Response to planned treatment interruptions in HIV infection varies across childhood

Response to planned treatment interruptions in HIV infection varies across childhood

The aim of this study was to evaluate clinical, immunological, and virological consequences of CD4-guided antiretroviral therapy planned treatment interruptions compared with continuous therapy in children with chronic HIV infection in the Paediatric European Network for Treatment of AIDS 11 trial. This was a multicentre, 72-week, open, randomized, phase II trial. One hundred and nine children with HIV-RNA below 50 copies/ml and CD4% of at least 30% (2-6 years) or at least 25% and CD4 cell count of at least 500 cells/microl (7-15 years) were randomized to continuous therapy (53) or planned treatment interruptions (56). In planned treatment interruptions, antiretroviral therapy was restarted if confirmed CD4% was less than 20% or more than 48 weeks had been spent off antiretroviral therapy. The primary outcome was Centers for Disease Control and Prevention (CDC) stage C event, death, or CD4% less than 15% (and CD4 cell count less than 200 cells/microl for children aged 7-15 years). At baseline, median (interquartile range) age was 9 (6-12) years, CD4% 37% (33-41), CD4 cell count 966 (793-1258) cells/microl, nadir CD4% before combination antiretroviral therapy 18% (10-27), time on antiretroviral therapy 6 (3-6) years, and 26% were CDC stage C. After median (range) 130 (33-180) weeks of follow-up, 4 versus 48% of time was spent off antiretroviral therapy in continuous therapy and planned treatment interruptions, respectively. No child died or had a new CDC stage C event; one (2%) continuous therapy versus four (7%) planned treatment interruptions children had a primary outcome based on CD4%/cell count (P = 0.2). Lower nadir CD4% predicted faster CD4% decline after stopping antiretroviral therapy. Younger age and higher nadir CD4% predicted being off ART for at least 48 weeks and better CD4% recovery following planned treatment interruptions. In this first paediatric trial of planned treatment interruption, there were no serious clinical outcomes. Younger children had better CD4% recovery after planned treatment interruptions. Immunology substudies and long-term follow-up in Paediatric European Network for Treatment of AIDS 11 trial are ongoing. Further research into the role of treatment interruption in children is required, particularly, as guidelines now recommend early antiretroviral therapy for all infected infants.

starting antiretroviral treatment, children have a greater potential for immune regeneration than do adults because the thymus is more active in childhood. Furthermore, the risk-benefit balance of lifelong continuous treatment versus planned treatment interruptions in vertically HIV-infected children may be different than for adults, considering the risks of long-term drug toxicity and viral resistance. The encouraging results of this PENTA II pilot study, the first planned treatment interruption trial to take place in children, support continuation of two large treatment interruption trials ongoing in Africa. These are the CHER trial in South Africa studying 400 infants starting antiretroviral treatment before 12 weeks of age and stopping at first or second birthday, and the Bana trial in Botswana of 600 children which has a similar design to PENTA II with different CD4% thresholds for stopping and restarting. Given that it is recommended that all infants start antiretroviral treatment as soon as HIV infection is diagnosed, learning whether planned treatment interruptions are a good idea in children is an important clinical research question.