Children under 3 years of age who have HIV infection have a high risk of dying without antiretroviral therapy (ART). However, treatment in this age group is challenging because there are high levels of virus in the blood and few suitable drug choices. Results from this systematic review show that ART soon after birth is preferable to delaying treatment, because infants are less likely to die or become sick. Starting a first-line treatment regimen that includes lopinavir/ritonavir rather than nevirapine is preferable, because infants and young children are less likely to have to stop treatment, whether or not they had previously been exposed to nevirapine. However, lopinavir/ritonavir is more expensive than nevirapine. It is also currently only available as an inconvenient liquid, which tastes bitter and has to be refrigerated, making it challenging to implement in all parts of the world. While waiting for better formulations to become available, it may be possible to switch from lopinavir/ritonavir to nevirapine once the HIV virus levels become undetectable. However, based on the evidence currently available, a viral load test would be required to identify those children who could safely substitute lopinavir/ritonavir with nevirapine. Viral loads are expensive and not widely available in most countries in sub-Saharan Africa. An alternative treatment approach is to give a stronger drug combination (four different drugs together) when treatment is first started, then reduce down to three drugs after a short while. However, this strategy did not appear to have long-term benefits. A 'treatment interruption' strategy, in which infants start ART soon after birth but then stop medication after 1-2 years, is difficult to implement. Children stopping ART need to restart it very quickly to prevent them becoming sick, and monitoring a child off treatment is challenging in settings with few resources.
ART initiation in asymptomatic children under 1 year of age reduces morbidity and mortality, but it remains unclear whether there are clinical benefits to starting ART in asymptomatic children diagnosed with HIV infection between 1-3 years.
The available evidence shows that a LPV/r-based first-line regimen is more efficacious than a NVP-based regimen, regardless of PMTCT exposure status. New formulations of LPV/r are urgently required to enable new WHO recommendations to be implemented. An alternative approach to long-term LPV/r is substituting LPV/r with NVP once virological suppression is achieved. This strategy looked promising in the one trial undertaken, but may be difficult to implement in the absence of routine viral load testing.
A 4-drug induction-maintenance approach showed short-term virological and immunological benefits during the induction phase but, in the absence of sustained benefits, is not recommended as a routine treatment strategy. Treatment interruption following early ART initiation in infancy was challenging for children who were severely immunocompromised in the context of poor clinical immunological condition at ART initiation due to the short duration of interruption, and is therefore not practical in ART treatment programmes where close monitoring is not feasible.
In the absence of antiretroviral therapy (ART), over 50% of HIV-infected infants progress to AIDS and death by 2 years of age. However, there are challenges to initiation of ART in early life, including the possibility of drug resistance in the context of prevention of mother-to-child transmission (PMTCT) programs, a paucity of drug choices , uncertain dosing for some medications and long-term toxicities. Key management decisions include when to start ART, what regimen to start, and whether and when to substitute drugs or interrupt therapy. This review, an update of a previous review, aims to summarize the currently available evidence on this topic and inform the ART management in HIV-infected children less than 3 years of age.
To evaluate 1) when to start ART in young children (less than 3 years); 2) what ART to start with, comparing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)-based regimens; and 3) whether alternative strategies should be used to optimize antiretroviral treatment in this population: induction (initiation with 4 drugs rather than 3 drugs) followed by maintenance ART, interruption of ART and substitution of PI with NNRTI drugs once virological suppression is achieved on a PI-based regimen.
Search methods
We searched for published studies in the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Pubmed, EMBASE and CENTRAL. We screened abstracts from relevant conference proceedings and searched for unpublished and ongoing trials in clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform).
We identified RCTs that recruited perinatally HIV-infected children under 3 years of age without restriction of setting. We rejected trials that did not include children less than 3 years of age, did not provide stratified outcomes for those less than 3 years or did not evaluate either timing of ART initiation, choice of drug regimen or treatment switch/interruption strategy.
Two reviewers independently applied study selection criteria, assessed study quality and extracted data. Effects were assessed using the hazard ratio (HR) for time-to-event outcomes, relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes.
A search of the databases identified a total of 735 unique, previously unreviewed studies, of which 731 were excluded to leave 4 new studies to incorporate into the review. Four additional studies were identified in conference proceedings, for a total of 8 studies addressing when to start treatment (n=2), what to start (n=3), whether to substitute lopinavir/ritonavir (LPV/r) with nevirapine (NVP) (n=1), whether to use an induction-maintenance ART strategy (n=1) and whether to interrupt treatment (n=1).
Treatment initiation in asymptomatic infants with good immunological status was associated with a 75% reduction (HR=0.25; 95%CI 0.12-0.51; p=0.0002) in mortality or disease progression in the one trial with sufficient power to address this question. In a smaller pilot trial, median CD4 cell count was not significantly different between early and deferred treatment groups 12 months after ART.
Regardless of previous exposure to nevirapine for PMTCT, the hazard for treatment failure at 24 weeks was 1.79 (95%CI 1.33, 2.41) times higher in children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0001) with no clear difference in the effect observed for children younger or older than 1 year. The hazard for virological failure at 24 weeks was overall 1.84 (95%CI 1.29, 2.63) times higher for children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0008) with a larger difference in time to virological failure (or death) between the NVP and LPV/r-based regimens when ART was initiated in the first year of life.
Infants starting a LPV/r regimen and achieving sustained virological suppression who then substituted LPV/r with NVP after median 9 months on LPV/r were less likely to develop virological failure (defined as at least one VL greater than 50 copies/mL) compared with infants who started and stayed on LPV/r (HR=0.62, 95%CI 0.41, 0.92, p=0.02). However the hazard for confirmed failure at a higher viral load (>1000 copies/mL) was greater among children who switched to NVP compared to those who remained on LPV/r (HR=10.19, 95% CI 2.36, 43.94, p=0.002).
Children undergoing an induction-maintenance ART approach with a 4-drug NNRTI-based regimen for 36 weeks, followed by 3-drug ART, had significantly greater CD4 rise than children receiving a standard 3-drug NNRTI-based ART at 36 weeks (mean difference 1.70 [95%CI 0.61, 2.79] p=0.002) and significantly better viral load response at 24 weeks (OR 1.99 [95%CI 1.09, 3.62] p=0.02). However, the immunological and virological benefits were short-term.
The one trial of treatment interruption that compared children initiating continuous ART from infancy with children interrupting ART was terminated early because the duration of treatment interruption was less than 3 months in most infants. Children interrupting treatment had similar growth and occurrence of serious adverse events as those in the continuous arm.