A breather from daily antiretroviral therapy for adolescents
Authors: Rashida A Ferrand
Journal: The Lancet HIV (2016)

The global scale-up of antiretroviral therapy (ART) has resulted in HIV infection being transformed from an inevitably fatal disease to a chronic, albeit incurable, infection requiring life-long treatment.1UNAIDSHow AIDS Changed Everything—MDG6: 15 years, 15 lessons of hope from the AIDS responses. UNAIDS, Geneva2015Google Scholar Increasing numbers of children infected through mother-to-child HIV transmission, who would have died in infancy in the pre-ART era, are now reaching adolescence and face the prospect of having to take ART daily with optimum adherence for the rest of their lives.2Newell M-L Coovadia H Cortina-Borja M Rollins N Gaillard P Dabis F Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis.Lancet. 2004; 364: 1236-1243Summary Full Text Full Text PDF PubMed Scopus (907) Google Scholar, 3Hazra R Siberry GK Mofenson LM Growing up with HIV: children, adolescents, and young adults with perinatally acquired HIV infection.Annu Rev Med. 2010; 61: 169-185Crossref PubMed Scopus (170) Google Scholar, 4Foster C Judd A Tookey P et al.Young people in the United Kingdom and Ireland with perinatally acquired HIV: the pediatric legacy for adult services.AIDS Patient Care STDS. 2009; 23: 159-166Crossref PubMed Scopus (80) Google Scholar In The Lancet HIV, the PENTA 16 trial group report the findings of the BREATHER study, an open-label, non-inferiority trial, comparing continuous daily ART with short cycle treatment enabling 2 days off treatment every week.5Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial.Lancet HIV. 2016; (published online June 20.)http://dx.doi.org/10.1016/S2352-3018(16)30054-6Google Scholar 199 participants aged 8–24 years who had been virally suppressed for at least 12 months before enrolment and were taking an ART regimen containing the long-actingdrug efavirenz were recruited from 11 countries worldwide. At 48 weeks, six (6%) of 99 children in the short cycle treatment group versus seven (7%) of 100 in the continuous treatment group had virological rebound (HIV viral load >50 copies per mL; difference −1·2%, 90% CI −7·3 to 4·9), showing that short cycle treatment is non-inferior to continuous treatment. There was no statistical difference between the groups in the proportion of participants who developed major resistance mutations or in the proportion of adverse events. This is the first trial to show that controlled interruption seems to be safe in terms of both maintenance of viral suppression and emergence of drug resistance. Notably, the trial was done in geographically diverse settings and achieved an impressive retention rate with only one participant lost to follow-up. Children are expected to take ART for 20 years longer on average than adults and strategies that enable time off ART could be an effective way to reduce treatment fatigue.6Lowenthal ED Bakeera-Kitaka S Marukutira T Chapman J Goldrath K Ferrand RA Perinatally acquired HIV infection in adolescents from sub-Saharan Africa: a review of emerging challenges.Lancet Infect Dis. 2014; 14: 627-639Summary Full Text Full Text PDF PubMed Scopus (299) Google Scholar Additionally, reduced ART usage through short cycle treatment might provide potential cost savings. The short cycle treatment strategy was highly acceptable to participants, particularly because it enabled socialising at weekends, which is otherwise a key barrier to taking medication. Even patients who are virologically suppressed report intermittently missing drugs, and short cycle treatment provides regulated time off medication and a legitimate way to miss doses.7Bernays S, Seeley J, Paparini S, Rhodes T. ‘I am scared of getting caught up in my lie’: challenges to self-reported adherence for young people living with HIV. AIDS Impact; Amsterdam, Netherlands; July 28–31, 2015.Google Scholar Of concern is that such a strategy might give out the message that missing doses is acceptable and seems not to affect viral load. Therefore, appropriate counselling is crucial to ensure that the results are not misinterpreted and that patients understand that there is a maximum break in treatment of the designated 2 days per week. Notably, the findings of this study are only generalisable to patients who are stable and well established on ART. The median time on ART before randomisation in this trial was 6 years and children had been virally suppressed for at least 12 months. Additionally, the results cannot be extrapolated to children who have had previous treatment failure, or to ART containing reduced doses of efavirenz (equivalent to 400 mg for adults) or indeed to other long-acting ART regimens. The follow-up period was short and the planned 2 year trial extension will provide data for longer term sustainability of the short cycle treatment strategy. Other questions remain to be answered before short cycle treatment can become a viable option. The trial was done in tightly controlled conditions with intensive viral load monitoring. Research is needed to understand whether the trial could be safely implemented in resource-constrained settings where routine viral load monitoring is unavailable or infrequent. Further research could also assess short cycle treatment with the newer long-acting drugs becoming available that have a higher barrier to resistance and are more tolerable, such as tenofovir alafenamide and dolutegravir.8Elliot E Amara A Jackson A et al.Dolutegravir and elvitegravir plasma concentrations following cessation of drug intake.J Antimicrob Chemother. 2016; 71: 1031-1036Crossref PubMed Scopus (21) Google Scholar Viral suppression is the ultimate goal to improve health outcomes and reduce HIV transmission, thus conferring individual and public health benefits.9Attia S Egger M Muller M Zwahlen M Low N Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis.AIDS. 2009; 23: 1397-1404Crossref PubMed Scopus (758) Google Scholar, 10Mills EJ Bakanda C Birungi J et al.Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda.Ann Intern Med. 2011; 155: 209-216Crossref PubMed Scopus (306) Google Scholar Optimum adherence to ART is crucial to ensure sustained virological suppression. Adherence to treatment of chronic illnesses drops off during adolescence and unfortunately HIV is no exception.11Nachega JB Hislop M Nguyen H et al.Antiretroviral therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in southern Africa.J Acquir Immune Defic Syndr. 2009; 51: 65-71Crossref PubMed Scopus (306) Google Scholar Adolescents face several barriers to adherence, and our experience is that no single intervention will be sufficient to ensure the high levels of adherence needed to maintain virological suppression.12Adejumo OA Malee KM Ryscavage P Hunter SJ Taiwo BO Contemporary issues on the epidemiology and antiretroviral adherence of HIV-infected adolescents in sub-Saharan Africa: a narrative review.J Int AIDS Soc. 2015; 18: 20049Crossref PubMed Scopus (133) Google Scholar Therefore, we need several different approaches in our armamentarium to support adherence in this age group. We now have a promising and innovative option on the horizon that could be offered to young people who face the prospect of taking lifelong ART. I declare no competing interests. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trialNon-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. Full-Text PDF Open Access