Tuberculosis treatment in the private healthcare sector in India: an analysis of recent trends and volumes using drug sales data.

BACKGROUND: There is a pressing need for systematic approaches for monitoring how much TB treatment is ongoing in the private sector in India: both to cast light on the true scale of the problem, and to help monitor the progress of interventions currently being planned to address this problem. METHODS: We used commercially available data on the sales of rifampicin-containing drugs in the private sector, adjusted for data coverage and indication of use. We examined temporal, statewise trends in volumes (patient-months) of TB treatment from 2013 to 2016. We additionally analysed the proportion of drugs that were sold in combination packaging (designed to simplify TB treatment), or as loose pills. RESULTS: Drug sales suggest a steady trend of TB treatment dispensed by the private sector, from 18.4 million patient-months (95% CI 17.3-20.5) in 2013 to 16.8 patient-months (95% CI 15.5-19.0) in 2016. Overall, seven of 29 states in India accounted for more than 70% of national-level TB treatment volumes, including Uttar Pradesh, Maharashtra and Bihar. The overwhelming majority of TB treatment was dispensed not as loose pills, but in combination packaging with other TB drugs, accounting for over 96% of private sector TB treatment in 2017. CONCLUSIONS: Our findings suggest consistent levels of TB treatment in the private sector over the past 4 years, while highlighting specific states that should be prioritized for intervention. Drug sales data can be helpful for monitoring a system as large, disorganised and opaque as India's private sector.

Individuals' Vulnerability Based Active Surveillance for TB: Experiences from India.

Community-based active TB case finding (ACF) has become an essential part of TB elimination efforts in high-burden settings. In settings such as the state of Kerala in India, which has reported an annual decline of 7.5% in the estimated TB incidence since 2015, if ACF is not well targeted, it may end up with a less-than-desired yield, the wastage of scarce resources, and the burdening of health systems. Program managers have recognized the need to optimize resources and workloads, while maximizing the yield, when implementing ACF. We developed and implemented the concept of 'individuals'-vulnerability-based active surveillance' as a substitute for the blanket approach for population/geography-based ACF for TB. Weighted scores, based on an estimate of relative risk, were assigned to reflect the TB vulnerabilities of individuals. Vulnerability data for 22,042,168 individuals were available to the primary healthcare team. Individuals with higher cumulative vulnerability scores were targeted for serial ACF from 2019 onwards. In 2018, when a population-based ACF was conducted, the number needed to screen to diagnose one microbiologically confirmed pulmonary TB case was 3772 and the number needed to test to obtain one microbiologically confirmed pulmonary TB case was 112. The corresponding figures in 2019 for individuals'-vulnerability-based ACF were 881 and 39, respectively. Individuals'-vulnerability-based active surveillance is proposed here as a practical solution to improve health system efficiency in settings where the population is relatively stationary, the TB disease burden is low, and the health system is strong.

Engaging with the private healthcare sector for the control of tuberculosis in India: cost and cost-effectiveness.

BACKGROUND: The control of tuberculosis (TB) in India is complicated by the presence of a large, disorganised private sector where most patients first seek care. Following pilots in Mumbai and Patna (two major cities in India), an initiative known as the 'Public-Private Interface Agency' (PPIA) is now being expanded across the country. We aimed to estimate the cost-effectiveness of scaling up PPIA operations, in line with India's National Strategic Plan for TB control. METHODS: Focusing on Mumbai and Patna, we collected cost data from implementing organisations in both cities and combined this data with models of TB transmission dynamics. Estimating the cost per disability adjusted life years (DALY) averted between 2014 (the start of PPIA scale-up) and 2025, we assessed cost-effectiveness using two willingness-to-pay approaches: a WHO-CHOICE threshold based on per-capita economic productivity, and a more stringent threshold incorporating opportunity costs in the health system. FINDINGS: A PPIA scaled up to ultimately reach 50% of privately treated TB patients in Mumbai and Patna would cost, respectively, US$228 (95% uncertainty interval (UI): 159 to 320) per DALY averted and US$564 (95% uncertainty interval (UI): 409 to 775) per DALY averted. In Mumbai, the PPIA would be cost-effective relative to all thresholds considered. In Patna, if focusing on adherence support, rather than on improved diagnosis, the PPIA would be cost-effective relative to all thresholds considered. These differences between sites arise from variations in the burden of drug resistance: among the services of a PPIA, improved diagnosis (including rapid tests with genotypic drug sensitivity testing) has greatest value in settings such as Mumbai, with a high burden of drug-resistant TB. CONCLUSIONS: To accelerate decline in TB incidence, it is critical first to engage effectively with the private sector in India. Mechanisms such as the PPIA offer cost-effective ways of doing so, particularly when tailored to local settings.

Pathways to diagnosis of pediatric TB patients: A mixed methods study from India.

BACKGROUND: A significant proportion of pediatric tuberculosis (TB) patients go unnotified due to the challenges in diagnosis of TB among children. The experiences of this vulnerable group while going through the TB care cascade remain largely undocumented. The aim of this study was to explore the experiences of pediatric TB patients and families along the pathway to TB diagnosis and appropriate treatment in four cities of India. METHODS: The study used a mixed methods, single phased, embedded design. The primary qualitative and secondary quantitative data were collected simultaneously by interviewing families of 100 randomly selected Xpert MTB/RIF positive pediatric TB patients, under the pediatric TB project, in 4 Indian cities using a semi-structured questionnaire. The qualitative component was analyzed to deduce patterns and themes on the patient and family experiences. Descriptive statistics were used to quantify various events along the TB care pathway including various delays (patient, diagnosis and total) and number of providers visited by patients during the diagnostic process. RESULTS: The median patient, diagnostic and total delays were 3 (IQR: 2,5), 39 (IQR: 23, 91) and 43 days (IQR: 28.5, 98.5), respectively. Patients visited a median of 3 (IQR: 2,4) providers before accessing Xpert MTB/RIF testing. On an average, 68.4% of physicians ordered any test most of them being irrelevant for TB diagnosis. Qualitative data showed considerable suffering for children and their families before and after TB diagnosis including serious concerns of stigma, disruption in education and social life and recurrence of the disease. CONCLUSION: Our study highlights the significant physical and social distress that the children with TB and their families undergo along the TB care pathway. It also shows diagnostic delay in excess of a month during which multiple providers were met and the patients underwent several diagnostic tests, most of them being inappropriate. Efforts to make Xpert MTB/RIF testing more accessible and part of physicians' toolkit will be of considerable value to ease the complexity of TB diagnosis in children. In addition, communication strategy needs to be developed and implemented to generate awareness among general population around pediatric TB and its management.

Lung Health Care pilot project trims patient pill load and antibiotic prescription in primary health care settings in Kerala, India.

INTRODUCTION: Kerala, the southern Indian state piloted Lung Health Care Project (LHCP) which is a locally adopted version of WHO recommended Practical Approach to Lung health (PAL). The current study assessed the impact of the project on the prescribing practices of doctors and consumption of antibiotics and other drugs. METHODS: This study compared performance of primary health care institutions with regard to drug prescriptions and consumptions before and after the implementation of the project. Chronic respiratory disease (CRD) patients in institutions implemented the project were interviewed in the OPD at exit and their prescriptions were documented at baseline and after six months. Focus group discussions were conducted with doctors to explore the reasons behind changes in drug consumption pattern. RESULTS: In the project implementing institutions, mean number of drugs prescribed for CRDs was 3.88 (SD 1.50) and 2.73 (SD 1.18) at baseline and after six months respectively (p < 0.001). Adjusted odds ratio for prescribing an antibiotic and injection to a CRD patient during impact assessment at institutions implementing project was 0.34 (95% CI 0.15-0.75 p 0.008) and 0.39 (95% CI 0.20-0.74 p 0.004) respectively, as compared to baseline. The factors which helped in reducing antibiotic and injection use as felt by the doctors were presence of a protocol, good quality trainings, supportive supervision and monitoring, availability of alternate drugs and good participation of staff nurses especially in-patient education. CONCLUSION: Strict adherence to diagnostic and management algorithms of Lung health care project in a primary health care setting in India helped in reducing pill burden to patients and prescription of antibiotics and injections.

The potential deployment of a pan-tuberculosis drug regimen in India: A modelling analysis.

There is increasing interest in future, highly-potent 'pan-TB' regimens against tuberculosis (TB), that may be equally effective in both drug-susceptible and rifampicin-resistant (RR) forms of TB. Taking the example of India, the country with the world's largest burden of TB, we show that adoption of these regimens could be: (i) epidemiologically impactful, and (ii) cost-saving to the national TB programme, even if the regimen itself is more costly than current TB treatment. Mathematical modelling suggests that deployment of a pan-TB regimen in 2022 would reduce the annual incidence of TB in 2030 by 23.9% [95% Bayesian credible intervals [CrI] 17.6-30.8%] if used to treat all TB cases, and by 2.30% [95% CrI 1.57-3.48%] if used to treat only RR-TB. Notably, with a regimen costing less than USD 359 (95% CrI 287-441), treating all diagnosed TB cases with the pan-TB regimen yielded greater cost-savings than treating just those diagnosed with RR-TB. One limitation of our approach is that it does not capture the risk of resistance to the new regimen. We discuss ways in which this risk could be mitigated using modern adherence support mechanisms, as well as drug sensitivity testing at the point of TB diagnosis, to prevent new resistant forms from becoming established. A combination of such approaches would be important for maximising the useful lifetime of any future regimen.

The potential impact of the COVID-19 pandemic on the tuberculosis epidemic a modelling analysis.

BACKGROUND: Routine services for tuberculosis (TB) are being disrupted by stringent lockdowns against the novel SARS-CoV-2 virus. We sought to estimate the potential long-term epidemiological impact of such disruptions on TB burden in high-burden countries, and how this negative impact could be mitigated. METHODS: We adapted mathematical models of TB transmission in three high-burden countries (India, Kenya and Ukraine) to incorporate lockdown-associated disruptions in the TB care cascade. The anticipated level of disruption reflected consensus from a rapid expert consultation. We modelled the impact of these disruptions on TB incidence and mortality over the next five years, and also considered potential interventions to curtail this impact. FINDINGS: Even temporary disruptions can cause long-term increases in TB incidence and mortality. If lockdown-related disruptions cause a temporary 50% reduction in TB transmission, we estimated that a 3-month suspension of TB services, followed by 10 months to restore to normal, would cause, over the next 5 years, an additional 1⋅19 million TB cases (Crl 1⋅06-1⋅33) and 361,000 TB deaths (CrI 333-394 thousand) in India, 24,700 (16,100-44,700) TB cases and 12,500 deaths (8.8-17.8 thousand) in Kenya, and 4,350 (826-6,540) cases and 1,340 deaths (815-1,980) in Ukraine. The principal driver of these adverse impacts is the accumulation of undetected TB during a lockdown. We demonstrate how long term increases in TB burden could be averted in the short term through supplementary "catch-up" TB case detection and treatment, once restrictions are eased. INTERPRETATION: Lockdown-related disruptions can cause long-lasting increases in TB burden, but these negative effects can be mitigated with rapid restoration of TB services, and targeted interventions that are implemented as soon as restrictions are lifted. FUNDING: USAID and Stop TB Partnership.

Upfront Xpert MTB/RIF for diagnosis of pediatric TB-Does it work? Experience from India.

BACKGROUND: Diagnosis of TB in pediatric population poses several challenges. A novel initiative was implemented in several major cities of India aimed at providing upfront access to free-of-cost Xpert MTB/RIF to presumptive pediatric TB cases. This paper aims to describe the experience of implementing this large initiative and assess feasibility of the intervention in high TB burden settings. METHODS: Data were drawn from the pediatric TB project implemented in 10 major cities of India between April 2014 and March 2018. In each city, providers, both public and private, were engaged and linked with a high throughput Xpert MTB/RIF lab (established in that city) through rapid specimen transportation and electronic reporting system. Rates and proportions were estimated to describe the characteristics of this cohort. RESULTS: Of the total 94,415 presumptive pediatric TB cases tested in the project, 6,270 were diagnosed positive for MTB (6.6%) on Xpert MTB/RIF (vs 2% on smear microscopy). Among MTB positives, 545 cases were rifampicin resistant (8.7%). The median duration between collection of specimens and reporting of results was 0 days (same day) and >89% cases were initiated on treatment. Approximately 50% of the specimens tested were non-sputum. The number of providers/facilities engaged under the project increased >10-fold (from 124 in Q2'14 to 1416 in Q1'18). CONCLUSION: This project, which was one of the largest initiatives globally among pediatric population, demonstrated the feasibility of sustaining rapid and upfront access to free-of-cost Xpert MTB/RIF testing. The project underscores the efficiency of this rapid diagnostic assay in tackling several challenges in pediatric TB diagnosis, identifies opportunities for further interventions as well as brings to light scope for effective engagement with healthcare providers. The findings have facilitated a policy decision by National TB Programme mandating the use of Xpert MTB/RIF as a primary diagnostic tool for TB diagnosis in children, which is being scaled-up.

Tapping private health sector for public health program? Findings of a novel intervention to tackle TB in Mumbai, India.

BACKGROUND: India carries one-fourth of the global tuberculosis (TB) burden. Hence the country has drafted the ambitious National Strategic Plan to eliminate tuberculosis by 2025. To realise this goal, India's Revised National Tuberculosis Control Programme (RNTCP) and partners piloted a novel strategy to engage private-providers for tuberculosis care via a "Private-provider Interface Agency" (PPIA) in Mumbai and other locations. INTERVENTION: The program mapped and engaged private-providers, chemists, and laboratories; facilitated TB notification via call centers and field staff; provided free tuberculosis diagnostic tests and anti-TB drugs using novel electronic vouchers; monitored quality of care; and supported patients to ensure anti-TB treatment adherence and completion. This report summarises the descriptive analysis of PPIA implementation data piloted in Mumbai from 2014 to 2017. FINDINGS: The program mapped 8789 private doctors, 3438 chemists, and 985 laboratories. Of these, 3836 (44%) doctors, 285 (29%) laboratories, and 353 (10%) chemists were prioritized and engaged in the program. Over three and a half years, the program recorded 60,366 privately-notified tuberculosis patients, of which, 24,146 (40%) were microbiologically-confirmed, 5203 (9%) were rifampicin-resistant, and 4401 (7%) were paediatric TB patients. Mumbai's annual total TB case notification rate increased from a pre-program baseline of 272 per 100,000/year in 2013 to 416 per 100,000/year in 2017. Overall, 42,300 (78%) patients completed the TB treatment, and 4979 (9%) could not be evaluated. INTERPRETATION: The PPIA program in Mumbai demonstrated that private-providers can be effectively engaged for TB control in urban India. This program has influenced national policy and has been adapted and funded for a country-wide scale up. The model may also be considered in conditions where private-provider engagement is needed to improve access and quality of care for any area of public health.

Higher risk of developing active TB among adult diabetics exposed to TB during childhood: A study from Kerala, India.

INTRODUCTION: Factors associated with tuberculosis (TB) in Kerala, the southern Indian state that notifies approximately 33 microbiologically confirmed new cases per 100,000 population every year for the past two decades, are still unclear. We did a community-based case-control study in Kollam district, Kerala, to identify the individual-level risk factors for TB. METHODS: Structured questionnaire was applied to 101 microbiologically confirmed new TB cases registered under Revised National Tuberculosis Control Program and 202 age- and gender-matched neighborhood controls without present or past TB. Information was sought on socioeconomic status (SES), smoking, consumption of alcohol, close contact with active TB during childhood or recent past, diabetes mellitus (DM), and other comorbid conditions. RESULTS: Close contact with TB during childhood [odds ratio (OR) 15.88, 95% confidence interval (CI) 3.21-78.55], recent close contact with TB (OR 4.81, 95% CI 2.09-11.07), DM (OR 1.64, 95% CI 1.04-3.06), SES (OR 2.16, 95% CI 1.16-4.03), smoking more than 10 cigarettes/beedis per day (OR 3.32, 95% CI 1.27-8.96), consuming more than 10 standard drinks per week (OR 2.91, 95% CI 1.33-6.37), and the interaction term of having close contact with TB during childhood and DM at present (OR 7.37, 95% CI 1.18-50.29) were found to be associated with TB. CONCLUSION: Close contact with a case of TB, presence of DM, lower SES, smoking, and alcohol consumption were associated with active TB in Kollam. Having close contact with a case of TB during childhood and development of DM in later life together are significantly associated with active TB in the study population. The findings also direct further studies to confirm and explore mechanisms of interaction of diabetes with childhood exposure to TB.

Modelling the impact of effective private provider engagement on tuberculosis control in urban India.

In India, the country with the world's largest burden of tuberculosis (TB), most patients first seek care in the private healthcare sector, which is fragmented and unregulated. Ongoing initiatives are demonstrating effective approaches for engaging with this sector, and form a central part of India's recent National Strategic Plan: here we aimed to address their potential impact on TB transmission in urban settings, when taken to scale. We developed a mathematical model of TB transmission dynamics, calibrated to urban populations in Mumbai and Patna, two major cities in India where pilot interventions are currently ongoing. We found that, when taken to sufficient scale to capture 75% of patient-provider interactions, the intervention could reduce incidence by upto 21.3% (95% Bayesian credible interval (CrI) 13.0-32.5%) and 15.8% (95% CrI 7.8-28.2%) in Mumbai and Patna respectively, between 2018 and 2025. There is a stronger impact on TB mortality, with a reduction of up to 38.1% (95% CrI 20.0-55.1%) in the example of Mumbai. The incidence impact of this intervention alone may be limited by the amount of transmission that has already occurred by the time a patient first presents for care: model estimates suggest an initial patient delay of 4-5 months before first seeking care, followed by a diagnostic delay of 1-2 months before ultimately initiating TB treatment. Our results suggest that the transmission impact of such interventions could be maximised by additional measures to encourage early uptake of TB services.

Unacceptable treatment outcomes and associated factors among India's initial cohorts of multidrug-resistant tuberculosis (MDR-TB) patients under the revised national TB control programme (2007-2011): Evidence leading to policy enhancement.

BACKGROUND: Globally, India has the world's highest burden of multidrug-resistant tuberculosis (MDR-TB). Programmatic Management of Drug Resistant TB (PMDT) in India began in 2007 and nationwide coverage was achieved in early 2013. Poor initial microbiological outcomes under the Revised National Tuberculosis Control Programme (RNTCP) prompted detailed analysis. This is the first study on factors significantly associated with poor outcomes in MDR-TB patients treated under the RNTCP. OBJECTIVE: To evaluate initial sputum culture conversion, culture reversion and final treatment outcomes among MDR-TB patients registered in India from 2007 to early 2011 who were treated with a standard 24-month regimen under daily-observed treatment. METHODS: This is a retrospective cohort study. Clinical and microbiological data were abstracted from PMDT records. Initial sputum culture conversion, culture reversion and treatment outcomes were defined by country adaptation of the standard WHO definitions (2008). Cox proportional hazards modeling with logistic regression, multinomial logistic regression and adjusted odds ratio was used to evaluate factors associated with interim and final outcomes respectively, controlling for demographic and clinical characteristics. RESULTS: In the cohort of 3712 MDR-TB patients, 2735 (73.6%) had initial sputum culture conversion at 100 median days (IQR 92-125), of which 506 (18.5%) had culture reversion at 279 median days (IQR 202-381). Treatment outcomes were available for 2264 (60.9%) patients while 1448 (39.0%) patients were still on treatment or yet to have a definite outcome at the time of analysis. Of 2264 patients, 781 (34.5%) had treatment success, 644 (28.4%) died, 670 (29.6%) were lost to follow up, 169 (7.5%) experienced treatment failure or were changed to XDR-TB treatment. Factors significantly associated with either culture non-conversion, culture reversion and/or unfavorable treatment outcomes were baseline BMI < 18; ≥ seven missed doses in intensive phase (IP) and continuation phase (CP); cavitary disease; prior treatment episodes characterized by re-treatment regimen taken twice, longer duration and more episodes of treatment; any weight loss during treatment; males and additional resistance to first line drugs (Ethambutol, Streptomycin). In a subgroup of 104 MDR-TB patients, 62 (59.6%) had Ofloxacin resistance among whom only 25.8% had treatment success, half of the success (54.8%) seen in Ofloxacin sensitive patients. Baseline susceptibility to Ofloxacin (HR 2.04) and Kanamycin (HR 4.55) significantly doubled and quadrupled the chances for culture conversion respectively while baseline susceptibility to Ofloxacin (AOR 0.37) also significantly reduced the odds of unfavorable treatment outcomes (p value ≤0.05) in multinomial logistic regression model. CONCLUSION: India's initial MDR-TB patients' cohort treated under the RNTCP experienced poor treatment outcomes. To address the factors associated with poor treatment outcomes revealed in our study, a systematic multi-pronged approach would be needed. A series of policies and interventions have been developed to address these factors to improve DR-TB treatment outcomes and are being scaled-up in India.

Active case finding of rifampicin sensitive and resistant TB among household contacts of drug resistant TB patients in Andhra Pradesh and Telangana states of India - A systematic screening intervention.

BACKGROUND: India has the world's highest estimated burden of multi-drug-resistant tuberculosis (MDR-TB). While prevalence of MDR-TB is known to be 2-3% among new TB patients and 12-17% in previously treated patients, programmatic information on the extent of transmission of TB and MDR-TB among household contacts of known MDR-TB patients is scarce. Systematic screening of household contacts of all MDR-TB patients on treatment was implemented as an intervention in the states of Andhra Pradesh and Telangana states of India. We undertook this prospective interventional study to measure the extent of TB symptoms developed among the household contacts of the known MDR-TB patients treated under Revised National TB Control Programme (RNTCP). The extent of rifampicin sensitive or resistance TB, bacteriologically confirmed using Xpert MTB-RIF, was examined among the symptomatic household contacts. METHODS: All MDR-TB patients registered and on treatment under RNTCP between July 2011 and Sep 2013 in Andhra Pradesh and Telangana States were selected for the study. They were contacted through home visit by the trained RNTCP teams during 11th Dec 2013 and 7th Jan 2014. All household contacts of MDR-TB patients were screened once for TB symptoms such as cough, fever, weight loss, night sweats, and haemoptysis and extra pulmonary site specific symptoms if any. If found symptomatic, two sputum specimen were collected (spot-morning) from each of the contact and transported for testing on Xpert MTB-RIF for detection of pulmonary TB with or without RR-TB. RESULTS: A total of 1750 MDR-TB patients were registered between July 2011 and Sep 2013. Of these, 1602 (91.5%) MDR-TB patients were included in the study. A total of 4858 household contacts of these 1602 patients were identified with an average of 3 contacts per MDR-TB patient. Of these, after excluding 87 (1.8%) contacts with past history of diagnosis and/or treatment for TB, 4771 (98.2%) contacts were screened for current signs and symptoms suggestive of TB. Their mean age was 28.5 years and 2151 (45%) were females. Of the 4771 contacts screened, 793 (16.6%) had at least one of the symptoms suggestive of TB of whom 781 (98.5%) had two sputum specimen transported and tested on Xpert MTB-Rif. Specimen could not be collected during the study period in 12 symptomatic patients including 4 with symptoms of extra pulmonary TB. Among 781 symptomatic contacts examined, 34 (4.4%) were bacteriologically confirmed with TB and 15 (44%) also had Rif resistance (RR). CONCLUSIONS: High extent of TB, particularly RR-TB was observed among household contacts of known MDR-TB patients with symptom screening and early diagnosis using Xpert-MTB-Rif. Regular systematic active screening for TB and MDR-TB among this highly vulnerable group using Xpert-MTB-Rif is useful in India for early diagnosis among close contacts of known MDR-TB patients.

"Before Xpert I only had my expertise": A qualitative study on the utilization and effects of Xpert technology among pediatricians in 4 Indian cities.

BACKGROUND: Diagnosing tuberculosis (TB) in children presents considerable challenges. Upfront testing on Xpert® MTB/RIF ('Xpert')-a rapid molecular assay with high sensitivity and specificity-for pediatric presumptive TB patients, as recommended by India's Revised National Tuberculosis Control Program (RNTCP), can pave the way for early TB diagnosis. As part of an ongoing project implemented by Foundation for Innovative New Diagnostics (FIND) dedicated to providing upfront free-of-cost (FOC) Xpert testing to children seeking care in the public and private sectors, a qualitative assessment was designed to understand how national guidelines on TB diagnosis and Xpert technology have been integrated into the pediatric TB care practices of different health providers. METHODS: We conducted semi-structured interviews with a sample of health providers from public and private sectors engaged in the ongoing pediatric project in 4 major cities of India. Providers were sampled from intervention data based on sector of practice, number of Xpert referrals, and TB detection rates amongst referrals. A total of 55 providers were interviewed with different levels of FOC Xpert testing uptake. Data were transcribed and analyzed inductively by a medical anthropologist using thematic content analysis and narrative analysis. RESULTS: It was observed that despite guidance from RNTCP on the use of Xpert and significant efforts by FIND and state authorities to disseminate these guidelines, there was notable diversity in their implementation by different health care providers. Xpert, apart from being utilized as intended, i.e. as a first diagnostic test for children, was utilized variably-as an initial screening test (to rule out TB), confirmatory test (once TB diagnosis is established based on antibiotic trial or clinically) and/or only for drug susceptibility testing after TB diagnosis was confirmed. Most providers who used Xpert frequently reported that Xpert was an important tool for managing pediatric TB cases, by reducing the proportion of cases diagnosed only on clinical suspicion and by providing upfront information on drug resistance, which is seldom suspected in children. Despite non-standard use, these results showed that Xpert access helped raise awareness, aided in antibiotic stewardship, and reduced dependence on clinical diagnosis among those who diagnose and treat TB in children. CONCLUSION: Access to free and rapid Xpert testing for all presumptive pediatric TB patients has had multiple positive effects on pediatricians' diagnosis and treatment of TB. It has important effects on speed of diagnosis, empirical treatment, and awareness of drug resistance among TB treatment naive children. In addition, our study shows that access to public sector Xpert machines may be an important way to encourage Public-Private integration and facilitate the movement of patients from the private to public sector for anti-TB treatment. Despite availability of rapid and free Xpert testing, our study showed an alarming diversity of Xpert utilization strategies across different providers who may be moving toward suggested practice over time. The degree of diversity in TB diagnostic approaches in children reported here highlights the urgent need for concerted efforts to place Xpert early in diagnostic algorithms to positively impact the pediatric TB care pathway. A positive change in diagnostic algorithms may be possible with continued advocacy, time, and increased access.

Catalysing progressive uptake of newer diagnostics by health care providers through outreach and education in four major cities of India.

BACKGROUND: Unlike in adults, diagnosis of TB can be challenging in children, as signs and symptoms of paediatric TB can be very non-specific and similar to other common childhood chest infections, which may lead to under or delayed diagnosis of TB disease. In spite of the increasing availability of rapid high-sensitivity diagnostics in public and private sectors, majority of paediatric TB cases are empirically diagnosed, without laboratory confirmation. To address these diagnostic challenges, World Health Organization (WHO) has recommended upfront Xpert MTB/RIF (Xpert) testing for the diagnosis of TB in paediatric presumptive pulmonary and extra-pulmonary TB (EPTB) cases. However, in spite of the increasing availability of rapid high-sensitivity diagnostics, a significant gap exists in its application with Xpert being rarely used as an upfront diagnostic among patients presumed to have TB. Under an ongoing paediatric project since April 2014, which provided free-of-cost upfront Xpert testing, several low-cost outreach and education interventions were undertaken to increase the diagnostic uptake by different providers catering to the paediatric population, thereby increasing adherence to global guidance. METHODS: Providers catering to paediatric population in the project cities were systematically mapped and contacted using different outreach strategies. The focus of outreach efforts was to increase provider literacy and increase their awareness of the availability of free rapid diagnostic services with the goal of changing their diagnostic approaches. RESULTS: From April 2014 to June 2016, more than 5,700 providers/facilities were mapped and 3,670 of them were approached. The number of providers/facilities engaged under the project increased more than 10-fold (43 in April, 2014 to 466 in June, 2016), with significant increase in project uptake, both from public and private sector. Overall 42,238 paediatric presumptive TB cases were enrolled in the project, across the four cities. Over the project period, quarterly diagnostic uptake and paediatric TB cases detection rates increased more than two-fold. TB detection rates were similar in patients from public and private sectors. CONCLUSIONS: Ongoing efforts in scaling up new rapid diagnostics involves significant investments. These efforts need to be complemented with proactive provider engagement to ensure provider-literacy and awareness, for maximizing impact of this scale-up. The current project demonstrated the usefulness of outreach and education interventions for the effective uptake of newer diagnostics.

Upfront Xpert MTB/RIF testing on various specimen types for presumptive infant TB cases for early and appropriate treatment initiation.

BACKGROUND: Diagnosis of tuberculosis (TB) in infants is challenging due to non-specific clinical presentations of the disease in this age-group and low sensitivity of widely available TB diagnostic tools, which in turn delays prompt access to TB treatment. Upfront access to Xpert/MTB RIF (Xpert) testing, a highly sensitive and specific rapid diagnostic tool, could potentially address some of these challenges. Under the current project, we assessed the utility and feasibility of applying upfront Xpert for diagnosis of tuberculosis in infants, including for testing of non-sputum specimens. METHODS: A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city, through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all infant (<2 years of age) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities. RESULTS: A total of 7,994 presumptive infant TB cases were enrolled in the project from April 2014 to October 2016, detecting 465 (5.8%, CI: 5.3-6.4) TB cases. The majority (93.9%; CI: 93.4-94.4) of patient specimens were non-sputum and TB positivity was higher amongst non-sputum specimens. Further, a high proportion (5.6% CI 3.8-8.1) of infant TB cases were found to be rifampicin resistant. Covering large cities with a single lab per city over more than two years, the project demonstrated the feasibility of same-day diagnosis with upfront Xpert testing. This in turn led to prompt treatment initiation, with a two-day median turnaround time to treatment initiation. Case mortality observed in the project cohort of diagnosed TB cases was 11.0% (CI 8.4-14.1), the majority of which was pre- or early treatment mortality, in spite of prompt access to treatment for most diagnosed cases. CONCLUSION: The current project demonstrated the feasibility of applying rapid and upfront Xpert testing for presumptive infant TB cases. Rapid TB diagnosis in turn facilitates prompt and appropriate treatment initiation. Further, levels of rifampicin resistance observed in infants TB cases highlight the additional benefit of upfront resistance testing. However, high rates of early case mortality, in spite of prompt diagnosis and treatment initiation, highlight the need for further research in infant patient pathways for overall improvement in TB care for infant populations.

Accelerating access to quality TB care for pediatric TB cases through better diagnostic strategy in four major cities of India.

BACKGROUND: Diagnosis of TB in children is challenging, and is largely based on positive history of contact with a TB case, clinical and radiological findings, often without microbiological confirmation. Diagnostic efforts are also undermined by challenges in specimen collection and the limited availability of high sensitivity, rapid diagnostic tests that can be applied with a quick turnaround time. The current project was undertaken in four major cities of India to address TB diagnostic challenges in pediatric population, by offering free of cost Xpert testing to pediatric presumptive TB cases, thereby paving the way for better TB care. METHODS: A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all pediatric (0-14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities. RESULTS: The current project enrolled 42,238 pediatric presumptive TB cases from April, 2014 to June, 2016. A total of 3,340 (7.91%, CI 7.65-8.17) bacteriologically confirmed TB cases were detected, of which 295 (8.83%, CI 7.9-9.86) were rifampicin-resistant. The level of rifampicin resistance in the project cohort was high. Overall Xpert yielded a high proportion of valid results and TB detection rates were more than three-fold higher than smear microscopy. The project provided same-day testing and early availability of results led to rapid treatment initiation and success rates and very low rates of treatment failure and loss to follow-up. CONCLUSION: The current project demonstrated the feasibility of rolling out rapid and upfront Xpert testing for pediatric presumptive TB cases through a single Xpert lab per city in an efficient manner. Rapid turnaround testing time facilitated prompt and appropriate treatment initiation. These results suggest that the upfront Xpert assay is a promising solution to address TB diagnosis in children. The high levels of rifampicin resistance detected in presumptive pediatric TB patients tested under the project are a major cause of concern from a public health perspective which underscores the need to further prioritize upfront Xpert access to this vulnerable population.

Operational research within a Global Fund supported tuberculosis project in India: why, how and its contribution towards change in policy and practice.

BACKGROUND: The Global Fund encourages operational research (OR) in all its grants; however very few reports describe this aspect. In India, Project Axshya was supported by a Global Fund grant to improve the reach and visibility of the government Tuberculosis (TB) services among marginalised and vulnerable communities. OR was incorporated to build research capacity of professionals working with the national TB programme and to generate evidence to inform policies and practices. OBJECTIVES: To describe how Project Axshya facilitated building OR capacity within the country, helped in addressing several TB control priority research questions, documented project activities and their outcomes, and influenced policy and practice. METHODS: From September 2010 to September 2016, three key OR-related activities were implemented. First, practical output-oriented modular training courses were conducted (n = 3) to build research capacity of personnel involved in the TB programme, co-facilitated by The Union, in collaboration with the national TB programme, WHO country office and CDC, Atlanta. Second, two large-scale Knowledge, Attitude and Practice (KAP) surveys were conducted at baseline and mid-project to assess the changes pertaining to TB knowledge, attitudes and practices among the general population, TB patients and health care providers over the project period. Third, studies were conducted to describe the project's core activities and outcomes. RESULTS: In the training courses, 44 participant teams were supported to develop research protocols on topics of national priority, resulting in 28 peer-reviewed scientific publications. The KAP surveys and description of project activities resulted in 14 peer-reviewed publications. Of the published papers at least 12 have influenced change in policy or practice. CONCLUSIONS: OR within a Global Fund supported TB project has resulted in building OR capacity, facilitating research in areas of national priority and influencing policy and practice. We believe this experience will provide guidance for undertaking OR in Global Fund projects.

Tuberculosis preventive treatment: the next chapter of tuberculosis elimination in India.

The End TB Strategy envisions a world free of tuberculosis-zero deaths, disease and suffering due to tuberculosis by 2035. This requires reducing the global tuberculosis incidence from >1250 cases per million people to <100 cases per million people within the next two decades. Expanding testing and treatment of tuberculosis infection is critical to achieving this goal. In high-burden countries, like India, the implementation of tuberculosis preventive treatment (TPT) remains a low priority. In this analysis article, we explore potential challenges and solutions of implementing TPT in India. The next chapter in tuberculosis elimination in India will require cost-effective and sustainable interventions aimed at tuberculosis infection. This will require constant innovation, locally driven solutions to address the diverse and dynamic tuberculosis epidemiology and persistent programme monitoring and evaluation. As new tools, regimens and approaches emerge, midcourse adjustments to policy and practice must be adopted. The development and implementation of new tools and strategies will call for close collaboration between local, national and international partners-both public and private-national health authorities, non-governmental organisations, research community and the diagnostic and pharmaceutical industry. Leading by example, India can contribute to global knowledge through operational research and programmatic implementation for combating tuberculosis infection.

Scaling-up the Xpert MTB/RIF assay for the detection of tuberculosis and rifampicin resistance in India: An economic analysis.

BACKGROUND: India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India. METHODS: Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients. RESULTS: The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US$ 1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert-for-all scenario (US$ 11,099). CONCLUSIONS: The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care.