Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.

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.).

Clinical Outcomes in Children With Human Immunodeficiency Virus Treated for Nonsevere Tuberculosis in the SHINE Trial.

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.

Virological failure among people living with HIV receiving second-line antiretroviral therapy in Pune, India.

BACKGROUND: The number of people receiving second-line antiretroviral therapy (ART) has increased as global access to ART has expanded. Data on the burden and factors associated with second-line ART virologic failure (VF) from India remain limited. METHODS: We conducted cross-sectional viral load (VL) testing among adults (≥ 18 years) who were registered at a publicly funded ART center in western India between 2014 and 2015 and had received second-line ART for at least 6 months. Sociodemographic and clinical characteristics were abstracted from routinely collected programmatic data. Logistic regression evaluated factors associated with VF (defined as VL > 1000 copies/mL). RESULTS: Among 400 participants, median age was 40 years (IQR 34-44), 71% (285/400) were male, and 15% (59/400) had VF. Relative to participants without VF, those with VF had lower median CD4 counts (230 vs 406 cells/mm3, p < 0.0001), lower weight at first-line failure (49 vs 52 kg, p = 0.003), were more likely to have an opportunistic infection (17% vs 3%, p < 0.0001) and less likely to have optimal ART adherence (71% vs 87%, p = 0.005). In multivariable analysis, VF was associated with opportunistic infection (aOR, 4.84; 95% CI, 1.77-13.24), lower CD4 count (aOR 4.15; 95% CI, 1.98-8.71) and lower weight at first-line failure (aOR, 2.67; 95% CI, 1.33-5.34). CONCLUSIONS: We found second-line VF in about a sixth of participants in our setting, which was associated with nearly fivefold increased odds in the context of opportunistic infection. Weight could be a useful clinical indicator for second-line VF.

The association of household fine particulate matter and kerosene with tuberculosis in women and children in Pune, India.

OBJECTIVES: Household air pollution (HAP) is a risk factor for respiratory disease, however has yet to be definitively associated with tuberculosis (TB). We aimed to assess the association between HAP and TB. METHODS: A matched case-control study was conducted among adult women and children patients with TB and healthy controls matched on geography, age and sex. HAP was assessed using questionnaires for pollution sources and 24-hour household concentrations of particulate matter <2.5 µm in diameter (PM2.5). RESULTS: In total, 192 individuals in 96 matched pairs were included. The median 24-hour time-weighted average PM2.5 was nearly seven times higher than the WHO's recommendation of 25 µg/m3, and did not vary between controls (179 µg/m3; IQR: 113-292) and cases (median 157 µg/m3; 95% CI 93 to 279; p=0.57). Reported use of wood fuel was not associated with TB (OR 2.32; 95% CI 0.65 to 24.20) and kerosene was significantly associated with TB (OR 5.49, 95% CI 1.24 to 24.20) in adjusted analysis. Household PM2.5 was not associated with TB in univariate or adjusted analysis. Controlling for PM2.5 concentration, kerosene was not significantly associated with TB, but effect sizes ranged from OR 4.30 (95% CI 0.78 to 30.86; p=0.09) to OR 5.49 (0.82 to 36.75; p=0.08). CONCLUSIONS: Use of kerosene cooking fuel is positively associated with TB in analysis using reported sources of exposure. Ubiquitously high levels of particulates limited detection of a difference in household PM2.5 between cases and controls.

Antibiotic Utilization and the Role of Suspected and Diagnosed Mosquito-borne Illness Among Adults and Children With Acute Febrile Illness in Pune, India.

Background: Antibiotic resistance mechanisms originating in low- and middle- income countries are among the most common worldwide. Reducing unnecessary antibiotic use in India, the world's largest antibiotic consumer, is crucial to control antimicrobial resistance globally. Limited data describing factors influencing Indian clinicians to start or stop antibiotics are available. Methods: Febrile adults and children admitted to a public tertiary care hospital in Pune, India, were enrolled. Antibiotic usage and clinical history were recorded. Immunoassays for mosquito-borne disease and bacterial cultures were performed by protocol and clinician-directed testing. Clinical factors were assessed for association with empiric antibiotic initiation and discontinuation by day 5 using multivariable logistic regression and propensity score-matched Cox proportional hazard models. Results: Among 1486 participants, 683 (82%) adults and 614 (94%) children received empiric antibiotics. Participants suspected of having mosquito-borne disease were less likely to receive empiric antibiotics (adjusted odds ratio [AOR], 0.5; 95% confidence interval [CI], .4-.8). Empiric antibiotics were discontinued in 450 (35%) participants by day 5. Dengue or malaria testing performed before day 4 was positive in 162 (12%) participants, and was associated with antibiotic discontinuation (AOR, 1.7; 95% CI, 1.2-2.4). In a propensity score-matched model accounting for admission suspicion of mosquito-borne disease, positive dengue or malaria tests increased hazard of antibiotic discontinuation (hazard ratio, 1.6; 95% CI, 1.2-2.0). Conclusions: Most patients with acute febrile illness in an Indian public hospital setting receive empiric antibiotics. Mosquito-borne disease identification is associated with reduced empiric antibiotic use and faster antibiotic discontinuation.

Drug-resistant Enterobacteriaceae colonization is associated with healthcare utilization and antimicrobial use among inpatients in Pune, India.

BACKGROUND: Healthcare exposure may increase drug-resistant Enterobacteriaceae colonization risk. Nascent antimicrobial stewardship efforts in low- and middle-income countries require setting-specific data. We aimed to evaluate risk factors for inpatient drug resistant Enterobacteriaceae colonization in a resource-limited setting in India. METHODS: Patients age ≥ 6 months admitted with ≥24 h of fever to a tertiary hospital in Pune, India were enrolled in a prospective cohort. Perirectal swabs, collected on admission and hospitalization day 3 or 4, were cultured in vancomycin- and ceftriaxone-impregnated media to assess for ceftriaxone-resistant Enterobacteriaceae (CTRE) and carbapenem-resistant Enterobacteriaceae (CPRE). Multivariable analyses assessed risk factors for drug-resistant Enterobacteriaceae colonization among participants without admission colonization. RESULTS: Admission perirectal swabs were collected on 897 participants; 87 (10%) had CTRE and 14 (1.6%) had CPRE colonization. Admission CTRE colonization was associated with recent healthcare contact (p < 0.01). Follow-up samples were collected from 620 participants, 67 (11%) had CTRE and 21 (3.4%) had CPRE colonization. Among 561 participants without enrollment CTRE colonization, 49 (9%) participants were colonized with CTRE at follow-up. Detection of CTRE colonization among participants not colonized with CTRE at admission was independently associated with empiric third generation cephalosporin treatment (adjusted odds ratio [OR] 2.9, 95% CI 1.5-5.8). Follow-up transition to CPRE colonization detection was associated with ICU admission (OR 3.0, 95% CI 1.0-8.5). CONCLUSIONS: Patients who receive empiric third generation cephalosporins and are admitted to the ICU rapidly develop detectable CTRE and CPRE colonization. Improved antimicrobial stewardship and infection control measures are urgently needed upon hospital admission.

High Burden of Antimicrobial Resistance and Mortality Among Adults and Children With Community-Onset Bacterial Infections in India.

Background: In India, antimicrobial consumption is high, yet systematically collected data on the epidemiology, risk factors, and outcomes of antimicrobial-resistant infections are limited. Methods: A prospective study of adults and children hospitalized for acute febrile illness was conducted between August 2013 and December 2015. In-hospital outcomes were recorded, and logistic regression was performed to identify independent predictors of community-onset antimicrobial-resistant infections. Results: Among 1524 patients hospitalized with acute febrile illness, 133 isolates were found among 115 patients with community-onset infections; 66 isolates (50.0%) were multidrug resistant and, of 33 isolates tested for carbapenem susceptibility, 12 (36%) were resistant. Multidrug-resistant infections were associated with recent antecedent antibiotic use (adjusted odds ratio [aOR], 4.17; 95% confidence interval [CI], 1.19-19.7) and were independently associated with mortality (aOR, 6.06; 95% CI, 1.2-55.7). Conclusion: We found a high burden of community-onset antimicrobial-resistant infection among patients with acute febrile illness in India. Multidrug-resistant infection was associated with prior antibiotic use and an increased risk of mortality.

Trends and Sex Differences in Access to HIV Care with Scale Up of National HIV Treatment Guidelines in Pune, India.

Test and treat is the current global standard, yet sex differences persist in access to HIV care. We assessed the differences in presentation and antiretroviral therapy (ART) uptake by sex and ART-eligibility period among ART-naive adults registered at a public ART center in India. Four ART eligibility periods were defined by programmatically determined CD4 criteria (periods I-IV: CD4 <200, <350, ≤500 cells/µL, and any CD4) between January 2005 and December 2017. Of 23 957 participants, 12 510 were male. Men consistently presented with lower median CD4 count (period I-IV, P < .05) and higher median age (period I-III, P < .001) than women. From period I to IV, median age increased in women (P < .0001), ART initiation time decreased in both sexes (P < .001), and median CD4 remained <200 cells/µL in men. Advanced HIV disease and increasing age at presentation are persistent sex-specific trends which warrant innovative HIV testing strategies in both sexes.

Sources of household air pollution and their association with fine particulate matter in low-income urban homes in India.

INTRODUCTION: Household air pollution (HAP) is poorly characterized in low-income urban Indian communities. MATERIALS AND METHODS: A questionnaire assessing sources of HAP and 24 h household concentrations of particulate matter less than 2.5 microns in diameter (PM2.5) were collected in a sample of low-income homes in Pune, India. RESULTS: In 166 homes, the median 24 h average concentration of PM2.5 was 167 µg/m3 (IQR: 106-294). Although kerosene and wood use were highly prevalent (22% and 25% of homes, respectively), primarily as secondary fuel sources, high PM2.5 concentrations were also found in 95 (57%) homes reporting LPG use alone (mean 141 µg/m3; IQR: 92-209). In adjusted linear regression, log PM2.5 concentration was positively associated with wood cooking fuel (GMR 1.5, 95% CI: 1.1-2.0), mosquito coils (GMR 1.5, 95% CI: 1.1-2.1), and winter season (GMR 1.7, 95% CI: 1.4-2.2). Households in the highest quartile of exposure were positively associated with wood cooking fuel (OR 1.3, 95% CI: 1.1-1.5), incense (OR 1.1, 95% CI: 1.0-1.3), mosquito coils (OR 1.3, 95% CI: 1.1-1.6), and winter season (OR 1.2, 95% CI: 1.1-1.4). DISCUSSION: We observed high concentrations of PM2.5 and identified associated determinants in urban Indian homes.

Secondhand Smoke Exposure and Validity of Self-Report in Low-Income Women and Children in India.

BACKGROUND: There is limited validation of self-reported measures for secondhand smoke (SHS) exposure in low- and middle-income countries. We evaluated the validity of standard self-reported measures among women and children in urban India. METHODS: Structured questionnaires were administered, and household air and hair samples were analyzed for nicotine concentration. RESULTS: In total, 141 households of 70 child and 71 adult participants were included. Air nicotine was detected in 72 (51%) homes, and 35 (75%) child and 12 (56%) adult participants had detectable hair nicotine. Correlation between air and hair nicotine was significant in children (r = 0.5; P = .0002) but not in adults (r = -0.1; P = .57). Poor correlation was found between self-reported measures of exposure and both air and hair nicotine. No questions were significantly correlated with hair nicotine, and the highest-magnitude correlation with air nicotine was for how often someone smoked inside for adults (r = 0.4; P = .10) and for home preparation of mishri (a smokeless tobacco product prepared for consumption by roasting) for children (r = 0.4; P = .39). The highest value for sensitivity by using air nicotine as the gold standard was for whether people smelled other families preparing mishri (47%; 95% confidence interval: 31-62) and prepared mishri in their own homes (50%; 95% confidence interval: 19-81). CONCLUSIONS: These results raise caution in using or evaluating self-reported SHS exposure in these communities. More appropriate questions for this population are needed, including mishri preparation as a source of SHS exposure.

Vector-Borne Disease is a Common Cause of Hospitalized Febrile Illness in India.

Acute febrile illness (AFI) is a major cause of morbidity and mortality in India and other resource-limited settings, yet systematic etiologic characterization of AFI has been limited. We prospectively enrolled adults (N = 970) and children (age 6 months to 12 years, N = 755) admitted with fever from the community to Sassoon General Hospital in Pune, India, from July 2013 to December 2015. We systematically obtained a standardized clinical history, basic laboratory testing, and microbiologic diagnostics on enrolled participants. Results from additional testing ordered by treating clinicians were also recorded. A microbiological diagnosis was found in 549 (32%) participants; 211 (12%) met standardized case definitions for pneumonia and meningitis without an identified organism; 559 (32%) were assigned a clinical diagnosis in the absence of a confirmed diagnosis; and 406 (24%) had no diagnosis. Vector-borne diseases were the most common cause of AFI in adults including dengue (N = 188, 19%), malaria (N = 74, 8%), chikungunya (N = 15, 2%), and concurrent mosquito-borne infections (N = 23, 2%) occurring most frequently in the 3 months after the monsoon. In children, pneumonia was the most common cause of AFI (N = 214, 28%) and death. Bacteremia was found in 68 (4%) participants. Central nervous system infections occurred in 58 (6%) adults and 64 (8%) children. Etiology of AFI in India is diverse, highly seasonal, and difficult to differentiate on clinical grounds alone. Diagnostic strategies adapted for season and age may reduce diagnostic uncertainty and identify causative organisms in treatable, fatal causes of AFI.

Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial.

BACKGROUND: Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. METHODS/DESIGN: SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations. DISCUSSION: Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number: ISRCTN63579542 , 14 October 2014. Pan African Clinical Trials Registry Number: PACTR201505001141379 , 14 May 2015. Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017.