Effect of Bedaquiline and Delamanid Pharmacokinetics on Sputum Culture Conversion and Adverse Events in Drug-Resistant Tuberculosis.

BACKGROUND: Pharmacokinetic studies of bedaquiline and delamanid in patients with pre-extensively drug-resistant tuberculosis (pre-XDR TB) will help in the optimization of these drugs for both culture conversion and adverse events. METHODS: A prospective cohort of 165 adult patients (56% male with mean [SD] age 29 [9.7] years) with pre-XDR TB was treated with bedaquiline, delamanid, clofazimine, and linezolid for 24 weeks at 5 sites in India. Bedaquiline was administered at 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks, whereas delamanid was administered at 100 mg twice daily. In 23 consenting participants at 8 and 16 weeks of treatment, blood was collected at 0, 2, 4, 5, 6, 8, 12, and 24 hours postdosing for an intense pharmacokinetic study. Pharmacokinetic parameters were correlated with sputum culture conversion and adverse events. RESULTS: The mean (SD) age and weight of patients were 30 (10) years and 54 kg, respectively. The median minimum concentration (C min ) and time-concentration curve (AUC) for bedaquiline, respectively, were 0.6 mcg/mL and 27 mcg/mL·h at week 8 and 0.8 mcg/mL and 36 mcg/mL·h at week 16, suggesting drug accumulation over time. The median C min and AUC of delamanid, respectively, were 0.17 mcg/mL and 5.1 mcg/mL·h at week 8 and 0.20 mcg/mL and 7.5 mcg/mL·h at week 16. Delay in sputum conversion was observed in patients with drug concentrations lower than the targeted concentration. At weeks 8 and 16, 13 adverse events were observed. Adverse events were resolved through symptomatic treatment. Body mass index was found to be significantly associated with drug-exposure parameters. CONCLUSIONS: Bedaquiline and delamanid when co-administered exhibit plasma drug levels within the targeted concentrations, showing an exposure-response relationship.

Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis.

BACKGROUND: Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) remain low globally. Availability of newer drugs has given scope to develop regimens that can be patient-friendly, less toxic, with improved outcomes. We proposed to determine the effectiveness of an entirely oral, short-course regimen with Bedaquiline and Delamanid in treating MDR-TB with additional resistance to fluoroquinolones (MDR-TBFQ+) or second-line injectable (MDR-TBSLI+). METHODS: We prospectively determined the effectiveness and safety of combining two new drugs with two repurposed drugs - Bedaquiline, Delamanid, Linezolid, and Clofazimine for 24-36 weeks in adults with pulmonary MDR-TBFQ+ or/and MDR-TBSLI+. The primary outcome was a favorable response at end of treatment, defined as two consecutive negative cultures taken four weeks apart. The unfavorable outcomes included bacteriologic or clinical failure during treatment period. RESULTS: Of the 165 participants enrolled, 158 had MDR-TBFQ+. At the end of treatment, after excluding 12 patients due to baseline drug susceptibility and culture negatives, 139 of 153 patients (91%) had a favorable outcome. Fourteen patients (9%) had unfavorable outcomes: four deaths, seven treatment changes, two bacteriological failures, and one withdrawal. During treatment, 85 patients (52%) developed myelosuppression, 69 (42%) reported peripheral neuropathy, and none had QTc(F) prolongation >500msec. At 48 weeks of follow-up, 131 patients showed sustained treatment success with the resolution of adverse events in the majority. CONCLUSION: After 24-36 weeks of treatment, this regimen resulted in a satisfactory favorable outcome in pulmonary MDR-TB patients with additional drug resistance. Cardiotoxicity was minimal, and myelosuppression, while common, was detected early and treated successfully.

Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis.

We evaluated the relationship between the pharmacokinetic parameters of linezolid (LZD) and development of adverse drug reactions (ADRs) in patients with pulmonary drug-resistant tuberculosis. A prospective cohort of adults with pulmonary multidrug-resistant tuberculosis with additional resistance to fluoroquinolone (MDR-TBFQ+) received treatment with bedaquiline, delamanid, clofazimine, and LZD. Blood samples were collected during weeks 8 and 16 at eight time points over 24 h. The pharmacokinetic parameters of LZD were measured using high-performance liquid chromatography and associated with ADRs. Of the 165 MDR-TBFQ+ patients on treatment, 78 patients developed LZD-associated anemia and 69 developed peripheral neuropathy. Twenty-three patients underwent intense pharmacokinetic testing. Plasma median trough concentration was 2.08 µg/mL and 3.41 µg/mL, (normal <2 µg/mL) and AUC0-24 was 184.5 µg/h/mL and 240.5 µg/h/mL at weeks 8 and 16, respectively, showing a linear relationship between duration of intake and plasma levels. Nineteen patients showed LZD-associated ADRs-nine at week 8, twelve at week 16, and two at both weeks 8 and 16. Thirteen of the nineteen had high plasma trough and peak concentrations of LZD. A strong association between LZD-associated ADRs and plasma LZD levels was noted. Trough concentration alone or combinations of trough with peak levels are potential targets for therapeutic drug monitoring.

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.

Association of Tuberculosis With Household Catastrophic Expenditure in South India.

Importance: The high household costs associated with tuberculosis (TB) diagnosis and treatment can create barriers to access and adherence, highlighting the urgency of achieving the World Health Organization's End TB Strategy target that no TB-affected households should face catastrophic costs by 2020. Objective: To estimate the occurrence of catastrophic costs associated with TB diagnosis and treatment and to identify socioeconomic indicators associated with catastrophic costs in a setting where TB control strategies have been implemented effectively. Design, Setting, and Participants: In this cross-sectional study, 455 patients with TB in the Chennai metropolitan area of South India who were treated under the TB control program between February 2017 and March 2018 were interviewed. Patients were interviewed by trained field investigators at 3 time points: at the initiation of treatment, at the end of the intensive phase of treatment, and at the end of the continuation phase of treatment. A precoded interview schedule was used to collect information on demographic, socioeconomic, and clinical characteristics and direct medical, direct nonmedical, and indirect costs. Data analysis was performed from August 2018 to November 2019. Main Outcomes and Measures: Direct, indirect, and total costs to patients with TB. Catastrophic costs associated with TB were defined as costs exceeding 20% of the household's annual income. A binary response model was used to determine the factors that were significantly associated with catastrophic costs. Results: Of 455 patients with TB interviewed, 205 (53%) were aged 19 to 45 years (mean [SD] age, 38.4 [16.0] years), 128 (33%) were female, 72 (19%) were illiterate, 126 (33%) were employed, and 186 (48%) had a single earning member in the family (percentages are based on the 384 patients who were interviewed through the end of the continuation phase of treatment). Sixty-one percent of patients (234 patients) had pulmonary smear positive TB. The proportion of patients with catastrophic costs was 31%. Indirect costs contributed more toward catastrophic cost than did direct costs. Multivariate logistic regression analysis found that unemployment (adjusted odds ratio, 0.2; 95% CI, 0.1-0.5; P < .001) and higher annual household income (Rs 1-200 000, adjusted odds ratio, 0.4; 95% CI, 0.2-0.7; P = .004; Rs >200 000, adjusted odds ratio, 0.2; 95% CI, 0.1-0.5; P < .001) were associated with a decreased likelihood of experiencing catastrophic costs. Conclusions and Relevance: Despite the implementation of free diagnostic and treatment services under a national TB control program, TB-affected households had a high risk of catastrophic costs and further impoverishment. There is an urgent demand to provide additional financial protection for patients with TB.

Identifying costs contributing to catastrophic expenditure among TB patients registered under RNTCP in Delhi metro city in India.

BACKGROUND: Tuberculosis (TB) patients often incur large costs related to illness, as well as for seeking and receiving health care. Despite TB treatment being free under RNCTP, out of pocket expenditure incurred (OOP) by patients for TB diagnosis and treatment impoverishes the households. This expenditure may turn catastrophic (more than 20% of their family income) impacting adherence and leading to poor treatment outcomes. OBJECTIVE: To estimate the proportion of households experiencing catastrophic expenditure due to TB and also to find out the various costs contributing to catastrophic expenditure. METHODS: In this cohort study, 450 TB patients (including 96 children) registered under Revised National Tuberculosis Control Programme (RNTCP) in Delhi were interviewed at three different time points (in the beginning of treatment, end of intensive phase, end of treatment). Interview schedule was used to collect information on direct medical and non-medical, and indirect costs. The TB-specific indicator of "catastrophic total costs" incorporates both, direct medical and non-medical payments for treatment such as transportation, lodging charges and indirect costs such as wage loss. RESULTS: A total of 450 patients were enrolled in this study, out of which 425 were followed up to the end of treatment. It was observed that 7% of TB patients registered under RNTCP in Delhi experienced catastrophic expenditure due to TB. The total mean cost to patients with TB was Rs. 12165 (Rs. 1406 during diagnosis and Rs. 10759 during treatment). The indirect cost was higher compared to direct cost i.e.Rs. 7564 and Rs. 4601 respectively). CONCLUSION: This information will be useful for policy makers to design an intervention to provide financial protection to TB patients. In addition, findings of this study will aid in providing baseline evidence to periodically measure the OOP which is the one of the End TB strategy target.

Early efficacy and safety of Bedaquiline and Delamanid given together in a "Salvage Regimen" for treatment of drug-resistant tuberculosis.

BACKGROUND: Drug-Resistant Tuberculosis (DR-TB) patients for whom a WHO recommended regimen along with Bedaquiline (BDQ) cannot be prescribed, Delamanid (DLM) was added along with other drugs to provide a "Salvage Regimen". The experience of the Institute in respect of early efficacy and safety of both drugs given together is presented. OBJECTIVE: To ascertain the early efficacy, safety and tolerability of Bedaquline and Delamanid given together as a part of salvage regimen. METHODS: BDQ and DLM were used together to make regimens along with other drugs where four effective anti TB drugs could not be prescribed as per WHO recommendations. Patients were followed up for sputum smear and culture conversion and adverse events during the treatment. RESULTS: In this cohort study, 53 DR-TB patients (Median age-24) were initiated on regimens containing both BDQ and DLM. Sputum smear conversion was seen in 35% and 94% patients at the end of 1st week and 3rd month respectively. 84% patients had culture conversion at the end of 4th month. 29 adverse events (AE) were reported among 17 patients and there were 11 deaths. QTc prolongation more than 500 MS was seen in only 1 patient. CONCLUSION: BDQ and DLM given together in a salvage regimen is efficacious with low rate of adverse events. The combination provides hope to DR-TB patients with limited treatment options and should be provided as a life saving option.

Initial experience of bedaquiline implementation under the National TB Programme at NITRD, Delhi, India.

BACKGROUND: Bedaquiline (BDQ) was approved for treatment of drug resistant TB (DR-TB) under Conditional Access Programme (CAP) of Revised National Tuberculosis Control Programme (RNTCP) and was also implemented in the National Institute of TB and Respiratory Diseases (NITRD). We present early efficacy and safety of BDQ containing regimens for DR-TB. OBJECTIVE: To ascertain the early efficacy and safety of Bedaquline containing regimens in treatment of DR-TB. METHODS: BDQ containing regimens along with other drugs were designed as per WHO recommendations for DR-TB patients. They were followed up for sputum smear and culture conversion, adverse events during the treatment. RESULTS: A cohort of 290 DR-TB patients (Median age-29.77) were initiated on BDQ containing regimens. Of the available Sputum results, smear conversion was seen in 51% and 91% patients at the end of 1st week and 3rd month respectively. Similarly, 93% and 98% patients had culture conversion at the end of 3rd and 6th month respectively. 201 adverse events (AE) including 47 deaths were reported among 109 patients. QTc prolongation was seen in 29% patients but only 4 required discontinuation of BDQ. Lost to follow up of treatment was about 6%. CONCLUSION: Bedaquiline along with an optimized background regimen has shown early sputum conversion in larger number of difficult to treat patients having additional resistance of second line drugs along with INH and Rifampicin. The regimen is feasible in programmatic conditions and is relatively safe.

Prevalence of pulmonary tuberculosis among adults in selected slums of Delhi city.

BACKGROUND: A survey was carried out to estimate the point prevalence of bacteriologically positive pulmonary tuberculosis (PTB) among persons ≥15 years of age residing in Jhuggi-Jhopri (JJ) colonies - urban slums in Delhi, India implementing Directly Observed Treatment strategy since 1998. METHODS: Among 12 JJ colonies selected by simple random sampling, persons having persistent cough for ≥2 weeks at the time of the survey or cough of any duration along with history of contact/currently on ant-TB treatment/known HIV positive were subjected to sputum examination - 2 specimens, by smear microscopy for Acid Fast Bacilli and culture for Mycobacterium tuberculosis. Persons with at least one specimen positive were labelled as bacteriologically confirmed PTB. Prevalence was estimated after imputing missing values to correct bias introduced by incompleteness of data and corrected for non-screening by X-ray by a multiplication factor derived from recently conducted surveys. RESULTS: Of 40,756 persons registered, 40,529 (99.4%) were screened. Of them, 691 (2%) were eligible for sputum examination. Spot specimens were collected from 659 (99.2%) and early morning sputum specimens from 647 (98.1%). Using screening by interview alone, prevalence of bacteriologically positive PTB in persons ≥15 years of age was estimated at 160.4 (123.7-197.1) per 100,000 populations and210.0 (CI: 162.5-258.2) after correcting for non-screening by X-ray. CONCLUSION: Observed prevalence suggests further strengthening of TB control program in urban slums.

Evaluating the technique of using inhalation device in COPD and bronchial asthma patients.

BACKGROUND: In asthma management, poor handling of inhalation devices and wrong inhalation technique are associated with decreased medication delivery and poor disease control. The key to overcome the drawbacks in inhalation technique is to make patients familiar with issues related to correct use and performance of these medical devices. The objective of this study was to evaluate and analyse technique of use of the inhalation device used by patients of COPD and Bronchial Asthma. METHODS: A total of 300 cases of BA or COPD patients using different types of inhalation devices were included in this observational study. Data were captured using a proforma and were analysed using SPSS version 15.0. RESULT: Out of total 300 enrolled patients, 247 (82.3%) made at least one error. Maximum errors observed in subjects using MDI (94.3%), followed by DPI (82.3%), MDI with Spacer (78%) while Nebulizer users (70%) made least number of errors (p = 0.005). Illiterate patients showed 95.2% error while post-graduate and professionals showed 33.3%. This difference was statistically significant (p < 0.001). Self-educated patients committed 100% error, while those trained by a doctor made 56.3% error. CONCLUSION: Majority of patients using inhalation devices made errors while using the device. Proper education to patients on correct usage may not only improve control of the symptoms of the disease but might also allow dose reduction in long term.

Sputum smear positivity at two months in previously untreated pulmonary tuberculosis patients.

BACKGROUND AND OBJECTIVES: In pulmonary tuberculosis, bacteriological status at two months affects subsequent treatment and prognosis. The effect on treatment outcome and risk factors for sputum conversion at two months treatment in previously untreated pulmonary tuberculosis (PTB) patients was studied in the following report. METHODS: A 1:1 case-control study was performed from June 2006 to February 2008 on patients in the Revised National Tuberculosis Control Program in a tertiary level institute in Delhi, India. Patients with previously untreated PTB with sputum smear positive at 2months of treatment (cases) were compared with those who achieved conversion (controls). RESULTS: In 74 cases and 74 controls, independent risk factors for sputum smear positive at two months were: illness for >2months, presence of cavity or extensive disease on chest X-ray, and interruption in intensive phase of treatment. Patients with smear positive at 2 or 3months of treatment were more likely to fail or default from treatment. Aforesaid factors were also associated with sputum culture positive status at 2months in univariate analysis. Patients who interrupted treatment ⩾3 times in the first two months were more likely to be culture positive at two months and had a higher rate of default and failure. CONCLUSIONS: Illness for more than 2months, presence of cavity or extensive disease on chest X-ray, and interruption in intensive phase of treatment are independent risk factors for sputum smear positivity at two months, which in turn is associated with poor treatment outcomes. Patients with these factors merit special attention under the national program.