7.2.3 First-line ART for children younger than three years of age

Consolidated ARV guidelines, June 2013

Rationale and supporting evidence (part 1)

This recommendation is based on evidence of the superiority of a LPV/r-based regimen for young children balanced against feasibility considerations.

Efficacy of a LPV/r-based regimen for infants and young children

A systematic review of two randomized trials (153,154) shows that children younger than 36 months have a reduced risk of discontinuing treatment and virological failure or death if they are started on a LPV/r-based regimen instead of a NVP-based regimen. At 24 weeks, LPV/r was demonstrated to be superior to NVP regardless of NNRTI exposure for PMTCT (Web Annex). In addition, surveillance of drug resistance among children younger than 18 months (149,155) provides further evidence of detectable NNRTI resistance even among children without any history of exposure to ARV drugs for PMTCT or whose exposure status is unknown, suggesting that a history of exposure for PMTCT may not be an accurate marker for identifying children at higher risk of HIV resistance to NNRTI.

LPV/r is known to have a better resistance profile that protects against the selection of NRTI resistance without compromising the use of other PIs in second-line regimens (156,157–159). In addition, a potential advantage is offered by the considerable reduction in the incidence of malaria among children receiving LPV/r-based, as recently demonstrated in a randomized trial comparing the use of LPV/r versus NVP or EFV among children in Uganda receiving an artemether + lumefantrine combination for treating malaria episodes (160).

Feasibility of LPV/r in resource-limited settings

Providing an LPV/r-based regimen to infants and children younger than three years in some resource-limited settings may be challenging. The current LPV/r syrup formulation has coldchain requirements until the point of dispensing. The syrup is unpalatable, with the potential for suboptimal adherence, as highlighted in the values and preferences survey among health workers, and the risk of metabolic complications among children who initiate LPV/r early in life is unknown. Further, LPV/r is costly and administering this with TB treatment is complex. Alternative approaches are proposed to overcome these challenges.

A recent randomized clinical trial (148,161) and an ongoing randomized clinical trial (162) have evaluated a strategy in which LPV/r is started and later substituted with an NNRTI (NVP or EFV). Such PI-sparing strategies aim to reduce exposure to LPV/r, offer an easier approach to maintaining treatment and preserve PI-based therapy for second-line ART. This approach has been shown to be safe and effective in the trial setting for children with sustained virological suppression achieved after receiving LPV/r-based first-line therapy, especially in the absence of HIV resistance to NNRTI before initiating ART (148,161). However, this approach may also add complexity to treatment programmes and may require access to virological monitoring. This strategy may therefore only be viable in settings in which viral load and/or genotype testing are available.

In settings in which none of these approaches is feasible or affordable, an NVP-based regimen provides an effective alternative, especially given the availability of two- and three-drug fixed-dose combinations. As observed in a recent randomized controlled trial, good virological outcomes (83% had a viral load less than 400 copies per ml for 3.7 years irrespective of age) can be achieved by starting children on ABC, 3TC and an NNRTI (163). EFV has not been used in this age group, however during the finalization of these guidelines the United States Food and Drug Administration approved this drug for children 3 months to 3 years old weighing more than 3.5 kg. Dosing for this population is provided in Annex 7 and further guidance on how best to use this drug as an alternative to LPV/r or NVP will be provided when additional data are available.