The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (C max ) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median C max and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC 0 -8 ]) of INH (C max , 2.5 versus 5.1 g/ml, respectively [P ‫؍‬ 0.016]; AUC 0 -8 , 11.1 versus 22.0 g/ml · h, respectively [P ‫؍‬ 0.047[) and PZA (C max , 34.1 versus 42.3 g/ml, respectively [P ‫؍‬ 0.055]; AUC 0 -8 , 177.9 versus 221.7 g/ml · h, respectively [P ‫؍‬ 0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median C max of RMP (1.0 versus 2.8 g/ml, respectively; P ‫؍‬ 0.002) and PZA (31.9 versus 44.4 g/ml, respectively; P ‫؍‬ 0.045) were significantly lower. Among all factors studied, the PZA C max influenced TB treatment outcome (P ‫؍‬ 0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP C max . The PZA C max significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.

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In the background of high food insecurity and malnutrition, cardiometabolic abnormalities were seen in 20%-35% of ART-naïve CLHIV in India emphasizing close monitoring of these children for long-term cardiovascular morbidities after initiation of ART.

Adherence to ART, fundamental to treatment success, has been poorly studied in India. Caregivers of children attending HIV clinics in southern India were interviewed using structured questionnaires. Adherence was assessed using a visual analogue scale representing past-month adherence and treatment interruptions >48 hours during the past 3 months. Clinical features, correlates of adherence and HIV-1 viral-load were documented. Based on caregiver reports, 90.9% of the children were optimally adherent. In multivariable analysis, experiencing ART-related adverse effects was significantly associated with suboptimal adherence (p=0.01). The proportion of children who experienced virological failure was 16.5%. Virological failure was not linked to suboptimal adherence. Factors influencing virological failure included running out of medications (p=0.002) and the child refusing to take medications (p=0.01). Inclusion of drugs with better safety profiles and improved access to care could further enhance outcomes.

BackgroundStudies relating to long-term virological outcomes among children on first-line antiretroviral therapy (ART) from low and middle-income countries are limited.MethodsPerinatally HIV infected, ART-naive children, between 2 and 12 years of age, initiating NNRTI-based ART during 2010–2015, with at least 12 months of follow-up, were included in the analysis. CD4 cell counts and plasma HIV-1 RNA were measured every 24 weeks post-ART initiation. Immunologic failure was defined as a decrease in the CD4 count to pre-therapy levels or below and virologic failure as HIV-RNA of > 1000 copies/ml at 48 weeks after ART initiation. Genotypic resistance testing was performed for children with virologic failure. Logistic regression analysis was done to identify predictors of virologic failure.ResultsThree hundred and ninety-three ART-naïve children living with HIV [mean (SD) age: 7.6 (3) years; mean (SD) CD4%: 16% (8); median (IQR) HIV-RNA: 5.1 (3.5–5.7) log10 copies/ml] were enrolled into the study. At 48 weeks, significant improvement occurred in weight-for-age and height-for-age z-scores from baseline (all p < 0.001). The immunologic response was good; almost 90% of children showing an increase in their absolute CD4+ T cell count to more than 350 cells/mm3. Immunological failure was noted among 11% (28/261) and virologic failure in 29% (94/328) of children. Of the 94 children with virologic failure at 12 months, 36 children showed immunologic failure while the rest had good immunologic improvement. There was no demonstrable correlation between virologic and immunologic failure. 62% had reported > 90% adherence to ART. At the time of virologic failure, multiple NNRTI-associated mutations were observed: 80%—K103N and Y181C being the major NNRTI mutations—observed. Sensitivity (95% CI) of immunologic failure to detect virologic failure was 7% (2–12), specificity 97% (92.4–98.9), PPV 44% (13.7–78.8) and NPV was 72% (65–77.9). There were no statistically significant predictors to detect children who will develop virologic failure on treatment.ConclusionsConsiderable immunological improvement is seen in children with ART initiation, but may not be an effective tool to monitor treatment response in the long-term. There is a lack of correlation between immunologic and virologic response while on ART, which may lead to a delay in identifying treatment failures. Periodic viral load monitoring is, therefore, a priority.

This study was designed to examine the rates of HIV serostatus disclosure in a sample of HIV-infected children in the state of Karnataka in South India, their reactions to learning their HIV-positive status and the reasons for and barriers to disclosure from the point of view of their caregivers. We enrolled 233 HIV-infected children, aged 5-18 years and their caregivers between July 2011 and February 2013 at HIV clinics in three tertiary care centers. Caregiver interviews included information about demographic characteristics, medical history, type of disclosure to the child and other related factors, including disclosure barriers. Three quarters (n = 185) of the caregivers reported that there had been no disclosure to the child, 15.4% (n = 38) reported partial disclosure (e.g. telling the child he or she had a 'chronic illness') and only 9.7% (n = 24) reported full disclosure, at a mean age of 10.9 (SD: 2.5) years. Caregivers, who planned to disclose in the future, stated on average that 16 years would be the right age. Those who favored a later disclosure reported that they feared strong negative emotional reactions from the child (p = 0.03) and social isolation (p < 0.001) following disclosure. These results show that that the level of full disclosure is low among South Indian youth living with HIV, and that when disclosure occurs, it is most likely to be partial. The majority of children who learned their status had been informed by a health-care provider, possibly reflecting the difficulty for a caregiver of having this conversation. The caregivers reported multiple disadvantages of disclosure, mostly because of fears of stigma and discrimination. Despite some evidence from the literature that disclosure can have positive effects on a child's health, it is thus clear that we need to develop, implement and evaluate community-based stigma reduction programs to reduce the social barriers to disclosure.

The mortality rate in the index study cohort was 4.9/100 child-years and tuberculosis was the major cause of death. Younger age, baseline advanced clinical and immunological staging were predictors of mortality. Even though mortality was significantly higher in Pre-ART children, treatment status was not found to be an independent predictor of mortality.

Clinical suspicion is vital for early detection of PWS. Confirmation of the diagnosis requires complex multi-tier molecular genetic testing.