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Rifampicin-resistant (RR) tuberculosis (TB) in children is a major global health concern but is often neglected in economics research. Accurate cost estimations across the spectrum of paediatric RR-TB treatment regimens are critical inputs for prioritisation and budgeting decisions, and an existing knowledge gap at local and international levels. This normative cost analysis was nested in a Phase I/II pharmacokinetics, safety, tolerability, and acceptability trial of TB medications in children in South Africa, the Philippines and India. It assessed the pharmaceutical costs of 36 childhood RR-TB regimens using combinations from 16 different medicines in 34 oral formulations (adult and child-friendly) in 11 weight bands in children

Despite improvements in HIV testing and earlier antiretroviral therapy (ART) initiation in children living with HIV through the years, a considerable proportion start treatment with advanced disease. We studied characteristics of children and adolescents living with HIV and their level of immunodeficiency at ART initiation using data from a multi-country Asian cohort. We included children and adolescents who were ART-naïve and

The World Health Organization (WHO) recently changed its guidance for tuberculosis (TB) preventive treatment (TPT) recommending TPT for all pulmonary TB (PTB) exposed household contacts (HHC) to prevent incident TB disease (iTBD), regardless of TB infection (TBI) status. However, this recommendation was conditional as the strength of evidence was not strong. We assessed risk factors for iTBD in recently-exposed adult and pediatric Indian HHC, to determine which HHC subgroups might benefit most from TPT. We prospectively enrolled consenting HHC of adult PTB patients in Pune and Chennai, India. They underwent clinical, microbiologic and radiologic screening for TB disease (TBD) and TBI, at enrollment, 4-6, 12 and 24 months. TBI testing was performed by tuberculin skin test (TST) and Quantiferon®- Gold-in-Tube (QGIT) assay. HHC without baseline TBD were followed for development of iTBI and iTBD. Using mixed-effect Poisson regression, we assessed baseline characteristics including TBI status, and incident TBI (iTBI) using several TST and/or QGIT cut-offs, as potential risk factors for iTBD. Of 1051 HHC enrolled, 42 (4%) with baseline TBD and 12 (1%) with no baseline TBI test available, were excluded. Of the remaining 997 HHC, 707 (71%) had baseline TBI (TST #x2265; 5 mm or QGIT #x2265; 0.35 IU/ml). Overall, 20 HHC (2%) developed iTBD (12 cases/1000 person-years, 95%CI: 8-19). HIV infection (aIRR = 29.08, 95% CI: 2.38-355.77, p = 0.01) and undernutrition (aIRR = 6.16, 95% CI: 1.89-20.03, p = 0.003) were independently associated with iTBD. iTBD was not associated with age, diabetes mellitus, smoking, alcohol, and baseline TBI, or iTBI, regardless of TST (#x2265; 5 mm, #x2265; 10 mm, #x2265; 6 mm increase) or QGIT (#x2265; 0.35 IU/ml, #x2265; 0.7 IU/ml) cut-offs. Given the high overall risk of iTBD among recently exposed HHCs, and the lack of association between TBI status and iTBD, our findings support the new WHO recommendation to offer TPT to all HHC of PTB patients residing in a high TB burden country such as India, and do not suggest any benefit of TBI testing at baseline or during follow-up to risk stratify recently-exposed HHC for TPT.

Despite substantial exposure to infectious pulmonary tuberculosis (TB) cases, some household contacts (HHC) never acquire latent TB infection (LTBI). Characterizing these "resisters" can inform who to study immunologically for the development of TB vaccines. We enrolled HHCs of culture-confirmed adult pulmonary TB in India who underwent LTBI testing using tuberculin skin test (TST) and QuantiFERON TB Gold Test-in-tube (QFT-GIT) at baseline and, if negative by both (

Defining occupational latent tuberculosis infection (LTBI) risk among healthcare workers is needed to support implementation of prevention guidelines. Prospective cohort study of 200 medical residents and nursing students in India was conducted May 2016-December 2017. Tuberculin skin test (TST) and QuantiFERON TB Gold Test-in-tube (QFT-GIT) were performed at study entry and 12 months. Primary outcome was incident LTBI (≥10mm TST induration and/or ≥0.35IU/mL QFT-GIT) at 12 months; secondary outcomes included baseline LTBI prevalence and risk factors for incident and prevalent LTBI using Poisson regression. Among 200, [90 nursing students and 110 medical residents], LTBI prevalence was 30% (95% CI, 24-37); LTBI incidence was 26.8 (95% CI, 18.6-37.2) cases per 100 person-years and differed by testing method (28.7 [95% CI, 20.6-38.9] vs 17.4 [95% CI, 11.5-25.4] cases per 100 person-years using TST and QFT-GIT, respectively). Medical residents had two-fold greater risk of incident LTBI than nursing students (Relative Risk, 2.16; 95% CI, 1.05-4.42). During study period 6 (3%) HCWs were diagnosed with active TB disease. Overall, median number of self-reported TB exposures was 5 (Interquartile Range, 1-15). Of 60 participants with prevalent and incident LTBI who were offered free isoniazid preventive therapy (IPT), only 2 participants initiated and completed IPT. High risk for LTBI was noted among medical residents compared to nursing students. Self-reported TB exposure is underreported, and uptake of LTBI prevention therapy remains low. New approaches are needed to identify HCWs at highest risk for LTBI.

We measured hair and plasma concentrations of isoniazid among sixteen children with tuberculosis who underwent personal or video-assisted directly observed therapy and thus had 100% adherence. This study therefore defined typical isoniazid exposure parameters after two months of treatment among fully-adherent patients in both hair and plasma (plasma area under the concentration-time curve, AUC, estimated using pharmacokinetic data collected 0, 2, 4, and 6 hours after drug administration). We found that INH levels in hair among highly-adherent individuals did not correlate well with plasma AUC or trough concentrations, suggesting that each measure may provide incremental and complementary information regarding drug exposure in the context of TB treatment.

Latest World Health Organization guidelines recommend weight-based nevirapine prophylaxis for all HIV-exposed infants in resource-limited settings, yet low birth weight (LBW) infants (< 2500 g) have been understudied. Using data from the NIH-funded India six-week extended-dose nevirapine (SWEN) study, a randomized clinical trial of SWEN versus single-dose nevirapine (SD) for prevention of breast-milk HIV-1 transmission, we examined the relative impact of SWEN among 737 mother-infant pairs stratified by infant birth weight. Birth weight groups were defined as very LBW (VLBW) ≤ 2000 g, moderate LBW (MLBW) >2000 g and ≤ 2500 g, and normal birth weight (NBW) > 2500 g. Outcomes were HIV-1 infection, HIV-1 infection or death by 12 months, and severe adverse events (SAEs). The Kaplan-Meier method was used to estimate probability of efficacy outcomes in birth weight groups, and differential effects of SWEN by birth weight group were examined using Cox proportional hazards models adjusting for independent risk factors for HIV maternal-to-child transmission and significant covariates. Among 50 VLBW, 249 MLBW, and 433 NBW infants, 50% were randomized to SWEN; median gestational age was 36, 38 and 38 weeks, respectively; and there was no difference in breastfeeding duration (p = 0.99). Compared to SD: SWEN-treated VLBW had lower estimates of HIV-1 infection (13% vs. 38%, p = 0.004) and HIV-1 infection or death (13% vs. 41%, p = 0.002); SWEN-treated MLBW had lower estimated HIV-1 infection (13% vs. 17%, p = 0.042); and efficacy endpoints were similar by treatment arm in NBW. In multivariate analysis, SWEN was associated with reduced risk of HIV-1 infection or death by 83% (p = 0.03) in VLBW versus 45% (p = 0.05) in MLBW. SAE frequency was similar by treatment arm in VLBW (68% vs. 76%, p = 0.53) and MLBW (37% vs. 36%, p = 0.93). SWEN may safely increase HIV-free survival among HIV-exposed LBW infants with greatest protective advantage among infants ≤ 2000 g.