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RECENT PUBLICATIONS

 From Our September 2020 Newsletter

Major Depression and Stigma among Individuals with Multidrug-Resistant  Tuberculosis in South Africa.
 Am J Trop Med Hyg. 2020 Sep;103(3):1067-1071. doi: 10.4269/ajtmh.19-0426.
 
Naidu T(1), Pillay SR(2)(3), Ramlall S(3), Mthembu SS(4), Padayatchi N(5), Burns JK(6)(3), Tomita A(7)(8).
 
Stigma is an important social determinant of health-seeking behavior; however, the nature and extent of its association with depression among people living with multidrug-resistant tuberculosis (MDR-TB) are not well-understood. We enrolled 200 microbiologically confirmed MDR-TB inpatients at a TB specialist hospital in KwaZulu-Natal Province, an area considered the epicenter for MDR-TB coinfection in South Africa. Four aspects of stigma and their association with major depression were assessed through individual interviews: 1) community and 2) patient perspectives toward TB, and 3) community and 4) patient perspectives toward HIV. A major depressive episode (MDE), HIV coinfection, and low income were significantly associated with greater stigma subscales. Based on an adjusted regression model, the MDE was the only factor independently associated with (all aspects of) stigma. These results indicate the potential utility of addressing stigma associated with the MDE as an important step in improving health-seeking behavior to promote adherence and retention in care.
 
DOI: 10.4269/ajtmh.19-0426
PMCID: PMC7470525
PMID: 32700662

Population Pharmacokinetics of Linezolid in Tuberculosis Patients: Dosing  Regimen Simulation and Target Attainment Analysis.

 

Antimicrob Agents Chemother. 2020 Sep 21;64(10):e01174-20. doi: 10.1128/AAC.01174-20. Print 2020 Sep 21.
 
Alghamdi WA(1), Al-Shaer MH(2), An G(3), Alsultan A(4), Kipiani M(5), Barbakadze K(5), Mikiashvili L(5), Ashkin D(6), Griffith DE(7), Cegielski JP(8), Kempker RR(9), Peloquin CA(10).
 
The prolonged treatment duration for multidrug-resistant tuberculosis (MDR-TB) makes linezolid dosing difficult because of adverse effects associated with long-term use. We sought to find the optimal dosing regimen for linezolid across different MIC values. Pharmacokinetic (PK) data from TB patients were included from Brazil, Georgia, and two U.S. sites. Population PK modeling and simulation were performed. We used an fAUC (area under the unbound drug concentration-time curve)/MIC ratio of >119 as the PK/pharmacodynamic (PD) target and minimum (trough) concentrations of drug (C mins) of 2 and 7 mg/liter as thresholds for toxicity. The PK/PD breakpoint was defined as the highest MIC at which the probability of target attainment is >90%. A total of 104 patients with pulmonary TB were included, with a median age and weight of 37 years and 60 kg. Eighty-one percent had drug-resistant TB. The PK data were best described by a one-compartment model. The PK/PD breakpoint was 0.125 mg/liter for a total daily dose of 300 mg, while daily doses of 450 to 600 mg and 900 to 1,200 mg had PK/PD breakpoints of 0.25 and 0.50 mg/liter, respectively. The probability of achieving a C min of ≤2 mg/liter was higher when the dose was given at once than when dividing it into 2 doses. Linezolid at a daily dose of 300 mg may not be optimal. We predicted an excellent and comparable efficacy of linezolid using total daily doses of 900 and 1,200 mg for MICs of ≤0.5 mg/liter but with the potential for more toxicity than with 600 mg daily. The increase in C min was noticeable when the daily dose was divided and may incur greater toxicity.
 
Copyright © 2020 American Society for Microbiology.
 
DOI: 10.1128/AAC.01174-20
PMID: 32778547

Bacterial and host determinants of cough aerosol culture positivity in patients  with drug-resistant versus drug-susceptible tuberculosis.

 

Nat Med. 2020 Sep;26(9):1435-1443. doi: 10.1038/s41591-020-0940-2. Epub 2020 Jun 29.
 
Theron G(1)(2), Limberis J(1), Venter R(2), Smith L(1)(2), Pietersen E(1), Esmail A(1), Calligaro G(1), Te Riele J(3), de Kock M(2), van Helden P(2), Gumbo T(4), Clark TG(5)(6), Fennelly K(7), Warren R(2), Dheda K(8)(9).
 
A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesized that lower proportions of patients with drug-resistant TB would have culturable Mycobacterium tuberculosis from respirable, cough-generated aerosols compared to patients with drug-susceptible TB, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated the colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with drug resistance), compared clinical characteristics, and performed mycobacterial whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of the patients with drug-resistant TB were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive, thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture positivity; however, this was not always rapid. These data question current paradigms, inform public health strategies and suggest the need to redirect TB transmission-associated research efforts toward host-pathogen interactions.
 
DOI: 10.1038/s41591-020-0940-2
PMID: 32601338

Public investments in the clinical development of bedaquiline.

 

PLoS One. 2020 Sep 18;15(9):e0239118. doi: 10.1371/journal.pone.0239118. eCollection 2020.
 
Gotham D(1), McKenna L(2), Frick M(2), Lessem E(2).
 
INTRODUCTION: In 2012, bedaquiline became the first new treatment from a novel class to be approved for tuberculosis in nearly five decades and is now a core component of the standard of care for multidrug-resistant tuberculosis. In addition to the originator pharmaceutical company, Janssen, a range of governmental and non-profit entities have contributed to the development of bedaquiline.
MATERIALS AND METHODS: We identified various avenues of public investments in the development of bedaquiline: direct funding of clinical trials and a donation programme, tax credits and deductions, and revenues resulting from the priority review voucher (PRV) awarded to the originator. Data on investments were gathered through contact with study leads and/or funders; for non-responses, published average costs were substituted. The originator company's expenses were estimated by similar methods. Tax credits and deductions were calculated based on estimated originator trial costs and donation expenses. The value of the PRV was estimated by application of a published model.
RESULTS: Public contributions through clinical trials funding were estimated at US$109-252 million, tax credits at US$22-36 million, tax deductions at US$8-27 million, administration of a donation programme at US$5 million, PRV revenues at US$300-400 million. Total public investments were US$455-747 million and originator investments were US$90-240 million (if capitalized and risk-adjusted, US$647-1,201 million and US$292-772 million, respectively).
CONCLUSIONS: Estimating the investments in the development of a medicine can inform discussions regarding fair pricing and future drug development. We estimated that total public investments exceeded the originator's by a factor of 1.6-5.1.
 
DOI: 10.1371/journal.pone.0239118
PMID: 32946474

 From Our August 2020 Newsletter

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid: A  Prospective Multi-country Study
 
Am J Respir Crit Care Med. 2020 Jul 24. doi: 10.1164/rccm.202001-0135OC. Online ahead of print.
 
Franke MF(1)(2), Khan P(3), Hewison C(4), Khan U(5), Huerga H(6), Seung KJ(7)(8), Rich ML(9)(8), Zarli K(10), Samieva N(11), Oyewusi L(12), Nair P(13), Mudassar M(14), Melikyan N(15), Lenggogeni P(16), Lecca L(17), Kumsa A(18), Khan M(19), Islam S(20), Hussein K(21), Docteur W(22), Chumburidze N(23), Berikova E(24), Atshemyan H(25), Atwood S(9), Alam M(20), Ahmed S(14), Bastard M(26), Mitnick CD(27)(28)(8); endTB observational study team.
 
Background Bedaquiline and delamanid offer the possibility of more effective and less toxic multidrug-resistant tuberculosis (MDR-TB) treatment. With this treatment, however, some patients, remain at high risk for an unfavorable treatment outcome. The endTB observational study is the largest multicountry cohort of patients with rifampin-resistant/MDR-TB treated in routine care, according to WHO guidance, with delamanid- and/or bedaquiline-containing regimens. We report frequency of sputum culture conversion within six-months of treatment initiation and risk factors for non-conversion. Methods We included patients with a positive baseline culture who initiated a first endTB regimen prior to April 2018. Two consecutive negative cultures collected > 15 days apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups. Findings 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%) or both (10%). Of these, 939 (85%) experienced culture conversion within six months. In adjusted analyses, patients with HIV had a lower probability of conversion (0·73 [95% CI: 0·62, 0·84]) than patients without HIV (0·84 [95% CI: 0·79, 0·90]; p=0·03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0·68 [95% CI: 0·57, 0·79]) relative to patients without either (0·89; 95% CI: 0·84, 0·95; p=0·0004). Hepatitis C infection, diabetes mellitus/glucose intolerance, and baseline resistance were not associated with conversion. Interpretation Frequent sputum conversion in patients with rifampin-resistant/MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.
 
DOI: 10.1164/rccm.202001-0135OC
PMID: 32706644

(Article not publicly available)


Nomogram for individualized prediction of incident multidrug-resistant  tuberculosis after completing pulmonary tuberculosis treatment
 
Sci Rep. 2020 Aug 13;10(1):13730. doi: 10.1038/s41598-020-70748-x.
 
Cheng Q(1)(2), Zhao G(1), Wang X(1), Wang L(1), Lu M(1), Li Q(1), Wu Y(1), Huang Y(1), Jia Q(1), Xie L(3).
 
The purposes of this study were to construct a comprehensive nomogram for providing a simple, precise and personalized prediction of incident multidrug-resistant tuberculosis (MDR-TB) after completing pulmonary tuberculosis treatment (CPTBT). A matched case-control study (1:2 ratios) was performed between 2005 and 2018. A multivariable Cox regression analysis was used to evaluate independent predictors of incident MDR-TB after the CPTBT. A comprehensive nomogram was developed based on the multivariable Cox model. Overall, 1, 836 participants were included in this study. We developed and validated a simple-to-use nomogram that predicted the individualized risk of incident MDR-TB by using 10 parameters after the CPTBT. The concordance index of this nomogram was 0.833 [95% confidence interval (CI) 0.807-0.859] and 0.871 (95% CI 0.773-0.969) for the training and validation sets, respectively, which indicated adequate discriminatory power. The calibration curves for the risk of incident MDR-TB showed an optimal agreement between nomogram prediction and actual observation in the training and validation sets, respectively. The high sensitivity and specificity of nomogram was indicated by using a receiver operating characteristic curve analysis. Through this clinic tool, TB control executives could more precisely monitor, estimate and intervene the risk of incident MDR-TB among individuals with CPTBT.
 
DOI: 10.1038/s41598-020-70748-x
PMCID: PMC7426812
PMID: 32792606



Population pharmacokinetics of cycloserine, and pharmacokinetic/pharmacodynamic  target attainment, in MDR-tuberculosis patients dosed with terizidone
 
Antimicrob Agents Chemother. 2020 Aug 17:AAC.01381-20. doi: 10.1128/AAC.01381-20. Online ahead of print.
 
Chirehwa MT(1), Court R(1), De Kock M(2), Wiesner L(1), de Vries N(3), Harding J(4), Gumbo T(5), Maartens G(1)(6), Warren R(2), Denti P(1), McIlleron H(7)(6).
 
Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis. Pharmacokinetic/pharmacodynamic data for cycloserine when dosed as terizidone are sparse. The aim of this analysis was to describe the population pharmacokinetics of cycloserine, administered as terizidone, and predict doses of terizidone attaining cycloserine exposures associated with efficacy. Plasma cycloserine was measured 2-6 weeks after treatment initiation in patients hospitalized for second-line tuberculosis treatment. Pre-treatment MICs of cycloserine were determined on clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. Median pre-treatment MIC was 16 mg/L. A one compartment disposition model with two clearance pathways, non-renal (0.35 L/h) and renal (0.43 L/h) described cycloserine pharmacokinetics well. Non-renal clearance and volume were allometrically scaled using fat-free mass. Smoking increased non-renal clearance by 41%. Simulations showed that wit daily doses of terizidone (750 mg and 1000 mg for patients weighing ≤ 45 kg and > 45 kg, respectively), the probability of maintaining plasma cycloserine above the MIC (T>MIC) for more than 30% of the dosing interval (which is associated with a 1.0 log10 CFU/mL kill in vitro) exceeds, 90% at MIC values ≤ 16 mg/L, but the proportion of patients achieving 100% T>MIC (which is associated with prevention of resistance) is more than 90% only with MICs ≤ 8 mg/L. Based on a target derived in vitro, the WHO recommended doses of terizidone are effective for cycloserine MICs ≤ 8 mg/L and higher doses are required to prevent the development of resistance.
 
Copyright © 2020 American Society for Microbiology.
 
DOI: 10.1128/AAC.01381-20
PMID: 32816738



Population Pharmacokinetics of Linezolid in Tuberculosis Patients: Dosing  Regimens Simulation and Target Attainment Analysis

 Antimicrob Agents Chemother. 2020 Aug 10:AAC.01174-20. doi: 10.1128/AAC.01174-20. Online ahead of print.
 
Alghamdi WA(1), Al-Shaer MH(2), An G(3), Alsultan A(4), Kipiani M(5), Barbakadze K(5), Mikiashvili L(5), Ashkin D(6), Griffith DE(7), Cegielski JP(8), Kempker RR(9), Peloquin CA(10).
 
BACKGROUND: The prolonged treatment duration for multidrug-resistant (MDR) tuberculosis (TB) makes dosing linezolid difficult because of adverse effects associated with long-term use. We sought to find the optimal dosing regimen for linezolid given different MIC values.
METHODS: Pharmacokinetic (PK) data from TB patients were included from Brazil, Georgia, and two U.S. sites. Population PK modeling and simulation were performed. We used fAUC/MIC >119 as the pharmacokinetic/pharmacodynamic (PK/PD) target, and Cmin of 2 and 7 mg/L as thresholds for toxicity. The PK/PD breakpoint was defined as the highest MIC at which the probability of target attainment is >90%.
RESULTS: A total of 104 patients with pulmonary TB were included, with a median age and weight of 37 years and 60 kilograms. 81% had drug-resistant TB. The PK data were best described by a one-compartment model. The PK/PD breakpoint was 0.125 mg/L for a total daily dose of 300 mg, while the daily dose of 450-600 mg and 900-1200 mg had PK/PD breakpoints of 0.25 and 0.50 mg/L, respectively. The probability of achieving Cmin ≤2 mg/L was higher when the dose was given at once versus dividing it to two doses.
CONCLUSION: Linezolid daily dose of 300 mg may not be optimal. We predicted excellent and comparable efficacy of linezolid using total daily doses of 900 and 1200 mg for MICs ≤0.5 mg/L, but with a potential for more toxicity compared to 600 mg daily. The increase in Cmin was noticeable when the daily dose was divided and may incur greater toxicity.
 
Copyright © 2020 American Society for Microbiology.
 
DOI: 10.1128/AAC.01174-20
PMID: 32778547



Population-level emergence of bedaquiline and clofazimine resistance-associated  variants among patients with drug-resistant tuberculosis in southern Africa: a  phenotypic and phylogenetic analysis

Lancet Microbe. 2020 Aug;1(4):e165-e174. doi: 10.1016/S2666-5247(20)30031-8.
 
Nimmo C(1)(2)(3), Millard J(3)(4)(5), van Dorp L(2), Brien K(3), Moodley S(3), Wolf A(6), Grant AD(3)(7)(8), Padayatchi N(9), Pym AS(3), Balloux F(2), O'Donnell M(6)(10)(9).
 
BACKGROUND: Bedaquiline and clofazimine are important drugs in the treatment of drug-resistant tuberculosis and are commonly used across southern Africa, although drug susceptibility testing is not routinely performed. In this study, we did a genotypic and phenotypic analysis of drug-resistant Mycobacterium tuberculosis isolates from cohort studies in hospitals in KwaZulu-Natal, South Africa, to identify resistance-associated variants (RAVs) and assess the extent of clofazimine and bedaquiline cross-resistance. We also used a comprehensive dataset of whole-genome sequences to investigate the phylogenetic and geographical distribution of bedaquiline and clofazimine RAVs in southern Africa.
METHODS: In this study, we included M tuberculosis isolates reported from the PRAXIS study of patients with drug-resistant tuberculosis treated with bedaquiline (King Dinuzulu Hospital, Durban) and three other cohort studies of drug-resistant tuberculosis in other KwaZulu-Natal hospitals, and sequential isolates from six persistently culture-positive patients with extensively drug-resistant tuberculosis at the KwaZulu-Natal provincial referral laboratory. Samples were collected between 2013 and 2019. Microbiological cultures were done as part of all parent studies. We sequenced whole genomes of included isolates and measured bedaquiline and clofazimine minimum inhibitory concentrations (MICs) for isolates identified as carrying any Rv0678 variant or previously published atpE, pepQ, and Rv1979c RAVs, which were the subject of the phenotypic study. We combined all whole-genome sequences of M tuberculosis obtained in this study with publicly available sequence data from other tuberculosis studies in southern Africa (defined as the countries of the Southern African Development Community), including isolates with Rv0678 variants identified by screening public genomic databases. We used this extended dataset to reconstruct phylogenetic relationships across lineage 2 and 4 M tuberculosis isolates.
FINDINGS: We sequenced the whole genome of 648 isolates from 385 patients with drug-resistant tuberculosis recruited into cohort studies in KwaZulu-Natal, and 28 isolates from six patients from the KwaZulu-Natal referral laboratory. We identified 30 isolates with Rv0678 RAVs from 16 (4%) of 391 patients. We did not identify any atpE, pepQ, or Rv1979c RAVs. MICs were measured for 21 isolates with Rv0678 RAVs. MICs were above the critical concentration for bedaquiline resistance in nine (43%) of 21 isolates, in the intermediate category in nine (43%) isolates, and within the wild-type range in three (14%) isolates. Clofazimine MICs in genetically wild-type isolates ranged from 0·12-0·5 μg/mL, and in isolates with RAVs from 0·25-4·0 μg/mL. Phylogenetic analysis of the extended dataset including M tuberculosis isolates from southern Africa resolved multiple emergences of Rv0678 variants in lineages 2 and 4, documented two likely nosocomial transmission events, and identified the spread of a possibly bedaquiline and clofazimine cross-resistant clone in eSwatini. We also identified four patients with pepQ frameshift mutations that may confer resistance.
INTERPRETATION: Bedaquiline and clofazimine cross-resistance in southern Africa is emerging repeatedly, with evidence of onward transmission largely due to Rv0678 mutations in M tuberculosis. Roll-out of bedaquiline and clofazimine treatment in the setting of limited drug susceptibility testing could allow further spread of resistance. Designing strong regimens would help reduce the emergence of resistance. Drug susceptibility testing is required to identify where resistance does emerge.
FUNDING: Wellcome Trust, National Institute of Allergy and Infectious Diseases and National Center for Advancing Translational Sciences of the National Institutes of Health.
 
© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
 
DOI: 10.1016/S2666-5247(20)30031-8
PMCID: PMC7416634
PMID: 32803174

From Our July 2020 Newsletter

Ethionamide population pharmacokinetic model and target attainment in multidrug-resistant tuberculosis.
 

Antimicrob Agents Chemother. 2020 Jul 6:AAC.00713-20. doi: 10.1128/AAC.00713-20. Online ahead of print.
 
Al-Shaer MH(1), Märtson AG(2), Alghamdi WA(3), Alsultan A(4), An G(5), Ahmed S(6), Alkabab Y(7), Banu S(6), Houpt ER(7), Ashkin D(8), Griffith DE(9), Cegielski JP(9), Heysell SK(7), Peloquin CA(10).
 
Ethionamide (ETA), an isonicotinic acid derivative, is part of multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines deprioritized ETA due to potential less effectiveness compared to other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens to assess target attainment. This study included subjects from four different sites, including both healthy volunteers and patients with MDR-TB. The TB centers included were two in the US and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, 1,000-2,250 mg total daily regimens were simulated, and target attainment using published minimum inhibitory concentrations (MICs) and 1.0-log kill and resistance suppression targets were assessed using Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag-time. The mean (SD) final population parameter estimates were: absorption rate constant 1.02 hr-1 (1.11), elimination rate constant 0.69 hr-1 (0.46), volume of distribution 104.16 L (59.87), and lag-time 0.43 hr (0.32). Total daily dose of 1,500 mg or more was needed to achieve ≥90% 1.0-log kill target attainment at MIC 1 mg/L, and 2,250 mg/day achieved 80% resistance suppression target attainment at MIC 0.5 mg/L. In conclusion, we developed a population PK
model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the predefined targets supporting current recommendations for ETA deprioritization.
 
Copyright © 2020 American Society for Microbiology.
 
DOI: 10.1128/AAC.00713-20 PMID: 32631828

(Article not publicly available)


Bacterial and host determinants of cough aerosol culture positivity in patients with drug-resistant versus drug-susceptible tuberculosis.
 
Nat Med. 2020 Jun 29. doi: 10.1038/s41591-020-0940-2. Online ahead of print.
 
Theron G(1)(2), Limberis J(1), Venter R(2), Smith L(1)(2), Pietersen E(1), Esmail A(1), Calligaro G(1), Te Riele J(3), de Kock M(2), van Helden P(2), Gumbo T(4), Clark TG(5)(6), Fennelly K(7), Warren R(2), Dheda K(8)(9).
 
A burgeoning epidemic of drug-resistant tuberculosis (TB) threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesized that lower proportions of patients with drug-resistant TB would have culturable Mycobacterium tuberculosis from respirable, cough-generated aerosols compared to patients with drug-susceptible TB, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated the colony forming units in aerosols (≤10 µm) from 452 patients with TB (227 with drug resistance), compared clinical characteristics, and performed mycobacterial whole-genome sequencing, dormancy phenotyping and drug-susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of the patients with drug-resistant TB were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive, thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture positivity; however, this was not always rapid. These data question current paradigms, inform public health strategies and suggest the need to redirect TB transmission-associated research efforts toward host-pathogen interactions.
 
DOI: 10.1038/s41591-020-0940-2
PMID: 32601338

(Article not publicly available)


Culture Conversion at 6 Months in Patients Receiving Delamanid-containing  Regimens for the Treatment of Multidrug-resistant Tuberculosis.
 
Clin Infect Dis. 2020 Jul 11;71(2):415-418. doi: 10.1093/cid/ciz1084.
 
Seung KJ(1), Khan P(2), Franke MF(3), Ahmed S(2), Aiylchiev S(4), Alam M(5), Putri FA(6), Bastard M(7), Docteur W(8), Gottlieb G(1), Hewison C(9), Islam S(5), Khachatryan N(10), Kotrikadze T(11), Khan U(12), Kumsa A(13), Lecca L(14), Tassew YM(15), Melikyan N(15), Naing YY(16), Oyewusi L(17), Rich M(1), Wanjala S(18), Yedilbayev A(1), Huerga H(7), Mitnick CD(3).
 
Delamanid should be effective against highly resistant strains of Mycobacteriumtuberculosis, but uptake has been slow globally. In the endTB (expand new drug markets for TB) Observational Study, which enrolled a large, heterogeneous cohorts of patients receiving delamanid as part of a multidrug regimen, 80% of participants experienced sputum culture conversion within 6 months. Clinical Trials Registration. NCT02754765.
 
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciz1084
PMID: 31676905

(Article not publicly available)


Direct and indirect patient costs of tuberculosis care in India.
 
Trop Med Int Health. 2020 Jul;25(7):803-812. doi: 10.1111/tmi.13402. Epub 2020 May 12.
 
Chandra A(1), Kumar R(1), Kant S(1), Parthasarathy R(1), Krishnan A(1).
 
OBJECTIVE: To synthesize the evidence for estimating the direct and indirect patient costs of drug-sensitive and drug-resistant tuberculosis care in India. 
METHOD: PubMed, Embase, Web of Science, IndMED and Google Scholar were searched
for studies conducted in India between 2000 and 2018 and published in English. The search terms were "tuberculosis" AND "costs" (cost Analysis, economics, cost of illness, health care costs, health expenditures, direct service costs, catastrophic cost) AND "India". The cost of TB care was from the patient's perspective. Data regarding costs were extracted, indexed to the year 2018 using cumulative inflation rate and converted to US dollars at the exchange rate of 2018.
RESULTS: Thirteen studies were included in this review. The mean (unweighted) total cost incurred by patients being treated for drug-sensitive TB in a public health facility was $ 235.00 (SD- 222.10), and the median of means was $ 170.60 (range - 43.70-718.40). The mean direct cost was 45.5% of the total cost. Only one study, which was conducted in a private facility, reported the mean total cost for drug-resistant TB as $ 7778.04. Catastrophic cost (total cost ≥ 20% of the total annual household income) was experienced by 7% to 32.4% of drug-sensitive TB patients and by 68% of drug-resistant TB patients.
CONCLUSION: Despite free diagnostic and treatment services provided under the Revised National Tuberculosis Control Programme, the patient cost of tuberculosis care is high. Relevant studies vary widely in methodology and cost reporting.
 
© 2020 John Wiley & Sons Ltd.
 
DOI: 10.1111/tmi.13402
PMID: 32306481

From Our June 2020 Newsletter

Bedaquiline resistance in drug-resistant tuberculosis HIV co-infected patients.
 

Eur Respir J. 2020 Jun 4;55(6):1902383. doi: 10.1183/13993003.02383-2019. Print 2020 Jun.
 
Nimmo C(1)(2)(3), Millard J(3)(4)(5), Brien K(3), Moodley S(3), van Dorp L(2), Lutchminarain K(6), Wolf A(7), Grant AD(3)(8), Balloux F(2), Pym AS(3), Padayatchi N(9), O'Donnell M(10)(11).

 
Genetic mutations linked to bedaquiline resistance were found before starting treatment and acquired during treatment in patients with drug-resistant TB and HIV in KwaZulu-Natal, South Africa. Routine bedaquiline resistance testing needs to be accelerated. http://bit.ly/2vnL4VY
 
Global tuberculosis (TB) control is threatened by drug resistance, with over 500 000 cases resistant to first line drugs in 2018 [1]. Bedaquiline is a highly effective TB drug and has improved drug-resistant TB (DR-TB) outcomes in trial and programmatic settings [2, 3]. The World Health Organization (WHO) recommends its inclusion in most DR-TB regimens [4] and it is under further evaluation in clinical trials. There have been several reports of clinical bedaquiline resistance [5–8]. Resistance-associated variants (RAVs) in clinical isolates identified to date are almost exclusively caused by Rv0678 mutations which can raise Mycobacterium tuberculosis minimum inhibitory concentrations (MICs) for bedaquiline and clofazimine [9].
 
DOI: 10.1183/13993003.02383-2019
PMCID: PMC7270361
PMID: 32060065

Ambulatory management of pre- and extensively drug resistant tuberculosis  patients with imipenem delivered through port-a-cath: A mixed methods study on  treatment outcomes and challenges.
 
PLoS One. 2020 Jun 16;15(6):e0234651. doi: 10.1371/journal.pone.0234651. eCollection 2020.
 
Chavan VV(1), Dalal A(2), Nagaraja S(3), Thekkur P(4)(5), Mansoor H(1), Meneguim A(1), Paryani R(1), Singh P(1), Kalon S(1), Das M(1), Ferlazzo G(6), Isaakidis P(6).
 
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.
 
DOI: 10.1371/journal.pone.0234651
PMCID: PMC7297304
PMID: 32544174


Concordance of drug resistance profiles between persons with drug-resistant tuberculosis and their household contacts: a systematic review and meta-analysis.
 
Clin Infect Dis. 2020 May 25:ciaa613. doi: 10.1093/cid/ciaa613. Online ahead of print.
 
Chiang SS(1)(2), Brooks MB(3), Jenkins HE(4), Rubenstein D(1), Seddon JA(5)(6), van de Water BJ(3), Lindeborg MM(3), Becerra MC(3)(7), Yuen CM(3)(7).
 
BACKGROUND: Household contacts of patients with drug-resistant tuberculosis are at high risk for being infected with Mycobacterium tuberculosis and for developing tuberculosis disease. To guide regimen composition for the empirical treatment of tuberculosis infection and disease in these household contacts, we estimated drug resistance profile concordance between index patients with drug-resistant tuberculosis and their household contacts.
METHODS: We performed a systematic review and meta-analysis of studies published through July 24, 2018 and reported resistance profiles of drug-resistant tuberculosis index and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only.
RESULTS: We identified 33 eligible studies, which evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI]: 40.7-67.6, I2=85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI: 72.3-90.9; I2=73%). Concordance estimates were similar in a sub-analysis of 16 studies from high tuberculosis-burden countries. There were insufficient data to perform a sub-analysis among pediatric secondary cases.
CONCLUSION: Household contacts of drug-resistant TB patients should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.
 
© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:
journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciaa613
PMID: 32448887

Isoniazid Preventive Therapy in Contacts of Multidrug-resistant Tuberculosis.
 
Am J Respir Crit Care Med. 2020 Jun 17. doi: 10.1164/rccm.201908-1576OC. Online ahead of print.
 
Huang CC(1)(2), Becerra MC(2), Calderon R(3), Contreras C(3), Galea J(4), Grandjean L(5)(6)(7), Lecca L(3), Yataco R(3), Zhang Z(1), Murray M(2)(8).
 
RATIONALE: The World Health Organization recommends the use of isoniazid alone or in combination with rifapentine to treat latent tuberculosis infection. The recent rise of drug-resistant tuberculosis has complicated the choice of latent tuberculosis infection treatment regimen.
OBJECTIVES: To evaluate the effects of isoniazid preventive therapy on contacts of multidrug-resistant tuberculosis patients Methods: In a prospective cohort study conducted between September 2009 and August 2012, we identified 4,500 index tuberculosis patients and 14,044 tuberculosis-exposed household contacts whom we followed for one year for the occurrence of incident tuberculosi disease. Although Peruvian national guidelines specify that isoniazid preventive therapy should be provided to contacts aged 19 and under, only half this group received isoniazid preventive therapy.
MEASUREMENTS AND MAIN RESULTS: Among 4,216 contacts under 19 years of age, 2,106
(50%) initiated isoniazid preventive therapy at enrollment. The protective effect of isoniazid was more extreme in contacts exposed to drug-sensitive (adjusted hazard ratio, 0.30 [95% confidence interval, 0.18-0.48]) and to multidrug-resistant tuberculosis (0.19 [0.05-0.66]) compared to those exposed to mono-isoniazid-resistant (0.80 [0.23-2.80]). In the second independent study, tuberculosis occurred in none of the 76 household contacts who received isoniazid preventive therapy compared to 3% (8/273) of those who did not.
CONCLUSION: Household contacts who received isoniazid preventive therapy had a lower incidence of tuberculosis disease even when they had been exposed to an index patient with multidrug-resistant tuberculosis. Isoniazid may have a role in the management of latent multidrug-resistant tuberculosis infection.
 
DOI: 10.1164/rccm.201908-1576OC
PMID: 32551948

Challenges in Tuberculosis Clinical Trials in the Face of the COVID-19 Pandemic:  A Sponsor's Perspective.
 
Trop Med Infect Dis. 2020 May 27;5(2):E86. doi: 10.3390/tropicalmed5020086.
 
Rusen ID(1).
 
The COVID-19 pandemic has caused unforeseen and extreme changes in societal and health system functioning not previously experienced in most countries in a lifetime. The impact of the pandemic on clinical trials can be especially profound given their complexities and operational requirements. The STREAM
Clinical Trial is the largest trial for MDR-TB ever conducted. Currently operating in seven countries, the trial had 126 participants on treatment and 312 additional participants in active follow up as of March 31, 2020. Areas of particular concern during this global emergency include treatment continuity,
supply chain management and participant safety monitoring. This commentary highlights some of the challenges faced due to the pandemic and the steps taken to protect the safety of trial participants and the integrity of the trial.
 
DOI: 10.3390/tropicalmed5020086
PMID: 32471274


Responding to SARS-CoV-2 in South Africa: What can we learn from drug-resistant tuberculosis?
 
Eur Respir J. 2020 May 29:2001369. doi: 10.1183/13993003.01369-2020. Online ahead of print.
 
Ndjeka N(1)(2), Conradie F(3)(2), Meintjes G(4), Reuter A(5), Hughes J(6), Padanilam X(7), Ismail N(8), Kock Y(1), Master I(9), Romero R(10), Te Riele J(11), Enwerem M(12), Ferreira H(13), Maartens G(4).
 
Rapid adoption of new diagnostic tools, parallel process of research and implementation, decentralization of services, the use of personal protective equipment as well as strong partnership and collaboration could strengthen the fight against COVID-19.
 
The novel coronavirus strain, SARS-CoV-2, was first reported from China in December 2019 [1]. As of the 14th May 2020, more than 4.4 million individuals have tested positive for SARS-COV-2 globally [2]. More than 300,000 individuals have died globally due to SARS-COV-2 [2].
 
DOI: 10.1183/13993003.01369-2020
PMCID: PMC7257618
PMID: 32471936

From our May 2020 Newsletter

Ambulatory management of pre- and extensively drug resistant tuberculosis  patients with imipenem delivered through port-a-cath: A mixed methods study on  treatment outcomes and challenges.
 
PLoS One. 2020 Jun 16;15(6):e0234651. doi: 10.1371/journal.pone.0234651. eCollection 2020.
 
Chavan VV(1), Dalal A(2), Nagaraja S(3), Thekkur P(4)(5), Mansoor H(1), Meneguim A(1), Paryani R(1), Singh P(1), Kalon S(1), Das M(1), Ferlazzo G(6), Isaakidis P(6).
 
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.
 
DOI: 10.1371/journal.pone.0234651
PMCID: PMC7297304
PMID: 32544174

Concordance of drug resistance profiles between persons with drug-resistant tuberculosis and their household contacts: a systematic review and meta-analysis.
 
Clin Infect Dis. 2020 May 25:ciaa613. doi: 10.1093/cid/ciaa613. Online ahead of print.
 
Chiang SS(1)(2), Brooks MB(3), Jenkins HE(4), Rubenstein D(1), Seddon JA(5)(6), van de Water BJ(3), Lindeborg MM(3), Becerra MC(3)(7), Yuen CM(3)(7).
 
BACKGROUND: Household contacts of patients with drug-resistant tuberculosis are at high risk for being infected with Mycobacterium tuberculosis and for developing tuberculosis disease. To guide regimen composition for the empirical treatment of tuberculosis infection and disease in these household contacts, we estimated drug resistance profile concordance between index patients with drug-resistant tuberculosis and their household contacts.
METHODS: We performed a systematic review and meta-analysis of studies published through July 24, 2018 and reported resistance profiles of drug-resistant tuberculosis index and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only.
RESULTS: We identified 33 eligible studies, which evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI]: 40.7-67.6, I2=85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI: 72.3-90.9; I2=73%). Concordance estimates were similar in a sub-analysis of 16 studies from high tuberculosis-burden countries. There were insufficient data to perform a sub-analysis among pediatric secondary cases.
CONCLUSION: Household contacts of drug-resistant TB patients should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.
 
© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:
journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciaa613
PMID: 32448887

Isoniazid Preventive Therapy in Contacts of Multidrug-resistant Tuberculosis.
 
Am J Respir Crit Care Med. 2020 Jun 17. doi: 10.1164/rccm.201908-1576OC. Online ahead of print.
 
Huang CC(1)(2), Becerra MC(2), Calderon R(3), Contreras C(3), Galea J(4), Grandjean L(5)(6)(7), Lecca L(3), Yataco R(3), Zhang Z(1), Murray M(2)(8).
 
RATIONALE: The World Health Organization recommends the use of isoniazid alone or in combination with rifapentine to treat latent tuberculosis infection. The recent rise of drug-resistant tuberculosis has complicated the choice of latent tuberculosis infection treatment regimen.
OBJECTIVES: To evaluate the effects of isoniazid preventive therapy on contacts of multidrug-resistant tuberculosis patients Methods: In a prospective cohort study conducted between September 2009 and August 2012, we identified 4,500 index tuberculosis patients and 14,044 tuberculosis-exposed household contacts whom we followed for one year for the occurrence of incident tuberculosi disease. Although Peruvian national guidelines specify that isoniazid preventive therapy should be provided to contacts aged 19 and under, only half this group received isoniazid preventive therapy.
MEASUREMENTS AND MAIN RESULTS: Among 4,216 contacts under 19 years of age, 2,106
(50%) initiated isoniazid preventive therapy at enrollment. The protective effect of isoniazid was more extreme in contacts exposed to drug-sensitive (adjusted hazard ratio, 0.30 [95% confidence interval, 0.18-0.48]) and to multidrug-resistant tuberculosis (0.19 [0.05-0.66]) compared to those exposed to mono-isoniazid-resistant (0.80 [0.23-2.80]). In the second independent study, tuberculosis occurred in none of the 76 household contacts who received isoniazid preventive therapy compared to 3% (8/273) of those who did not.
CONCLUSION: Household contacts who received isoniazid preventive therapy had a lower incidence of tuberculosis disease even when they had been exposed to an index patient with multidrug-resistant tuberculosis. Isoniazid may have a role in the management of latent multidrug-resistant tuberculosis infection.
 
DOI: 10.1164/rccm.201908-1576OC
PMID: 32551948

Eur Respir J. 2020 Jun 4;55(6):1902383. doi: 10.1183/13993003.02383-2019. Print 2020 Jun.
 
Nimmo C(1)(2)(3), Millard J(3)(4)(5), Brien K(3), Moodley S(3), van Dorp L(2), Lutchminarain K(6), Wolf A(7), Grant AD(3)(8), Balloux F(2), Pym AS(3), Padayatchi N(9), O'Donnell M(10)(11).

Bedaquiline resistance in drug-resistant tuberculosis HIV co-infected patients.

From our April 2020 Newsletter

Risk factors for adverse events in household contacts prescribed preventive treatment for drug-resistant TB exposure.

 

Clin Infect Dis. 2020 Apr 8. pii: ciaa327. doi: 10.1093/cid/ciaa327. [Epub ahead
of print]

Malik AA(1)(2)(3), Becerra MC(4)(5)(6), Lash TL(1), Cranmer LM(7), Omer
SB(8)(9)(10), Fuad J(2), Siddiqui S(2), Amanullah F(11), Jaswal M(2), Salahuddin
N(11), Keshavjee S(4)(5)(6), Hussain H(3), Gandhi NR(1).

BACKGROUND: Completion of TB preventive treatment is important to optimize
efficacy; treatment-related adverse events sometimes result in discontinuation.
This study describes the occurrence of adverse events and their risk factors
during a 6-month 2-drug fluoroquinolone-based preventive treatment for household
contacts of drug-resistant TB patients in Karachi, Pakistan.
METHODS: The primary outcome was development of any clinical adverse event during
preventive treatment. Adverse events were categorized using the adverse events
grading tables of National Institute of Health. Time to event analysis with
Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence
were used to analyze associated risk factors.
RESULTS: Of the 172 household contacts on preventive treatment, 36 (21%)
developed 64 adverse events during 813 months of treatment. The incidence of
adverse events over 6-months treatment was 7.9 per 100 person-months (p-m); 16
per 100 p-m with a fluoroquinolone and ethionamide and 4.4 per 100 p-m with a
fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2
adverse events with no grade 3 or 4 adverse event. In multivariable analysis, the
risk of adverse events was higher in contacts prescribed ethionamide as compared
to ethambutol adjusting for age, sex and BMI (aHR: 2.1 [95% CI: 1.2-3.6]).
Overall, there was no notable difference in treatment completion amongst the
contacts who experienced an adverse event and those who did not (cOR: 1.1 [95%
CI: 0.52-2.5]).
CONCLUSION: A fluoroquinolone-based preventive treatment regimen for DR-TB
exposure is well tolerated. Regimens with ethionamide are more likely to result
in adverse events.

© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:
journals.permissions@oup.com.

DOI: 10.1093/cid/ciaa327
PMID: 32266942

 

Read the full article here.

 

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid.
 

Antibiotics (Basel). 2020 Mar 23;9(3). pii: E133. doi:
10.3390/antibiotics9030133.

Nieto Ramirez LM(1), Quintero Vargas K(2), Diaz G(3)(4).

Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially
due to the increasing dissemination of multidrug and extensively drug-resistant
(MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline
(BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR or
XDR-TB. Unfortunately, resistant cases to these drugs emerged just one year after
their introduction in clinical practice. Early detection of resistant strains to
BDQ and DLM is crucial to preserving the effectiveness of these drugs. Here, we
present a systematic review aiming to define all available genotypic variants
linked to different levels of resistance to BDQ and DLM that have been described
through whole genomic sequencing (WGS) and the available drug susceptibility
testing methods. During the review, we performed a thorough analysis of 18
articles. BDQ resistance was associated with genetic variants in Rv0678 and atpE,
while mutations in pepQ were linked to a low-level of resistance for BDQ. For
DLM, mutations in the genes ddn, fgd1, fbiA, and fbiC were found in
phenotypically resistant cases, while all the mutations in fbiB were reported
only in DLM-susceptible strains. Additionally, WGS analysis allowed the detection
of heteroresistance to both drugs. In conclusion, we present a comprehensive
panel of gene mutations linked to different levels of drug resistance to BDQ and
DLM.

DOI: 10.3390/antibiotics9030133
PMID: 32209979

 

Read the full article here.

Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med. 2020 Apr;8(4):383-394. doi: 10.1016/S2213-2600(20)30047-3.
Epub 2020 Mar 17.

Lan Z(1), Ahmad N(2), Baghaei P(3), Barkane L(4), Benedetti A(1), Brode SK(5),
Brust JCM(6), Campbell JR(1), Chang VWL(7), Falzon D(8), Guglielmetti L(9),
Isaakidis P(10), Kempker RR(11), Kipiani M(12), Kuksa L(4), Lange C(13),
Laniado-Laborín R(14), Nahid P(15), Rodrigues D(16), Singla R(17), Udwadia
ZF(18), Menzies D(19); Collaborative Group for the Meta-Analysis of Individual
Patient Data in MDR-TB treatment 2017.

BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term
therapy with a combination of multiple second-line drugs. These drugs are
associated with numerous adverse events that can cause severe morbidity, such as
deafness, and in some instances can lead to death. Our aim was to estimate the
absolute and relative frequency of adverse events associated with different
tuberculosis drugs to provide useful information for clinicians and tuberculosis
programmes in selecting optimal treatment regimens.
METHODS: We did a meta-analysis using individual-level patient data that were
obtained from studies that reported adverse events that resulted in permanent
discontinuation of anti-tuberculosis medications. We used a database created for
our previous meta-analysis of multidrug-resistant tuberculosis treatment and
outcomes, for which we did a systematic review of literature published between
Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual
patient-level information from authors. We also considered for this analysis
studies contributing patient-level data in response to a public call made by WHO
in 2018. Meta-analysis for proportions and arm-based network meta-analysis were
done to estimate the incidence of adverse events for each tuberculosis drug.
FINDINGS: 58 studies were identified, including 50 studies from the updated
individual patient data meta-analysis for multidrug-resistant tuberculosis
treatment. 35 of these studies, with 9178 patients, were included in our
analysis. Using meta-analysis of proportions, drugs with low risks of adverse
event occurrence leading to permanent discontinuation included levofloxacin (1·3%
[95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]),
and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events
leading to permanent discontinuation was seen with three second-line injectable
drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2%
[6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1%
[9·9-19·6]). Risk of bias in selection of studies was judged to be low because
there were no important differences between included and excluded studies.
Variability between studies was significant for most outcomes analysed.
INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest
incidence of adverse events leading to permanent drug discontinuation, whereas
second-line injectable drugs, aminosalicylic acid, and linezolid had the highest
incidence. These results suggest that close monitoring of adverse events is
important for patients being treated for multidrug-resistant tuberculosis. Our
results also underscore the urgent need for safer and better-tolerated drugs to
reduce morbidity from treatment itself for patients with multidrug-resistant
tuberculosis.
FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and
Prevention (USA), American Thoracic Society, European Respiratory Society, and
Infectious Diseases Society of America.

Copyright © 2020 World Health Organization. Published by Elsevier Ltd. All rights
reserved. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S2213-2600(20)30047-3
PMID: 32192585

 

This article is not available via Open Access.

 

Validation of Bedaquiline Phenotypic Drug Susceptibility Testing Methods and Breakpoints: a Multilaboratory, Multicountry Study.
 

J Clin Microbiol. 2020 Mar 25;58(4). pii: e01677-19. doi: 10.1128/JCM.01677-19.
Print 2020 Mar 25.

Kaniga K(1), Aono A(2), Borroni E(3), Cirillo DM(3), Desmaretz C(4), Hasan
R(5)(6), Joseph L(7), Mitarai S(2), Shakoor S(5), Torrea G(4), Ismail
NA(7)(8)(9), Omar SV(7).

Drug-resistant tuberculosis persists as a major public health concern. Alongside
efficacious treatments, validated and standardized drug susceptibility testing
(DST) is required to improve patient care. This multicountry, multilaboratory
external quality assessment (EQA) study aimed to validate the sensitivity,
specificity, and reproducibility of provisional bedaquiline MIC breakpoints and
World Health Organization interim critical concentrations (CCs) for categorizing
clinical Mycobacterium tuberculosis isolates as susceptible/resistant to the
drug. Three methods were used: Middlebrook 7H11 agar proportion (AP) assay, broth
microdilution (BMD) assay, and mycobacterial growth indicator tube (MGIT) assay.
Each of the five laboratories tested the 40-isolate (20 unique isolates,
duplicated) EQA panel at three time points. The study validated the sensitivity
and specificity of a bedaquiline MIC susceptibility breakpoint of 0.12 μg/ml for
the BMD method and WHO interim CCs of 1 μg/ml for MGIT and 0.25 μg/ml for the
7H11 AP methods. Categorical agreements between observed and expected results and
sensitivities/specificities for correctly identifying an isolate as
susceptible/resistant were highest at the 0.25, 0.12, and 1 μg/ml bedaquiline
concentrations for the AP method, BMD (frozen or dry plates), and MGIT960,
respectively. At these concentrations, the very major error rates for erroneously
categorizing an isolate as susceptible when it was resistant were the lowest and
within CLSI guidelines. The most highly reproducible bedaquiline DST methods were
MGIT960 and BMD using dry plates. These findings validate the use of standardized
DST methodologies and interpretative criteria to facilitate routine phenotypic
bedaquiline DST and to monitor the emergence of bedaquiline resistance.

Copyright © 2020 Kaniga et al.

DOI: 10.1128/JCM.01677-19
PMCID: PMC7098739
PMID: 31969421

 

Read the full article here.

From our March 2020 Newsletter

Triumph and Tragedy of 21st Century Tuberculosis Drug Development.

 

N Engl J Med. 2020 Mar 5;382(10):959-960. doi: 10.1056/NEJMe2000860.

Thwaites G(1), Nahid P(1).

Comment on
    N Engl J Med. 2020 Mar 5;382(10):893-902.

DOI: 10.1056/NEJMe2000860
PMID: 32130819  [Indexed for MEDLINE]

 

This article is not available via open access. 

 

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.

 

N Engl J Med. 2020 Mar 5;382(10):893-902. doi: 10.1056/NEJMoa1901814.

Conradie F(1), Diacon AH(1), Ngubane N(1), Howell P(1), Everitt D(1), Crook
AM(1), Mendel CM(1), Egizi E(1), Moreira J(1), Timm J(1), McHugh TD(1), Wills
GH(1), Bateson A(1), Hunt R(1), Van Niekerk C(1), Li M(1), Olugbosi M(1),
Spigelman M(1); Nix-TB Trial Team.

Collaborators: Mvuna N, Upton C, Vanker N, Greyling L, Eriksson M, Fabiane SM,
Canseco JO, Solanki P.

Comment in
    N Engl J Med. 2020 Mar 5;382(10):959-960.

BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have
limited treatment options and historically have had poor outcomes.
METHODS: In an open-label, single-group study in which follow-up is ongoing at
three South African sites, we investigated treatment with three oral drugs -
bedaquiline, pretomanid, and linezolid - that have bactericidal activity against
tuberculosis and to which there is little preexisting resistance. We evaluated
the safety and efficacy of the drug combination for 26 weeks in patients with
extensively drug-resistant tuberculosis and patients with multidrug-resistant
tuberculosis that was not responsive to treatment or for which a second-line
regimen had been discontinued because of side effects. The primary end point was
the incidence of an unfavorable outcome, defined as treatment failure
(bacteriologic or clinical) or relapse during follow-up, which continued until 6
months after the end of treatment. Patients were classified as having a favorable
outcome at 6 months if they had resolution of clinical disease, a negative
culture status, and had not already been classified as having had an unfavorable
outcome. Other efficacy end points and safety were also evaluated.
RESULTS: A total of 109 patients were enrolled in the study and were included in
the evaluation of efficacy and safety end points. At 6 months after the end of
treatment in the intention-to-treat analysis, 11 patients (10%) had an
unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had
a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during
treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent
during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The
expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of
patients) and myelosuppression (48%), although common, were manageable, often
leading to dose reductions or interruptions in treatment with linezolid.
CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a
favorable outcome at 6 months after the end of therapy in a high percentage of
patients with highly drug-resistant forms of tuberculosis; some associated toxic
effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov
number, NCT02333799.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1901814
PMCID: PMC6955640
PMID: 32130813  [Indexed for MEDLINE]

 

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 Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.

 

Lancet Respir Med. 2020 Mar 16. pii: S2213-2600(20)30047-3. doi:
10.1016/S2213-2600(20)30047-3. [Epub ahead of print]

Lan Z(1), Ahmad N(2), Baghaei P(3), Barkane L(4), Benedetti A(1), Brode SK(5),
Brust JCM(6), Campbell JR(1), Chang VWL(7), Falzon D(8), Guglielmetti L(9),
Isaakidis P(10), Kempker RR(11), Kipiani M(12), Kuksa L(4), Lange C(13),
Laniado-Laborín R(14), Nahid P(15), Rodrigues D(16), Singla R(17), Udwadia
ZF(18), Menzies D(19); Collaborative Group for the Meta-Analysis of Individual
Patient Data in MDR-TB treatment 2017.

Collaborators: Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, Brust J,
Campbell JR, Chang V, Falzon D, Guglielmetti L, Isaakidis P, Kempker RR, Kipiani
M, Kuksa L, Lan Z, Lange C, Laniado-Laborín R, Nahid P, Rodrigues D, Singla R,
Udwadia ZF, Menzies D.

BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term
therapy with a combination of multiple second-line drugs. These drugs are
associated with numerous adverse events that can cause severe morbidity, such as
deafness, and in some instances can lead to death. Our aim was to estimate the
absolute and relative frequency of adverse events associated with different
tuberculosis drugs to provide useful information for clinicians and tuberculosis
programmes in selecting optimal treatment regimens.
METHODS: We did a meta-analysis using individual-level patient data that were
obtained from studies that reported adverse events that resulted in permanent
discontinuation of anti-tuberculosis medications. We used a database created for
our previous meta-analysis of multidrug-resistant tuberculosis treatment and
outcomes, for which we did a systematic review of literature published between
Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual
patient-level information from authors. We also considered for this analysis
studies contributing patient-level data in response to a public call made by WHO
in 2018. Meta-analysis for proportions and arm-based network meta-analysis were
done to estimate the incidence of adverse events for each tuberculosis drug.
FINDINGS: 58 studies were identified, including 50 studies from the updated
individual patient data meta-analysis for multidrug-resistant tuberculosis
treatment. 35 of these studies, with 9178 patients, were included in our
analysis. Using meta-analysis of proportions, drugs with low risks of adverse
event occurrence leading to permanent discontinuation included levofloxacin (1·3%
[95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]),
and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events
leading to permanent discontinuation was seen with three second-line injectable
drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2%
[6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1%
[9·9-19·6]). Risk of bias in selection of studies was judged to be low because
there were no important differences between included and excluded studies.
Variability between studies was significant for most outcomes analysed.
INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest
incidence of adverse events leading to permanent drug discontinuation, whereas
second-line injectable drugs, aminosalicylic acid, and linezolid had the highest
incidence. These results suggest that close monitoring of adverse events is
important for patients being treated for multidrug-resistant tuberculosis. Our
results also underscore the urgent need for safer and better-tolerated drugs to
reduce morbidity from treatment itself for patients with multidrug-resistant
tuberculosis.
FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and
Prevention (USA), American Thoracic Society, European Respiratory Society, and
Infectious Diseases Society of America.

Copyright © 2020 World Health Organization. Published by Elsevier Ltd. All rights
reserved. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S2213-2600(20)30047-3
PMID: 32192585

 

This article is not available via open access.

Sources of multi-drug resistance in patients with previous isoniazid resistant tuberculosis identified using whole genome sequencing: A longitudinal cohort study.

 

Clin Infect Dis. 2020 Mar 13. pii: ciaa254. doi: 10.1093/cid/ciaa254. [Epub ahead
of print]

Srinivasan V(1)(2), Ha VTN(1), Vinh DN(1), Thai PVK(3), Ha DTM(3), Lan NH(3), Hai
HT(1), Walker TM(2), Thu DDA(1), Dunstan SJ(4), Thwaites GE(1)(2), Ashton
PM(1)(2), Caws M(5), Thuong NTT(1).

BACKGROUND: Meta-analysis of patients with isoniazid-resistant tuberculosis given
standard first-line anti-tuberculosis treatment indicated an increased risk of
multi-drug resistant tuberculosis (MDR-TB) emerging (8%), compared to
drug-sensitive tuberculosis (0.3%). Here we use whole genome sequencing (WGS) to
investigate whether treatment of patients with pre-existing isoniazid resistant
disease with first-line anti-tuberculosis therapy risks selecting for rifampicin
resistance, and hence MDR-TB.
METHODS: Patients with isoniazid-resistant pulmonary TB were recruited and
followed up for 24 months. Drug-susceptibility testing was performed by
Microscopic observation drug-susceptibility assay (MODS), Mycobacterial Growth
Indicator Tube (MGIT) and by WGS on isolates at first presentation and in the
case of re-presentation. Where MDR-TB was diagnosed, WGS was used to determine
the genomic relatedness between initial and subsequent isolates. De novo
emergence of MDR-TB was assumed where the genomic distance was five or fewer
single nucleotide polymorphisms (SNPs) whereas reinfection with a different
MDR-TB strain was assumed where the distance was 10 or more SNPs.
RESULTS: 239 patients with isoniazid-resistant pulmonary tuberculosis were
recruited. Fourteen (14/239, 5.9%) patients were diagnosed with a second episode
of tuberculosis that was multi-drug resistant. Six (6/239, 2.5%) were identified
as having evolved MDR-TB de novo and six as having been re-infected with a
different strain. In two cases the genomic distance was between 5-10 SNPs and
therefore indeterminate.
CONCLUSIONS: In isoniazid-resistant TB, de novo emergence and reinfection of
MDR-TB strains equally contributed to MDR development. Early diagnosis and
optimal treatment of isoniazid resistant TB are urgently needed to avert the de
novo emergence of MDR-TB during treatment.

© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America.

DOI: 10.1093/cid/ciaa254
PMID: 32166306

 

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Improving Quality of Patient Data for Treatment of Multidrug- or Rifampin-Resistant Tuberculosis.


Emerg Infect Dis. 2020 Mar;26(3). doi: 10.3201/eid2603.190997. Epub 2020 Mar 17.

Campbell JR, Falzon D, Mirzayev F, Jaramillo E, Migliori GB, Mitnick CD, Ndjeka
N, Menzies D.

International policy for treatment of multidrug- and rifampin-resistant
tuberculosis (MDR/RR TB) relies largely on individual patient data (IPD) from
observational studies of patients treated under routine conditions. We prepared
guidance on which data to collect and what measures could improve consistency and
utility for future evidence-based recommendations. We highlight critical stages
in data collection at which improvements to uniformity, accuracy, and
completeness could add value to IPD quality. Through a repetitive development
process, we suggest essential patient- and treatment-related characteristics that
should be collected by prospective contributors of observational IPD in MDR/RR
TB.

DOI: 10.3201/eid2603.190997
PMCID: PMC7045826
PMID: 31922953

 

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Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.
 

Eur Respir J. 2020 Mar 20;55(3). pii: 1901467. doi: 10.1183/13993003.01467-2019.
Print 2020 Mar.

Abidi S(1)(2), Achar J(3), Assao Neino MM(4), Bang D(5), Benedetti A(1)(2)(6),
Brode S(7), Campbell JR(1)(2), Casas EC(8), Conradie F(9), Dravniece G(10), du
Cros P(3)(11), Falzon D(12), Jaramillo E(12), Kuaban C(13), Lan Z(1)(2), Lange
C(14)(15)(16)(17), Li PZ(2), Makhmudova M(18), Maug AKJ(19), Menzies D(1)(2),
Migliori GB(20), Miller A(21), Myrzaliev B(22), Ndjeka N(23), Noeske J(24),
Parpieva N(25), Piubello A(19)(26), Schwoebel V(26), Sikhondze W(27), Singla
R(28), Souleymane MB(19), Trébucq A(26), Van Deun A(29), Viney K(30)(31)(32),
Weyer K(12), Zhang BJ(1)(2), Ahmad Khan F(33)(2).

Comment in
    Eur Respir J. 2020 Mar 20;55(3):.

We sought to compare the effectiveness of two World Health Organization
(WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant
(RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter
regimen") and individualised regimens of ≥20 months ("longer regimens").We
collected individual patient data from observational studies identified through
systematic reviews and a public call for data. We included patients meeting WHO
eligibility criteria for the shorter regimen: not previously treated with
second-line drugs, and with fluoroquinolone- and second-line injectable
agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects
meta-regression to calculate adjusted odds ratios and adjusted risk differences
(aRDs) for failure or relapse, death within 12 months of treatment initiation and
loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine
studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53
studies of longer regimens. Treatment success was higher with the shorter regimen
than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less
loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk
difference for failure or relapse was slightly higher with the shorter regimen
overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline
resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16),
prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09,
95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised
shorter regimen was associated with substantially less loss to follow-up during
treatment compared with individualised longer regimens and with more failure or
relapse in the presence of resistance to component medications. Our findings
support the need to improve access to reliable drug susceptibility testing.

The content of this work is copyright of the authors or their employers. Design
and branding are copyright ©ERS 2020.

DOI: 10.1183/13993003.01467-2019
PMID: 31862767

 

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Challenges in TB regimen development: preserving evidentiary standards for regulatory decisions and policymaking.
 

Expert Rev Anti Infect Ther. 2020 Apr 28:1-3. doi:
10.1080/14787210.2020.1756776. Online ahead of print.

Guglielmetti L(1)(2)(3), Low M(4)(5)(6), McKenna L(5)(7).

DOI: 10.1080/14787210.2020.1756776
PMID: 32345064

 

 

 

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High prevalence of hepatitis C infection among multidrug-resistant tuberculosis patients.


J Hepatol. 2020 May;72(5):1028-1029. doi: 10.1016/j.jhep.2019.10.018. Epub 2020
Mar 6.

Seung KJ(1), Franke MF(2), Hewison C(3), Huerga H(4), Khan U(5), Mitnick CD(6);
end TB Study Group.

DOI: 10.1016/j.jhep.2019.10.018
PMID: 32147086

 

 

Progress in the roll-out of multidrug-resistant tuberculosis (MDR-TB) treatments.


Int J Tuberc Lung Dis. 2020 May 1;24(5):535-536. doi: 10.5588/ijtld.19.0717.

Heng M(1), Allmendinger S(1), Chiang CY(2), Trébucq A(2), Horsburgh CR(1).

Please see the document below. Corrections to this publication are in-press for next month's IJTLD issue.

 

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