Alarming Levels of Drug-Resistant Tuberculosis in HIV-Infected Patients in Metropolitan Mumbai,India

Background

Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India.

Methods

A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases.

Results

Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%–40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models.

Conclusion

The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and health facilities. These data highlight the need to promptly diagnose drug-resistance among all HIV-infected patients by systematically offering access to first and second-line DST to all patients with ‘presumptive TB’ rather than ‘presumptive DR-TB’ and tailor the treatment regimen based on the resistance patterns.     

Correlates of Treatment Outcomes and Drug Resistance among Pulmonary Tuberculosis Patients Attending Tertiary Care Hospitals of Kolkata,India

Background

Worldwide highest number of new pulmonary tuberculosis (PTB) cases, was reported from India in 2012. Adverse treatment outcomes and emergence of drug resistance further complicated the prevailing scenario owing to increased duration, cost and toxicity associated with the treatment of drug-resistant cases. Hence to reinforce India’s fight against TB, identification of the correlates of adverse treatment outcomes and drug resistance, seemed critical.

Methods

To estimate the associations between diagnostic findings, patient types (based on treatment outcomes), drug resistance and socio-demographic characteristics of PTB patients, a cross-sectional study was conducted in two tertiary-care hospitals in Kolkata between April 2010 and March 2013. Altogether, 350 consenting Mycobacterium tuberculosis sputum-culture positive PTB patients were interviewed about their socio-demographic background, evaluated regarding their X-ray findings (minimal/moderately advanced/far advanced/cavities), sputum-smear positivity, and treatment history/outcomes (new/defaulter/relapse/treatment-failure cases). Multiple-allele-specific polymerase chain reaction (MAS-PCR) was conducted to diagnose drug resistance.

Results

Among all participants, 31.43% were newly diagnosed, while 44%, 15.43% and 9.14% patients fell into the categories of relapsed, defaulters and treatment-failures, respectively. 12.29% were multi-drug-resistant (MDR: resistant to at least isoniazid and rifampicin), 57.71% had non-MDR two-drug resistance and 12% had single-drug resistance. Subjects with higher BMI had lower odds of being a relapse/defaulter/treatment failure case while females were more likely to be defaulters and older age-groups had more relapse. Elderly, females, unmarried, those with low BMI and higher grade of sputum-smear positivity were more likely to have advanced X-ray features. Higher grade of sputum-smear positivity and advanced chest X-ray findings were associated with relapse/treatment-failures. Elderly, unmarried, relapse/defaulter/treatment-failure cases had higher odds and those with higher BMI and moderately/far advanced X-ray findings had lower odds of having MDR/non-MDR two-drug resistant PTB.

Conclusion

Targeted intervention and appropriate counseling are needed urgently to prevent adverse treatment outcomes and development of drug resistance among PTB patients in Kolkata.     

High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai,India

Background

Adverse events (AEs) among HIV-infected patients with multidrug-resistant tuberculosis (MDR-TB) receiving anti-TB and antiretroviral treatments (ART) are under-researched and underreported. Hypothyroidism is a common AE associated with ethionamide, p-aminosalicylic acid (PAS), and stavudine. The aim of this study was to determine the frequency of and risk factors associated with hypothyroidism in HIV/MDR-TB co-infected patients.

Methods

This was a prospective, observational cohort study, using routine laboratory data in a Médecins Sans Frontières (MSF) clinic in collaboration with Sewri TB Hospital, Mumbai, India. Hypothyroidism was defined as a thyroid stimulating hormone (TSH) result >10 mIU/L at least once during treatment. Patients having a baseline result and one additional result after 3 months were eligible for enrolment.

Results

Between October 2006 and March 2013, 116 patients were enrolled, 69 of whom were included. The median (IQR) age was 38 years (34-43) and 61% were male. By March 2013, 37/69 (54%) had hypothyroidism after at least 90 days of treatment. Age, gender, CD4 counts and stavudine-based ART were not associated with the occurrence of hypothyroidism in multivariate models. The co-administration of PAS and ethionamide was found to double the risk of hypothyroidism (RR: 1.93, 95% CI: 1.06-3.54).

Discussion

High rate of hypothyroidism was recorded in a Mumbai cohort of MDR-TB/HIV co-infected patients on treatment. This is a treatable and reversible AE, however, it may go undiagnosed in the absence of regular monitoring. Care providers should not wait for clinical symptoms, as this risks compromising treatment adherence. Simple, affordable and reliable point-of-care tools for measuring TSH are needed, especially in high MDR-TB burden countries. Our findings suggest the need for TSH screening at baseline, three months, six months, and every six months thereafter for HIV-infected patients on MDR-TB treatment regimens containing PAS and/or ethionamide, until newer, safer and more efficacious MDR-TB regimens become available.     

Delays before Diagnosis and Initiation of Treatment in Patients Presenting to Mental Health Services with Bipolar Disorder

BackgroundBipolar disorder is a significant cause of morbidity and mortality. Although existing treatments are effective, there is often a substantial delay before diagnosis and treatment initiation. We sought to investigate factors associated with the delay before diagnosis of bipolar disorder and the onset of treatment in secondary mental healthcare.MethodRetrospective cohort study using anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register on 1364 adults diagnosed with bipolar disorder between 2007 and 2012. The following predictor variables were analysed in a multivariable Cox regression analysis: age, gender, ethnicity, compulsory admission to hospital under the UK Mental Health Act, marital status and other diagnoses prior to bipolar disorder. The outcomes were time to recorded diagnosis from first presentation to specialist mental health services (the diagnostic delay), and time to the start of appropriate therapy (treatment delay).ResultsThe median diagnostic delay was 62 days (interquartile range: 17–243) and median treatment delay was 31 days (4–122). Compulsory hospital admission was associated with a significant reduction in both diagnostic delay (hazard ratio 2.58, 95% CI 2.18–3.06) and treatment delay (4.40, 3.63–5.62). Prior diagnoses of other psychiatric disorders were associated with increased diagnostic delay, particularly alcohol (0.48, 0.33–0.41) and substance misuse disorders (0.44, 0.31–0.61). Prior diagnosis of schizophrenia and psychotic depression were associated with reduced treatment delay.ConclusionsSome individuals experience a significant delay in diagnosis and treatment of bipolar disorder after initiation of specialist mental healthcare, particularly those who have prior diagnoses of alcohol and substance misuse disorders. These findings highlight a need for further study on strategies to better identify underlying symptoms and offer appropriate treatment sooner in order to facilitate improved clinical outcomes, such as developing specialist early intervention services to identify and treat people with bipolar disorder.     

Poor Outcomes in a Cohort of HIV-Infected Adolescents Undergoing Treatment for Multidrug-Resistant Tuberculosis in Mumbai,India

Background

Little is known about the treatment of multidrug-resistant tuberculosis (MDR-TB) in HIV-co-infected adolescents. This study aimed to present the intermediate outcomes of HIV-infected adolescents aged 10–19 years receiving second-line anti-TB treatment in a Médecins Sans Frontières (MSF) project in Mumbai, India.

Methods

A retrospective review of medical records of 11 adolescents enrolled between July 2007 and January 2013 was undertaken. Patients were initiated on either empirical or individualized second-line ambulatory anti-TB treatment under direct observation.

Results

The median age was 16 (IQR 14–18) years and 54% were female. Five (46%) adolescents had pulmonary TB (PTB), two (18%) extrapulmonary disease (EPTB) and four (36%) had both. Median CD4 count at the time of MDR-TB diagnosis was 162.7 cells/µl (IQR: 84.8–250.5). By January 2013, eight patients had final and 3 had interim outcomes. Favourable results were seen in four (36.5%) patients: one was cured and three were still on treatment with negative culture results. Seven patients (64%) had poor outcomes: four (36.5%) died and three (27%) defaulted. Three of the patients who died never started on antiretroviral and/or TB treatment and one died 16 days after treatment initiation. Two of the defaulted died soon after default. All patients (100%) on-treatment experienced adverse events (AEs): two required permanent discontinuation of the culprit drug and two were hospitalized due to AEs. No patient required permanent discontinuation of the entire second-line TB or antiretroviral regimens.

Conclusions

Early mortality and mortality after default were the most common reasons for poor outcomes in this study. Early mortality suggests the need for rapid diagnosis and prompt treatment initiation, and adolescents might benefit from active contact-tracing and immediate referral. Default occurred at different times, suggesting the need for continuous, intensified and individualized psychosocial support for co-infected adolescents. Operational research among co-infected adolescents will be especially important in designing effective interventions for this vulnerable group.     

LED-Fluorescence Microscopy for Diagnosis of Pulmonary Tuberculosis under Programmatic Conditions in India

Background

Light-emitting diode fluorescence microscopy (LED-FM) has been shown to be more sensitive than conventional bright field microscopy using Ziehl-Neelsen (ZN) stain in detecting sputum smear positive tuberculosis in controlled laboratory conditions. In 2012, Auramine O staining based LED-FM replaced conventional ZN microscopy in 200 designated microscopy centres (DMC) of medical colleges operating in collaboration with India’s Revised National Tuberculosis Control Programme. We aimed to assess the impact of introduction of LED-FM services on sputum smear positive case detection under program conditions.

Methods

This was a before and after comparison study. In 15 randomly selected medical college DMCs, all presumptive TB patients who underwent sputum smear examination in the years 2011 (before LED-FM) and 2012 (after LED-FM) were compared. An additional 15 comparable DMCs that implemented conventional ZN sputum smear microscopy were also selected for comparison between 2011 and 2012.

Results

The proportion of presumptive TB patients (PTP)found sputum smear positive increased by 30%- from 13.6% (3432/25159) in 2011 to 17.8% (4706/26426) in 2012 (P value <0.01) in the sites that implemented LED-FM microscopy, whereas in DMCs where the ZN staining procedure is followed the proportion of sputum smear positive had remained unchanged (13.0%versus 12.6%;P value0.31).

Conclusion

Use of LED-FM significantly increased the proportion of smear positive cases among presumptive TB patients under routine program conditions in high workload laboratories. The study provides operational evidence needed to scale-up the use of LED-FM in similar settings in India and beyond.     

Treatment Seeking,Vaginal Discharge and Psychosocial Distress Among Women in Urban Mumbai

Vaginal discharge (safed pani in Hindi, meaning “white water”) is one of the leading symptoms for which women in India seek care. Treatment-seeking for safed pani is disproportionately high among poor women, representing a physical, emotional and financial burden for low-income families. Safed pani is only rarely indicative of a reproductive tract or sexually transmitted infection. The discrepancy between symptom reports and observed pathology has led some researchers to characterize safed pani as a culturally based expression of more generalized negative life situation. Data are drawn from two prevention intervention studies (2002–2006 and 2007–2012) conducted in economically marginal communities in Mumbai. Results show that husbands as problem generators and spousal abusers and women’s greater perceived empowerment and reported tension are significantly associated with safed pani. These results provide the basis for identifying women at greater risk for psychosocial distress and providing supports at the locations at which they seek treatment.     

Risk Factors for Treatment Default among Re-Treatment Tuberculosis Patients in India, 2006

Setting

Under India''s Revised National Tuberculosis Control Programme (RNTCP), >15% of previously-treated patients in the reported 2006 patient cohort defaulted from anti-tuberculosis treatment.

Objective

To assess the timing, characteristics, and risk factors for default amongst re-treatment TB patients.

Methodology

For this case-control study, in 90 randomly-selected programme units treatment records were abstracted from all 2006 defaulters from the RNTCP re-treatment regimen (cases), with one consecutively-selected non-defaulter per case. Patients who interrupted anti-tuberculosis treatment for >2 months were classified as defaulters.

Results

1,141 defaulters and 1,189 non-defaulters were included. The median duration of treatment prior to default was 81 days (25%–75% interquartile range 44–117 days) and documented retrieval efforts after treatment interruption were inadequate. Defaulters were more likely to have been male (adjusted odds ratio [aOR] 1.4, 95% confidence interval [CI] 1.2–1.7), have previously defaulted anti-tuberculosis treatment (aOR 1.3 95%CI 1.1–1.6], have previous treatment from non-RNTCP providers (AOR 1.3, 95%CI 1.0–1.6], or have public health facility-based treatment observation (aOR 1.3, 95%CI 1.1–1.6).

Conclusions

Amongst the large number of re-treatment patients in India, default occurs early and often. Improved pre-treatment counseling and community-based treatment provision may reduce default rates. Efforts to retrieve treatment interrupters prior to default require strengthening.     

Incidence and Prevalence of Tuberculosis among Household Contacts of Pulmonary Tuberculosis Patients in a Peri-Urban Population of South Delhi,India

Background

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of mortality and morbidity across all age groups throughout the world, especially in developing countries.

Methodology/Principal Findings

In this study, we have included 432 open index cases with their 1608 household contacts in a prospective cohort study conducted from May 2007 to March 2009. The follow-up period was 2 years. All Index cases were diagnosed on the basis of suggestive signs and symptoms and sputum being AFB positive. Among the 432 index patients, 250 (57.9%) were males and 182 (42.1%) females; with mean age of 34±14.4 yr and 26±11.1 yr, respectively. Out of 1608 household contacts, 866 (53.9%) were males and 742 (46.1%) females; with mean age of 26.5±15.8 and 26.5±16.0 yr, respectively. Of the total 432 households, 304 (70.4%) had ≤4 members and 128 (29.6%) had ≥5 members. The median size of the family was four. Of the 1608 contacts, 1206 were able to provide sputum samples, of whom 83 (6.9%) were found MTB culture positive. Household contacts belonging to adult age group were predominantly (74, 89.2%) infected as compared to the children (9, 10.8%). On screening the contact relationship status with index patients, 52 (62.7%) were first-degree relatives, 18 (34.6%) second-degree relatives and 12 (14.5%) spouses who got infected from their respective index patients. Co-prevalent and incident tuberculosis was found in 52 (4.3%) and 31 (2.6%) contacts, respectively. In incident cases, the diagnosis could be made between 4 to 24 months of follow-up, after their baseline evaluation.

Conclusion

Active household contact investigation is a powerful tool to detect and treat tuberculosis at early stages and the only method to control TB in high-TB-burden countries.     

Adherence to Tuberculosis Treatment among Migrant Pulmonary Tuberculosis Patients in Shandong,China: A Quantitative Survey Study

Adherence to TB treatment is the most important requirement for efficient TB control. Migrant TB patients’ “migratory” nature affects the adherence negatively, which presents an important barrier for National TB Control Program in China. Therefore, TB control among migrants is of high importance.The aim of this study is to describe adherence to TB treatment among migrant TB patients and to identify factors associated with adherence. A total of 12 counties/districts of Shandong Province, China were selected as study sites. 314 confirmed smear positive TB patients were enrolled between August 2^nd 2008 and October 17^th 2008, 16% of whom were non-adherent to TB therapy. Risk factors for non-adherence were: the divorced or bereft of spouse, patients not receiving TB-related health education before chemotherapy, weak incentives for treatment adherence, and self supervision on treatment. Based on the risk factors identified, measures are recommended such as implementing health education for all migrant patients before chemotherapy and encouraging primary care workers to supervise patients.     

Cardiorespiratory Studies in Patients with Pulmonary Tuberculosis

Cardiorespiratory studies in 13 young females and 11 middle-aged men with localized acute pulmonary tuberculosis revealed evidence of significant resting hyperventilation and reduction in the dynamics of ventilation indicative of restrictive lung disease. Indices of intrapulmonary mixing and pulmonary diffusing capacities were normal, as were alveolar-arterial pCO₂ gradients.The ventilation/perfusion ratios were slightly elevated in both groups, while pulmonary artery pressure and total pulmonary vascular resistance (TPVR) showed a rise in the males only.Both groups showed an increase in actual QBF flows and a resultant significant decrease in arterial pO₂, which suggests that the areas of tuberculous infection are metabolically active.     

Nutritional Status of Adult Patients with Pulmonary Tuberculosis in Rural Central India and Its Association with Mortality

Under-nutrition is a known risk factor for TB and can adversely affect treatment outcomes. However, data from India are sparse, despite the high burden of TB as well as malnutrition in India. We assessed the nutritional status at the time of diagnosis and completion of therapy, and its association with deaths during TB treatment, in a consecutive cohort of 1695 adult patients with pulmonary tuberculosis in rural India during 2004 - 2009.Multivariable logistic regression was used to obtain adjusted estimates of the association of nutritional status with deaths during treatment. At the time of diagnosis, median BMI and body weights were 16.0 kg/m²and 42.1 kg in men, and 15.0 kg/m²and 34.1 kg in women, indicating that 80% of women and 67% of men had moderate to severe under-nutrition (BMI<17.0 kg/m²). Fifty two percent of the patients (57% of men and 48% of women) had stunting indicating chronic under-nutrition. Half of women and one third of men remained moderately to severely underweight at the end of treatment. 60 deaths occurred in 1179 patients (5%) in whom treatment was initiated. Severe under-nutrition at diagnosis was associated with a 2 fold higher risk of death. Overall, a majority of patients had evidence of chronic severe under-nutrition at diagnosis, which persisted even after successful treatment in a significant proportion of them. These findings suggest the need for nutritional support during treatment of pulmonary TB in this rural population.     

Outcome of Tuberculosis Treatment in Patients with Diabetes Mellitus Treated in the Revised National Tuberculosis Control Programme in Malappuram District,Kerala, India

Settings

Kerala State, India has reported the greatest dual burden of Tuberculosis (TB) and Diabetes Mellitus (DM). Malappuram district in Kerala has monitored and recorded DM status and its control from 2010 under Revised National Tuberculosis Control Program (RNTCP).

Objectives

To assess, under programme conditions, comprehensiveness of recording DM status among TB cases and the TB treatment outcomes among DM patients (disaggregated by glycemic control) and compare with-non DM patients.

Design

This retrospective record review included 3,116TB patients from April 2010 to September 2011.DM was defined as per international guidelines and TB treatment outcomes were categorized as favourable(cured and treatment completed) and unfavourable(death, default, failure and transfer out). Relative Risk (RR) and 95% confidence intervals(CI) were calculated to assess the risk of unfavourable outcomes.

Results

DM status was recorded in 90% of TB cases and 667 (24%) had DM. 17% of DM patients and 23% of patients with unknown DM status had unfavourable outcomes but this difference was not statistically significant. Unadjusted RR for poor glycemic control or unknown control status for unfavourable outcome were (2.00; 95% CI 0.97–4.13) and (2.14; 95% CI 1.11–4.13).

Conclusion

This study could not confirm an adverse association between DM or its control during treatment and the course of response to TB treatment.DM screening in TB cases and recording of DM care needs to be improved to enable more conclusive evidence.     

Genotypic,Phenotypic and Clinical Validation of GeneXpert in Extra-Pulmonary and Pulmonary Tuberculosis in India

Background

Newer molecular diagnostics have brought paradigm shift in early diagnosis of tuberculosis [TB]. WHO recommended use of GeneXpert MTB/RIF [Xpert] for Extra-pulmonary [EP] TB; critics have since questioned its efficiency.

Methods

The present study was designed to assess the performance of GeneXpert in 761 extra-pulmonary and 384 pulmonary specimens from patients clinically suspected of TB and compare with Phenotypic, Genotypic and Composite reference standards [CRS].

Results

Comparison of GeneXpert results to CRS, demonstrated sensitivity of 100% and 90.68%, specificity of 100% and 99.62% for pulmonary and extra-pulmonary samples. On comparison with culture, sensitivity for Rifampicin [Rif] resistance detection was 87.5% and 81.82% respectively, while specificity was 100% for both pulmonary and extra-pulmonary TB. On comparison to sequencing of rpoB gene [Rif resistance determining region, RRDR], sensitivity was respectively 93.33% and 90% while specificity was 100% in both pulmonary and extra-pulmonary TB. GeneXpert assay missed 533CCG mutation in one sputum and dual mutation [517 & 519] in one pus sample, detected by sequencing. Sequencing picked dual mutation [529, 530] in a sputum sample sensitive to Rif, demonstrating, not all RRDR mutations lead to resistance.

Conclusions

Current study reports observations in a patient care setting in a high burden region, from a large collection of pulmonary and extra-pulmonary samples and puts to rest questions regarding sensitivity, specificity, detection of infrequent mutations and mutations responsible for low-level Rif resistance by GeneXpert. Improvements in the assay could offer further improvement in sensitivity of detection in different patient samples; nevertheless it may be difficult to improve sensitivity of Rif resistance detection if only one gene is targeted. Assay specificity was high both for TB detection and Rif resistance detection. Despite a few misses, the assay offers major boost to early diagnosis of TB and MDR-TB, in difficult to diagnose pauci-bacillary TB.