As in other paediatric HIV care programmes in sub-Saharan Africa (8
), the majority of children initiated ART at advanced stages of disease having WHO stage 3 or 4 and advanced or severe immune suppression. Incidence of LTFU in this study was 8.4 and 5.0 per 100 child-years in the first and second year of ART, respectively.
In the first year on ART the incidence rate of LTFU was highest in the first 3 months. This mirrors the previously reported high rate of death in the first 90 days on ART (18
) and may be partly attributable to unreported early mortality. The cumulative probability of LTFU at 12 months was 7.3% (95% CI 7.1–8.8). This is comparable with the 1-year LTFU rate of 7% reported by the International epidemiologic Databases to Evaluate AIDS in Southern Africa (IeDEA-SA) study in a pooled analysis of 10 paediatric ART programmes from South Africa, Malawi, Mozambique, and Zimbabwe (10
). The incidence of LTFU in Asian children on ART with an average follow-up time of 3 years was found to be lower at 4.2 per 100 person-years (19
). In the first 12 months on ART, independent predictors of LTFU were age <1 year at initiation, recent year of ART, having one's biological mother as a primary caregiver, and being underweight (WAZ ≤ −2).The risk of LTFU increased progressively in successive enrolment calendar periods with those initiated between 2009 and 2011 having the highest LTFU. This increase in LTFU in children enrolled in more recent years is consistent with findings of studies of ART outcomes in similar settings (8
). This might reflect the effect of rapid scale-up and subsequently higher workloads on quality of care. A study of temporal trends in four South African provinces which comprised smaller, rural paediatric cohorts did not demonstrate the same progressive increase in LTFU in subsequent calendar cohorts as shown in this study (5
). This suggests that the increase in LTFU might be related to rapid ART scale-up in large urban cohorts where the impact of high workloads on quality of care would be significant.
Haitian children who were LTFU had lower baseline median WAZ (−3, IQR −3.7 to −1.8) than those retained in care (20
). WAZ is a marker of disease severity associated with mortality in the HSCC cohort (18
). Among children who were still in care at 12 months since ART initiation, 12-month characteristics which predicted LTFU were recent year of ART, having one's biological mother as a primary caregiver, and being underweight (WAZ ≤ −2). The hazard of LTFU in the second year decreased by 3% for every unit increase in CD4 cell percentage. Baseline CD4 cell percentage had no effect on LTFU in the first year on ART, but children who still had a low CD4% after 12 months on ART were more likely to get LTFU in the second year. This may be explained by possible suboptimal adherence and consequent higher risk of death in children with a poor immune response at 12 months. Those who had higher CD4 cell percentage at 12 months were probably more adherent and less likely to suffer opportunistic diseases that may lead to death and LTFU.
The finding that children with their biological mothers as primary caregivers at baseline and at 1 year were more likely to be LTFU can be explained by the possibility that a number of these mothers may have died during the follow-up period resulting in the children becoming LTFU. Keeping HIV-positive mothers alive by effective ART has been shown to reduce under-five childhood mortality to levels seen in children of HIV-negative mothers (21
). While it is likely that these mothers were enrolled in ART programmes themselves, it is possible that they might not be accessing ART due to the differences in the eligibility criteria for ART in adults and children in South Africa (13
). At the time of the study, women would be initiated on ART if their CD4 count were ≤200 cells/mm3
or if they had a WHO stage 4 condition according to the 2004 guidelines (13
). According to the 2010 ART guidelines women can access treatment at CD4 ≤200 cells/mm3
except in pregnancy and active tuberculosis, where therapy is started at CD4 ≤350 cells/mm3
). The paradox becomes that children are eligible for ART in South Africa at earlier disease stages than their non-pregnant mothers, with possible negative consequences on children's treatment outcomes. The adoption of the WHO Option B plus for prevention of mother to child transmission (PMTCT), which offers the best protection of maternal health by starting all pregnant HIV-infected women on ART for life (23
), may positively impact children's outcomes.
Another explanation could be misclassification of mothers as caregivers since the caregiver status might not have been updated promptly on the HSCC database. A recent study of paediatric ART adherence in Gugulethu, Cape Town, showed that children cared for by their mothers were more adherent than those cared for by other relatives or foster parents, contradictory findings to those in our study (24
This study draws its strength from a large sample size of children accessing care at the same site. The data was prospectively collected in an electronic format and includes social factors such as caregiver relationship which other cohorts elsewhere may not be able to collect adequately. Sensitivity analyses yielded similar results with the main analyses.
Our study had some limitations. The study was observational and key variables at baseline such as CD4 cell percentage, and log10 viral load had high proportions of missing data. Additionally, the quality of care at a referral academic hospital such the HSCC is likely to differ from that of lower levels of care or in rural areas. We used data from only one non-randomly selected urban site; therefore, these results cannot be generalised to children accessing care in non-urban settings.