Optimization of antiretroviral therapy in HIV-infected children under 3 years of age: a systematic review.
BACKGROUND
Treatment of young HIV-infected children is challenging because of rapid disease progression, high viral loads and few drug options. This review was undertaken to update evidence on the management of young HIV-infected children and to inform the development of the 2013 WHO guidelines for antiretroviral therapy (ART) in low and middle-income countries.


METHODS
A systematic review and meta-analysis.


METHODS
We identified and critically assessed randomized controlled trials that evaluated treatment strategies in perinatally HIV-infected infants and young children (aged <3 years).


RESULTS
Eight studies were included. Antiretroviral therapy (ART) initiation in asymptomatic infants led to 74% reduction in mortality or disease progression [hazard ratio 0.36, 95% confidence interval (CI) 0.18-0.74, P = 0.0002]. Regardless of previous exposure to prevention of mother to child transmission (PMTCT), treatment failure at 24 weeks was more likely in children starting nevirapine-based than in those starting lopinavir/ritonavir (lopinavir/r)-based ART (hazard ratio 1.79, 95% CI 1.33-2.41, P = 0.0001). Infants starting lopinavir/r-based ART and substituting lopinavir/r with nevirapine once virologic suppression was achieved were less likely to experience viral load more than 50 copies/ml (hazard ratio 0.62, 95% CI 0.41-0.92, P = 0.02) but more likely to have confirmed virologic failure (>1000 copies/ml) than those remaining on lopinavir/r (hazard ratio 10.19, 95% CI 2.36-43.94, P = 0.002). Children receiving induction-maintenance ART (four-drug NNRTI-based regimen for 36 weeks followed by three-drug ART) showed better short-term immunologic and virologic responses, but no long-term benefits. The only trial comparing continuous ART from infancy with interrupted ART beyond infancy was terminated early because the duration of treatment interruption was less than 3 months in most infants.


CONCLUSIONS
ART initiation in asymptomatic infants reduces morbidity and mortality. Lopinavir/r-based first-line ART is superior to nevirapine-based regimens in young children, regardless of PMTCT exposure, but lopinavir/r use is challenging. Substituting lopinavir/r with nevirapine following virologic suppression may be feasible where viral load testing is available. Considering current evidence, induction-maintenance and treatment interruption strategies are not recommended. This review contributed to the evidence base for the 2013 WHO guidelines on antiretroviral therapy, which recommend that all children below 3 years start lopinavir/r-based ART and that lopinavir/r can be substituted with nevirapine once sustained virologic suppression is achieved.
aMRC Clinical Trials Unit at UCL, London, UK bHIV Department, World Health Organization, Geneva, Switzerland cCentre for Paediatrics, Blizard Institute, Queen Mary University of London, London, UK dZvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe eAfrican Network for the Care of Children Affected by HIV/AIDS (ANECCA), Kampala, Uganda fICAP, Mailman School of Public Health and College of Physicians and Surgeons, Columbia University, Columbia, New York, USA. *Martina Penazzato and Andrew J. Prendergast contributed equally to the development of this manuscript.
Martina
M
Penazzato
Andrew J
AJ
Prendergast
Lulu M
LM
Muhe
Denis
D
Tindyebwa
Elaine J
EJ
Abrams
D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D002675:Child, Preschool; D018450:Disease Progression; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000635:transmission; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D044966:Anti-Retroviral Agents