Kuldeep Singh Sachdeva

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.

The Potential Impact of Up-Front Drug Sensitivity Testing on India’s Epidemic of Multi-Drug Resistant Tuberculosis

Background In India as elsewhere, multi-drug resistance (MDR) poses a serious challenge in the control of tuberculosis (TB). The End TB strategy, recently approved by the world health assembly, aims to reduce TB deaths by 95% and new cases by 90% between 2015 and 2035. A key pillar of this approach is early diagnosis of tuberculosis, including use of higher-sensitivity diagnostic testing and universal rapid drug susceptibility testing (DST). Despite limitations of current laboratory assays, universal access to rapid DST could become more feasible with the advent of new and emerging technologies. Here we use a mathematical model of TB transmission, calibrated to the TB epidemic in India, to explore the potential impact of a major national scale-up of rapid DST. To inform key parameters in a clinical setting, we take GeneXpert as an example of a technology that could enable such scale-up. We draw from a recent multi-centric demonstration study conducted in India that involved upfront Xpert MTB/RIF testing of all TB suspects. Results We find that widespread, public-sector deployment of high-sensitivity diagnostic testing and universal DST appropriately linked with treatment could substantially impact MDR-TB in India. Achieving 75% access over 3 years amongst all cases being diagnosed for TB in the public sector alone could avert over 180,000 cases of MDR-TB (95% CI 44187 – 317077 cases) between 2015 and 2025. Sufficiently wide deployment of Xpert could, moreover, turn an increasing MDR epidemic into a diminishing one. Synergistic effects were observed with assumptions of simultaneously improving MDR-TB treatment outcomes. Our results illustrate the potential impact of new and emerging technologies that enable widespread, timely DST, and the important effect that universal rapid DST in the public sector can have on the MDR-TB epidemic in India.

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.

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

Background Newer molecular diagnostics have brought paradigm shift in early diagnosis of tuberculosis [TB]. WHO recommended use of GeneXpert MTB/RIF [Xpert] for Extra-pulmonary [EP] TB; critics have since questioned its efficiency. Methods The present study was designed to assess the performance of GeneXpert in 761 extra-pulmonary and 384 pulmonary specimens from patients clinically suspected of TB and compare with Phenotypic, Genotypic and Composite reference standards [CRS]. Results Comparison of GeneXpert results to CRS, demonstrated sensitivity of 100% and 90.68%, specificity of 100% and 99.62% for pulmonary and extra-pulmonary samples. On comparison with culture, sensitivity for Rifampicin [Rif] resistance detection was 87.5% and 81.82% respectively, while specificity was 100% for both pulmonary and extra-pulmonary TB. On comparison to sequencing of rpoB gene [Rif resistance determining region, RRDR], sensitivity was respectively 93.33% and 90% while specificity was 100% in both pulmonary and extra-pulmonary TB. GeneXpert assay missed 533CCG mutation in one sputum and dual mutation [517 & 519] in one pus sample, detected by sequencing. Sequencing picked dual mutation [529, 530] in a sputum sample sensitive to Rif, demonstrating, not all RRDR mutations lead to resistance. Conclusions Current study reports observations in a patient care setting in a high burden region, from a large collection of pulmonary and extra-pulmonary samples and puts to rest questions regarding sensitivity, specificity, detection of infrequent mutations and mutations responsible for low-level Rif resistance by GeneXpert. Improvements in the assay could offer further improvement in sensitivity of detection in different patient samples; nevertheless it may be difficult to improve sensitivity of Rif resistance detection if only one gene is targeted. Assay specificity was high both for TB detection and Rif resistance detection. Despite a few misses, the assay offers major boost to early diagnosis of TB and MDR-TB, in difficult to diagnose pauci-bacillary TB.

Catching the Missing Million: Experiences in Enhancing TB & DR-TB Detection by Providing Upfront Xpert MTB/RIF Testing for People Living with HIV in India

Background A critical challenge in providing TB care to People Living with HIV (PLHIV) is establishing an accurate bacteriological diagnosis. Xpert MTB/RIF, a highly sensitive and specific rapid tool, offers a promising solution in addressing these challenges. This study presents results from PLHIV taking part in a large demonstration study across India wherein upfront Xpert MTB/RIF testing was offered to all presumptive PTB cases in public health facilities. Method The study covered a population of 8.8 million across 18 sub-district level tuberculosis units (TU), with one Xpert MTB/RIF platform established at each TU. All HIV-infected patients suspected of TB (both TB and Drug Resistant TB (DR-TB)) accessing public health facilities in study area were prospectively enrolled and provided upfront Xpert MTB/RIF testing. Result 2,787 HIV-infected presumptive pulmonary TB cases were enrolled and 867 (31.1%, 95% Confidence Interval (CI) 29.4‒32.8) HIV-infected TB cases were diagnosed under the study. Overall 27.6% (CI 25.9–29.3) of HIV-infected presumptive PTB cases were positive by Xpert MTB/RIF, compared with 12.9% (CI 11.6–14.1) who had positive sputum smears. Upfront Xpert MTB/RIF testing of presumptive PTB and DR-TB cases resulted in diagnosis of 73 (9.5%, CI 7.6‒11.8) and 16 (11.2%, CI 6.7‒17.1) rifampicin resistance cases, respectively. Positive predictive value (PPV) for rifampicin resistance detection was high 97.7% (CI 89.3‒99.8), with no significant difference with or without prior history of TB treatment. Conclusion The study results strongly demonstrate limitations of using smear microscopy for TB diagnosis in PLHIV, leading to low TB and DR-TB detection which can potentially lead to either delayed or sub-optimal TB treatment. Our findings demonstrate the usefulness and feasibility of addressing this diagnostic gap with upfront of Xpert MTB/RIF testing, leading to overall strengthening of care and support package for PLHIV.

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

Bottom-up or top-down: unit cost estimation of tuberculosis diagnostic tests in India.

619,042 for SSM-only; (ii) US

Factors Associated with Tuberculosis and Rifampicin-Resistant Tuberculosis amongst Symptomatic Patients in India: A Retrospective Analysis.

575,377 in the LPA replacement scenario; (iii) US