7.2.3 First-line ART for children younger than three years of age
Consolidated ARV guidelines, June 2013
Rationale and supporting evidence (part 2)
Choice of NRTIs
The choice of NRTIs should aim to construct a robust and durable backbone that balances minimizing toxicity, minimizing cost and maximizing feasibility. Only limited evidence (164) from head-to-head comparisons informs the selection of NRTIs (AZT or ABC) combined with 3TC in a triple ART regimen. However, the choice of first-line NRTIs affects second-line ART, and failure of AZT is known to result in the accumulation of thymidine analogue mutations, reducing susceptibility to ABC or TDF in a subsequent regimen (if two or more thymidine analogue mutations are present). The risk of this occurring is greater with an NNRTI-based regimen; using it in the context of an LPV/r-based regimen may therefore not be as problematic. By contrast, HIV resistance to ABC does not lead to resistance to thymidine analogues and preserves or even increases the susceptibility of HIV to AZT and d4T for second-line use (159).
Although ABC may be preferable in the interest of ART sequencing (159,165) and harmonizing with the regimens for older children, availability is limited in resource-limited settings. In addition, the cost of ABC may be a significant barrier to adopting it in many countries, especially when combined with LPV/r. Definitive data on the comparative efficacy of ABC and AZT are expected from ongoing studies (166).
Since 2010, WHO has recommended that d4T be phased out because of its known long-term toxicity. However, in settings in which using AZT may not be advisable because of the high risk of anaemia (such as malaria-endemic settings) and in which ABC is not available, d4T remains an option within the limited treatment options for this specific age group. d4T also remains important in the situation in which toxicity to AZT is suspected or confirmed and ABC cannot be used. However, the duration of therapy with this drug should be limited to the shortest time possible. Box 10.7 provides guidance on phasing out d4T.
In developing these recommendations, the Guidelines Development Group emphasized:
- the importance of potent, first-line regimens for which there is evidence of better virological response as indicated by randomized controlled trials in this age group;
- the need to address the increasing evidence of HIV resistance to NNRTI among children younger than 18 months, especially in the context of the recommendation to treat pregnant women with EFV-based regimens for PMTCT;
- the desirability of having one preferred regimen for children younger than three years while providing alternative strategies that remain less costly, preserve second-line options and address feasibility concerns;
- anticipating the availability of new formulations during the next few years (sprinkles or sachets containing LPV/r);
- using non-thymidine analogues in first-line regimens to preserve the response to AZT in second-line regimens and to harmonize the regimens for older children and adults, while also recognizing the additional expense;
- identifying a subset of children who can benefit from alternative strategies to preserve PIs for use in second-line ART as indicated by a randomized trial; and
- identifying a manageable regimen, such as ABC + 3TC + AZT, for use in the context of TB co-treatment that can maintain good clinical and immunological response after virological suppression on standard ART.