Showing papers by "Soumya Swaminathan published in 2013"

Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts

Abstract: Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment.

Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) in HIV Patients with Culture Confirmed Pulmonary Tuberculosis in India and the Potential Role of IL-6 in Prediction

Abstract: Background: The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively. Methods: HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS. Results: Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14–47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7–16) after ART initiation. Corticosteroids were required for treatment of most IRIS events that resolved within a median of 13 days (IQR: 9–23). Two patients died due to CNS TB-IRIS. Lower CD4 + T-cell counts, higher plasma HIV RNA levels, lower CD4/CD8 ratio, lower hemoglobin, shorter ATT to ART interval, extra-pulmonary or miliary TB and higher plasma IL-6 and CRP levels at baseline were associated with paradoxical TB-IRIS in the univariate analysis. Shorter ATT to ART interval, lower hemoglobin and higher IL-6 and CRP levels remained significant in the multivariate analysis. Conclusion: Paradoxical TB–IRIS frequently complicates HIV-TB therapy in India. IL-6 and CRP may assist in predicting IRIS events and serve as potential targets for immune interventions.

Prevalence of tobacco use in urban, semi urban and rural areas in and around Chennai city, India

Abstract: Background Tobacco use leads to many health complications and is a risk factor for the occurrence of cardio vascular diseases, lung and oral cancers, chronic bronchitis etc. Almost 6 million people die from tobacco-related causes every year. This study was conducted to measure the prevalence of tobacco use in three different areas around Chennai city, south India. Methods A survey of 7510 individuals aged > = 15 years was undertaken covering Chennai city (urban), Ambattur (semi-urban) and Sriperumbudur (rural) taluk. Details on tobacco use were collected using a questionnaire adapted from both Global Youth Tobacco Survey and Global Adults Tobacco Survey. Results The overall prevalence of tobacco use was significantly higher in the rural (23.7%) compared to semi-urban (20.9%) and urban (19.4%) areas (P value <0.001) Tobacco smoking prevalence was 14.3%, 13.9% and 12.4% in rural, semi-urban and urban areas respectively. The corresponding values for smokeless tobacco use were 9.5%, 7.0% and 7.0% respectively. Logistic regression analysis showed that the odds of using tobacco (with smoke or smokeless forms) was significantly higher among males, older individuals, alcoholics, in rural areas and slum localities. Behavioural pattern analysis of current tobacco users led to three groups (1) those who were not reached by family or friends to advice on harmful effects (2) those who were well aware of harmful effects of tobacco and even want to quit and (3) those are exposed to second hand/passive smoking at home and outside. Conclusions Tobacco use prevalence was significantly higher in rural areas, slum dwellers, males and older age groups in this region of south India. Women used mainly smokeless tobacco. Tobacco control programmes need to develop strategies to address the different subgroups among tobacco users. Public health facilities need to expand smoking cessation counseling services as well as provide pharmacotherapy where necessary.

Consensus Statement on Research Definitions for Drug-Resistant Tuberculosis in Children

Abstract: Few children with drug-resistant (DR) tuberculosis (TB) are identified, diagnosed, and given an appropriate treatment. The few studies that have described this vulnerable population have used inconsistent definitions. The World Health Organization (WHO) definitions used for adults with DR-TB and for children with drug-susceptible TB are not always appropriate for children with DR-TB. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis was formed in 2011 as a network of experts and stakeholders in childhood DRTB. An early priority was to establish standardized definitions for key parameters in order to facilitate study comparisons and the development of an evidence base to guide future clinical management. This consensus statement proposes standardized definitions to be used in research. In particular, it suggests consistent terminology, as well as definitions for measures of exposure, drug resistance testing, previous episodes and treatment, certainty of diagnosis, site and severity of disease, adverse events, and treatment outcome.

Improving screening and chemoprophylaxis among child contacts in India's RNTCP: a pilot study.

Abstract: BACKGROUND: While contact screening and chemoprophylaxis is recommended by India's Revised National Tuberculosis Control Programme for asymptomatic children aged < 6 years who are household contacts of smear-positive pulmonary tuberculosis (PTB) patients, implementation is suboptimal. OBJECTIVE: To evaluate the effectiveness of an isoniazid preventive therapy (IPT) register and card in improving the adherence of health care workers (HCWs) to programmatic guidelines. METHODOLOGY: This prospective study was conducted in two Tuberculosis Units in South India. Child contacts of smear-positive PTB patients initiated on treatment between November 2009 and January 2010 were screened, and IPT was initiated in asymptomatic children. HCWs were trained in the use of the IPT register and card. The process was evaluated using patient and HCW interviews. RESULTS: Of 87 children identified aged < 6 years, 71 (82%) were traced by HCWs; 53 were screened for TB and initiated on IPT, and 39 completed treatment. HCWs expressed satisfaction with the use of the IPT card and register, saying that it helped them to remember to complete required tasks. CONCLUSION: In a programme setting, with HCW training and introduction of specific documentation (IPT card and register), implementation of contact tracing and chemoprophylaxis for child contacts improved from 19% to 61%.

Evaluation of a diagnostic algorithm for sputum smear-negative pulmonary tuberculosis in HIV-infected adults.

Abstract: BACKGROUND: The Revised National TB Control Program bases diagnosis of tuberculosis (TB) on sputum smear examination and response to a course of antibiotics, whereas World Health Organization recommends early chest radiography [chest x-ray (CXR)] for HIV-infected symptomatic patients. We evaluated the utility of initial CXR in the diagnostic algorithm for symptomatic HIV-infected patients with negative sputum smears. METHODS: HIV-infected ambulatory patients with cough or fever of ≥2 weeks and 3 sputum smears negative for acid-fast bacilli were enrolled in Chennai and Pune, India, between 2007 and 2009. After a CXR and 2 sputum cultures, a course of broad-spectrum antibiotics was given and patients were reviewed after 14 days. Sensitivity, specificity, positive and negative predictive values of symptoms, CXR, and various combinations for diagnosing pulmonary tuberculosis (PTB) were determined, using sputum culture as gold standard. RESULTS: Five hundred four patients (330 males; mean age: 35 years; median CD4: 175 cells per cubic millimeter) were enrolled. CXR had a sensitivity and specificity of 72% and 57%, respectively, with positive predictive value (PPV) of 21% and negative predictive value (NPV) of 93% to diagnose PTB. TB culture was positive in 49 of 235 patients (21%) with an abnormal initial CXR and 19 of 269 patients (7%) with a normal CXR (P <0.001). Sensitivity and specificity of cough ≥2 weeks for predicting PTB was 97% and 6%, with PPV and NPV of 14% and 94%, respectively. CONCLUSIONS: Although moderately sensitive, basing a diagnosis of TB on initial CXR leads to overdiagnosis. An absence of weight loss had a high NPV, whereas none of the combinations had a good PPV. A rapid and accurate diagnostic test is required for HIV-infected chest symptomatic.

Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB patients in India.

Abstract: SETTING: Rifabutin (RBT) is reported to be as effective as and to have less inducing effect on cytochrome P450 enzymes than rifampicin against tuberculosis (TB). The optimal dose of RBT during ritonavir (RTV) co-administration remains a matter of debate. OBJECTIVE: To study the pharmacokinetics of 150 mg RBT thrice weekly during concomitant atazanavir/RTV administration in human immunodeficiency virus (HIV) infected TB patients. METHODS: This observational study was conducted in 16 adult HIV-infected TB patients being treated for TB with an RBT-containing regimen and an antiretroviral therapy regimen with RTV; the dose of RBT was 150 mg thrice weekly. Serial blood draws were performed at pre-dosing and at 1, 2, 4, 6, 8, 12 and 24 h after the drug was administered. Plasma RBT was estimated using high-performance liquid chromatography. RESULTS AND CONCLUSIONS: Peak RBT concentration was below the lower therapeutic limit (<0.3 μg/ml) in seven patients, while 10 patients had trough concentrations below the minimal inhibitory concentration against Mycobacterium tuberculosis (0.06 μg/ml), suggesting that the RBT dosage may be inadequate. Prospective studies in different settings are required to arrive at the proper therapeutic dose for RBT to be used during co-administration with RTV.

Drug-Resistant Tuberculosis: Pediatric Guidelines

Abstract: The World Health Organization estimates that there are 650,000 prevalent cases of multidrug-resistant (MDR) tuberculosis (TB) globally, and since children (<15 years of age) constitute up to 20 % of the TB caseload in high-burden settings, the number of children with drug-resistant (DR) TB is likely to be substantial. Because bacterial burden at the site of disease is often low, diagnosis involves collection of multiple specimens and a laboratory capable of performing culture, although the Xpert MTB/RIF assay has improved sensitivity over smear examination. The basic principles of treatment for children are the same as those for adults with MDR-TB; however, the treatment regimen is often empiric and based on the drug susceptibility pattern of the source case, if available, or on past history of treatment. Additional challenges arise when MDR-TB is diagnosed and managed in the context of HIV coinfection. HIV-infected children are also treated with antiretroviral therapy medications, which have the potential to interact with second-line anti-TB drugs. Lack of pediatric formulations of second-line drugs and paucity of pharmacokinetic data make dosage challenging. However, when treated appropriately, children with DR TB have good outcomes.

Estimation of content of anti-TB drugs supplied at centres of the Revised National TB Control Programme in Tamil Nadu, India.

Abstract: Objective To determine the content of certain antituberculosis (TB) drugs supplied at TB treatment centres of the Revised National TB Control Programme (RNTCP) in the state of Tamil Nadu, India. Methods Eight districts across the state were selected, and the following drugs were collected from five settings (District TB centre, TB unit, designated microscopy centres, DOT providers) in each district: rifampicin (150 and 450 mg), isoniazid (300 mg), pyrazinamide (500 and 750 mg), ethambutol (400 and 600 mg), ethionamide (250 mg), levofloxacin (500 mg) and cycloserine (250 mg). A maximum of 10 tablets/capsules were collected from each setting. The drugs were coded prior to analysis. All drugs were assayed by validated spectrophotometric methods. The acceptable limits for drug content were taken as 90–110% of the stated content. Results More than 90% of tablets of rifampicin 450 mg, isoniazid 300 mg, pyrazinamide 500 and 750 mg, ethambutol 400 and 600 mg and ethionamide 250 mg were within acceptable limits. Eighty per cent of rifampicin 150 mg, 21% of cycloserine 250 mg and 87% of levofloxacin 500 mg were within acceptable limits. The mean cycloserine content was below the acceptable limit in all districts, the mean drug content being 200 mg (range: 108–245 mg). Conclusion This systematic study showed that the stated drug content of cycloserine was not reached in all districts. Deterioration of cycloserine could be minimised by storing the drug in refrigerators. The geographical location of the districts had no influence on the drug content. Objectif Determiner la teneur de certains medicaments antituberculeux fournis dans les centres de traitement de la TB du Programme National Revise de Lutte Contre la TB (RNTCP) dans l'Etat du Tamil Nadu, en Inde. Methodes Huit districts de l'Etat ont ete selectionnes et les medicaments suivants ont ete collectes dans cinq endroits (centre de la TB du district, unite de la TB, centres de microscopie designes, fournisseurs du DOT) dans chaque district: rifampicine (150 mg et 450 mg), isoniazide (300 mg), pyrazinamide (500 mg et 750 mg), ethambutol (400 mg et 600 mg), ethionamide (250 mg), levofloxacin (500 mg) et cycloserine (250 mg). Un maximum de 10 comprimes/gelules a ete collecte dans chaque endroit. Les medicaments ont ete codes avant l'analyse. Tous les medicaments ont ete analyses par des methodes de spectrophotometrie validees. Les limites acceptables pour la teneur des medicaments ont ete fixees a entre 90% et 110% de la teneur indiquee. Resultats Plus de 90% des comprimes de rifampicine 450 mg, d'isoniazide 300 mg, de pyrazinamide 500 mg et 750 mg, ethambutol 400 mg et 600 mg et ethionamide 250 mg etaient dans les limites acceptables. 80% de la rifampicine a 150 mg, 21% de la cycloserine a 250 mg et 87% de la levofloxacin a 500 mg etaient dans des limites acceptables. La teneur moyenne en cycloserine etait inferieure a la limite acceptable dans tous les districts, la teneur moyenne du medicament etant de 200 mg (intervalle: 108 a 245 mg). Conclusion Cette etude systematique a montre que la teneur en medicament indique pour la cycloserine n’etait pas atteinte dans tous les districts. La degradation de la cycloserine pourrait etre minimisee en la stockant au refrigerateur. La localisation geographique des districts n'avait aucune influence sur la teneur des medicaments. Objetivo Determinar el contenido de ciertos medicamentos anti-tuberculosis (TB) suministrados por centros para el tratamiento de la TB del Programa Nacional Revisado de Control de la TB en el estado de Tamil Nadu, India. Metodos Se seleccionaron ocho distritos a lo largo del estado, y se recolectaron los siguientes medicamentos: rifampicina (150 mg & 450 mg), isoniazida (300 mg), pirazinamida (500 mg & 750 mg), etambutol (400 mg & 600 mg), etionamide (250 mg), levofloxacina (500 mg) y cicloserina (250 mg), de cinco lugares diferentes en cada uno de los distritos (centro distrital de TB, unidad de TB, centros de microscopia, proveedores de DOTS). Se recolectaron un maximo de 10 comprimidos/capsulas de cada emplazamiento. Los medicamentos se codificaron antes del analisis. Todos los medicamentos fueron evaluados mediante metodos espectrofotometricos validados. Los limites aceptables para el contenido del medicamento se establecieron entre 90–110% del contenido declarado. Resultados Mas del 90% de los comprimidos de rifampicina 450 mg, isoniazida 300 mg, pirazinamida 500 mg & 750 mg, etambutol 400 mg & 600 mg y etionamida 250 mg estaban dentro de los limites aceptables. Un 80% de la rifampicina de 150 mg, 21% de la cicloserina de 250 mg y 87% de la levofloxacina de 500 mg estaban dentro de los limites aceptables. El contenido medio de la cicloserina estaba por debajo del limite aceptable en todos los distritos, siendo el contenido medio de medicamento de 200 mg (rango: 108–245 mg). Conclusion Este estudio sistematico muestra que el contenido declarado de ingrediente activo para la cicloserian no se alcanzaba en todos los distritos. El deterioro de la cicloserina podria minimizarse guardando la medicacion en neveras. La localizacion geografica de los distritos no tenia influencia alguna sobre el contenido del medicamento.

Defective dendritic cell response to Toll-like receptor 7/8 agonists in perinatally HIV-infected children.

Abstract: Understanding the defects in innate immunity associated with perinatal HIV infection is a prerequisite for effective antiretroviral treatment. We therefore compared the innate immune response [dendritic cell (DC) phenotype and function] in peripheral blood by flow cytometry at baseline and 12 months in HIV-infected children to determine the defect associated with perinatal HIV infection. As compared with controls, patients had decreased numbers of total DCs including plasmacytoid (p)DCs and myeloid (m)DCs and impaired function based on induction of maturation markers (CD83, CD80, CCR7) and cytokines tumor necrosis factor-α and interferon-α (exclusive to pDC) upon stimulation with the TLR7/8 agonist Resiquimod. These abnormalities were evident in all three CD4 immune categories and persisted over 12 months; pDC function worsened in HIV+ children without treatment and improved slightly in those on highly active antiretroviral therapy (HAART). In conclusion, a majority of perinatally HIV-infected older children without HAART remain clinically stable in the short term, but have demonstrable immunologic abnormalities indicative of defects in the innate immune system. Children initiated on HAART showed improvement in CD4 counts but did not show improvement in DC function over the short term.

Lack of association between plasma levels of non-nucleoside reverse transcriptase inhibitors & virological outcomes during rifampicin co-administration in HIV-infected TB patients.

Abstract: Background & objectives: Among patients with HIV-associated tuberculosis (TB), reduced plasma non-nucleoside reverse transcriptase inhibitors (NNRTI) concentrations during rifampicin (RMP) co-administration could lead to HIV treatment failure. This study was undertaken to examine the association between plasma nevirapine (NVP) and efavirenz (EFV) concentrations and virological outcomes in patients infected with HIV-1 and TB. Methods: This was a nested study undertaken in a clinical trial of patients with HIV-1 and TB, randomized to two different once-daily antiretroviral treatment (ART) regimens along with anti-TB treatment (ATT). Trough concentrations of plasma NVP and EFV were estimated at months 1 (during ATT and ART) and 6 months (ART only) by HPLC. Plasma HIV-1 RNA level >400 copies/ml or death within 6 months of ART were considered as unfavourable outcomes. Genotyping of CYP2B6 516G>T polymorphism was performed. Results: Twenty nine per cent of patients in NVP arm had an unfavourable outcome at 6 months compared to 9 per cent in EFV arm (P T polymorphism significantly associated with virologic outcome in patients receiving EFV-based regimen. Interpretation & conclusions: Trough plasma concentrations of NVP and EFV did not show any association with response to ART in patients on ATT and once-daily ART. CYP2B6 516G>T polymorphism was associated with virologic outcome among patients on EFV.

What do we need to know about sexual risk vulnerability among married HIV positive individuals in serodiscordant relationships? - A study from South India

Abstract: We studied the issues around marriage and sexual behaviour in persons living with HIV whose married partners were HIV negative. This was a descriptive study on 111 persons living with HIV, 83 of them being male and 28 of them being female. Early marriages were reported by both males and females but more among the females and most of the respondents reported their spouse to be a relative. A quarter of the female respondents were married the second time, having lost their husbands of the first marriage, early in their marriage. Premarital unsafe sexual intercourse was reported by 55 (66%) of the males thus posing risk to their partner. Furthermore extra marital sexual intercourse after diagnosis of HIV was reported by one third of the males. Those who have reported extra marital sexual intercourse report less condom usage with their spouse (HIV negative) as compared to those who have not had extra-marital sex. (Adjusted O.R. = 0.29 (95% C.I.: 0.12, 0.73); p-value = 0.008). This furthers the risk of HIV transmission.This information calls for the need to evolve strategies that could work toward HIV risk reduction which needs to be included in premarital counselling as well as within the marriage.

Reply to Holm et al

Abstract: TO THE EDITOR—We welcome the feedback provided by Holm et al [1] relating to the application of recently published proposed clinical case definitions for reporting of research findings when evaluating diagnostic tests in young children with suspected intrathoracic tuberculosis. The definitions are intended for research use to evaluate diagnostic assays and strategies under controlled circumstances and not for making individual patient clinical diagnoses for treatment decisions under field conditions. These research case definitions were developed to address the need to standardize reporting for diagnostic studies of tuberculosis in children so that consistency in definitions and methods could allow for more valid comparisons between populations and settings [2]. The need to improve the quantity and quality of diagnostic research in children with suspected tuberculosis is universally recognized, and the opportunity provided by the emergence of novel approaches has made this need stronger. The aim is to strengthen diagnostic research in children, and we hope that these definitions can be revised and improved in the future, informed by data and experience obtained by applying and validating them in real-life studies. We recognize that these definitions have limitations. Although we arrived at these definitions by using formal group consensus rules following careful consideration, not surprisingly agreement was not unanimous for all definitions. There is often a tension between conducting research in locations where there are many eligible children but limited resources and locations with excellent research infrastructure but few eligible children. Similarly, clinical and public health perspectives often apportion different emphasis to the contribution of factors and the level of detail required to make a diagnosis, and there is a lack of data to inform specific definitions. Holm et al [1] highlight some of these limitations, the definition of immunological evidence of infection with Mycobacterium tuberculosis and the definition of treatment response. Another challenge for the panel was to agree on the methodological approach to reading and reporting radiological findings. Chest radiographic findings were considered a critical aspect of the case definition, and the panel applied particular rigor to ensure standard interpreting and reporting of these findings. However, we were aware that the feasibility of this approach might be constrained in the very resource-limited settings where the results of this research need to be applicable. We emphasize the need for rigorous clinical research for pediatric diagnostic studies, while recognizing the tensions of variable levels of resources and pragmatic constraints. Holm et al [1] indicate that a followup period of 2 months might be too short to define treatment response, especially because many children may not have started or may have only recently started anti-tuberculosis therapy at this point. This might be a misunderstanding, as the proposed definitions indicate the follow-up assessment should occur 2 months after initiation of therapy, not from the time of initial assessment or enrollment for suspected disease, which may be considerably earlier. Nonetheless, we accept the inherent potential bias in the classification of children who die or are lost to follow-up before that time, whether receiving anti-tuberculosis therapy or not. These children represent an important high-risk group that should be reported on separately.