Response to planned treatment interruptions in HIV infection varies across childhood

AIDS (Impact Factor: 5.55). 01/2010; 24(2):231-241. DOI: 10.1097/QAD.0b013e328333d343


Objective: To evaluate clinical, immunological and virological consequences of CD4-guided antiretroviral therapy (ART) planned treatment interruptions (PTIs) compared with continuous therapy in children with chronic HIV infection in the Paediatric European Network for Treatment of AIDS 11 trial. Design: This was a multicentre, 72-week, open, randomized, phase 11 trial. Methods: 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/mu l (7-15 years) were randomized to continuous therapy (53) or PTI (56). In PTI, ART was restarted if confirmed CD4% was less than 20% or more than 48 weeks had been spent off ART. 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/mu l for children aged 7-15years). Results: At baseline, median (interquartile range) age was 9 (6-12) years, CD4% 37% (33-41), CD4 cell count 966 (793-11258)cells/mu l, nadir CD41/0 before combination ART 18% (10-27), time on ART 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 ART in continuous therapy and PTI, respectively. No child died or had a new CDC stage C event; one (2%) continuous therapy versus four (7%) PTI children had a primary outcome based on CD4%/cell count (P=0.2). Lower nadir CD4% predicted faster CD4% decline after stopping ART. Younger age and higher nadir CD4% predicted being off ART for at least 48 weeks and better CD4% recovery following PTI. Conclusion: In this first paediatric trial of PTI, there were no serious clinical outcomes. Younger children had better CD4% recovery after PTIs. 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 ART for all infected infants. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

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    ABSTRACT: Paediatric HIV infection is a substantial global public health problem in its own right. Approximately one in six new HIV infections worldwide arises as a result of mother-to-child transmission (MTCT). In contrast to adult infection, progression to AIDS and death is rapid in most infected children and cannot be satisfactorily predicted in the youngest children based on viral load or CD4 count. For this reason, the current revised WHO guidelines recommending antiretroviral therapy (ART) be initiated in HIV-infected children from birth, or as soon after birth as possible, are fully justified. However, this presents the daunting challenge of a life-time on ART, starting from the perinatal period. Given the major difficulties of maintaining adherence and avoiding toxicity from infancy through to adolescence, it would seem imperative to consider what alternative strategies to a life-time on ART may be considered in paediatric HIV infection, to avoid the prospect in 10 years of an epidemic of HIV-infected adolescents on failing salvage therapy regimens. Furthermore, at the current rate of growth, the number of children living with HIV will double within 5 years, and the cost of maintaining ART, together with monitoring of CD4 counts and viral load, in these numbers would be hard to sustain. This review addresses, first, the particular differences between paediatric and adult HIV infection, and the immune responses most effective in control of HIV, with specific reference to the anti-HIV CD8+ T-cell response; and, second, the ART interruption strategies currently being explored that could provide an alternative to lifelong ART for infected children.
    No preview · Article · Jan 2011 · Advances in Experimental Medicine and Biology
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    ABSTRACT: There have been no paediatric randomised trials describing the effect of planned treatment interruptions (PTIs) of antiretroviral therapy (ART) on adherence, or evaluating acceptability of such a strategy. In PENTA 11, HIV-infected children were randomised to CD4-guided PTIs (n = 53) or continuous therapy (CT, n = 56). Carers, and children if appropriate, completed questionnaires on adherence to ART and acceptability of PTIs. There was no difference in reported adherence on ART between CT and PTI groups; non-adherence (reporting missed doses over the last 3 days or marking <100 % adherence since the last clinical visit on a visual analogue scale) was 18 % (20/111) and 14 % (12/83) on carer questionnaires in the CT and PTI groups respectively (odds ratios, OR (95 % CI) = 1.04 (0.20, 5.41), χ(2) (1) = 0.003, p = 0.96). Carers in Europe/USA reported non-adherence more often (31/121, 26 %) than in Thailand (1/73, 1 %; OR (95 % CI) = 54.65 (3.68, 810.55), χ(2) (1) = 8.45, p = 0.004). The majority of families indicated they were happy to have further PTIs (carer: 23/36, 64 %; children: 8/13, 62 %), however many reported more clinic visits during PTI were a problem (carer: 15/36, 42 %; children: 6/12, 50 %).
    Full-text · Article · May 2012 · AIDS and Behavior
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    ABSTRACT: To evaluate the immunological and viral consequences of planned treatment interruptions (PTI) in children with HIV. This was an immunological and virological sub-study of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial, which compared CD4-guided PTI of antiretroviral therapy (ART) with continuous therapy (CT) in children. HIV-1 RNA and lymphocyte subsets, including CD4 and CD8 cells, were quantified on fresh samples collected during the study; CD45RA, CD45RO and CD31 subpopulations were evaluated in some centres. For 36 (18 PTI, 18 CT) children, immunophenotyping was performed and cell-associated HIV-1 DNA analysed on stored samples to 48 weeks. In the PTI group, CD4 cell count fell rapidly in the first 12 weeks off ART, with decreases in both naïve and memory cells. However, the proportion of CD4 cells expressing CD45RA and CD45RO remained constant in both groups. The increase in CD8 cells in the first 12 weeks off ART in the PTI group was predominantly due to increases in RO-expressing cells. PTI was associated with a rapid and sustained increase in CD4 cells expressing Ki67 and HLA-DR, and increased levels of HIV-1 DNA. PTI in children is associated with rapid changes in CD4 and CD8 cells, likely due to increased cell turnover and immune activation. However, children off treatment may be able to maintain stable levels of naïve CD4 cells, at least in proportion to the memory cell pool, which may in part explain the observed excellent CD4 cell recovery with re-introduction of ART.
    Full-text · Article · Oct 2013 · PLoS ONE
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