Conference Material > Slide Presentation
Khan S, Silsarma A, Iyer AS, Galindo MA, Chavan VV, et al.
MSF Scientific Days International 2023. 2023 June 7; DOI:10.57740/0dpv-wz08
Conference Material > Poster
Mankar S, Vengurlekar D, Khan S, Silsarma A, Sutar N, et al.
MSF Scientific Days International 2022. 2022 May 9; DOI:10.57740/awnn-kh70
Journal Article > LetterFull Text
Int J Tuberc Lung Dis. 2023 July 1; 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. 2023 July 1; Volume 27 (Issue 7); 567-569.; DOI:10.5588/ijtld.22.0632
Conference Material > Poster
Mongia H, Mansoor H, Mamnoon F, Silsarma A, Davuluri P, et al.
MSF Scientific Days International 2022. 2022 May 9; DOI:10.57740/4qe4-m903
Conference Material > Poster
Singh SN, Singh P, Silsarma A, Iyer AS, Galindo MA, et al.
MSF Paediatric Days 2022. 2022 November 30; DOI:10.57740/jnqv-bc66
Conference Material > Slide Presentation
Mansoor H, Hirani N, Chavan VV, Joshi A, Oswal V, et al.
MSF Scientific Days International 2022. 2022 May 11; DOI:10.57740/x7k7-xj13
Conference Material > Abstract
Khan S, Silsarma A, Iyer AS, Galindo MA, Chavan VV, et al.
MSF Scientific Days International 2023. 2023 June 7; 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
Conference Material > Video (talk)
Mansoor H, Hirani N, Chavan VV, Joshi A, Oswal V, et al.
MSF Scientific Days International 2022. 2022 June 7; DOI:10.57740/3gdn-kn91
Conference Material > Abstract
Mansoor H, Hirani N, Chavan VV, Joshi A, Oswal V, et al.
MSF Scientific Days International 2022. 2022 May 11; DOI:10.57740/atfq-6s03
INTRODUCTION
In countries with a high tuberculosis (TB) burden, poor access to drug susceptibility testing is a major bottleneck in diagnosing drug-resistant (DR) TB. India is estimated to account for a quarter of multidrug-resistant (MDR)-TB patients globally, with around 124,000 cases in 2020. Mumbai, a densely populated city in Maharashtra State, is a DR-TB hotspot with 24% of treatment- naïve cases, and 41% of previously-treated cases, having MDR-TB, and a high frequency of fluoroquinolone resistance occurring among these MDR-TB cases. Targeted next- generation sequencing (tNGS) is a promising technology for rapid detection of resistance. We assessed the role of tNGS for diagnosis of DR-TB.
METHODS
We performed a laboratory-based study involving Mycobacterium tuberculosis (MTB)-positive samples from patients with presumptive TB or DR-TB identified by GeneXpert in Shatabdi Hospital, Mumbai. A total of 161 sputum samples from bacteriologically-confirmed TB cases were included in the study. The study was conducted at Sir JJ Hospital’s TB lab, with sample collection occurring from patients living in M-East Ward (MEW), Mumbai. Two sputum samples were collected from each presumptive TB patient at MEW. Spot samples with a positive result on Xpert MTB/Rif were sent for tNGS and conventional testing (phenotypic drug sensitivity testing (pDST), line probe assays (LPA), and mycobacteria growth indicator tubes (MGIT)) at Sir JJ Hospital’s TB lab. tNGS samples were processed using Deeplex MycTB-kit (GenoScreen, France) and sequenced on a MiSeq platform (Illumina, USA). These samples were also processed for pDST using 16 drugs on MGIT (Becton Dickinson, USA) and LPA (MTBDRplus and MTBDRsl, Hain Lifesciences, Germany). To ensure sequence quality, Xpert results with cycle threshold values <20 or direct smear results >2+ were prepared for tNGS using direct sputum sediments. Primary cultures were prepared for samples with lower bacterial loads.
ETHICS
This study was approved by the ethics committee of the Grant Medical College & Sir J J Group of Hospitals, Mumbai, India. Permission was granted by the Medical Director of MSF, Operational Centre Brussels.
RESULTS
The median age of patients with samples included was 24 years (interquartile range, 20-40), and 57% were female. Approximately 70% of cases had no previous history of TB. Of 161 samples evaluated, 15 (9.3%) were rifampicin-sensitive and 146 (90.7%) were rifampicin-resistant (RR). 161 samples with completed pDST, tNGS and LPA were analysed. Of these, 88.2% had RR/MDR-TB resistance per WHO definitions, 58.5% had additional fluoroquinolone-resistance (pre-XDR) and 9.2% had fluoroquinolone resistance plus resistance to either linezolid or bedaquiline (extensively drug-resistant (XDR). Thirteen of 161 samples (8%) were culture-negative, yet resistance to one or more drugs was demonstrated in 8/13 samples with tNGS. Resistance frequency was similar across methods, with discordance in drugs less reliable in pDST or limited mutational representation within databases. Sensitivities aligned with the WHO catalogue for most drugs. 10% of the sample showed hetero-resistance and 75% of strains were of lineages 2 and 3.
CONCLUSION
In countries with a high burden of DR-TB, and high transmission rates, tNGS can provide information to rapidly design individualised regimens for early initiation and effective case management. It also gives information regarding lineages, uncharacterized mutations, hetero-resistance and mixed infection status of TB cases. Potentially tNGS could provide a diagnostic tool for rapid initiation of treatment in high DR-TB settings.
CONFLICTS OF INTEREST
None declared.
In countries with a high tuberculosis (TB) burden, poor access to drug susceptibility testing is a major bottleneck in diagnosing drug-resistant (DR) TB. India is estimated to account for a quarter of multidrug-resistant (MDR)-TB patients globally, with around 124,000 cases in 2020. Mumbai, a densely populated city in Maharashtra State, is a DR-TB hotspot with 24% of treatment- naïve cases, and 41% of previously-treated cases, having MDR-TB, and a high frequency of fluoroquinolone resistance occurring among these MDR-TB cases. Targeted next- generation sequencing (tNGS) is a promising technology for rapid detection of resistance. We assessed the role of tNGS for diagnosis of DR-TB.
METHODS
We performed a laboratory-based study involving Mycobacterium tuberculosis (MTB)-positive samples from patients with presumptive TB or DR-TB identified by GeneXpert in Shatabdi Hospital, Mumbai. A total of 161 sputum samples from bacteriologically-confirmed TB cases were included in the study. The study was conducted at Sir JJ Hospital’s TB lab, with sample collection occurring from patients living in M-East Ward (MEW), Mumbai. Two sputum samples were collected from each presumptive TB patient at MEW. Spot samples with a positive result on Xpert MTB/Rif were sent for tNGS and conventional testing (phenotypic drug sensitivity testing (pDST), line probe assays (LPA), and mycobacteria growth indicator tubes (MGIT)) at Sir JJ Hospital’s TB lab. tNGS samples were processed using Deeplex MycTB-kit (GenoScreen, France) and sequenced on a MiSeq platform (Illumina, USA). These samples were also processed for pDST using 16 drugs on MGIT (Becton Dickinson, USA) and LPA (MTBDRplus and MTBDRsl, Hain Lifesciences, Germany). To ensure sequence quality, Xpert results with cycle threshold values <20 or direct smear results >2+ were prepared for tNGS using direct sputum sediments. Primary cultures were prepared for samples with lower bacterial loads.
ETHICS
This study was approved by the ethics committee of the Grant Medical College & Sir J J Group of Hospitals, Mumbai, India. Permission was granted by the Medical Director of MSF, Operational Centre Brussels.
RESULTS
The median age of patients with samples included was 24 years (interquartile range, 20-40), and 57% were female. Approximately 70% of cases had no previous history of TB. Of 161 samples evaluated, 15 (9.3%) were rifampicin-sensitive and 146 (90.7%) were rifampicin-resistant (RR). 161 samples with completed pDST, tNGS and LPA were analysed. Of these, 88.2% had RR/MDR-TB resistance per WHO definitions, 58.5% had additional fluoroquinolone-resistance (pre-XDR) and 9.2% had fluoroquinolone resistance plus resistance to either linezolid or bedaquiline (extensively drug-resistant (XDR). Thirteen of 161 samples (8%) were culture-negative, yet resistance to one or more drugs was demonstrated in 8/13 samples with tNGS. Resistance frequency was similar across methods, with discordance in drugs less reliable in pDST or limited mutational representation within databases. Sensitivities aligned with the WHO catalogue for most drugs. 10% of the sample showed hetero-resistance and 75% of strains were of lineages 2 and 3.
CONCLUSION
In countries with a high burden of DR-TB, and high transmission rates, tNGS can provide information to rapidly design individualised regimens for early initiation and effective case management. It also gives information regarding lineages, uncharacterized mutations, hetero-resistance and mixed infection status of TB cases. Potentially tNGS could provide a diagnostic tool for rapid initiation of treatment in high DR-TB settings.
CONFLICTS OF INTEREST
None declared.
Journal Article > ResearchFull Text
Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 2024 April 1; 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. 2024 April 1; 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.