Journal Article > ResearchFull Text
Clin Infect Dis. 13 March 2025; Online ahead of print; DOI:10.1093/cid/ciaf068
Singla R, Khan S, Silsarma A, Chavan V, Mahajan R, et al.
Clin Infect Dis. 13 March 2025; Online ahead of print; DOI:10.1093/cid/ciaf068
BACKGROUND
Bedaquiline (BDQ) resistance presents a critical challenge in the fight against tuberculosis (TB), particularly multidrug-resistant (MDR) strains. The emergence of resistance to BDQ, a key drug in treating MDR-TB, poses significant threats to TB treatment effectiveness.
METHODS
The National Institute of Tuberculosis and Respiratory Diseases in Delhi and the Médecins Sans Frontières clinic in Mumbai provide BDQ, delamanid, and carbapenem-based regimens for patients with suspected or confirmed treatment failure. BDQ phenotypic drug-susceptibility testing (DST) was performed for all BDQ-exposed patients. Treatment regimens were individualized based on exposure history, comorbidities, drug interactions, prior adverse drug reactions, and DST results.
RESULTS
Of 117 BDQ-exposed patients from December 2020–December 2022, 42 (36%) exhibited a BDQ-resistant strain. Median (IQR) age was 24 (22–32) years, with 63 (54%) females and 94% with pulmonary TB. Patients with a BDQ-resistant strain were older (median age: 27 vs 23 years; P = .04), more likely to have lung cavities (risk ratio [RR]: 1.8; 95%-CI: 1.1–3.1; P = .02), and be resistant to clofazimine (RR: 2.3; 95%-CI: 1.5–3.6; P = .001). Overall, 102 patients initiated treatment. Patients with BDQ-resistance had higher risk of unfavorable outcomes compared with BDQ-susceptible patients (RR:2.1; 95%-CI: 1.5–2.8; P < .001). Overall, 87% (33/38) of patients with BDQ-resistance experienced unfavorable treatment outcomes: 15 (40%) died, 15 (40%) had treatment failure, and 3 (8%) were lost-to-follow-up.
CONCLUSIONS
The study highlights a concerning rate of BDQ-resistance among previously treated patients, resulting in poor treatment outcomes. To prevent treatment failure, we recommend implementing BDQ-DST, developing affordable and accurate rapid tests for BDQ-resistance, and intensifying research and development efforts for newer TB drugs.
Journal Article > LetterFull Text
IJTLD OPEN. 1 February 2025; Volume 2 (Issue 2); 107-109.; DOI:10.5588/ijtldopen.24.0600
Chavan V, Silsarma A, Mahajan R, Khan S, Singh P, et al.
IJTLD OPEN. 1 February 2025; Volume 2 (Issue 2); 107-109.; DOI:10.5588/ijtldopen.24.0600
Conference Material > Poster
Chavan V, Silsarma A, Khan S, Singh P, Iyer A, et al.
MSF Scientific Days Asia 2024. 8 November 2024
Journal Article > ResearchFull Text
Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 1 April 2024; Volume 35; 100433.; DOI:10.1016/j.jctube.2024.100433
Mongia H, Mamnoon F, Silsarma A, Mahajan R, Dalal A, et al.
Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 1 April 2024; Volume 35; 100433.; DOI:10.1016/j.jctube.2024.100433
BACKGROUND
World Health Organization suggests concurrent bedaquiline-delamanid (BDQ-DLM) as part of individualised regimens for eligible patients with pulmonary drug-resistant tuberculosis (DR-TB); however, data for patients with drug-resistant extrapulmonary tuberculosis (EPTB) is extremely limited. This study documents the treatment outcomes and adverse events associated with concurrent BDQ-DLM-based regimens in patients with drug-resistant EPTB at a Médecins Sans Frontières clinic in Mumbai, India.
METHODS
Retrospective cohort study based on routinely collected programmatic data. Individualised regimens were based on drug-susceptibility testing and previous drug exposure. Drug-resistant EPTB patients initiated on regimens containing concurrent BDQ and DLM from April 2016 to October 2019 were included. Patients who completed treatment were followed up at 12 months.
RESULTS
Of 17 patients, median age was 23 years (IQR = 21-30 years) and 12/17 (71 %) were female. Pre-extensively drug-resistant tuberculosis and extensively drug-resistant TB was reported in 13/17 (76.4 %) and 2/17 (11.7 %) patients respectively. Microbiological reports were unavailable for two patients with central nervous system TB. Lymph node TB was the commonest form of EPTB in 9/17 (53 %) of patients. Median duration of treatment was 18.9 months. At least one grade three or four severe adverse event (SAE) was reported by 13/17 (76.4 %) patients. Thirteen (76.4 %) patients had favourable outcomes. None of the patients relapsed or died in the one-year period of post-treatment follow-up.
CONCLUSION
Concurrent BDQ-DLM-based regimens in drug-resistant EPTB were effective and associated with manageable adverse events.
World Health Organization suggests concurrent bedaquiline-delamanid (BDQ-DLM) as part of individualised regimens for eligible patients with pulmonary drug-resistant tuberculosis (DR-TB); however, data for patients with drug-resistant extrapulmonary tuberculosis (EPTB) is extremely limited. This study documents the treatment outcomes and adverse events associated with concurrent BDQ-DLM-based regimens in patients with drug-resistant EPTB at a Médecins Sans Frontières clinic in Mumbai, India.
METHODS
Retrospective cohort study based on routinely collected programmatic data. Individualised regimens were based on drug-susceptibility testing and previous drug exposure. Drug-resistant EPTB patients initiated on regimens containing concurrent BDQ and DLM from April 2016 to October 2019 were included. Patients who completed treatment were followed up at 12 months.
RESULTS
Of 17 patients, median age was 23 years (IQR = 21-30 years) and 12/17 (71 %) were female. Pre-extensively drug-resistant tuberculosis and extensively drug-resistant TB was reported in 13/17 (76.4 %) and 2/17 (11.7 %) patients respectively. Microbiological reports were unavailable for two patients with central nervous system TB. Lymph node TB was the commonest form of EPTB in 9/17 (53 %) of patients. Median duration of treatment was 18.9 months. At least one grade three or four severe adverse event (SAE) was reported by 13/17 (76.4 %) patients. Thirteen (76.4 %) patients had favourable outcomes. None of the patients relapsed or died in the one-year period of post-treatment follow-up.
CONCLUSION
Concurrent BDQ-DLM-based regimens in drug-resistant EPTB were effective and associated with manageable adverse events.
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 1 July 2023; Volume 27 (Issue 7); 567-569.; DOI:10.5588/ijtld.22.0632
Vengurlekar D, Walker C, Mahajan R, Dalal A, Chavan VV, et al.
Int J Tuberc Lung Dis. 1 July 2023; Volume 27 (Issue 7); 567-569.; DOI:10.5588/ijtld.22.0632
Conference Material > Slide Presentation
Khan S, Silsarma A, Iyer AS, Galindo MA, Chavan VV, et al.
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/0dpv-wz08
Conference Material > Abstract
Khan S, Silsarma A, Iyer AS, Galindo MA, Chavan VV, et al.
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/k4rh-s938
INTRODUCTION
Bedaquiline (BDQ) and linezolid (LZD) are Group A drugs and form part of shorter and longer BDQ-based regimens under India’s National Tuberculosis (TB) Programme. A systematic review including some data from India on acquired BDQ resistance reports 2.2% phenotypic and 4.4% genotypic resistance in patients treated with BDQ-based regimens. The pooled frequency of LZD resistance among drug-resistant tuberculosis (DR-TB) isolates was 4.2% in a different study. The emergence of resistance to BDQ is concerning as it results in difficulties in constructing regimens, and is associated with unsuccessful treatment outcomes among DR-TB patients. Since 2015, Médecins Sans Frontières (MSF) has provided treatment for TB patients in Mumbai with extensive resistance patterns, who need newer drugs and have limited treatment options under India’s National TB Elimination Programme.
METHODS
We carried out a descriptive retrospective study of routinely collected programmatic data from December 2020 to February 2022. The study population consisted of culture-positive DR-TB patients with BDQ and LZD exposure for over one month, referred to the MSF clinic with 1) suspected or confirmed treatment failure; 2) DR-TB diagnosed household contacts of BDQ-exposed DR-TB patients.
ETHICS
This research fulfilled the exemption criteria set by the MSF Ethics Review Board (ERB) for a posteriori analyses of routinely collected clinical data, and thus did not require MSF ERB review.
RESULTS
88 culture-positive samples were subjected to BDQ and LZD drug susceptibility testing (DST). Of these, 27 showed resistance to BDQ, LZD, or both. 22.7% (20/88) showed BDQ resistance, 17% (15/88) LZD resistance, and eight patients (9%) were simultaneously resistant to BDQ and LZD. Of 88 samples, two were DR-TB diagnosed contacts of BDQ-exposed index cases, and the remaining were BDQ-exposed patients (> one month). In the resistant cohort of 27, equal proportions were male and female, and mean exposure to all Group A drugs was 14 months. 74% (20/27) patients had bilateral disease; 26% (7/27) had unilateral disease, of which 67% (18/27) had lung cavities. Simultaneous resistance to clofazimine and fluoroquinolones was found among 30% (8/27) and 78% (21/27) patients respectively. Within the resistant cohort, two patients refused treatment and 25 started on treatment. Out of 25 patients starting treatment, 8% (2/25) successfully completed treatment, 48% (12/25) died, 20% (5/25) failed, 4% (1/25) were lost to follow-up, and 20% (5/25) were still on treatment at the time of analysis. Of the five patients still on treatment patients, two culture-converted and three are still culture-positive after three months of treatment.
CONCLUSION
We observed a high proportion of BDQ and LZD resistance in patients who previously failed on BDQ and LZD-based regimens. We observe high mortality and unsuccessful outcomes in treating such cases. Designing effective treatment regimens for patients with retreatment episodes and a history of BDQ and LZD exposure is extremely challenging. We urgently recommend increased programmatic access to DST for LZD and BDQ, to ensure early access to effective regimens.
CONFLICTS OF INTEREST
None declared
Bedaquiline (BDQ) and linezolid (LZD) are Group A drugs and form part of shorter and longer BDQ-based regimens under India’s National Tuberculosis (TB) Programme. A systematic review including some data from India on acquired BDQ resistance reports 2.2% phenotypic and 4.4% genotypic resistance in patients treated with BDQ-based regimens. The pooled frequency of LZD resistance among drug-resistant tuberculosis (DR-TB) isolates was 4.2% in a different study. The emergence of resistance to BDQ is concerning as it results in difficulties in constructing regimens, and is associated with unsuccessful treatment outcomes among DR-TB patients. Since 2015, Médecins Sans Frontières (MSF) has provided treatment for TB patients in Mumbai with extensive resistance patterns, who need newer drugs and have limited treatment options under India’s National TB Elimination Programme.
METHODS
We carried out a descriptive retrospective study of routinely collected programmatic data from December 2020 to February 2022. The study population consisted of culture-positive DR-TB patients with BDQ and LZD exposure for over one month, referred to the MSF clinic with 1) suspected or confirmed treatment failure; 2) DR-TB diagnosed household contacts of BDQ-exposed DR-TB patients.
ETHICS
This research fulfilled the exemption criteria set by the MSF Ethics Review Board (ERB) for a posteriori analyses of routinely collected clinical data, and thus did not require MSF ERB review.
RESULTS
88 culture-positive samples were subjected to BDQ and LZD drug susceptibility testing (DST). Of these, 27 showed resistance to BDQ, LZD, or both. 22.7% (20/88) showed BDQ resistance, 17% (15/88) LZD resistance, and eight patients (9%) were simultaneously resistant to BDQ and LZD. Of 88 samples, two were DR-TB diagnosed contacts of BDQ-exposed index cases, and the remaining were BDQ-exposed patients (> one month). In the resistant cohort of 27, equal proportions were male and female, and mean exposure to all Group A drugs was 14 months. 74% (20/27) patients had bilateral disease; 26% (7/27) had unilateral disease, of which 67% (18/27) had lung cavities. Simultaneous resistance to clofazimine and fluoroquinolones was found among 30% (8/27) and 78% (21/27) patients respectively. Within the resistant cohort, two patients refused treatment and 25 started on treatment. Out of 25 patients starting treatment, 8% (2/25) successfully completed treatment, 48% (12/25) died, 20% (5/25) failed, 4% (1/25) were lost to follow-up, and 20% (5/25) were still on treatment at the time of analysis. Of the five patients still on treatment patients, two culture-converted and three are still culture-positive after three months of treatment.
CONCLUSION
We observed a high proportion of BDQ and LZD resistance in patients who previously failed on BDQ and LZD-based regimens. We observe high mortality and unsuccessful outcomes in treating such cases. Designing effective treatment regimens for patients with retreatment episodes and a history of BDQ and LZD exposure is extremely challenging. We urgently recommend increased programmatic access to DST for LZD and BDQ, to ensure early access to effective regimens.
CONFLICTS OF INTEREST
None declared
Journal Article > ResearchFull Text
Public Health Action. 21 September 2016; Volume 6 (Issue 3); 193-198.; DOI:10.5588/pha.16.0043
Shirodkar S, Anande L, Dalal A, Desai C, Correa G, et al.
Public Health Action. 21 September 2016; Volume 6 (Issue 3); 193-198.; DOI:10.5588/pha.16.0043
SETTING
While surgery for pulmonary tuberculosis (PTB) is considered an important adjunct for specific cases, including drug-resistant tuberculosis, operational evidence on its feasibility and effectiveness is limited.
OBJECTIVE
To describe surgical outcomes and programmatic challenges of providing surgery for PTB in Mumbai, India.
DESIGN
A descriptive study of routinely collected data of surgical interventions for PTB from 2010 to 2014 in two Mumbai hospitals, one public, one private.
RESULTS
Of 85 patients, 5 (6%) died and 17 (20%) had complications, with wound infection being the most frequent. Repeat operation was required in 12 (14%) patients. Most procedures were performed on an emergency basis, and eligibility was established late in the course of treatment. Median time from admission to surgery was 51 days. Drug susceptibility test (DST) patterns and final treatment outcomes were not systematically collected.
CONCLUSION
In a high-burden setting such as Mumbai, important data on surgery for PTB were surprisingly limited in both the private and public sectors. Eligibility for surgery was established late, culture and DST were not systematically offered, the interval between admission and surgery was long and TB outcomes were not known. Systematic data collection would allow for proper evaluation of surgery as adjunctive therapy for all forms of TB under programmatic conditions.
While surgery for pulmonary tuberculosis (PTB) is considered an important adjunct for specific cases, including drug-resistant tuberculosis, operational evidence on its feasibility and effectiveness is limited.
OBJECTIVE
To describe surgical outcomes and programmatic challenges of providing surgery for PTB in Mumbai, India.
DESIGN
A descriptive study of routinely collected data of surgical interventions for PTB from 2010 to 2014 in two Mumbai hospitals, one public, one private.
RESULTS
Of 85 patients, 5 (6%) died and 17 (20%) had complications, with wound infection being the most frequent. Repeat operation was required in 12 (14%) patients. Most procedures were performed on an emergency basis, and eligibility was established late in the course of treatment. Median time from admission to surgery was 51 days. Drug susceptibility test (DST) patterns and final treatment outcomes were not systematically collected.
CONCLUSION
In a high-burden setting such as Mumbai, important data on surgery for PTB were surprisingly limited in both the private and public sectors. Eligibility for surgery was established late, culture and DST were not systematically offered, the interval between admission and surgery was long and TB outcomes were not known. Systematic data collection would allow for proper evaluation of surgery as adjunctive therapy for all forms of TB under programmatic conditions.
Journal Article > ResearchFull Text
PLOS One. 16 June 2020 (Issue 6); DOI:10.1371/journal.pone.0234651.
Chavan VV, Dalal A, Nagaraja SB, Thekkur P, Mansoor H, et al.
PLOS One. 16 June 2020 (Issue 6); DOI:10.1371/journal.pone.0234651.
Background
Imipenem, an intravenous antibiotic is recommended for use in drug resistant tuberculosis (DR-TB) when an effective regimen with combination of other second line drugs is not possible. Though the treatment success rates with carbapenems are promising, the twice daily injection of Imipenem usually requires patients to be hospitalized. The Médecins Sans Frontières independent clinic in Mumbai, India implemented ambulatory and home based management of patients receiving Imipenem through the use of port-a-cath.
Objective
We aimed to describe the adverse events and treatment outcomes of ambulatory pre- and XDR-TB patients initiated on imipenem through port-a-cath between January 2015 and June 2018 and to explore the challenges with this regimen as perceived by healthcare providers and patients.
Methods
A convergent mixed methods study with quantitative (longitudinal descriptive study using the routine data) and qualitative (descriptive study) part conducted concurrently. For the quantitative component, all XDR-TB and pre-XDR-TB initiated on imipenem containing regimen during January 2015-June 2018 were included. For qualitative component, interviews were carried out including patients who initiated on imipenem (n = 5) and healthcare providers (n = 7) involved in providing treatment. Treatment outcomes, culture conversion and adverse events during treatment were described. Thematic analysis was carried out for qualitative component.
Results
Of the 70 patients included, the mean age was 28.1 (standard deviation: 11.2) years and 36 (51.4%) were females. Fifty one (72.9%) had XDR-TB. All patients were resistant to fluoroquinilone, levofloxacin. Vomiting was reported by 55 (78.6%) patients and at least one episode of QTC prolongation (more than 500 msec by Fredrecia method) was detected in 25 (35.7%). Port-a-cath block and infection was seen in 11 (15.7%) and 20 (28.6%) patients respectively. Favourable outcomes were seen in 43 (61.4%) patients. Mortality was seen in 22 (31.4%) patients, 2 (2.9%) were lost-to-follow-up and 3 (4.3%) were declared as treatment failure. The overarching theme of the qualitative analysis was: Challenges in delivering Imipenem via port-a-cath device in ambulatory care. Major challenges identified were difficulties in adhering to drug dose timelines, vomiting, restricted mobility due to port-a-cath, paucity of infection control and space constraints at patients’ home for optimal care.
Conclusion
Administration of imipenem was feasible through port-a-cath. Though outcomes with ambulatory based imipenem containing regimens were promising, there were several challenges in providing care. The feasibility of infusion at day care facilities needs to explored to overcome challenges in infusion at patients home.
Imipenem, an intravenous antibiotic is recommended for use in drug resistant tuberculosis (DR-TB) when an effective regimen with combination of other second line drugs is not possible. Though the treatment success rates with carbapenems are promising, the twice daily injection of Imipenem usually requires patients to be hospitalized. The Médecins Sans Frontières independent clinic in Mumbai, India implemented ambulatory and home based management of patients receiving Imipenem through the use of port-a-cath.
Objective
We aimed to describe the adverse events and treatment outcomes of ambulatory pre- and XDR-TB patients initiated on imipenem through port-a-cath between January 2015 and June 2018 and to explore the challenges with this regimen as perceived by healthcare providers and patients.
Methods
A convergent mixed methods study with quantitative (longitudinal descriptive study using the routine data) and qualitative (descriptive study) part conducted concurrently. For the quantitative component, all XDR-TB and pre-XDR-TB initiated on imipenem containing regimen during January 2015-June 2018 were included. For qualitative component, interviews were carried out including patients who initiated on imipenem (n = 5) and healthcare providers (n = 7) involved in providing treatment. Treatment outcomes, culture conversion and adverse events during treatment were described. Thematic analysis was carried out for qualitative component.
Results
Of the 70 patients included, the mean age was 28.1 (standard deviation: 11.2) years and 36 (51.4%) were females. Fifty one (72.9%) had XDR-TB. All patients were resistant to fluoroquinilone, levofloxacin. Vomiting was reported by 55 (78.6%) patients and at least one episode of QTC prolongation (more than 500 msec by Fredrecia method) was detected in 25 (35.7%). Port-a-cath block and infection was seen in 11 (15.7%) and 20 (28.6%) patients respectively. Favourable outcomes were seen in 43 (61.4%) patients. Mortality was seen in 22 (31.4%) patients, 2 (2.9%) were lost-to-follow-up and 3 (4.3%) were declared as treatment failure. The overarching theme of the qualitative analysis was: Challenges in delivering Imipenem via port-a-cath device in ambulatory care. Major challenges identified were difficulties in adhering to drug dose timelines, vomiting, restricted mobility due to port-a-cath, paucity of infection control and space constraints at patients’ home for optimal care.
Conclusion
Administration of imipenem was feasible through port-a-cath. Though outcomes with ambulatory based imipenem containing regimens were promising, there were several challenges in providing care. The feasibility of infusion at day care facilities needs to explored to overcome challenges in infusion at patients home.
Journal Article > ResearchFull Text
PLOS One. 21 January 2015; Volume 10 (Issue 1); DOI:10.1371/journal.pone.0116798
Dalal A, Pawaskar A, Das M, Desari R, Prabhudesai P, et al.
PLOS One. 21 January 2015; Volume 10 (Issue 1); DOI:10.1371/journal.pone.0116798
While the high burden of multidrug-resistant tuberculosis (MDR-TB) itself is a matter of great concern, the emergence and rise of advanced forms of drug-resistance such as extensively drug-resistant TB (XDR-TB) and extremely drug-resistant TB (XXDR-TB) is more troubling. The aim of this study was to investigate the trends over time of patterns of drug resistance in a sample of MDR-TB patients in greater metropolitan Mumbai, India.