Optimization of pediatric antiretroviral therapy in sub-Saharan Africa : timing of initiation in HIV/TB co-infected children and using gains in weight, height, or CD4 count to monitor the response
Backgroung: Antiretroviral therapy (ART) has revolutionized the treatment of HIV, but substantial drug interactions between anti-TB and ART and the lack of health care infrastructures complicate the management of HIV/TB co-infected children in resource poor countries. More than 50% of TB infected children in some high burden countries in sub-Saharan Africa are also infected with HIV, but the optimal timing of ART in those children is unknown. In addition, though the drug-interactions and the high pill burden to treat HIV and TB require strict monitoring, regular measurements of viral load that is routine for ART monitoring in developed countries is not always possible in sub-Saharan Africa. This study had two aims. 1) Construct reference charts for gains in weight, height, absolute CD4 count, and CD4% in the first 6 months of ART, and to test the value of the 3rd, 10th, 25th, 33rd, and 50th percentiles as predictors of subsequent death, virological suppression, or treatment failure. 2) Determine the effect of delaying ART for at least 15, 30, or 60 days in HIV/TB co-infected children on virological suppression and survival. Methods: We used information from an observational clinical cohort of HIV-infected children who sought care at an outpatient clinic at Chris Hani Baragwanath Hospital in Soweto, South Africa. To construct the reference charts, we assumed a Box Cox power exponential distribution for the 6 month gains in weight, height, CD4 count and CD4% and used the generalized additive model for location, scale, and shape to estimate the parameters of each of the four distributions. Hazard ratios for the association of the selected centiles with the three outcomes were estimated using Cox proportional hazard model. For aim 2, though per guidelines all HIV-infected children with TB were eligible for ART, the decision whether to initiate or delay ART for a given child was made at each visit and sicker children were initiated earlier. Moreover, some children for whom ART was delayed could die before it was possible to classify them for exposure. To control for the time-dependent confounding by indication and the lead time on survival, mortality hazard ratios were estimated using the inverse-probability-of-treatment-weighting of marginal structural modelling. Adjusted hazard ratios for virological suppression were estimated using multivariate Cox proportional modelling. Results: Overall, information from 1394 and from 573 children was used for aim 1 and aim 2 respectively. Children whose weight, absolute CD4, or CD4% gain were below the 33rd percentile for age or gender had poorer ART outcomes with a three to four-fold higher hazard of death, about 0.75 -fold lower hazard of virological suppression and about two-fold higher hazard of treatment failure. Delaying ART tended to be associated with increased mortality: adjusted hazard ratios (aHR) for 15, 30, and 60 days delay were: 0.90 (95%CI: 0.30, 2.75), 1.05 (95%CI: 0.29, 3.75), 2.18 (95%CI: 0.64, 7.48) respectively. Delaying ART appear to be potentially detrimental for the hazard of viral suppression: aHR: 0.98 (95%CI: 0.76, 1.26), 0.95, (95%CI: 0.73, 1.23), 0.84 (95%CI: 0.61, 1.15) for 15, 30, and 60 days delay respectively. Conclusion: Six-month weight gain and CD4 cell gain (count and CD4%) below the 33rd percentile were equally strong predictors of poor ART outcomes suggesting that, pending construction of more generalizable charts, weight gain can be used in children on ART to discriminate those who are failing the treatment from those who are responding. Since delaying ART beyond 30 days appears to negatively affect both survival and viral response, the recommendation should be reevaluated and necessary delays should not exceed 30 days
