Risk factors of treatment interruptions among drug-sensitive and drug-resistant pulmonary tuberculosis patients - A study from South Delhi, New Delhi, India.

BACKGROUND: A variety of factors influence adherence to the lengthy duration of anti-tuberculosis treatment, making it a complicated and dynamic problem. The objective of this study was to investigate the treatment interruption patterns using pre-defined criteria among a cohort of pulmonary tuberculosis patients and to elicit the associated factors. METHODS: This prospective, observational study was conducted between October 2016 to May 2018. All smear and culture positive pulmonary tuberculosis patients (age ≥ 14 years) enrolled between October 1, 2016 to March 31, 2017 across 3 Designated Microscopy Centers (DMCs) were included and followed up till end of treatment for outcome in drug-sensitive, and till interim outcome at 6 months for drug-resistant TB patients. Patterns and reasons for interruptions were recorded as per the study protocol. RESULTS: 171 patients were enrolled in this study, of which 135 (78.94 %) were on Category-I and Category-II treatment (drug-sensitive tuberculosis), 23 (13 %) were multidrug-resistant (MDR) and 13 (8 %) were extensively drug resistant (XDR) tuberculosis patients. Among the drug-sensitive group, 65 (48 %) patients completed their treatment without any interruption while 70 (52 %) patients interrupted with at least one missed dose. Among the 36 MDR/XDR patients, 19 (53 %) patients did not interrupt treatment, but 17 (47 %) patients interrupted with at least one missing dose. The 87 patients in both sub-groups interrupted for 232 times/episodes of which 140 were short and 84 were long interruptions. The main reasons for interruption were found to be busy schedule in 63 (29 %) patients, adverse drug reactions in 40 (18.4 %) and comorbidities in 43 (19.8 %) patients. Feeling of early improvement/no improvement in 23 (10.5 %) patients, addictions in 27 (12.4 %) patients, lack of family support in 14 (6.4 %), unawareness of dosage and duration of treatment in 7 (3.20 %) patients were other common reasons. CONCLUSION: The plurality of patients studied were found to be in the younger age group i.e., 14-25 years (n = 75), constituting nearly 44 % of all the patients included and male treatment interrupters (62 %) outnumbered the females (38 %), possibly owing to work schedule or addictions. The majority of interruptions were related to patient related factors (93.5 %), followed by DOTS provided factors (6.40 %) and system related factors (3.01 %). Further studies should be conducted to classify the factors of treatment interruptions in detail and also to study the impact of these interruptions' patterns on final outcomes.

Current Prospects in Rheumatoid Arthritis: Pathophysiology, Genetics, and Treatments.

BACKGROUND: An autoimmune inflammatory disease, rheumatoid arthritis (RA), predominantly affects the synovium joint lining, augmenting disability, early mortality, and socioeconomic difficulty. Therefore, current updates on pharmacological therapies are crucial for developing drugs to treat the disease at each stage. OBJECTIVE: This review attempts to compile a thorough analysis of current developments in our knowledge of RA pathogenesis and disease-modifying drugs, with the aim of providing insights for next-generation RA therapeutics. RESULTS: According to the literature, the most successful drugs for treatment techniques described so far in this include (cs) DMARDs (sub-class of DMARDs), tsDMARDS (targeted synthetic DMARDS), and bDMARDs (biological DMARDs). However, current pharmacologic therapy (consisting of biological, conventional, and creative views of small molecule anti-rheumatic drugs that treat the disease or DMARD) remains the cornerstone of rheumatoid arthritis treatment with which significant progress toward disease remission has been accomplished. CONCLUSION: The pathobiology of RA involves cytokine messengers such as B and T-cells, and an intricate interplay of pro-inflammatory cytokines responsible for activating and developing effector cells, in turn, accountable for local disease and systemic symptoms. Despite the fact that the cause of rheumatoid arthritis is not known, new treatments have been created as a result of better approaches towards the biology of the disease. As they target molecules directly implicated in the genesis of rheumatoid arthritis, these drugs may be more effective, targeted, and less harmful in the short and long term than standard therapies.

Fluorescein Diacetate Vital staining for detecting viability of acid-fast bacilli in sputum of pulmonary tuberculosis patients.

OBJECTIVE: To compare the performance of the Fluorescein diacetate (FDA) vital staining method with Ziehl-Neelsen staining method in detecting the viability of acid-fast bacilli using MGIT culture as "reference standard". METHODS: This was a single centre prospective observational study conducted from October 2015 to November 2016. Microbiologically confirmed ZN-Smear positive (3+) sputum specimens were obtained from 30 pulmonary tuberculosis patients taking anti-tuberculosis treatment at DOTS centre of NITRD, New Delhi. Patients were made available to collect the first baseline sputum sample before commencing treatment, and an early morning sputum sample was collected as per RNTCP guidelines. After starting treatment, sputum specimens were collected weekly in the first month and thereafter twice-weekly until 18th week. All sputum specimens from patients receiving anti-tuberculosis treatment were examined using Ziehl-Neelsen (ZN) smear microscopy, FDA vital staining, and MGIT culture. RESULT: Out of 360 follow up sputum specimens collected from 30 adult microbiologically confirmed ZN- Smear (3+) pulmonary tuberculosis patients, 146 were ZN-positive and 130 FDA-positive. Of 130 FDA-positive sputum samples, mycobacteria tuberculosis (MTB) growth was found in 116 sputum samples, of which 116 sputum specimens were positive for FDA. Additionally, 14 culture-negative specimens were FDA positive. No FDA-negative sputum samples were positive for MGIT culture. Among ZN positive specimens, FDA had 100% sensitivity and 85.3% specificity with an accuracy of 96.58% for the detection of viable mycobacteria. Among ZN negative sputum specimens, FDA had comparatively high specificity (95.7%). Using positive MGIT culture as a reference for viability, negative predictive value (NPV) and positive predictive value (PPV) from FDA vital staining method were found to be 100 and 89% respectively. CONCLUSION: FDA staining is a simple and rapid tool for identifying viable MTB bacilli. Because of its excellent NPV and encouraging specificity, FDA staining is useful to identify patients with non-viable bacilli (FDA negative) among retreatment cases at diagnosis and patients on anti-tuberculosis treatment for both drug-sensitive and drug-resistant tuberculosis for follow up for the response of treatment.

To study the impact of active case finding (ACF) among the TB patients detected in South Delhi.

BACKGROUND: TB is one of the top 10 causes of death worldwide. The WHO adopted the End TB Strategy with ambitious goal of ending the global TB epidemic by 2030. The targets for this were 95% reduction in number of TB deaths, 90% reduction in TB incidence rate between 2015 and 2035 and to ensure that no family is burdened with catastrophic expenditure due to TB. Enhanced case detection is one of the components of End TB strategy adopted by WHO and within this Active Case Finding has an important place. However, its role in the Indian context needs to be assessed. AIMS AND OBJECTIVES: To study the impact of Active Case Finding (ACF) in National Tuberculosis Elimination Program (NTEP) implementing area of National Institute of TB and Respiratory Diseases New Delhi in terms of case detection and treatment outcome. MATERIALS AND METHODS: The TB patients detected during ACF through house to house survey in vulnerable population were identified, evaluated and followed up. Data from ACF records and TB treatment cards were filled in a pretested proforma and compared with passive case detection in the previous month from same area. RESULTS: In December 2017 a total 8600 vulnerable population (living in slums, camps and night shelters) were screened over two weeks of whom 85 were found to have symptoms suggestive of TB of whom 19 were PTB that gives a case detection rate of 220 per lakh population. PTB case detection rate by passive case finding (PCF) in November 2017 from the same area of our study was found to be 63 per lakh population. This difference between the detection rate in ACF and passive case findings was statistically significant with Z proportion test and p value <0.00001. Treatment success rate was 75% and lost to follow up rate was 25% patients among the PTB patients detected in ACF. In passive case detection from the same area in November 2017 treatment success rate was 81.8% and lost to follow up rate (LTFU) was 18% in PTB patients. Even though LTFU rate was slightly higher but was not statistically significant. CONCLUSION: ACF is an effective way to find additional cases of TB. ACF is more labour intensive than PCF but if judiciously used under national programme to target specific vulnerable population of society it can produce additional number of TB cases which otherwise would have gone undiagnosed. However, treatment outcome for these patients is below the target and hence to get the maximum impact of ACF there is a need to enhance the adherence to treatment through different methodologies. Poor treatment adherence will lead to increase transmission risk in communities and greater chance of developing drug resistance. Further studies with larger representative population should be undertaken in order to get more conclusive.

Impact of metformin therapy on health-related quality of life outcomes in tuberculosis patients with diabetes mellitus in India: A prospective study.

OBJECTIVE: To assess the impact of metformin use on health-related quality of life (HRQoL) in tuberculosis (TB) patients who are presented with type 2 diabetes mellitus (T2DM). METHODOLOGY: In this community-based prospective study, TB patients attending Hakeem Abdul Hameed Centenary Hospital, New Delhi (India) and had comorbidity of T2DM between April 2018 and July 2019 were enrolled. Patients were divided into metformin users and metformin non-users on the basis of the presence of metformin in their routine as antidiabetic drug(s). HRQoL was determined using a validated TB-specific tool (Dhingra and Rajpal-12 scale ie, DR-12) consists of symptom and socio-psychological and exercise adaptation domains. The HRQoL scores were compared at pretreatment (1st visit), end of intensive phase (2nd visit) and end of treatment (3rd visit) between the two groups. RESULTS: A total of 120 patients were enrolled, of which 24 were excluded as they did not respond at follow-up visits. Among the metformin users (n = 48) the mean age of patients was 47.56 years and 62.50% was males. Among the metformin non-users (n = 48), the mean age of patients was 49.02 years and 54.10% was males. The baseline characteristics were similar in both groups except for the substance used history (P = .025), literacy level (P = .048) and BMI (P = .028). Metformin users demonstrated significant improvement in symptom scores (2nd visit: P < .001; 3rd visit: P = .001) and socio-psychological and exercise adaptation scores (2nd visit: P < .0001; 3rd visit: P < .0001) as compared with metformin non-users at 2nd visit and 3rd visit. Overall, scores were also found to be significantly improved in metformin users (2nd visit: P < .001; 3rd visit: P = .001). CONCLUSION: Metformin therapy exerted favourable effects on HRQoL in patients with TB and T2DM and can be recommended as an adjuvant antitubercular drug in TB patients with co-morbidity of T2DM, unless contraindicated.

Determination of isoniazid acetylation patterns in tuberculosis patients receiving DOT therapy under the Revised National tuberculosis Control Program (RNTCP) in India.

Isoniazid is the most commonly used drug for treatment of tuberculosis, and is administered individually or in combination with other drugs as standard first line therapy. Offsetting its efficacy, severe adverse effects, especially peripheral neuropathy and hepatotoxicity, are associated with isoniazid therapy, limiting its use in tuberculosis. Isoniazid is acetylated in vivo producing hydrazine and acetyl hydrazine, which are responsible for hepatotoxicity. Marked pharmacogenetic differences in acetylation have been reported among different population across the globe. This study evaluates isoniazid acetylation patterns in tuberculosis patients receiving DOT therapy under the Revised National Tuberculosis Control Program (RNTCP) in a specialized tuberculosis hospital in north India. Of 351 patients from whom samples were taken for biochemical analysis of adverse events, 36 were assessed for acetylation patterns. Blood samples were taken 1 h after administration of a 600 mg dose of isoniazid, and plasma concentrations of isoniazid were determined using a validated HPLC method. Of these 36 patients, 20 (55.56%) were slow acetylators and 16 (44.44%) were fast acetylators. Our results are consistent with those of an earlier study conducted in a different region of India. Most biochemical changes produced during long-term isoniazid therapy resolve after therapy is terminated.

Nikshay Poshan Yojana (NPY) for tuberculosis patients: Early implementation challenges in Delhi, India.

BACKGROUND: Nutrition support is one of the essential factors for envisioning Tuberculosis (TB) elimination in India by 2025. In this regard, Government of India introduced Nikshay Poshan Yojana (NPY) through Direct Benefit Transfer (DBT) as monthly financial assistance towards nutrition for TB patients in April, 2018. Assessment of early implementation challenges of the scheme is essential. OBJECTIVE: (a) To determine the number (proportion) of TB patients who received the benefits (b) to explore the challenges encountered by the health care providers in delivering the NPY through DBT (c) to explore the ways the incentives were utilised by the patients. MATERIAL AND METHODS: It was a cross-sectional study conducted among patients registered for TB treatment at Ladosarai and Mehrauli DOTS centre between July-September, 2018.Health providers engaged in implementation of NPY at the study sites were also interviewed. The data were collected through structured questionnaires, double entered and analyzed in Epi Data. RESULTS: Out of 119 patients registered, we interviewed 57 (47.9%) patients. Of which, 30 (52.6%) had received NPY for 2 months in the fourth and fifth month of treatment. The health providers reported increased workload, lack of training and complex reporting formats as main hurdles in implementation of the scheme. While, the patients cited non-availability of bank accounts and unlinked bank account with Aadhar card as difficulties to receive NPY through DBT. CONCLUSION: Nearly half of the interviewed TB patients received nutritional incentives of NPY through DBT for 2 months. Non-availability of bank accounts and unlinked bank accounts were some challenges faced by both health providers and patient. It is recommended to address these implementation on time in order to reap the benefit of scheme in improving nutritional status of TB patients. Further studies are needed to determine the effect of nutrition support on TB patients.

Adverse drug reaction prevalence and mechanisms of action of first-line anti-tubercular drugs.

PURPOSE: Understanding the appearance of anti-tubercular drug-related adverse drug reactions (ADRs) in patients receiving tuberculosis (TB) treatment is important, and may be related to morbidity and mortality if not recognized early. Here, we aimed to characterize the mechanisms underlying adverse drug reactions due to combination anti-tuberculosis therapy of the Revised National Tuberculosis Control Program (RNTCP). METHODS: This was a prospective observational study conducted in 9 DOTS centers of New Delhi, India. All enrolled TB patients receiving first-line tuberculosis treatment as per RNTCP guidelines were monitored for ADRs. All ADRs that appeared during the treatment were recorded and analyzed. RESULTS: The study included 1011 TB patients on anti-TB treatment under DOTS. According to Naranjo's probability scale, of a total 351 (34.72%) reported adverse events, 102 (10.09%) were definite, 59 (5.83%) probable, 123 (12.17%) possible, and 67 (6.63%) doubtful. On the Hartwig severity scale, of the 351 adverse drug events, 225 (22.26%) were mild, 105 (10.38%) were moderate, and 21 (2.08%) were severe. Out of 102 reported adverse drug reactions, 81 (79.41%) were moderate and 21 (20.59%), while 65.28% did not experience any ADRs. CONCLUSIONS: Directly Observed Treatment (DOT) is effective and safe compared to daily treatment regimens. Patients receiving DOTS therapy needed close monitoring for adverse events. Therefore, a pharmacovigilance program should be added at the National level to accesses the adverse event incidence.

Potential role of adjuvant drugs on efficacy of first line oral antitubercular therapy: Drug repurposing.

Despite the availability of potent antitubercular drugs, tuberculosis (TB) still remains one of the world's leading causes of death. The current antitubercular therapy (ATT) suffers from a drawback of longer duration that imposes a major challenge of patient non compliance and resistance development. The current scenario necessitates alternative strategies with potential to shorten treatment duration that could pave the way for improved clinical outcomes. In recent years, host directed adjunctive therapies have raised considerable attention and emerged as a promising intervention which targets clinically relevant biological pathways in hosts to modulate pathological immune responses. Few of the approved drugs namely statins, metformin, ibuprofen, aspirin, valproic acid, adalimumab, bevacizumab, zileuton and vitamin D3 have shown promising results in clinical outcomes during their preliminary screening in TB patients and can be potentially repurposed as antitubercular drugs. This review highlights clinical and non clinical evidences of some already existing drug and their targets in hosts that could help in shortening treatment duration and reducing bacterial burden at minimal doses.

Detrimental association between diabetes and tuberculosis: An unresolved double trouble.

Despite significant efforts made to control tuberculosis (TB) through DOTS program, the increasing burden of diabetes mellitus (DM) threatens the progress in reducing TB-related mortality, particularly in developing countries. In recent years, TB-DM comorbidity continues to remain high in countries where DM is on rampant. DM increases the risk of TB, reactivates the dormant TB and worsens the TB treatment outcome. The present review highlights the current findings regarding the prevalence and association of TB-DM comorbidity along with their public health implications. This review will increase the awareness among researchers, policymakers and clinicians, regarding the current scenario of TB-DM association.

Diabetes prevalence and its impact on health-related quality of life in tuberculosis patients.

OBJECTIVE: To determine the prevalence of diabetes mellitus (DM), assess its influence on health-related quality of life (HRQoL) among patients with TB. METHODS: In this prospective study, eligible patients at three primary healthcare centres in urban slum region of south Delhi, India, underwent blood glucose screening at treatment initiation. HRQoL scores were determined by conducting face-to-face interviews using Dhingra and Rajpal (DR-12) scale at pre-treatment, end of intensive phase and end of the treatment. RESULTS: In 316 patients, the overall DM prevalence was 15.8%, of whom 9.5% were known to have diabetes, and 6.3% were diagnosed at TB treatment initiation. DM was more common among patients of older age (P < 0.001), with higher BMI (P < 0.001), with PTB (P = 0.02) and with poor psychological status. HRQoL was significantly poor in the socio-psychological & exercise adaptation domain in patients with DM ˃50 years of age at each visit. Older age, poor literacy, loss in workdays, alcohol use and socio-economic status significantly predict poor HRQoL scores in patients with DM. Uncontrolled DM patients demonstrated poor HRQoL at the end of the intensive phase (P = 0.04) of treatment and at its completion (P = 0.03) compared to those with controlled DM. CONCLUSION: Addressing screening measures and glycaemic control along with social determinants such as literacy level and alcohol consumption could be an important means of improving the HRQoL of TB with DM patients.

Effect of Diabetes Mellitus on Tuberculosis Treatment Outcome and Adverse Reactions in Patients Receiving Directly Observed Treatment Strategy in India: A Prospective Study.

Despite successful implementation of directly observed treatment, short course (DOTS) in India, the growing number of diabetes mellitus (DM) patients appears to be a cause in the increasing tuberculosis (TB) incidence, affecting their management. In this regard, a prospective study was conducted on DOTS patients in three primary health care centers in urban slum region of South Delhi, India, to evaluate the effect of DM on sputum conversion, treatment outcome, and adverse drug reactions (ADR) due to anti-TB treatment. Eligible TB patients underwent blood glucose screening at treatment initiation. Disease presentation, clinical outcome, and ADRs were compared between patients of TB with and without DM. Out of 316 patients, the prevalence of DM was found to be 15.8%, in which 19.4% and 9.6% were PTB and EPTB patients, respectively. DM patients have observed higher sputum positivity (OR 1.247 95% CI; 0.539-2.886) at the end of 2-month treatment and poor outcome (OR 1.176 95% CI; 0.310-4.457) at the completion of treatment compared with non DM patients. Presence of DM was significantly associated (OR 3.578 95% CI; 1.114-11.494, p = 0.032) with the development of ADRs. DM influences the treatment outcome of PTB patients in our setting and also on the ADR incidence.

First and second line drug resistance among treatment naïve pulmonary tuberculosis patients in a district under Revised National Tuberculosis Control Programme (RNTCP) in New Delhi.

There is limited information of level of drug resistance to first-line and second line anti-tuberculosis agents in treatment naïve pulmonary tuberculosis (PTB) patients from the Indian region. Therefore, the present prospective study was conducted to determine the antimicrobial susceptibility to first-line and second line anti-TB drug resistance in such patients. Sputum samples from consecutive treatment naïve PTB cases registered in Lala Ram Sarup (LRS) district, under RNTCP containing 12 Directly Observed Treatment Centre's (DOTS), were enrolled using cluster sampling technology. A total of 453 samples were received from July 2011 to June 2012. All samples were cultured on solid medium followed by drug susceptibility to first and second line anti-tubercular drugs as per RNTCP guidelines. Primary multi-drug resistance (MDR) was found to be 18/453; (4.0%). Extensively drug resistance (XDR) was found in one strain (0.2%), which was found to be resistant to other antibiotics. Data of drug resistant tuberculosis among treatment naïve TB patients are lacking in India. The presence of XDR-TB and high MDR-TB in small population studied, calls for conducting systematic multi-centric surveillance across the country.

Tuberculosis among health care workers in a tertiary care institute for respiratory diseases in New Delhi.

BACKGROUND: LRS Institute of Tuberculosis and Respiratory Diseases, a tertiary care pulmonary institute in Delhi, India. AIMS: To find out the risk of tuberculosis disease among health care workers (HCWs) of LRS Institute. METHODS: Retrospective study, where all members of the staff working in this hospital were interviewed regarding development of tuberculosis after joining this institute. RESULTS: A total of 40 cases of tuberculosis were reported by the health care workers between March 1999 to March 2008 yielding an overall risk of 727 per 1,00,000 population per year which is four times higher than the reported national average. Among these 40 cases, 25 (62.5%) were pulmonary and 15 (37.5%) were extra-pulmonary tuberculosis. CONCLUSION: This institute's health care workers have to deal with a large number of tuberculosis patients, the risk of exposure is more in them and thus having the disease. Multi-centric studies are needed to evaluate the true prevalence of tuberculosis among HCWs and effective intervention strategies are required to reduce nosocomial transmission.

Pyrazinamide-induced maculopapular rash.

Pyrazinamide is a commonly used first-line antitubercular drug. Gastric-related adverse drug reactions are common with pyrazinamide. Dermatological manifestations due to pyrazinamide are rare. This study aimed find out the dermatological manifestations/adverse drug reaction (ADR) due to pyrazinamide. We reported a case of maculopapular rash caused by pyrazinamide in a patient on antituberculosis treatment using structured questionnaires. The patient developed maculopapular rashes on receiving combination antituberculosis treatment. The rashes disappeared after stopping the suspected drug. The patient was rechallenged with pyrazinamide, which led to reappearance of a similar type of rash. The causality, preventability, and severity were assessed using the Naranjo algorithm and Hartwig scale. Since pyrazinamide is a commonly used drug in tuberculosis and which is a common infectious disease in developing countries, with the similar reports, we can predict early case detection and can prevent the occurrence of similar reactions in future.