wrote. “Acceptability of the short cycle therapy strategy was shown among participants from all backgrounds; in particular, it was valued because it allowed for more socialising with friends at weekends.”

Short-cycle therapy can reduce the costs and long-term toxic effects of ART, the researchers wrote. Two previous studies have shown that 5 days on and 2 days off worked as well as continuous ART in adults, but no studies have been performed in adolescents, who face longer-term therapy than adults.

In an phase 2/3 randomised non-inferiority trial called BREATHER, Butler and colleagues assessed 199 participants aged 8 to 24 years (median age = 14 years; median CD4 count = 735 cells per µL) who were stable on a first-line regiment of efavirenz with two nucleoside reverse transcriptase inhibitors, and had a viral load fewer than 50 copies per mL for at least 1 year. The primary outcome was a viral load higher than 50 copies per mL at any time during the 48-week assessment.

The rate of treatment failure (viral load higher than 50 copies per mL) did not differ between patients receiving short-cycle therapy and those receiving continuous therapy: 6% vs. 7%, respectively (difference = –1.2%; 90% CI, –7.3 to 4.9). In addition, there were 13 grade 3 or 4 events in the short-cycle group vs. 14 in continuous therapy group. Only two ART-related adverse events occurred in the short cycle group vs. 14 in the continuous therapy group (P = .02).

The results indicate no evidence that short-cycle therapy was inferior to continuous therapy, the researchers concluded.

“The results from this study show that short-cycle therapy might be a promising strategy for adherent children and adolescents well established on ART,” the researchers wrote. “The overall reduction in drug exposure could reduce long-term toxicity for individuals and, at a population level, result in cost savings, enabling more participants to receive treatment.”

Summary
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.

Authors
The BREATHER (PENTA 16) Trial Group

Healio material
The Lancet HIV article summary


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