Kuldeep Singh Sachdeva

How Did the TB Patients Reach DOTS Services in Delhi? A Study of Patient Treatment Seeking Behavior

Setting Revised National Tuberculosis Control Programme (RNTCP), Delhi, India. Objective To ascertain the number and sequence of providers visited by TB patients before availing treatment services from DOTS; to describe the duration between onset of symptoms to treatment. Study design A cross sectional, qualitative study. Information was gathered through in-depth interviews of TB patients registered during the month of Oct, 2012 for availing TB treatment under the Revised National TB Control Programme from four tuberculosis diagnosis and treatment centers in Delhi. Results Out of the 114 patients who registered, 108 participated in the study. The study showed that informal providers and retail chemists were the first point of contact and source of clinical advice for two-third of the patients, while the rest sought medical care from qualified providers directly. Most patients sought medical care from more than two providers, before being diagnosed as TB. Female TB patients and patients with extra-pulmonary TB had long mean duration between onset of symptoms to initiation of treatment (6.3 months and 8.4 months respectively). Conclusion The pathways followed by TB patients, illustrated in this study, provide valuable lessons on the importance of different types of providers (both formal and informal) in the health system in a society like India and the delays in the diagnosis and treatment of tuberculosis.

Comparative Evaluation of GenoType MTBDRplus Line Probe Assay with Solid Culture Method in Early Diagnosis of Multidrug Resistant Tuberculosis (MDR-TB) at a Tertiary Care Centre in India

Background The objectives of the study were to compare the performance of line probe assay (GenoType MTBDRplus) with solid culture method for an early diagnosis of multidrug resistant tuberculosis (MDR-TB), and to study the mutation patterns associated with rpoB, katG and inhA genes at a tertiary care centre in north India. Methods In this cross-sectional study, 269 previously treated sputum-smear acid-fast bacilli (AFB) positive MDR-TB suspects were enrolled from January to September 2012 at the All India Institute of Medical Sciences hospital, New Delhi. Line probe assay (LPA) was performed directly on the sputum specimens and the results were compared with that of conventional drug susceptibility testing (DST) on solid media [Lowenstein Jensen (LJ) method]. Results DST results by LPA and LJ methods were compared in 242 MDR-TB suspects. The LPA detected rifampicin (RIF) resistance in 70 of 71 cases, isoniazid (INH) resistance in 86 of 93 cases, and MDR-TB in 66 of 68 cases as compared to the conventional method. Overall (rifampicin, isoniazid and MDR-TB) concordance of the LPA with the conventional DST was 96%. Sensitivity and specificity were 98% and 99% respectively for detection of RIF resistance; 92% and 99% respectively for detection of INH resistance; 97% and 100% respectively for detection of MDR-TB. Frequencies of katG gene, inhA gene and combined katG and inhA gene mutations conferring all INH resistance were 72/87 (83%), 10/87 (11%) and 5/87 (6%) respectively. The turnaround time of the LPA test was 48 hours. Conclusion The LPA test provides an early diagnosis of monoresistance to isoniazid and rifampicin and is highly sensitive and specific for an early diagnosis of MDR-TB. Based on these findings, it is concluded that the LPA test can be useful in early diagnosis of drug resistant TB in high TB burden countries.

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.

A Multi-Site Validation in India of the Line Probe Assay for the Rapid Diagnosis of Multi-Drug Resistant Tuberculosis Directly from Sputum Specimens

Rifampicin (R) and isoniazid (H) are key first-line anti-tuberculosis drugs. Failure to detect resistance to these two drugs early results in treatment failure and poor clinical outcomes. The study purpose was to validate the use of the GenoType MTBDRplus line probe assay (LPA) to detect resistance to R and H in Mycobacterium tuberculosis strains directly from smear-positive sputum samples in India. Method Smear positive sputum specimens from 320 patients were subjected to LPA and results compared against those from conventional Lowenstein Jensen (LJ) culture and drug susceptibility testing (C&DST). All specimens with discordant R DST results were subjected to either sequencing of the rpoB gene and/or repeat DST on liquid culture (MGIT 960) at a National Reference Laboratory. Results Significantly higher proportion of interpretable results were observed with LPA compared to LJ C&DST (94% vs. 80%, p-value <0.01). A total of 248 patients had both LJ and LPA DST results available; 232 (93.5%) had concordant R DST results. Among the 16 discordant R DST results, 13 (81%) were resolved in agreement with LPA results. Final LPA performance characteristics were sensitivity 96% (CI: 90%–98%), specificity 99% (CI: 95%–99%), positive predictive value 99% (CI: 95%–99%), and negative predictive value 95% (CI: 89%–98%). The median turnaround testing time, including specimen transportation time, on LPA was 11 days as compared with 89 days for LJ C&DST. Conclusions LPA proved highly accurate in the rapid detection of R resistance. The reduction in time to diagnosis may potentially enable earlier commencement of the appropriate drug therapy, leading to some reduction of transmission of drug-resistant strains.

Impact of Introducing the Line Probe Assay on Time to Treatment Initiation of MDR-TB in Delhi, India

Setting National Institute of Tuberculosis and Respiratory Diseases (erstwhile Lala Ram Sarup Institute) in Delhi, India. Objectives To evaluate before and after the introduction of the line Probe Assay (LPA) a) the overall time to MDR-TB diagnosis and treatment initiation; b) the step-by-step time lapse at each stage of patient management; and c) the lost to follow-up rates. Methods A retrospective cohort analysis was done using data on MDR-TB patients diagnosed during 2009–2012 under Revised National Tuberculosis Control Programme at the institute. Results Following the introduction of the LPA in 2011, the overall median time from identification of patients suspected for MDR-TB to the initiation of treatment was reduced from 157 days (IQR 127–200) to 38 days (IQR 30–79). This reduction was attributed mainly to a lower diagnosis time at the laboratory. Lost to follow-up rates were also significantly reduced after introduction of the LPA (12% versus 39% pre-PLA). Conclusion Introduction of the LPA was associated with a major reduction in the delay between identification of patients suspected for MDR-TB and initiation of treatment, attributed mainly to a reduction in diagnostic time in the laboratory.

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.

Addressing poverty through disease control programmes: examples from Tuberculosis control in India.

IntroductionTuberculosis remains a major public health problem in India with the country accounting for one-fifth or 21% of all tuberculosis cases reported globally. The purpose of the study was to obtain an understanding on pro-poor initiatives within the framework of tuberculosis control programme in India and to identify mechanisms to improve the uptake and access to TB services among the poor.MethodologyA national level workshop was held with participation from all relevant stakeholder groups. This study conducted during the stakeholder workshop adopted participatory research methods. The data was elicited through consultative and collegiate processes. The research study also factored information from primary and secondary sources that included literature review examining poverty headcount ratios and below poverty line population in the country; and quasi-profiling assessments to identify poor, backward and tribal districts as defined by the TB programme in India.ResultsResults revealed that current pro-poor initiatives in TB control included collaboration with private providers and engaging community to improve access among the poor to TB diagnostic and treatment services. The participants identified gaps in existing pro-poor strategies that related to implementation of advocacy, communication and social mobilisation; decentralisation of DOT; and incentives for the poor through the available schemes for public-private partnerships and provided key recommendations for action. Synergies between TB control programme and centrally sponsored social welfare schemes and state specific social welfare programmes aimed at benefitting the poor were unclear.ConclusionFurther in-depth analysis and systems/policy/operations research exploring pro-poor initiatives, in particular examining service delivery synergies between existing poverty alleviation schemes and TB control programme is essential. The understanding, reflection and knowledge of the key stakeholders during this participatory workshop provides recommendations for action, further planning and research on pro-poor TB centric interventions in the country.

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.

Tuberculosis in BRICS: challenges and opportunities for leadership within the post-2015 agenda.

Tuberculosis is a disease of poverty that claims the lives of over a million people annually.1 Globally, tuberculosis is concentrated in low- to middle-income countries. The five countries – Brazil, the Russian Federation, India, China and South Africa – that make up the BRICS group account for 46% of all incident cases of tuberculosis and 40% of all tuberculosis-related mortality. China and India alone account for almost 40% of the estimated global burden of tuberculosis and a similar proportion of all cases notified to the World Health Organization (WHO). South Africa accounts for 30% of the estimated global number of incident cases of tuberculosis–human immunodeficiency virus (HIV) coinfection. In terms of multidrug-resistant tuberculosis (MDR-TB), China, India and the Russian Federation together account for more than half – 56% – of the estimated global burden. Brazil alone accounts for about a third of the western hemisphere’s estimated burdens of tuberculosis and MDR-TB.1 Global efforts to control tuberculosis have had considerable success. These efforts have resulted in substantial progress towards halving tuberculosis prevalence and mortality between 1990 and 2015 (current targets of the Stop TB Partnership) and halting and reversing the incidence of tuberculosis by 2015 (Millennium Development Goal 6c). Despite this progress, about three million people developing tuberculosis are missed by national notification systems each year, only a small fraction of MDR-TB cases are being treated and the poor and vulnerable continue to suffer disproportionally.1 It is time to look at the enormous challenges that will have to be faced in the post-2015 agenda and the expanded leadership role that BRICS can – and should – play in the fight against tuberculosis. The five BRICS countries were grouped together because they were all fast-growing economies but they also have another similarity: they each harbour more tuberculosis cases than any other country or territory in their respective WHO region. In terms of tuberculosis, each also has different weaknesses and challenges to confront. South Africa has a staggering burden of tuberculosis–HIV coinfection. Brazil and the Russian Federation are trying to eradicate intense foci of tuberculosis among some of their most vulnerable subgroups including homeless people, prisoners, people who use drugs and indigenous populations. China is now faced with the challenge of urgently scaling up access to treatment for MDR-TB. India has more missed cases than any other country and it is difficult to assess the quality of tuberculosis care provided in the country’s very active and diverse private sector. Despite these multiple challenges, the five BRICS countries are often considered to be regional and global leaders in the fight against tuberculosis. They provide models of care and are working together to strengthen efforts that may well be instrumental in setting and achieving future global tuberculosis targets. Several examples show how these countries have addressed local challenges on a large scale, delivered important evidence for improving tuberculosis prevention and care and provided critical political support for new tuberculosis-related initiatives and policy advances. In China – after years of poor tuberculosis notification – the government scaled up access to directly observed treatment and now sees a higher proportion of the estimated notifications (89%) than any other high-burden country. The engagement of hospitals in tuberculosis care has also produced major gains. Following problems with the surveillance of severe acute respiratory syndrome in 2003, the surveillance of all communicable diseases was improved and notification of tuberculosis cases became mandatory. Surveillance of tuberculosis is now based on a nationwide network of more than 3000 facilities that are linked in real time. This network has increased the annual number of notifications and improved the quality of the surveillance data.2 India has also recently developed a web-based national notification, banned the use of inaccurate serological tests and made tuberculosis notification mandatory.3 Although Brazil has a thriving private health-care sector, all of the country’s tuberculosis patients receive treatment free of charge, with publicly-provided drugs. This initiative should slow the development of drug resistance because it should reduce the use of substandard drugs and the risk of incomplete treatment. Improving tuberculosis care will require more research and the large-scale assessment of novel interventions. Several of the BRICS countries have been involved in trials of diagnostic tests, vaccines and new drugs. For example, South Africa has played a leading role in the introduction of Xpert MTB/RIF – a rapid molecular test. It was the first country to scale up the use of this test for initial diagnosis. In 2012, this scale-up, which had strong ministerial support, led to more people being diagnosed with MDR-TB than the number of cases that WHO estimated would occur in the country. Brazil and India have also taken leading roles in the large-scale programmatic implementation of new rapid diagnostic tests.4 In addition, China and India are developing “fast-follower” diagnostic technologies to drive down costs and improve access.1 Improving vulnerable populations’ access to quality tuberculosis care is vital in the world’s attempts to reach the three million missing cases of tuberculosis each year. Brazil already has a strong political commitment to reduce social inequalities in health by implementing large-scale social protection schemes. Brazil’s national tuberculosis programme works to enhance community participation, in the Stop TB Partnership.5 By working across the various ministries that handle health and the penal sector – to introduce tuberculosis screening and improve the general conditions, infection control and tuberculosis treatment in prisons – the Russian Federation reduced tuberculosis prevalence in its prisons.6 Over the last decade, the Russian Federation has also achieved major reductions in tuberculosis incidence, prevalence and mortality.1 As the result of India’s recent implementation of a plan to expand drug susceptibility testing, the annual number of people initiating treatment for MDR-TB in 2012 was fourfold higher than for 2011.3 Since the introduction of WHO’s DOTS/Stop TB Strategy, political commitment has formed the bedrock of all successful programmes of tuberculosis control – including those in BRICS. The Ministers of Health of Lesotho, South Africa and Swaziland led the development of the first Heads of State declaration on tuberculosis; the South African Development Community’s statement on tuberculosis in the mining sector. This declaration resulted in major progress in the planning, financing and implementation of multisectoral interventions against mining-associated tuberculosis in southern Africa. All five BRICS countries are providing large levels of domestic funding for tuberculosis care. The Russian Federation, for example, invests the equivalent of more than a billion United States dollars per year in such control. India produces large amounts of anti-tuberculosis medications that are either used domestically or exported. India’s pharmaceutical industry could play a leading role in lowering the cost of treatment of MDR-TB. China, India, the Russian Federation and, particularly, Brazil and South Africa played major roles in shaping WHO’s new post-2015 TB strategy that was initially approved by WHO’s Executive Board in early 2014. It is clear that, in the control of both tuberculosis and HIV, more opportunities exist for enhanced collaboration within BRICS. Senior officials from BRICS gathered in Paris in October 2013 to discuss tuberculosis and HIV. These officials agreed to work towards decreasing the price of drugs and diagnostics and to support research on several key topics: improving service delivery for tuberculosis and HIV, developing and improving electronic information systems and improving the health of individuals who migrate within or between countries. The officials also agreed to support greater collaboration – between BRICS – on economic analyses and modelling, to optimize the allocation of health resources and to maximize efficiency and effectiveness and promote the sustainability of investments. These discussions on tuberculosis and HIV were reported to BRICS’ ministers of health when they met in Cape Town in November 2013. The Ministers agreed that tuberculosis and HIV should be prioritized as areas of work. The senior officials who met in Paris have now been asked to develop an appropriate roadmap of activities to be undertaken and to report progress to the next meeting of BRICS’ ministers of health. BRICS have made progress in tuberculosis control and treatment thanks to high levels of political commitment, the availability of domestic resources, the use of each country’s capacities and strengths and good levels of collaboration between all relevant ministries and other partners. Since these countries bear much of the global burden posed by tuberculosis, it is not surprising that they have taken leading roles in the fight against tuberculosis. To accelerate the progress, each of the BRICS countries needs to continue to innovate, to provide data on the scaling up of new approaches, and to ensure that future global tuberculosis strategies and plans promote bold efforts and set ambitious – but achievable – post-2015 targets.