7.5.2 Second-line ART for children (including adolescents)
Consolidated ARV guidelines, June 2013
Rationale and supporting evidence
After reviewing data for adults and children and considering factors such as the availability of a heat-stable fixed-dose combination, optimal daily dose, regimen harmonization with adults, high cost and availability of alternatives, the main recommendations established in the 2010 guidelines were maintained.
For children for whom a LPV/r-based first-line regimen has failed, NNRTIs remain the only new drug class that can be introduced. Randomized data among older children (158) provide indirect evidence supporting the safe use of an NNRTI-based second-line regimen, but concerns remain about this approach for infants and young children. Based on the suboptimal performance of NVP-based regimens (and the limited data available to inform the use of EFV) in children younger than three years (153 154) and the potential rapid re-emergence of archived NNRTI-resistant HIV, second-line NNRTI-based regimens are expected to have limited durability in this age group (238).
Increasing evidence suggests that, in young children for whom LPV/r-based regimens have failed, selection of major PI mutations is rare and accumulation of thymidine analogue mutations is very limited (156 237 239 240). In this context and in the absence of robust second-line alternatives such as DRV/r-containing regimens, the Guidelines Development Group recommended that children younger than three years of age should be maintained on LPV/r until the age of three years, despite treatment failure. However, a more rapid switch should be considered in situations in which failure results from poor adherence because of the poor palatability of LPV/r or in cases of advanced HIV disease. In such cases, children younger than three years should be switched to a NVP-based regimen, and close monitoring should be provided to ensure adequate adherence.
For children starting first-line ART with an NNRTI-based regimen, PI-based regimens remain the recommended choice for second-line therapy. LPV/r is the preferred option, but ATV/r and DRV/r may be considered if more appropriate formulations become available.
Despite its toxicity profile and limited role in TB and HIV coinfection, ATV/r is a promising alternative to LPV/r for children older than six years of age. ATV/r has some advantages over LPV/r, including lower cost and the potential for once-daily dosing. DRV/r is the PI of choice following LPV/r or ATV/r treatment failure and would be valuable as a third-line drug or as second-line therapy in young children for whom first-line ART with LPV/r has failed. However, ATV/r is currently only licensed for use among children older than six years and DRV/r in children older than three years. Neither ATV/r nor DRV/r is currently available as a co-formulated fixed-dose combination for children. The Paediatric ARVs Working Group identified appropriate doses of both drugs using current WHO weight bands with scaling down from the current adult fixed-dose combination tablets. Validation studies are urgently needed to develop adequate paediatric formulations.
Unboosted PIs (such as fosamprenavir (FPV), DRV and ATV) and other PIs (such as IDV/r, SQV/r, FPV/r and TPV/r) are associated with reduced virological suppression, high pill burden and/or a higher frequency of side effects and are therefore discouraged (241).
Notably, liquid RTV requires cold storage, is unpalatable, has significant gastrointestinal intolerance and is poorly tolerated by infants and children. The heat-stable 100-mg fixeddose combination tablet formulation of LPV/r for children is better tolerated but cannot be cut or crushed; many children have difficulty in swallowing this tablet whole. Data on whether LPV/r can be given once daily are expected soon from an ongoing randomized trial (242). New heat-stable paediatric sprinkle formulations appear to be a suitable alternative and will be available in the near future (243).
The sequencing of NRTI was determined based on optimizing principles for ARV drugs and the need to maximize antiviral activity despite the selection of resistance mutations. If a thymidine analogue NRTI drug (AZT or d4T) was used in the failing first-line regimen, ABC or TDF should be used in the second-line regimen. If a non-thymidine analogue NRTI drug (ABC or TDF) was used in the failing first-line regimen, AZT should be used in the second-line regimen. The added value of ddI in second-line regimens is unclear; continuing 3TC despite the likely presence of 3TC resistance is the preferred option. HIV harbouring 3TC resistance with the M184V mutation may have reduced viral replication and may also induce some degree of resensitization to AZT or TDF, although this is based on in vitro data (165 244).