7.1.4 When to start ART in children
Consolidated ARV guidelines, June 2013
Rationale and supporting evidence (part 1)
These recommendations are based on strong operational and programmatic advantages resulting from simplification of criteria for initiating ART, despite the lack of clinical benefits to support treatment regardless of CD4 or clinical stage beyond infancy. Similarly, for programmatic purposes and given that disease progression in children five years and older is comparable to that of young adults, alignment with ART initiation criteria for adults was considered of high value.
Evidence for increasing the age threshold for early ART to five years
CD4 count and WHO clinical stage can identify children at increased risk of disease progression and death. Previous recommendations were based on observational studies demonstrating that untreated children in the second year of life continue to experience high rates of death and illness compared with children without HIV (106). Child-survival curves suggest that the mortality for children older than two years of age and with CD4 exceeding 25% is about 1–2% per year (107,108).
A systematic review identified only one randomized clinical trial, PREDICT (112), informing this issue (Web Annex). The trial enrolled 300 children (1–12 years old, median age 6.4 years) with CD4 counts above 15% and without CDC clinical stage C disease, randomizing them to either immediate treatment or deferred treatment until the CD4 count fell below 15%. AIDS-free survival, neurodevelopmental outcomes and growth parameters did not differ between groups (113).
A causal modelling study was also undertaken using prospective data collected by the IeDEASouthern Africa network on 5732 ART-naive children 24–59 months old (median age 3.3 years) who had CD4 counts above the existing eligibility thresholds of 25% or 750 cells/mm3 (114) (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). The study did not show any survival benefit from early treatment in this population, but a large proportion of children in this age range would rapidly become eligible under the existing criteria, since most children with CD4 count of 750 cells/mm3 or higher at enrolment into care reached the CD4 treatment threshold within three years. More specifically, 32% of this subset of the cohort fell below the thresholds for eligibility after one year and 60% after two years.
Operational and programmatic advantages
Despite the lower risk of progression in children 2–5 years old compared with children younger than two years and the low quality of evidence, the Guidelines Development Group emphasized the operational and programmatic advantages of removing the CD4 barrier to treatment for children under 5 years of age. Treating all children younger than five years of age is expected to simplify paediatric treatment and facilitate a significant expansion of ART coverage for young children. Although this has not been assessed as an outcome, programmatic data suggest that retention is better among children on ART than among those in care but not started on ART (109).
Increasing ART coverage and targeting these children for HIV care may also facilitate the treatment of other preventable causes of under-five mortality. This approach will likely represent a small increased burden on current systems (115). Note that late diagnosis is still occurring, and a large proportion of the children identified as infected with HIV would already be eligible for ART based on the 2010 recommendations.