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Background Children with human immunodeficiency virus (HIV, CWH) are at high risk of tuberculosis (TB) and face poor outcomes, despite antiretroviral therapy (ART). We evaluated outcomes in CWH and children not living with HIV treated for nonsevere TB in the SHINE trial. Methods SHINE was a randomized trial that enrolled children aged <16 years with smear-negative, nonsevere TB who were randomized to receive 4 versus 6 months of TB treatment and followed for 72 weeks. We assessed TB relapse/recurrence, mortality, hospitalizations, grade ≥3 adverse events by HIV status, and HIV virological suppression in CWH. Results Of 1204 children enrolled, 127 (11%) were CWH, of similar age (median, 3.6 years; interquartile range, 1.2, 10.3 versus 3.5 years; 1.5, 6.9; P =.07) but more underweight (weight-for-age z score, −2.3; (3.3, −0.8 versus −1.0; −1.8, −0.2; P <.01) and anemic (hemoglobin, 9.5 g/dL; 8.7, 10.9 versus 11.5 g/dL; 10.4, 12.3; P <.01) compared with children without HIV. A total of 68 (54%) CWH were ART-naive; baseline median CD4 count was 719 cells/mm3 (241–1134), and CD4% was 16% (10–26). CWH were more likely to be hospitalized (adjusted odds ratio, 2.4; 1.3–4.6) and to die (adjusted hazard ratio [aHR], 2.6; 95% confidence interval [CI], 1.2 to 5.8). HIV status, age <3 years (aHR, 6.3; 1.5, 27.3), malnutrition (aHR, 6.2; 2.4, 15.9), and hemoglobin <7 g/dL (aHR, 3.8; 1.3,11.5) independently predicted mortality. Among children with available viral load (VL), 45% and 61% CWH had VL <1000 copies/mL at weeks 24 and 48, respectively. There was no difference in the effect of randomized treatment duration (4 versus 6 months) on TB treatment outcomes by HIV status (P for interaction = 0.42). Conclusions We found no evidence of a difference in TB outcomes between 4 and 6 months of treatment for CWH treated for nonsevere TB. Irrespective of TB treatment duration, CWH had higher rates of mortality and hospitalization than their counterparts without HIV. Clinical Trials Registration.  ISRCTN63579542. [ABSTRACT FROM AUTHOR]

Background Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization–recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. Methods Children weighing 4.0–7.9, 8.0–11.9, 12.0–15.9, or 16.0–24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0–36.9 kg received doses recommended for adults <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. Results In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4–6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1–45.1), 16.7 (9.2–25.9), 317 (263–399), and 9.5 (7.5–11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0–7.9-, 8–11.9-, and ≥25-kg weight bands, isoniazid in the 4.0–7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. Conclusions Recommended weight band–based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization–recommended doses requires further evaluation. [ABSTRACT FROM AUTHOR]

In low-to-middle-income countries, acute lower respiratory infection (ALRI) remains the leading infectious cause of death among infants and children under 5 years old. Case-control studies based on upper respiratory sampling have informed current understandings of ALRI etiologies; in contrast, minimally invasive tissue sampling (MITS) offers a method of directly interrogating lower respiratory tract pathogens to establish etiologic distributions. This study performed in the postmortem setting used MITS and a Determination of Cause of Death (DeCoDe) panel to elucidate the causes of fatal pneumonia in the community in Lusaka, Zambia. For deceased infants and children under age 5 years whose next-of-kin provided consent, a verbal autopsy was obtained and 6 lung tissue biopsies from each case were sent for histopathology and multiplex polymerase chain reaction testing. Subsequently, a multi-disciplinary DeCoDe panel met to review each case, determine if the child died of respiratory causes, construct a causal chain of diagnoses directly leading to the death, and determine if the death was preventable (i.e., if an identifiable intervention would have averted the death). Among 106 deaths, 49 were adjudicated as respiratory deaths, with etiologic causes including Klebsiella pneumoniae (13), Streptococcus pneumoniae (5), and Pneumocystis jirovecii (4), among others. Of note, for 21 respiratory deaths, a causative pathogen could not be identified despite clinical and histopathologic evidence of ALRI. A large majority of all deaths were considered preventable (90/106 or 85%). This study demonstrates the impact of certain respiratory pathogens through direct in situ tissue sampling with supportive pathologic data and presents a useful method of studying the etiologic distribution of fatal ALRIs in settings where many deaths occur in the community., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen., Methods: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment., Results: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups)., Conclusions: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.)., (Copyright © 2022 Massachusetts Medical Society.)