Isoniazid concentrations in hair and plasma area-under-the-curve exposure among children with tuberculosis.

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

Retrospective analysis of necropsy findings in patients of H1N1 and their correlation to clinical features

India reported its first case of H1N1 in July 2009 in Pune and since then, the number of reported cases and deaths exploded in India. Since very little data is available about histopathological findings in patients of H1N1 fatal cases in India, a retrospective chart analysis of necropsy findings of 15 cases of 2009 H1N1 fatal cases was performed. Common clinical features were fever, cough , and breathlessness followed by sore throat and rhinorrhea. Common lung findings were mononuclear cell infiltration, thick alveolar septae, intraalveolar hemorrhage . The other findings were congested pulmonary blood vessels, pulmonary edema, cytomegaly, fibrin accumulation and formation of eosinophilic membrane. These findings are suggestive of diffuse alveolar damage ( DAD) and DAD with hemorrhage. All patients who underwent necropsy had radiographic findings suggestive of unilobar or multilobar pneumonia. This clinical finding can be correlated pathologically in these patients as all of them had either polymorphonuclear or mononuclear infiltrate. Furthermore, necrotizing pneumonitis pattern seen on these patients is the likely cause of mortality in these patients. Although clinical ARDS pattern was noted in all these patients, it was well correlated in lung pathology in all these cases

A prospective study of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected children from high prevalence countries

CITATION: Cotton, M. F. et al 2019. A prospective study of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected children from high prevalence countries. PLoS ONE, 14(7): e0211155, doi:10.1371/journal.pone.0211155.The original publication is available at https://journals.plos.org/plosoneBackground: The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected infants and young children is relatively understudied in regions endemic for HIV and TB. We aimed to describe incidence, clinical features and risk factors of pediatric IRIS in Sub-Saharan Africa and India. Methods and findings: We conducted an observational multi-centred prospective clinical study from December 2010 to September 2013 in children <72 months of age recruited from public antiretroviral programs. The main diagnostic criterion for IRIS was a new or worsening inflammatory event after initiating antiretroviral therapy (ART). Among 198 participants, median age 1.15 (0.48; 2.21) years, 38 children (18.8%) developed 45 episodes of IRIS. Five participants (13.2%) had two IRIS events and one (2.6%) had 3 events. Main causes of IRIS were BCG (n = 21; 46.7%), tuberculosis (n = 10; 22.2%) and dermatological, (n = 8, 17.8%). Four TB IRIS cases had severe morbidity including 1 fatality. Cytomegalovirus colitis and cryptococcal meningitis IRIS were also severe. BCG IRIS resolved without pharmacological intervention. On multivariate logistic regression, the most important baseline associations with IRIS were high HIV viral load (likelihood ratio [LR] 10.629; p = 0.0011), recruitment at 1 site (Stellenbosch University) (LR 4.01; p = 0.0452) and CD4 depletion (LR 3.4; p = 0.0654). Significantly more non-IRIS infectious and inflammatory events between days 4 and 17 of ART initiation were noted in cases versus controls (35% versus 15.2%: p = 0.0007). Conclusions: IRIS occurs commonly in HIV-infected children initiating ART and occasionally has severe morbidity. The incidence may be underestimated. Predictive, diagnostic and prognostic biomarkers are needed.Publisher's versio

Tuberculosis (TB) Aftermath: study protocol for a hybrid type I effectiveness-implementation non-inferiority randomized trial in India comparing two active case finding (ACF) strategies among individuals treated for TB and their household contacts

Background : Approximately 7% of all reported tuberculosis (TB) cases each year are recurrent, occurring among people who have had TB in the recent or distant past. TB recurrence is particularly common in India, which has the largest TB burden worldwide. Although patients recently treated for TB are at high risk of developing TB again, evidence around effective active case finding (ACF) strategies in this population is scarce. We will conduct a hybrid type I effectiveness-implementation non-inferiority randomized trial to compare the effectiveness, cost-effectiveness, and feasibility of two ACF strategies among individuals who have completed TB treatment and their household contacts (HHCs). Methods : We will enroll 1076 adults (≥ 18 years) who have completed TB treatment at a public TB unit (TU) in Pune, India, along with their HHCs (averaging two per patient, n = 2152). Participants will undergo symptom-based ACF by existing healthcare workers (HCWs) at 6-month intervals and will be randomized to either home-based ACF (HACF) or telephonic ACF (TACF). Symptomatic participants will undergo microbiologic testing through the program. Asymptomatic HHCs will be referred for TB preventive treatment (TPT) per national guidelines. The primary outcome is rate per 100 person-years of people diagnosed with new or recurrent TB by study arm, within 12 months following treatment completion. The secondary outcome is proportion of HHCs < 6 years, by study arm, initiated on TPT after ruling out TB disease. Study staff will collect socio-demographic and clinical data to identify risk factors for TB recurrence and will measure post-TB lung impairment. In both arms, an 18-month “mop-up” visit will be conducted to ascertain outcomes. We will use the RE-AIM framework to characterize implementation processes and explore acceptability through in-depth interviews with index patients, HHCs and HCWs (n = 100). Cost-effectiveness will be assessed by calculating the incremental cost per TB case detected within 12 months and projected for disability-adjusted life years averted based on modeled estimates of morbidity, mortality, and time with infectious TB. Discussion : This novel trial will guide India’s scale-up of post-treatment ACF and provide an evidence base for designing strategies to detect recurrent and new TB in other high burden settings. Trial registration : NCT04333485, registered April 3, 2020. CTRI/2020/05/025059 [Clinical Trials Registry of India], registered May 6 2020.Research reported in this manuscript was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health(NIH) under award number R01AI143748. See funding documentation in Additional file3. The funding body does not have a role in the collection, analysis, and interpretation of data for TB Aftermath nor were they involved in writing this manuscript

Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization-Recommended Weight Band Doses and Formulations.

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

Cohort for Tuberculosis Research by the Indo-US Medical Partnership (CTRIUMPH): protocol for a multicentric prospective observational study

INTRODUCTION: Tuberculosis disease (TB) remains an important global health threat. An evidence-based response, tailored to local disease epidemiology in high-burden countries, is key to controlling the global TB epidemic. Reliable surrogate biomarkers that predict key active disease and latent TB infection outcomes are vital to advancing clinical research necessary to ‘End TB’. Well executed longitudinal studies strengthening local research capacity for addressing TB research priorities and advancing biomarker discovery are urgently needed. METHODS AND ANALYSIS: The Cohort for Tuberculosis Research by the Indo-US Medical Partnership (CTRIUMPH) study conducted in Byramjee Jeejeebhoy Government Medical College (BJGMC), Pune and National Institute for Research in Tuberculosis (NIRT), Chennai, India, will establish and maintain three prospective cohorts: (1) an Active TB Cohort comprising 800 adults with pulmonary TB, 200 adults with extrapulmonary TB and 200 children with TB; (2) a Household Contact Cohort of 3200 adults and children at risk of developing active disease; and (3) a Control Cohort consisting of 300 adults and 200 children with no known exposure to TB. Relevant clinical, sociodemographic and psychosocial data will be collected and a strategic specimen repository established at multiple time points over 24 months of follow-up to measure host and microbial factors associated with (1) TB treatment outcomes; (2) progression from infection to active TB disease; and (3) Mycobacterium tuberculosis transmission among Indian adults and children. We anticipate CTRIUMPH to serve as a research platform necessary to characterise some relevant aspects of the TB epidemic in India, generate evidence to inform local and global TB control strategies and support novel TB biomarker discovery. ETHICS AND DISSEMINATION: This study is approved by the Institutional Review Boards of NIRT, BJGMC and Johns Hopkins University, USA. Study results will be disseminated through peer-reviewed journals and research conferences. FUNDING: NIH/DBT Indo-US Vaccine Action Programme and the Indian Council of Medical Research

Risk factors for early mortality on antiretroviral therapy in advanced HIV-infected adults.

CAPRISA, 2017.Abstract available in pdf

Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women

CITATION: Gupta, A. et al. 2019. Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women. The New England Journal of Medicine, 381(14):1333-1346. doi:10.1056/NEJMoa1813060The original publication is available at https://www.nejm.org/BACKGROUND: The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown. METHODS: In this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years. RESULTS: A total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], −4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, −0.39; 95% CI, −1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, −0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9). CONCLUSIONS: The risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038. opens in new tab.)https://www.nejm.org/doi/full/10.1056/NEJMoa1813060Publisher’s versio