Revisiting the susceptibility testing of Mycobacterium tuberculosis to ethionamide in solid culture medium.

BACKGROUND & OBJECTIVES: Increase in the isolation of drug resistant phenotypes of Mycobacterium tuberculosis necessitates accuracy in the testing methodology. Critical concentration defining resistance for ethionamide (ETO), needs re-evaluation in accordance with the current scenario. Thus, re-evaluation of conventional minimum inhibitory concentration (MIC) and proportion sensitivity testing (PST) methods for ETO was done to identify the ideal breakpoint concentration defining resistance. METHODS: Isolates of M. tuberculosis (n=235) from new and treated patients were subjected to conventional MIC and PST methods for ETO following standard operating procedures. RESULTS: With breakpoint concentration set at 114 and 156 µg/ml, an increase in specificity was observed whereas sensitivity was high with 80 µg/ml as breakpoint concentration. Errors due to false resistant and susceptible isolates were least at 80 µg/ml concentration. INTERPRETATION & CONCLUSIONS: Performance parameters at 80 µg/ml breakpoint concentration indicated significant association between PST and MIC methods.

Electronic-grade epitaxial (111) KTaO3 heterostructures.

KTaO3 heterostructures have recently attracted attention as model systems to study the interplay of quantum paraelectricity, spin-orbit coupling, and superconductivity. However, the high and low vapor pressures of potassium and tantalum present processing challenges to creating heterostructure interfaces clean enough to reveal the intrinsic quantum properties. Here, we report superconducting heterostructures based on high-quality epitaxial (111) KTaO3 thin films using an adsorption-controlled hybrid PLD to overcome the vapor pressure mismatch. Electrical and structural characterizations reveal that the higher-quality heterostructure interface between amorphous LaAlO3 and KTaO3 thin films supports a two-dimensional electron gas with substantially higher electron mobility, superconducting transition temperature, and critical current density than that in bulk single-crystal KTaO3-based heterostructures. Our hybrid approach may enable epitaxial growth of other alkali metal-based oxides that lie beyond the capabilities of conventional methods.

Modification of proportion sensitivity testing method for ethionamide.

Standardized methodology for drug susceptibility testing of second line drugs is vital for treatment of multi/extensively drug resistant tuberculosis. Discrepancy between laboratory methods and clinical interpretation is well established for bacteriostatic drugs such as ethionamide. Optimization of the standard proportion sensitivity testing (PST) method for ethionamide was under taken in 235 Mycobacterium tuberculosis isolates from new and previously treated pulmonary tuberculosis patients. An additional higher concentration of 57 µg/ml was evaluated against at the standard 40 µg/ml concentration in PST method. Performance parameters and agreement between the two drug concentrations was higher indicating the efficiency of PST method at its present format at 40 µg/ml and additional higher concentration of 57 µg/ml as an alternative when required.

Comprehensive assessment of invalid and indeterminate results in Truenat MTB-RIF testing across sites under the national TB elimination program of India.

Introduction: Truenat MTB-RIF assay (Truenat), a nucleic acid amplification test (NAAT), is a real-time polymerase chain reaction (RT-PCR) chip-based assay that can detect Mycobacterium tuberculosis (Mtb) and rifampicin (RIF) drug resistance using portable, battery-operated devices. The National TB Elimination Program (NTEP) in India introduced this novel tool at the district and subdistrict level in 2020. This study aimed to assess the level and causes of inconclusive results (invalid results, errors, and indeterminate results) in MTB and RIF testing at NTEP sites and the root causes of these in the programmatic setting. Methods: Truenat testing data from 1,690 functional Truenat sites under the NTEP from April to June 2021 were analyzed to assess the rates of errors, invalid MTB results, and indeterminate RIF results. Following this analysis, 12 Truenat sites were selected based on site performance in Truenat testing, diversity of climatic conditions, and geographical terrain. These sites were visited to assess the root causes of their high and low rates of inconclusive results using a structured checklist. Results: A total of 327,649 Truenat tests performed for MTB and RIF testing were analyzed. The rate of invalid MTB results was 5.2% [95% confidence interval (CI): 5.11-5.26; n = 16,998] and the rate of errors was 2.5% (95% CI: 2.46-2.57; n = 8,240) in Truenat MTB chip testing. For Mtb-positive samples tested using the Truenat RIF chip for detection of RIF resistance (n = 40,926), the rate of indeterminate results was 15.3% (95% CI: 14.97-15.67; n = 6,267) and the rate of errors was 1.6% (95% CI: 1.53-1.78; n = 675). There was a 40.1% retesting gap for Mtb testing and a 78.2% gap for inconclusive RR results. Among the inconclusive results retested, 27.9% (95% CI: 27.23-28.66; n = 4,222) were Mtb-positive, and 9.2% (95% CI: 7.84-10.76; n = 139) were detected as RR. Conclusion: The main causes affecting Truenat testing performance include suboptimal adherence to standard operating procedures (SOPs), inadequate training, improper storage of testing kits, inadequate sputum quality, lack of quality control, and delays in the rectification of machine issues. Root cause analysis identified that strengthening of training, external quality control, and supervision could improve the rate of inconclusive results. Ensuring hands-on training of technicians for Truenat testing and retesting of samples with inconclusive results are major recommendations while planning for Truenat scale-up. The recommendations from the study were consolidated into technical guidance documents and videos and disseminated to laboratory staff working at the tiered network of TB laboratories under the NTEP in order to improve Truenat MTB-RIF testing performance.

Experience of "One Stop TB Diagnostic Solution" Model in Engaging a Private Laboratory for End-to-End Diagnostic Services in the National TB Elimination Program in Hisar, India.

The complete diagnostic evaluation of tuberculosis based on its drug-resistance profile is critical for appropriate treatment decisions. The TB diagnostic landscape in India has been transformed with the scaling-up of WHO-recommended diagnostics, but challenges remain with specimen transportation, completing diagnostic assessment, turnaround time (TAT), and maintaining laboratories. Private laboratories have demonstrated efficiencies for specimen collection, transportation, and the timely testing and issue of results. A one-stop TB diagnostic model was designed to assess the feasibility of providing end-to-end diagnostic services in the Hisar district of Haryana state, India. A NTEP-certified private laboratory was engaged to provide the services, complementing the existing public sector diagnostic services. A total of 10,164 specimens were collected between May 2022 and January 2023 and these were followed for the complete diagnostic assessment of Drug-Susceptible TB (DS-TB) and Drug-Resistant TB (DR-TB) and the time taken for issuing results. A total of 2152 (21%) patients were detected with TB, 1996 (93%) Rifampicin-Sensitive and 134 (6%) with Rifampicin-Resistant TB. Nearly 99% of the patients completed the evaluation of DS-TB and DR-TB within the recommended TAT. The One-Stop TB/DR-TB Diagnostic Solution model has demonstrated that diagnostic efficiencies could be enhanced through the strategic purchase of private laboratory services.

Prevalence and factors associated with tuberculosis infection in India.

BACKGROUND: The risk of tuberculosis (TB) disease is higher in individuals with TB infection. In a TB endemic country like India, it is essential to understand the current burden of TB infection at the population level. The objective of the present analysis is to estimate the prevalence of TB infection in India and to explore the factors associated with TB infection. METHODS: Individuals aged > 15 years in the recently completed National TB prevalence survey in India who were tested for TB infection by QuantiFERON-TB Gold Plus (QFT-Plus) assay were considered for this sub-analysis. TB infection was defined as positive by QFT-Plus (value >0.35 IU/ml). The estimates for prevalence, prevalence ratio (PR) and adjusted risk ratio (aRR) estimates with 95% confidence intervals (CIs) were calculated. RESULTS: Of the 16864 individuals analysed, the prevalence of TB infection was 22.6% (95% CI:19.4 -25.8). Factors more likely to be associated with TB infection include age > 30 years (aRR:1.49;95% CI:1.29-1.73), being male (aRR:1.26; 95%CI: 1.18-1.34), residing in urban location (aRR:1.58; 95%CI: 1.03-2.43) and past history of TB (aRR:1.49; 95%CI: 1.26-1.76). CONCLUSION: About one fourth (22.6%) of the individuals were infected with TB in India. Individuals aged > 30 years, males, residing in urban location, and those with past history of TB were more likely to have TB infection. Targeted interventions for prevention of TB and close monitoring are essential to reduce the burden of TB in India.

Consistency of standard laboratory strain Mycobacterium tuberculosis H 37 Rv with ethionamide susceptibility testing.

Drug susceptibility pattern of standard Mycobacterium tuberculosis strain H 37 Rv showed discrepancy in minimum inhibitory concentration method for ethionamide and consistent results were obtained for the other second line drugs namely, kanamycin and ofloxacin. It is, therefore, necessary to revisit the susceptibility testing method for ethionamide for effective clinical management of patients with drug resistant tuberculosis.

Estimation of tuberculosis incidence at subnational level using three methods to monitor progress towards ending TB in India, 2015-2020.

OBJECTIVES: We verified subnational (state/union territory (UT)/district) claims of achievements in reducing tuberculosis (TB) incidence in 2020 compared with 2015, in India. DESIGN: A community-based survey, analysis of programme data and anti-TB drug sales and utilisation data. SETTING: National TB Elimination Program and private TB treatment settings in 73 districts that had filed a claim to the Central TB Division of India for progress towards TB-free status. PARTICIPANTS: Each district was divided into survey units (SU) and one village/ward was randomly selected from each SU. All household members in the selected village were interviewed. Sputum from participants with a history of anti-TB therapy (ATT), those currently experiencing chest symptoms or on ATT were tested using Xpert/Rif/TrueNat. The survey continued until 30 Mycobacterium tuberculosis cases were identified in a district. OUTCOME MEASURES: We calculated a direct estimate of TB incidence based on incident cases identified in the survey. We calculated an under-reporting factor by matching these cases within the TB notification system. The TB notification adjusted for this factor was the estimate by the indirect method. We also calculated TB incidence from drug sale data in the private sector and drug utilisation data in the public sector. We compared the three estimates of TB incidence in 2020 with TB incidence in 2015. RESULTS: The estimated direct incidence ranged from 19 (Purba Medinipur, West Bengal) to 1457 (Jaintia Hills, Meghalaya) per 100 000 population. Indirect estimates of incidence ranged between 19 (Diu, Dadra and Nagar Haveli) and 788 (Dumka, Jharkhand) per 100 000 population. The incidence using drug sale data ranged from 19 per 100 000 population in Diu, Dadra and Nagar Haveli to 651 per 100 000 population in Centenary, Maharashtra. CONCLUSION: TB incidence in 1 state, 2 UTs and 35 districts had declined by at least 20% since 2015. Two districts in India were declared TB free in 2020.

Efficacy and safety of once-daily nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated tuberculosis: a randomized clinical trial.

BACKGROUND: Nevirapine (NVP) can be safely and effectively administered once-daily but has not been assessed in human immunodeficiency virus (HIV)-infected patients with tuberculosis (TB). We studied the safety and efficacy of once-daily NVP, compared with efavirenz (EFV; standard therapy); both drugs were administered in combination with 2 nucleoside reverse-transcriptase inhibitors. METHODS: An open-label, noninferiority, randomized controlled clinical trial was conducted at 3 sites in southern India. HIV-infected patients with TB were treated with a standard short-course anti-TB regimen (2EHRZ(3)/4RH(3); [2 months of Ethambutol, Isoniazid, Rifampicin, Pyrazinamide / 4 months of Isoniazid and Rifampicin] thrice weekly) and randomized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg (after 14 days of 200 mg administered once daily) with didanosine 250/400 mg and lamivudine 300 mg after 2 months. Sputum smears and mycobacterial cultures were performed every month. CD4+ cell count, viral load, and liver function test results were monitored periodically. Primary outcome was a composite of death, virological failure, default, or serious adverse event (SAE) at 24 weeks. Both intent-to-treat and per protocol analyses were done, and planned interim analyses were performed. RESULTS: A total of 116 patients (75% [87 patients] of whom had pulmonary TB), with a mean age of 36 years, a median CD4+ cell count of 84 cells/mm(3), and a median viral load of 310 000 copies/mL, were randomized. At 24 weeks, 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression (P = .024). There were no deaths, 1 SAE, and 5 treatment failures in the EFV arm, compared with 5 deaths, 2 SAEs, and 10 treatment failures in the NVP arm. The trial was halted by the data and safety monitoring board at the second interim analysis. Favorable TB treatment outcomes were observed in 93% of the patients in the EFV arm and 84% of the patients in the NVP arm (P = .058). CONCLUSIONS: Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death. Clinical Trials Registration. NCT00332306.

Outcome of standardized treatment for patients with MDR-TB from Tamil Nadu, India.

BACKGROUND & OBJECTIVES: Programmatic management of MDR-TB using a standardized treatment regimen (STR) is being implemented under the Revised National Tuberculosis Control Programme (RNTCP) in India. This study was undertaken to analyse the outcomes of MDR-TB patients treated at the Tuberculosis Research Centre, Chennai, with the RNTCP recommended 24 months STR, under programmatic conditions. METHODS: Patients failed to the category II re-treatment regimen and confirmed to have MDR-TB, were treated with the RNTCP's STR in a prospective field trial on a predominantly ambulatory basis. Thirty eight patients were enrolled to the trial from June 2006 to September 2007. RESULTS: Time to culture conversion was two months or less for 82 per cent of patients. Culture conversion rates at 3 and 6 months were 84 and 87 per cent respectively. At the end of treatment, 25 (66%) were cured, 5 defaulted, 3 died and 5 failed. At 24 months, 30 (79%) patients, including 5 defaulters, remained culture negative for more than 18 months. Twenty two (58%) patients reported adverse drug reactions (ADRs) which required dose reduction or termination of the offending drug. No patient had XDR-TB initially, but 2 failure cases emerged as XDR-TB during treatment. INTERPRETATION & CONCLUSIONS: Outcomes of this small group of MDR-TB patients treated with the RNTCP's STR is encouraging in this setting. Close attention needs to be paid to ensure adherence, and to the timely recognition and treatment of ADRs.

Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial.

RATIONALE: The outcome of fully intermittent thrice-weekly antituberculosis treatment of various durations in HIV-associated tuberculosis is unclear. OBJECTIVES: To compare the efficacy of an intermittent 6-month regimen (Reg6M: 2EHRZ(3)/4HR(3) [ethambutol, 1,200 mg; isoniazid, 600 mg; rifampicin, 450 or 600 mg depending on body weight <60 or > or =60 kg; and pyrazinamide, 1,500 mg for 2 mo; followed by 4 mo of isoniazid and rifampicin at the same doses]) versus a 9-month regimen (Reg9M: 2EHRZ(3)/7HR(3)) in HIV/tuberculosis (TB). METHODS: HIV-infected patients with newly diagnosed pulmonary or extrapulmonary TB were randomly assigned to Reg6M (n = 167) or Reg9M (n = 160) and monitored by determination of clinical, immunological, and bacteriological parameters for 36 months. Primary outcomes included favorable responses at the end of treatment and recurrences during follow-up, whereas the secondary outcome was death. Intent-to-treat and on-treatment analyses were performed. All patients were antiretroviral treatment-naive during treatment. MEASUREMENTS AND MAIN RESULTS: Of the patients, 70% had culture-positive pulmonary TB; the median viral load was 155,000 copies/ml and the CD4(+) cell count was 160 cells/mm(3). Favorable response to antituberculosis treatment was similar by intent to treat (Reg6M, 83% and Reg9M, 76%; P = not significant). Bacteriological recurrences occurred significantly more often in Reg6M than in Reg9M (15 vs. 7%; P < 0.05) although overall recurrences were not significantly different (Reg6M, 19% vs. Reg9M, 13%). By 36 months, 36% of patients undergoing Reg6M and 35% undergoing Reg9M had died, with no significant difference between regimens. All 19 patients who failed treatment developed acquired rifamycin resistance (ARR), the main risk factor being baseline isoniazid resistance. CONCLUSIONS: Among antiretroviral treatment-naive HIV-infected patients with TB, a 9-month regimen resulted in a similar outcome at the end of treatment but a significantly lower bacteriological recurrence rate compared with a 6-month thrice-weekly regimen. ARR was high with these intermittent regimens and neither mortality nor ARR was altered by lengthening TB treatment. Clinical Trials Registry Information: ID# NCT00376012 registered at www.clinicaltrials.gov.

Impact of HIV infection on the recurrence of tuberculosis in South India.

BACKGROUND: There is limited information on the relative proportion of reactivation and reinfection at the time of recurrence among human immunodeficiency virus (HIV)-infected and HIV-uninfected patients who are successfully treated for tuberculosis infection in India. METHODS: HIV-infected and HIV-uninfected patients with sputum culture-positive pulmonary tuberculosis were treated with short-course regimens and followed up for 36 months at the Tuberculosis Research Centre, South India. Bacteriologic recurrences were documented, and typing of strains was performed using 3 different genotypic techniques: restriction fragment length polymorphism (RFLP) by IS6110, spoligotyping, and mycobacterial interspersed repeat unit (MIRU)-variable number tandem repeat (VNTR). DNA fingerprints of paired Mycobacterium tuberculosis isolates (baseline and recurrence) were compared. RESULTS: Among 44 HIV-infected and 30 HIV-uninfected patients with recurrent tuberculosis during the period July 1999 to October 2005, 25 and 23 paired isolates, respectively, were typed using all 3 methods. Recurrence was due to exogenous reinfection in 88% of HIV-infected and 9% of HIV-uninfected patients (P<.05). Among recurrent isolates, the HIV-infected patients showed more clustering, as well as a higher proportion of drug resistance, including multidrug resistance. CONCLUSIONS: In India, a tuberculosis-endemic country, most recurrences after successful treatment of tuberculosis are due to exogenous reinfection in HIV-infected persons and endogenous reactivation in HIV-uninfected persons. Strategies for prevention and treatment of tuberculosis infection must take these findings into consideration.

The paradigm shift in the approach to management of latent tuberculosis infection in high tuberculosis burden countries.

Introduction: Addressing the reservoir of Latent Tuberculosis Infection (LTBI) is critical to TB elimination because if left untreated LTBI can progress to active TB disease. This additional burden can prevent achieving the global targets of TB elimination. Management of LTBI has been a low priority target for National TB Elimination Programs (NTEP) due to various challenges in the field settings.Areas covered: This article reviews the most recent advances in the field of LTBI management including newer diagnostics, treatments, vaccines, programmatic challenges, and gaps and suggests a way forward that can be adopted by NTEPs for LTBI. We searched the electronic databases of PubMed, Scopus, and Web of Science for studies published between 2010 to 2020 using MeSH terms: Latent TB Diagnosis, TB preventive therapy, Vaccines, LTBI, and HIV/ COVID.Expert opinion: NTEPs of developing countries should offer a better, point-of-care diagnostic, and effective treatment for LTBI to reduce the number of new TB cases arising from people infected with M.tb. Awareness about LTBI should be increased among the health system staff and the public. More funding is needed to advance research as well as implement the newer findings in the NTEP to achieve the End TB targets by 2035.

Spectroscopic evidence of mixed angular momentum symmetry in non-centrosymmetric Ru[Formula: see text]B[Formula: see text].

Superconducting crystals with a lack of inversion symmetry can potentially host unconventional pairing. However, till today, no direct conclusive experimental evidence of such unconventional order parameters in non-centrosymmetric superconductors has been reported. In this paper, through direct measurement of the superconducting energy gap by scanning tunnelling spectroscopy, we report the existence of both s-wave (singlet) and p-wave (triplet) pairing symmetries in non-centrosymmetric Ru[Formula: see text]B[Formula: see text]. Our temperature and magnetic field-dependent studies also indicate that the relative amplitudes of the singlet and triplet components change differently with temperature.

Evolutionary journey of programmatic services and treatment outcomes among drug resistant tuberculosis (DR-TB) patients under National TB Elimination Programme in India (2005-2020).

Introduction: India, with one-fourth of global burden of tuberculosis as well as multidrug-resistant TB, made bold commitment to end TB by 2025. There is no documented comprehensive review of the evolutionary journey of India's DRTB service expansion and changes in the treatment outcome so far.Area Covered: The current document presents evolution and journey of programmatic services and the progress in treatment outcomes among DRTB patients since 2005 with efforts cum challenges in nationwide scale-up of evidence-based policies and services, opportunities and future prospects for universalizing quality care - an essential ingredient to end TB in India. In the era of standardized longer treatment regimen till 2017, only half of the patients were successfully treated. Interventions to address factors associated with access and quality of care introduced since 2018 like universal drug susceptibility testing (UDST) guided treatment with shorter regimen, newer drugs, social protection; accelerated detection and began enhancing survival and success rate in recent DR-TB patient cohorts.Expert Opinion: Patient-centric care; robust TB/DR-TB surveillance system, shorter effective safer regimens and innovations, a milestone essential to end TB in India by 2025 to accomplish the vision of the Prime Minister of India.

Domain structure evolution in the ferromagnetic Kagome-lattice Weyl semimetal Co$_3$Sn$_2$S$_2$.

Co$_3$Sn$_2$S$_2$, a Weyl semimetal that consists of layers of Kagome lattices, \textcolor{blue}{undergoes a transition from a high temperature paramagnetic phase} to a low temperature ferromagnetic phase below 177 K. The phase transition occurs through an intermediate non-trivial magnetic phase, the so called \lq\lq A\rq\rq-phase just below the Curie temperature. The \lq\lq A\rq\rq-phase was earlier linked with a competing anti-ferromagnetic phase, a spin-glass phase and certain indirect measurements indicated the possibility of magnetic Skyrmions in this phase. We have imaged the magnetic domain structure in a single crystal of Co$_3$Sn$_2$S$_2$ at different temperatures, magnetic fields and field-angles by magnetic force microscopy. At low temperatures, we observed stripe domains indicating presence of uniaxial anisotropy. Above 130 K, the domain walls become mobile and they tend to align relatively easily when the magnetic field is increased along the $c$-axis than in the $a-b$ plane. Our detailed study of field-dependent domain evolution reveal that the anomalous \textcolor{blue}{phase below $T_c$ through which the transition happens is most probably }governed by domain wall motion.

Mutation in atpE and Rv0678 genes associated with bedaquline resistance among drug-resistant tuberculosis patients: A pilot study from a high-burden setting in Northern India.

Background: Mutations in atpE gene or transcriptional repressor Rv0678 gene associated with inhibition of adenosine 5'-triphosphate synthase and upregulation of efflux pumps, respectively, may potentially lead to in vitro resistance to bedaquiline. This is the first study from India, which looks at mutations associated with this novel drug. Methods: In 2019 (January to June), a total of 68 laboratory-confirmed pre-extensively drug-resistant tuberculosis (XDR-TB) (fluoroquinolone resistant [n = 52] and second-line injectables resistant [n = 12]) and 4 × DR-TB culture specimens were included. All specimens were evaluated for genetic analysis using predesigned primers of atpE and Rv0678 genes. Results: Among the pre-XDR-TB isolates (n = 64), there were no mutations found in either atpE or Rv0678. However, among the XDR-TB isolates (n = 4), one specimen (25%) was found to be associated with a mutation in atpE gene at position 49, resulting in the amino acid leucine replaced by proline (L-49-P). No mutations were observed with the Rv0678 gene. Conclusion: In this study, genetic analysis showed that only one-fourth XDR-TB isolates had a mutation in the atpE gene; there were no other mutations found in the Rv0678 gene. To the best of our knowledge, this novel mutation (L-49-P) in atpE gene is being reported for the first time in northern India.

Diagnostic Evaluation of Non-Interpretable Results Associated with rpoB Gene in Genotype MTBDRplus Ver 2.0.

BACKGROUND: Line probe assay (LPA) is standard diagnostic tool to detect multidrug resistant tuberculosis. Noninterpretable (NI) results in LPA (complete missing or light wild-type 3 and 8 bands with no mutation band in rpoB gene region) poses a diagnostic challenge. METHODS: Sputum samples obtained between October 2016 and July 2017 at the Intermediate Reference Laboratory, All India Institute of Medical Sciences Hospital, New Delhi, India were screened. Smear-positive and smear-negative culturepositive specimens were subjected to LPA Genotype MTBDRplus Ver 2.0. Smear-negative with culture-negative and culture contamination were excluded. LPA NI samples were subjected to phenotypic drug susceptibility testing (pDST) using MGIT-960 and sequencing. RESULTS: A total of 1,614 sputum specimens were screened and 1,340 were included for the study (smear-positive [n=1,188] and smear-negative culture-positive [n=152]). LPA demonstrated 1,306 (97.5%) valid results with TUB (Mycobacterium tuberculosis) band, 24 (1.8%) NI, three (0.2%) valid results without TUB band, and seven (0.5%) invalid results. Among the NI results, 22 isolates (91.7%) were found to be rifampicin (RIF) resistant and two (8.3%) were RIF sensitive in the pDST. Sequencing revealed that rpoB mutations were noted in all 22 cases with RIF resistance, whereas the remaining two cases had wild-type strains. Of the 22 cases with rpoB mutations, the most frequent mutation was S531W (n=10, 45.5%), followed by S531F (n=6, 27.2%), L530P (n=2, 9.1%), A532V (n=2, 9.1%), and L533P (n=2, 9.1%). CONCLUSION: The present study showed that the results of the Genotype MTBDRplus assay were NI in a small proportion of isolates. pDST and rpoB sequencing were useful in elucidating the cause and clinical meaning of the NI results.

Evaluation of genotype MTBDRplus V2 and genotype MTBDRsl V2 for the diagnosis of extrapulmonary tuberculosis in India.

Microbiological diagnosis of extra-pulmonary tuberculosis (EPTB) has been one of the most difficult aspects of tuberculosis (TB) management. Availability of better imaging and diagnostic modalities has led to an increase in the number of diagnosed cases. The current upsurge in multidrug-resistant tuberculosis warrants routine testing of EPTB samples for resistance at baseline with shorter turn-around time. A total of 369 EPTB specimens were subjected to Ziehl-Neelsen (ZN) stain, liquid culture (LC) with phenotypic drug susceptibility testing, MTBDRplus V.2 and MTBDRsl V.2. The molecular categorisation of resistant specimens was further reconfirmed with sequencing. The sensitivity and specificity of MTBDRplus V.2 to detect Mycobacterium tuberculosis (MTB) when compared to ZN stain was 97.9% and 89.2%, respectively while it was 73.4% and 83.8%, respectively when compared to LC. Similarly, for MTBDRsl V.2, the sensitivity and specificity for detection of MTB when compared with ZN was 95.6% and 91.9%, respectively and 75% and 89.2%, respectively when compared to LC. In smear-positive specimens, 94% (141/150) and 86% (129/150) valid results were observed in MTBDRplus V.2 and MTBDRsl V.2, respectively. The utilisation of both MTBDRplus V.2 and MTBDRsl V.2 for the diagnosis of smear-positive EPTB specimens would be useful in programmatic management of TB in high-burden settings.

Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: An interim analysis.

BACKGROUND: India accounts for a quarter of the world's multidrug-resistant tuberculosis (MDR-TB); with less than 50% having successful treatment outcomes. Bedaquiline (BDQ) was approved for use under conditional access program in India in 2015. OBJECTIVE: We evaluate the effectiveness, safety, and tolerability of a BDQ containing regimen used under field settings in India. METHOD: Interim analysis of a prospective cohort of MDR-TB patients on a BDQ containing regimen at six sites in the country. RESULTS: Six hundred and twenty MDR-TB patients [349 (56%) males; 554 (89%) between 18 and 50 years and 240 (39%) severely malnourished] were started on BDQ containing regimen between June 2016 and August 2017. There 354 (57%) patients had MDR-TB with additional drug resistance to fluoroquinolone (MDRFQ); 31 (5%) with additional resistance to second-line injectable (MDRSLI) and 101 (16%) extensively drug-resistant TB. After 6 months of treatment, culture conversion was achieved in 513 of 620 (83%) patients. The median time to culture conversion was 60 days. Higher body mass index was the only factor associated with faster culture conversion (HR 1.97; 95% CI 1.24-2.9). Around 100 patients (16.3%) experienced a ≥60-ms increase in QTc interval during the treatment. Seventy-three (12%) deaths were reported, the majority of them (56%) occurring within the first 6 months of treatment. CONCLUSIONS: BDQ with a background regimen has the potential to achieve higher and faster culture conversion rates with a lower toxicity profile among DR-TB patients. Use of BDQ with additional monitoring may be safe and effective even in the field settings.