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Background: Many HIV-infected children are diagnosed with tuberculosis (TB), but the effect of TB treatment on virologic and immunologic response to combination antiretroviral therapy (cART) is not well documented., Methods: Secondary analysis of a prospective cohort of cART-naive HIV-infected South African children aged 0-8 years initiating cART to assess the effect of TB treatment at the time of cART initiation on virologic suppression (HIV RNA < 50 copies/mL), virologic rebound (HIV RNA > 1000 copies/mL after suppression), and CD4 cell percent (CD4%) increase during the first 24 months of cART., Results: Of 199 children (median age 2.1 years), 92 (46%) were receiving TB treatment at cART initiation. Children receiving and not receiving TB treatment at cART initiation had similar median baseline HIV RNA (5.4 vs. 5.6 copies/mL), median time to virologic suppression (6.2 months in each group, adjusted hazard ratio, 1.36, 95% confidence interval: 0.94 to 1.96), and rates of virologic rebound by 24 months (23% vs. 24%, adjusted hazard ratio 1.53, 95% confidence interval: 0.71 to 3.30). Children on TB treatment had significantly lower median CD4% at baseline (15.3% vs. 18.8%, P < 0.01) and during the first 12 months of cART but experienced similar median increases in CD4% at 6 months (9.9% vs. 9.6%), 12 months (14.2% vs. 11.9%), and 24 months of cART (14.5% vs. 14.2%). Exploratory analyses suggest that children receiving lopinavir/ritonavir-based cART and TB treatment may have inferior virologic and immunologic response compared with children receiving efavirenz-based cART., Conclusions: Receiving TB treatment at the time of cART initiation did not substantially affect virologic or immunologic response to cART in young children.

Background: Growth failure is common among children infected with HIV. The degree of growth recovery and its determinants in children initiating combination antiretroviral therapy (cART) are not well understood., Methods: We conducted a cohort study of children who initiated cART between 2004 and 2008 at a pediatric HIV clinic in Johannesburg, South Africa. To determine the effect of severe immunodeficiency at cART initiation on growth recovery (defined as attaining a z-score > -2), we generated Kaplan-Meier survival functions and fit a Cox proportional hazards model. In sensitivity analyses, we assessed selection bias due to loss to follow-up or death., Results: Of the 2399 children who initiated cART, 71% presented with growth failure. Within 2 years of cART, only 81% of underweight children achieved normal weight, and 64% of stunted children achieved length/height recovery. Severe immunodeficiency at cART initiation was not associated with weight recovery [hazards ratio: 1.05, 95% CI: 0.83 to 1.32] or length/height recovery (hazards ratio: 1.06, 95% CI: 0.83 to 1.34) in overall analyses, and modification by baseline growth failure and age were modest. Older children and those with severe growth failure were less likely to achieve growth recovery, regardless of baseline immunodeficiency status., Conclusions: A substantial proportion of children fail to achieve growth recovery despite 2 years of cART. Our analysis did not support an association between baseline immunodeficiency and growth recovery. Younger age and less-severe growth failure at cART initiation are strong predictors of achieving growth recovery. These findings support early initiation of cART, before the presence of growth failure, and independent of level of immunodeficiency.

Background: The prevention of mother-to-child transmission (PMTCT) of HIV has been focused mainly on women who are HIV positive at their first antenatal visit, but there is uncertainty regarding the contribution to overall transmission from mothers who seroconvert after their first antenatal visit and before weaning., Method: A mathematical model was developed to simulate changes in mother-to-child transmission of HIV over time, in South Africa. The model allows for changes in infant feeding practices as infants age, temporal changes in the provision of antiretroviral prophylaxis and counseling on infant feeding, as well as temporal changes in maternal HIV prevalence and incidence., Results: The proportion of mother-to-child transmission (MTCT) from mothers who seroconverted after their first antenatal visit was 26% [95% confidence interval (CI): 22% to 30%] in 2008, or 15,000 of 57,000 infections. It is estimated that by 2014, total MTCT will reduce to 39,000 per annum, and transmission from mothers seroconverting after their first antenatal visit will reduce to 13,000 per annum, accounting for 34% (95% CI: 29% to 39%) of MTCT. If maternal HIV incidence during late pregnancy and breastfeeding were reduced by 50% after 2010, and HIV screening were repeated in late pregnancy and at 6-week immunization visits after 2010, the average annual number of MTCT cases over the 2010-2015 period would reduce by 28% (95% CI: 25% to 31%), from 39,000 to 28,000 per annum., Conclusion: Maternal seroconversion during late pregnancy and breastfeeding contributes significantly to the pediatric HIV burden and needs greater attention in the planning of prevention of MTCT programs.

Background: With expanding pediatric antiretroviral therapy (ART) access, children will begin to experience treatment failure and require second-line therapy. We evaluated the probability and determinants of virologic failure and switching in children in South Africa., Methods: Pooled analysis of routine individual data from children who initiated ART in 7 South African treatment programs with 6-monthly viral load and CD4 monitoring produced Kaplan-Meier estimates of probability of virologic failure (2 consecutive unsuppressed viral loads with the second being >1000 copies/mL, after ≥24 weeks of therapy) and switch to second-line. Cox-proportional hazards models stratified by program were used to determine predictors of these outcomes., Results: The 3-year probability of virologic failure among 5485 children was 19.3% (95% confidence interval: 17.6 to 21.1). Use of nevirapine or ritonavir alone in the initial regimen (compared with efavirenz) and exposure to prevention of mother to child transmission regimens were independently associated with failure [adjusted hazard ratios (95% confidence interval): 1.77 (1.11 to 2.83), 2.39 (1.57 to 3.64) and 1.40 (1.02 to 1.92), respectively]. Among 252 children with ≥1 year follow-up after failure, 38% were switched to second-line. Median (interquartile range) months between failure and switch was 5.7 (2.9-11.0)., Conclusions: Triple ART based on nevirapine or ritonavir as a single protease inhibitor seems to be associated with a higher risk of virologic failure. A low proportion of virologically failing children were switched.

Background: Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account., Patients and Methods: Children who started ART before the age of 16 years in 10 ART programs in South Africa, Malawi, Mozambique, and Zimbabwe were included. Risk factors for death in the first year of ART were identified in Weibull models. A meta-analytic approach was used to estimate cumulative mortality at 1 year., Results: Eight thousand two hundred twenty-five children (median age 49 months, median CD4 cell percent 11.6%) were included; 391 (4.8%) died and 523 (7.0%) were LTFU in the first year. Mortality at 1 year was 4.5% [95% confidence interval (CI): 2.8% to 7.4%] in children remaining in care, but 8.7% (5.4% to 12.1%) at the program level, after taking mortality in children and LTFU into account. Factors associated with mortality in children remaining in care included age [adjusted hazard ratio (HR) 0.37; 95% CI: 0.25 to 0.54 comparing > or =120 months with <18 months], CD4 cell percent (HR: 0.56; 95% CI: 0.39 to 0.78 comparing > or =20% with <10%), and clinical stage (HR: 0.12; 95% CI: 0.03 to 0.45 comparing World Health Organization stage I with III/IV)., Conclusions: In children starting ART and remaining in care in Southern Africa mortality at 1 year is <5% but almost twice as high at the program level, when taking LTFU into account. Age, CD4 percentage, and clinical stage are important predictors of mortality at the individual level.