Malik Parmar

Use of Xpert MTB/RIF in Decentralized Public Health Settings and Its Effect on Pulmonary TB and DR-TB Case Finding in India

Background Xpert MTB/RIF, the first automated molecular test for tuberculosis, is transforming the diagnostic landscape in high-burden settings. This study assessed the impact of up-front Xpert MTB/RIF testing on detection of pulmonary tuberculosis (PTB) and rifampicin-resistant PTB (DR-TB) cases in India. Methods This demonstration study was implemented in 18 sub-district level TB programme units (TUs) in India in diverse geographic and demographic settings covering a population of 8.8 million. A baseline phase in 14 TUs captured programmatic baseline data, and an intervention phase in 18 TUs had Xpert MTB/RIF offered to all presumptive TB patients. We estimated changes in detection of TB and DR-TB, the former using binomial regression models to adjust for clustering and covariates. Results In the 14 study TUs, which participated in both phases, 10,675 and 70,556 presumptive TB patients were enrolled in the baseline and intervention phase, respectively, and 1,532 (14.4%) and 14,299 (20.3%) bacteriologically confirmed PTB cases were detected. The implementation of Xpert MTB/RIF was associated with increases in both notification rates of bacteriologically confirmed TB cases (adjusted incidence rate ratio [aIRR] 1.39; CI 1.18-1.64), and proportion of bacteriological confirmed TB cases among presumptive TB cases (adjusted risk ratio (aRR) 1.33; CI 1.6-1.52). Compared with the baseline strategy of selective drug-susceptibility testing only for PTB cases at high risk of drug-resistant TB, Xpert MTB/RIF implementation increased rifampicin resistant TB case detection by over fivefold. Among, 2765 rifampicin resistance cases detected, 1055 were retested with conventional drug susceptibility testing (DST). Positive predictive value (PPV) of rifampicin resistance detected by Xpert MTB/RIF was 94.7% (CI 91.3-98.1), in comparison to conventional DST. Conclusion Introduction of Xpert MTB/RIF as initial diagnostic test for TB in public health facilities significantly increased case-notification rates of all bacteriologically confirmed TB by 39% and rifampicin-resistant TB case notification by fivefold.

Feasibility of Decentralised Deployment of Xpert MTB/RIF Test at Lower Level of Health System in India

Background Xpert MTB/RIF is an automated cartridge-based nucleic acid amplification test that has demonstrated its potential to detect tuberculosis and rifampicin resistance with high accuracy. To assist scale-up decisions in India, a feasibility assessment of Xpert MTB/RIF implementation was conducted within microscopy centres of 18 RNTCP TB units. Methods As part of programme-based demonstration of Xpert MTB/RIF implementation, we recorded and analysed association between key implementation factors and the ability of test to produce valid results. Factors contributing to test failures were analysed from GeneXpert software data which provides ‘failure codes’ and causes for test failures. Results From March’12 to January’13, total 40,035 suspects were tested by Xpert MTB/RIF, and 39,680 (99.1%) received valid results (Cumulative: 37157 (92.8%) on first attempt, 39410 (98.4%) on second attempt, 39637 (99.0%) on third attempt and 39680 (99.1%) on more attempts). Overall initial test failure was 2,878 (7.2% (4%–17%)); of these, 2,594 (90.1%) were re-tested and produced valid results. Most frequent reason of test failure was inadequate sample processing or equipment malfunction (3.9%). Other reasons included power failure (1.1%), cartridge integrity/component failure (0.8%), device-computer communication error (0.5%), and temperature-related errors (0.08%). Significant variation was observed in failure rates both across instruments and over time; furthermore, substantial variation was observed in failure rate in two cartridges lots. Conclusion Installation required minimal infrastructure modifications and concerns about adequacy of human resources under public sector facilities and temperature extremes proved unfounded. Under routine conditions, Xpert MTB/RIF provided 99.1% valid results in TB suspects with low overall failure rates (7.2% initial failure, 0.9% final failure); devices provided valuable real-time feedback on reasons for test failure, which were used for rapid corrective action. High modular replacement (32%) and inter-lot cartridge performance variation remain sources of concern, and warrant close monitoring of failure rates as a key quality indicator.

Enhancing TB Case Detection: Experience in Offering Upfront Xpert MTB/RIF Testing to Pediatric Presumptive TB and DR TB Cases for Early Rapid Diagnosis of Drug Sensitive and Drug Resistant TB

Background Diagnosis of pulmonary tuberculosis (PTB) in children is challenging due to difficulties in obtaining good quality sputum specimens as well as the paucibacillary nature of disease. Globally a large proportion of pediatric tuberculosis (TB) cases are diagnosed based only on clinical findings. Xpert MTB/RIF, a highly sensitive and specific rapid tool, offers a promising solution in addressing these challenges. This study presents the results from pediatric groups taking part in a large demonstration study wherein Xpert MTB/RIF testing replaced smear microscopy for all presumptive PTB cases in public health facilities across India. Methods The study covered a population of 8.8 million across 18 programmatic sub-district level tuberculosis units (TU), with one Xpert MTB/RIF platform established at each study TU. Pediatric presumptive PTB cases (both TB and Drug Resistant TB (DR-TB)) accessing any public health facilities in study area were prospectively enrolled and tested on Xpert MTB/RIF following a standardized diagnostic algorithm. Results 4,600 pediatric presumptive pulmonary TB cases were enrolled. 590 (12.8%, CI 11.8–13.8) pediatric PTB were diagnosed. Overall 10.4% (CI 9.5–11.2) of presumptive PTB cases had positive results by Xpert MTB/RIF, compared with 4.8% (CI 4.2–5.4) who had smear-positive results. Upfront Xpert MTB/RIF testing of presumptive PTB and presumptive DR-TB cases resulted in diagnosis of 79 and 12 rifampicin resistance cases, respectively. Positive predictive value (PPV) for rifampicin resistance detection was high (98%, CI 90.1–99.9), with no statistically significant variation with respect to past history of treatment. Conclusion Upfront access to Xpert MTB/RIF testing in pediatric presumptive PTB cases was associated with a two-fold increase in bacteriologically-confirmed PTB, and increased detection of rifampicin-resistant TB cases under routine operational conditions across India. These results suggest that routine Xpert MTB/RIF testing is a promising solution to present-day challenges in the diagnosis of PTB in pediatric patients.

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.

Operational Challenges in Diagnosing Multi-Drug Resistant TB and Initiating Treatment in Andhra Pradesh, India

Background Revised National TB Control Programme (RNTCP), Andhra Pradesh, India. There is limited information on whether MDR-TB suspects are identified, undergo diagnostic assessment and are initiated on treatment according to the programme guidelines. Objectives To assess i) using the programme definition, the number and proportion of MDR-TB suspects in a large cohort of TB patients on first-line treatment under RNTCP ii) the proportion of these MDR-TB suspects who underwent diagnosis for MDR-TB and iii) the number and proportion of those diagnosed as MDR-TB who were successfully initiated on treatment. Methods A retrospective cohort analysis, by reviewing RNTCP records and reports, was conducted in four districts of Andhra Pradesh, India, among patients registered for first line treatment during October 2008 to December 2009. Results Among 23,999 TB patients registered for treatment there were 559 (2%) MDR-TB suspects (according to programme definition) of which 307 (55%) underwent diagnosis and amongst these 169 (55%) were found to be MDR-TB. Of the MDR-TB patients, 112 (66%) were successfully initiated on treatment. Amongst those eligible for MDR-TB services, significant proportions are lost during the diagnostic and treatment initiation pathway due to a variety of operational challenges. The programme needs to urgently address these challenges for effective delivery and utilisation of the MDR-TB services.

Source of previous treatment for re-treatment TB cases registered under the National TB control Programme, India, 2010.

Background In 2009, nearly half (289,756) of global re-treatment TB notifications are from India; no nationally-representative data on the source of previous treatment was available to inform strategies for improvement of initial TB treatment outcome. Objectives To assess the source of previous treatment for re-treatment TB patients registered under Indias Revised National TB control Programme (RNTCP). Methodology A nationally-representative cross sectional study was conducted in a sample of 36 randomly-selected districts. All consecutively registered retreatment TB patients during a defined 15-day period in these 36 districts were contacted and the information on the source of previous treatment sought. Results Data was collected from all 1712 retreatment TB patients registered in the identified districts during the study period. The data includes information on 595 ‘relapse’ cases, 105 ‘failure’ cases, 437 ‘treatment after default (TAD)’ cases and 575 ‘re-treatment others’ cases. The source of most recent previous anti-tuberculosis therapy for 754 [44% (95% CI, 38.2%–49.9%)] of the re-treatment TB patients was from providers outside the TB control programme. A higher proportion of patients registered as TAD (64%) and ‘retreatment others’ (59%) were likely to be treated outside the National Programme, when compared to the proportion among ‘relapse’ (22%) or ‘failure’ (6%). Extrapolated to national registration, of the 292,972 re-treatment registrations in 2010, 128,907 patients would have been most recently treated outside the national programme. Conclusions Nearly half of the re-treatment cases registered with the national programme were most recently treated outside the programme setting. Enhanced efforts towards extending treatment support and supervision to patients treated by private sector treatment providers are urgently required to improve the quality of treatment and reduce the numbers of patients with recurrent disease. In addition, reasons for the large number of recurrent TB cases from those already treated by the national programme require urgent detailed investigation.

Piloting Upfront Xpert MTB/RIF Testing on Various Specimens under Programmatic Conditions for Diagnosis of TB & DR-TB in Paediatric Population

Background India accounts for one-fifth of the global TB incidence. While the exact burden of childhood TB is not known, TB remains one of the leading causes of childhood mortality in India. Bacteriological confirmation of TB in children is challenging due to difficulty in obtaining quality specimens, in the absence of which diagnosis is largely based on clinical judgement. While testing multiple specimens can potentially contribute to higher proportion of laboratory confirmed paediatric TB cases, lack of high sensitivity tests adds to the diagnostic challenge. We describe here our experiences in piloting upfront Xpert MTB/RIF testing, for diagnosis of TB in paediatric population in respiratory and extra pulmonary specimens, as recently recommended by WHO. Method Xpert MTB/RIF testing was offered to all paediatric (0–14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities in the project areas covering 4 cities of India. Results Under this pilot project, 8,370 paediatric presumptive TB & presumptive DR-TB cases were tested between April and–November 2014. Overall, 9,149 specimens were tested, of which 4,445 (48.6%) were non-sputum specimens. Xpert MTB/RIF gave 9,083 (99.2%, CI 99.0–99.4) valid results. Of the 8,143 presumptive TB cases enrolled, 517 (6.3%, CI 5.8–6.9) were bacteriologically confirmed. TB detection rates were two fold higher with Xpert MTB/RIF as compared to smear microscopy. Further, a total of 60 rifampicin resistant TB cases were detected, of which 38 were detected among 512 presumptive TB cases while 22 were detected amongst 227 presumptive DR-TB cases tested under the project. Conclusion Xpert MTB/RIF with advantages of quick turnaround testing-time, high proportion of interpretable results and feasibility of rapid rollout, substantially improved the diagnosis of bacteriologically confirmed TB in children, while simultaneously detecting rifampicin resistance.

Patient and Provider Reported Reasons for Lost to Follow Up in MDRTB Treatment: A Qualitative Study from a Drug Resistant TB Centre in India

Introduction Multidrug-resistant Tuberculosis (MDR TB) is emerging public health concern globally. Lost to follow-up (LTFU) is one of the key challenge in MDRTB treatment. In 2013, 18% of MDR TB patients were reported LTFU in India. A qualitative study was conducted to obtain better understanding of both patient and provider related factors for LTFU among MDR TB treatment. Methods Qualitative semi-structured personal interviews were conducted with 20 MDRTB patients reported as LTFU and 10 treatment providers in seven districts linked to Nagpur Drug resistant TB Centre (DRTBC) during August 2012–February 2013. Interviews were transcribed and inductive content analysis was performed to derive emergent themes. Results We found multiple factors influencing MDR TB treatment adherence. Barriers to treatment adherence included drug side effects, a perceived lack of provider support, patient financial constraints, conflicts with the timing of treatment services, alcoholism and social stigma. Conclusions Patient adherence to treatment is multi-factorial and involves individual patient factors, provider factors, and community factors. Addressing issue of LTFU during MDRTB treatment requires enhanced efforts towards resolving medical problems like adverse drug effects, developing short duration treatment regimens, reducing pill burden, motivational counselling, flexible timings for DOT services, social, family support for patients & improving awareness about disease.

Airborne infection control in India: Baseline assessment of health facilities

BACKGROUND Tuberculosis transmission in health care settings represents a major public health problem. In 2010, national airborne infection control (AIC) guidelines were adopted in India. These guidelines included specific policies for TB prevention and control in health care settings. However, the feasibility and effectiveness of these guidelines have not been assessed in routine practice. This study aimed to conduct baseline assessments of AIC policies and practices within a convenience sample of 35 health care settings across 3 states in India and to assess the level of implementation at each facility after one year. METHOD A multi-agency, multidisciplinary panel of experts performed site visits using a standardized risk assessment tool to document current practices and review resource capacity. At the conclusion of each assessment, facility-specific recommendations were provided to improve AIC performance to align with national guidelines. RESULT Upon initial assessment, AIC systems were found to be poorly developed and implemented. Administrative controls were not commonly practiced and many departments needed renovation to achieve minimum environmental standards. One year after the baseline assessments, there were substantial improvements in both policy and practice. CONCLUSION A package of capacity building and systems development that followed national guidelines substantially improved implementation of AIC policies and practice.

Innovative social protection mechanism for alleviating catastrophic expenses on multidrug-resistant tuberculosis patients in Chhattisgarh, India

Background: Patients with multidrug-resistant tuberculosis (MDR-TB) incur huge expenditures for diagnosis and treatment; these costs can be reduced through a well-designed and implemented social health insurance mechanism. The State of Chhattisgarh in India successfully established a partnership between the Revised National TB Control Programme (RNTCP) and the Health Insurance Programme, to form a universal health insurance scheme for all, by establishing Rashtriya Swasthya Bima Yojna (RSBY) and Mukhyamantri Swasthya Bima Yojana (MSBY) MDR-TB packages. The objective of this partnership was to absorb the catastrophic expenses incurred by patients with MDR-TB, from diagnosis to treatment completion, in the public and private sector. This paper documents the initial experience of a tailor-made health insurance programme, linked to covering catastrophic health expenditure for patients with MDR-TB. Methods: In this descriptive study, data on uptake of insurance claims through innovative MDR-TB packages from January 2013 to April 2014 were collected. A simple survey of costs for clinical investigation and inpatient care was conducted across two major urban districts in Chhattisgarh. In these selected districts, three health facilities from the private sector and one medical college from the public sector with a functional drug-resistant tuberculosis (DR-TB) centre were chosen by the RSBY and MSBY State Nodal Agency to complete a simple, structured questionnaire on existing market rates. The mean costs for clinical investigations and hospital stay were calculated for an individual patient with MDR-TB who would seek services from the private or public sector. Results: A total of 207 insurance claims for RSBY and MSBY MDR-TB packages were processed, of which 20 were from private and 187 from public health establishments, covered under the health insurance programme, free of charge. An estimated catastrophic expenditure, of approximately US