Pharmacokinetics of anti-TB drugs in children and adolescents with drug-resistant TB: a multicentre observational study from India.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens. METHOD: A multicentre observational study was conducted among DR-TB children and adolescents (n = 200) aged 1-18 years (median: 12 years; IQR: 9-14) treated under programmatic settings in India. Steady-state PK (intensive: n = 89; and sparse: n = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods. RESULTS: In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing. CONCLUSIONS: Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment.

Estimating and Explaining the Differences in Health Care Seeking by Symptom Burden Among Persons With Presumptive Tuberculosis: Findings From a Population-Based Tuberculosis Prevalence Survey in a High-Burden Setting in India.

Background: There is a lack of research evidence on the quantitative relationship between symptom burden and health care seeking among individuals with presumptive tuberculosis (TB). Methods: Data were derived from a cross-sectional population-based TB survey conducted between February 2021 and July 2022 in 32 districts of India. Eligible and consented participants (age >15 years) underwent TB symptom screening and history elicitation. Fairlie decomposition analysis was used to estimate the net differences in health care seeking due to varied symptom burden-from 1+ burden (>1 symptom) to 4+ burden (>4 symptoms)-and decomposed by observable covariates based on logit models with 95% CIs. Results: Of the 130 932 individuals surveyed, 9540 (7.3%) reported at least 1 recent TB symptom, of whom 2678 (28.1%; 95% CI, 27.1%-28.9%) reportedly sought health care. The net differences in health care seeking among persons with symptom burden 1+ to 4+ ranged from 6.6 percentage points (95% CI, 4.8-8.4) to 7.7 (95% CI, 5.2-10.2) as compared with persons with less symptom burden. The presence of expectoration, fatigue, and loss of appetite largely explained health care seeking (range, 0.9-3.1 percentage points [42.89%-151.9%]). The presence of fever, cough, past TB care seeking, weight loss, and chest pain moderately explained (range, 5.3%-25.3%) health care seeking. Conclusions: Increased symptom burden and symptoms other than the commonly emphasized cough and fever largely explained health care seeking. Orienting TB awareness and risk communications toward symptom burden and illness perceptions could help address population gaps in health care seeking for TB.

Lessons Learned From a Peer-Supported Differentiated Care and Nutritional Supplementation for People With TB in a Southern Indian State.

Two critical components of patient support systems for people with TB are regular counseling and locally managed nutritional support. As part of an ongoing differentiated TB care initiative called Tamil Nadu Kasanoi Erappila Thittam (meaning TB death-free initiative in Tamil, TN-KET) to reduce TB deaths, adults with TB with very severe undernutrition, respiratory insufficiency, or poor performance status are identified at diagnosis (triage-positive) and prioritized for referral, comprehensive clinical assessment, and inpatient care. Between January and June 2023, in 6 districts, a pilot exercise was conducted in which trained TB survivors, known as TB champions, provided baseline counseling and additional counseling (if required) to triage-positive people with TB at diagnosis. Additionally, people with TB with severe undernutrition were prioritized for nutritional supplementation for at least 3 months. Among 652 people with TB who were triage-positive at diagnosis, the program staff shared details of 145 (22%), and all were counseled by TB champions (baseline counseling). Program staff identified 74 (11%) triage-positive people with TB who required additional counseling (i.e., those refusing referral or admission or continued admission), and 71 (96%) were counseled by TB champions. Among these, 54 (76%) were admitted or readmitted and successfully discharged. In addition, among 1,042 people with TB with severe undernutrition, program staff shared details of 390 (38%), of which 60% received nutritional supplementation through the efforts of TB champions. We conclude that TB champions were able to provide quality and timely peer support through direct counseling and by mobilizing local resources for nutritional support. The engagement of TB champions can be further strengthened by establishing robust coordination mechanisms with the TB program. Lessons from this pilot will contribute to the Tamil Nadu State TB Cell's plans to expand the role of TB champions and enhance community participation to end TB in India.

Operational Challenges in Conducting a Subnational TB Prevalence Survey in India: Lessons Learned for Resource-Limited, High-Burden Settings.

Estimating the burden of TB at the subnational level is critical to planning and prioritizing resources for TB control activities according to the local epidemiological situation. We report the experiences and operational challenges of implementing a TB prevalence survey at the subnational level in India. Information was collected from research reports that gathered data from periodic meetings, informal discussions with study teams, letters of communication, and various site visit reports. During the implementation of the survey, several challenges were encountered, including frequent turnover in human resources, lack of survey participation and community engagement, breakdown of X-ray machines, laboratory issues that delayed sputum sample testing, delays in X-ray reading, and network and Internet connectivity issues that impeded data management. To help ensure the survey was implemented in a timely manner, we developed several solutions, including planning ahead to anticipate challenges, ensuring timely communication, having a high commitment from all stakeholders, having strong team motivation, providing repetitive hands-on training, and involving local leaders to increase community engagement. This experience may help future states and countries that plan to conduct TB prevalence surveys to address these anticipated challenges and develop alternative strategies well in advance.

Plasma CXCL8 and MCP-1 as surrogate plasma biomarkers of latent tuberculosis infection among household contacts-A cross-sectional study.

Early detection of latent tuberculosis infection (LTBI) is critical to TB elimination in the current WHO vision of End Tuberculosis Strategy. The study investigates whether detecting plasma cytokines could aid in diagnosing LTBI across household contacts (HHCs) positive for IGRA, HHCs negative for IGRA, and healthy controls. The plasma cytokines were measured using a commercial Bio-Plex Pro Human Cytokine 17-plex assay. Increased plasma CXCL8 and decreased MCP-1, TNF-α, and IFN-γ were associated with LTBI. Regression analysis showed that a combination of CXCL8 and MCP-1 increased the risk of LTBI among HHCs to 14-fold. Our study suggests that CXCL-8 and MCP-1 could serve as the surrogate biomarkers of LTBI, particularly in resource-limited settings. Further laboratory investigations are warranted before extrapolating CXCL8 and MCP-1 for their usefulness as surrogate biomarkers of LTBI in resource-limited settings.

Genotype MTBDRsl version 2 and phenotypic drug resistance detection of Mycobacterium tuberculosis for fluoroquinolones and aminoglycosides.

Background: Information on genotypic with comparison of phenotypic drug sensitivity test of anti-tuberculosis (TB) has been reported in several studies, which have variable results. The present study aimed to assess the Genotype MTBDRsl version 2.0/Line probe assay (LPA) for the detection of fluoroquinolones (FQ) and aminoglycosides (AMGs) resistance mutations among drug-resistant Mycobacterium TB (MTB) strains and also to compare the patterns of genotypic mutations of gyrA/B, rrs, and eis with mycobacteria growth indicator tube (MGIT 960). Methods: A total of 1416 samples were subjected to Genotype MTBDRsl version 2.0 assay. One hundred and twenty sputum smear positive MTB isolates and 37 sputum smear negative MTB isolates confirmed multiple drug resistance resistant to FQ and AMG by the Genotype MTBDRsl version 2.0 were subjected to phenotypic drug susceptibility testing (DST) were analyzed. Results: The association sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the resistance detection between MGIT (DST) and the Genotype MTBDRsl version 2.0 assay was significant (P < 0.01) of moxifloxacin (MFX) concentration. Sensitivity and specificity value for kanamycin (KAN) resistance was 76% and 89%; 47% and 94% for capreomycin (CAP); and 60% and 76% for low-level KAN, respectively. Conclusion: Our results indicate that MFX (0.25and 1 µg/mL), KAN (2.5 µg/mL), and CAP (2.5 µg/mL) significantly (P < 0.01) and support the World Health Organization guidance to test FQ and AMG by genotypic test.

Plasma CXCL8 and MCP-1 as biomarkers of latent tuberculosis infection.

Background: Early detection of latent tuberculosis infection (LTBI) is critical to TB elimination in the current WHO vision of End Tuberculosis Strategy. Methods: We investigated whether detecting plasma cytokines could aid in diagnosing LTBI across household contacts (HHCs) positive for IGRA, HHCs negative for IGRA, and healthy controls. We also measured the plasma cytokines using a commercial Bio-Plex Pro Human Cytokine 17-plex assay. Results: Increased plasma CXCL8 and decreased MCP-1, TNF-α, and IFN-γ were associated with LTBI. Regression analysis showed that a combination of CXCL8 and MCP-1 increased the risk of LTBI among HHCs to 14-fold. Conclusions: We postulated that CXCL8 and MCP-1 could be the surrogate biomarkers of LTBI, especially in resource-limited settings.

Resistance Profiles to Second-Line Anti-Tuberculosis Drugs and Their Treatment Outcomes: A Three-Year Retrospective Analysis from South India.

Background: Patients with first-line drug resistance (DR) to rifampicin (RIF) or isoniazid (INH) as a first-line (FL) line probe assay (LPA) were subjected to genotypic DST using second-line (SL) LPA to identify SL-DR (including pre-XDR) under the National TB Elimination Program (NTEP), India. SL-DR patients were initiated on different DR-TB treatment regimens and monitored for their outcomes. The objective of this retrospective analysis was to understand the mutation profile and treatment outcomes of SL-DR patients. Materials and Methods: A retrospective analysis of mutation profile, treatment regimen, and treatment outcome was performed for SL-DR patients who were tested at ICMR-NIRT, Supra-National Reference Laboratory, Chennai between the years 2018 and 2020. All information, including patient demographics and treatment outcomes, was extracted from the NTEP Ni-kshay database. Results: Between 2018 and 2020, 217 patients out of 2557 samples tested were identified with SL-DR by SL-LPA. Among them, 158/217 were FQ-resistant, 34/217 were SLID-resistant, and 25/217 were resistant to both. D94G (Mut3C) of gyrA and a1401g of rrs were the most predominant mutations in the FQ and SLID resistance types, respectively. Favorable (cured and treatment complete) and unfavorable outcomes (died, lost to follow up, treatment failed, and treatment regimen changed) were recorded in a total of 82/217 and 68/217 patients in the NTEP Ni-kshay database. Conclusions: As per the testing algorithm, SL- LPA is used for genotypic DST following identification of first-line resistance, for early detection of SL-DR in India. The fluoroquinolone resistance pattern seen in this study population corelates with the global trend. Early detection of fluoroquinolone resistance and monitoring of treatment outcome can help achieve better patient management.

The First Differentiated TB Care Model From India: Delays and Predictors of Losses in the Care Cascade.

To reduce TB deaths in resource-limited settings, a differentiated care strategy can be used to triage patients with high risk of severe illness (i.e., those with very severe undernutrition, respiratory insufficiency, or inability to stand without support) at diagnosis and refer them for comprehensive assessment and inpatient care. Globally, there are few examples of implementing this type of strategy in routine program settings. Beginning in April 2022, the Indian state of Tamil Nadu implemented a differentiated care strategy called Tamil Nadu-Kasanoi Erappila Thittam (TN-KET) for all adults aged 15 years and older with drug-susceptible TB notified by public facilities. Before evaluating the impact on TB deaths, we sought to understand the retention and delays in the care cascade as well as predictors of losses. During April-June 2022, 14,961 TB patients were notified and 11,599 (78%) were triaged. Of those triaged, 1,509 (13%) were at high risk of severe illness; of these, 1,128 (75%) were comprehensively assessed at a nodal inpatient care facility. Of 993 confirmed as severely ill, 909 (92%) were admitted, with 8% unfavorable admission outcomes (4% deaths). Median admission duration was 4 days. From diagnosis, the median delay in triaging and admission of severely ill patients was 1 day each. Likelihood of triaging decreased for people with extrapulmonary TB, those diagnosed in high-notification districts or teaching hospitals, and those transferred out of district. Predictors of not being comprehensively assessed included: aged 25-34 years, able to stand without support, and diagnosis at a primary or secondary-level facility. Inability to stand without support was a predictor of unfavorable admission outcomes. To conclude, the first quarter of implementation suggests that TN-KET was feasible to implement but could be improved by addressing predictors of losses in the care cascade and increasing admission duration.

--Eleven tips for operational researchers working with health programmes: our experience based on implementing differentiated tuberculosis care in south India.

Due to the workload and lack of a critical mass of trained operational researchers within their ranks, health systems and programmes may not be able to dedicate sufficient time to conducting operational research (OR). Hence, they may need the technical support of operational researchers from research/academic organisations. Additionally, there is a knowledge gap regarding implementing differentiated tuberculosis (TB) care in programme settings. In this 'how we did it' paper, we share our experience of implementing a differentiated TB care model along with an inbuilt OR component in Tamil Nadu, a southern state in India. This was a health system initiative through a collaboration of the State TB cell with the Indian Council of Medical Research institutes and the World Health Organisation country office in India. The learnings are in the form of eleven tips: four broad principles (OR on priority areas and make it a health system initiative, implement simple and holistic ideas, embed OR within routine programme settings, aim for long-term engagement), four related to strategic planning (big team of investigators, joint leadership, decentralised decision-making, working in advance) and three about implementation planning (conducting pilots, smart use of e-tools and operational research publications at frequent intervals). These may act as a guide for other Indian states, high TB burden countries that want to implement differentiated care, and for operational researchers in providing technical assistance for strengthening implementation and conducting OR in health systems and programmes (TB or other health programmes). Following these tips may increase the chances of i) an enriching engagement, ii) policy/practice change, and iii) sustainable implementation.

Characterization of probes associated with rifampicin resistance in M.tuberculosis detected by GenXpert from a national reference laboratory at Chennai.

With increasing use of Xpert MTB/RIF a point of care molecular test for simultaneous detection of TB and resistance to rifampicin, a growing number of rifampicin resistant cases are being detected and notified. Insights into the variation and frequencies in the probe mutations obtained through Xpert testing in the RRTB case will form the baseline information for further investigation on drug resistance. In this study we did a retrospective analysis of the GeneXpert data obtained from patient samples received at a National reference laboratory in Chennai between the years 2014 and 2020 to look at the probe distribution, the variation in the mutation and explore its significance. Probe E mutation was most commonly identified followed by Probe D, Probe A, Probe B and Probe C. Coexistence of multiple probe mutations in low bacillary load samples could be related to prolonged amplification cycle leading to delayed hybridization of probes. In such instances reporting false RR in xpert testing is possible. The probe mutations of RR should be monitored in depth with inclusion of codon specific targets for management of drug sensitive TB. In addition, heteroresistance needs to be further tested by alternative genotypic methods to avoid false resistance.

Pharmacy based surveillance for identifying missing tuberculosis cases: A mixed methods study from South India.

BACKGROUND: No Indian studies have assessed the implementation of recent policy on pharmacy based surveillance and its contribution in TB notification. So, this study was conducted with objectives to describe: a) pharmacy based TB surveillance and TB notification, and b) experiences of pharmacy based surveillance implementation from the programme managers and pharmacists perspective. METHODS: A mixed methods study-quantitative (cross-sectional) and qualitative (in-depth interviews) in two selected districts Dharmapuri and Salem districts of Tamil Nadu State, India. RESULTS: In 2018, 45 (11%) of 397 pharmacies in Dharmapuri and 90 (6%) of 1457 pharmacies in Salem districts reported sale of anti-TB drugs to 1307 and 1673 persons respectively. Upon validation through direct patient contact 942 (72%) persons in Dharmapuri and 863 (52%) persons were identified as previously 'un-notified' TB patients. These patients constituted 20% and 29% of the total TB cases notified in Dharmapuri and Salem respectively. The enablers for implementing this activity were: understanding the importance of notification, availability of resources (manpower, computers) to record, report and validate the patient data, repeated trainings and partnerships. The barriers were: patients' hesitancy to share their details to pharmacists (confidentiality), cumbersome recording and reporting process, difficulties in recording patient details during high workload busy business hours. CONCLUSION: This process contributed about one-fourth of the TB patients notified in these districts. Its implementation needs to be strengthened and should be scaled up in other parts of the country.

Indicators to Ensure Treatment Initiation of All Diagnosed Sputum Positive Pulmonary Tuberculosis Patients under Tuberculosis Control Programme in India.

BACKGROUND: Pretreatment loss to follow-up (PTLFU) is used as performance indicator of Revised National Tuberculosis Control Programme (RNTCP) of India. OBJECTIVE: To document the PTLFU, identify additional indicators and examine documentation of all the diagnosed sputum positive pulmonary tuberculosis (PTB) patients under RNTCP. METHODOLOGY: Tuberculosis (TB) laboratory, referral for treatment registers, and referral forms were perused for information on sputum positive PTB patients diagnosed from January to June 2014, in 3 TB Units in Chennai. RESULTS: PTLFU was 24% (572 out of 2361). However, in pursuance with the principle of ensuring that all diagnosed patients must be started on treatment following referral, it was inflated to 44% (1046 out of 2361). CONCLUSION: The existing PTLFU indicator does not reflect the proportion of treatment initiation of all diagnosed smear-positive PTB patients. We propose additional indicators for monitoring referral and treatment initiation of all diagnosed sputum positive PTB patients.