PREVIOUS LITERATURE IN DR-TB

From Our June 2021 Newsletter

Evidence-based Definition for Extensively Drug-resistant Tuberculosis.
 
Am J Respir Crit Care Med. 2021 Jun 9. doi: 10.1164/rccm.202009-3527OC. Online ahead of print.
 
Roelens M(1), Battista Migliori G(2), Rozanova L(1), Estill J(1)(3), Campbell JR(4), Cegielski JP(5), Tiberi S(6)(7), Palmero D(8), Fox GJ(9), Guglielmetti L(10)(11), Sotgiu G(12), Brust JCM(13), Bang D(14)(15), Lange C(16)(17)(18), Menzies D(19), Keiser O(1), Raviglione M(20)(21).
 
RATIONALE: Until 2020, extensively drug-resistant tuberculosis (XDR-TB) was defined as resistance to rifampicin and isoniazid (multidrug-resistant tuberculosis, MDR-TB), any fluoroquinolone (FQ) and any second-line injectable drug (SLID). In 2019 the World Health Organization issued new recommendations for managing patients with drug-resistant tuberculosis, substantially limiting the role of SLID in MDR-TB treatment and thus putting that XDR-TB definition into question.
OBJECTIVE: To propose an up-to-date definition for XDR-TB.
METHODS: We used a large dataset to assess treatment outcomes for MDR-TB patients exposed to any type of longer regimen. We included patients with bacteriologically confirmed MDR-TB and known FQ and SLID resistance results. We did logistic regression to estimate adjusted odds ratios (aORs) for unfavourable treatment outcome (failure, relapse, death, loss-to-follow-up) by resistance pattern (FQ, SLID) and Group A drug use (moxifloxacin/levofloxacin, linezolid, bedaquiline).
MEASUREMENTS AND MAIN RESULTS: We included 11,666 patients with MDR-TB; 4653 (39.9%) had an unfavourable treatment outcome. Resistance to FQs increased the odds of an unfavourable treatment outcome (aOR 1.91; 95% confidence interval [95%CI] 1.63-2.23). Administration of bedaquiline and/or linezolid improved treatment outcomes regardless of resistance to FQ and/or SLID. Among XDR-TB 
patients, compared to persons receiving no Group A drug, aORs for unfavourable outcome were 0.37 (95%CI 0.20-0.69) with linezolid only, 0.40 (95%CI 0.21-0.77) with bedaquiline only, and 0.21 (95%CI 0.12-0.38) with both.
CONCLUSIONS: Our study supports a new definition of XDR-TB as MDR plus additional resistance to FQ plus bedaquiline and/or linezolid, and helps assess the adequacy of this definition for surveillance and treatment choice.
 
DOI: 10.1164/rccm.202009-3527OC
PMID: 34107231

Impact of bedaquiline on treatment outcomes of multidrug-resistant tuberculosis in a high-burden country.
 
Eur Respir J. 2021 Jun 10;57(6):2002544. doi: 10.1183/13993003.02544-2020. Print 2021 Jun.
 
Chesov D(1)(2)(3), Heyckendorf J(2)(3)(4), Alexandru S(5), Donica A(5), Chesov E(6)(2), Reimann M(2)(3), Crudu V(5), Botnaru V(6), Lange C(2)(3)(4).
 
BACKGROUND: Evaluation of novel anti-tuberculosis (TB) drugs for the treatment of multidrug-resistant (MDR)-TB continues to be of high interest on the TB research agenda. We assessed treatment outcomes in patients with pulmonary MDR-TB who received bedaquiline-containing treatment regimens in the Republic of Moldova, a high-burden MDR-TB country.
METHOD: We systematically analysed the SIMETB national electronic TB database and performed a retrospective propensity score-matched comparison of treatment outcomes in a cohort of patients with MDR-TB who started treatment during 2016-2018 with a bedaquiline-containing regimen (bedaquiline cohort) and a cohort of patients treated without bedaquiline (non-bedaquiline cohort).
RESULTS: Following propensity score matching, 114 patients were assigned to each cohort of MDR-TB patients. Patients in the bedaquiline cohort had a higher 6-month sputum culture conversion rate than those in the non-bedaquiline cohort (66.7% versus 40.3%; p<0.001). Patients under bedaquiline-containing regimens had a higher cure rate assessed by both World Health Organization (WHO) and TBnet definitions (55.3% versus 24.6%; p=0.001 and 43.5% versus 19.6%; p=0.004, respectively), as well as a lower mortality rate (8.8% versus 20.2%; p<0.001 and 10.9% versus 25.2%; p=0.01, respectively). In patients who previously failed on MDR-TB treatment, >40% of patients achieved a cure with a bedaquiline-containing regimen.
CONCLUSIONS: Bedaquiline-based MDR-TB treatment regimens result in better disease resolution when compared with bedaquiline-sparing MDR-TB treatment regimens under programmatic conditions in a country with a high burden of MDR-TB.
 
Copyright ©ERS 2021.
 
DOI: 10.1183/13993003.02544-2020
PMID: 33334942


World Health Organization recommendations on the treatment of drug-resistant tuberculosis, 2020 update.
 
Eur Respir J. 2021 Jun 4;57(6):2003300. doi: 10.1183/13993003.03300-2020. Print 2021 Jun.
 
Mirzayev F(1), Viney K(1), Linh NN(1), Gonzalez-Angulo L(1), Gegia M(1), Jaramillo E(1), Zignol M(1), Kasaeva T(1).
 
Antimicrobial resistance is a major public health problem globally. Likewise, forms of tuberculosis (TB) resistant to first- and second-line TB medicines present a major challenge for patients, healthcare workers and healthcare services. In November 2019, the World Health Organization (WHO) convened an independent international expert panel to review new evidence on the treatment of multidrug- (MDR) and rifampicin-resistant (RR) TB, using the Grading of Recommendations Assessment, Development and Evaluation approach.Updated WHO guidelines emerging from this review, published in June 2020, recommend a 
shorter treatment regimen for patients with MDR/RR-TB not resistant to fluoroquinolones (of 9-11 months), with the inclusion of bedaquiline instead of an injectable agent, making the regimen all oral. For patients with MDR-TB and additional fluoroquinolone resistance, a regimen composed of bedaquiline, pretomanid and linezolid may be used under operational research conditions (6-9 months). Depending on the drug-resistance profile, extent of TB disease or disease severity, a longer (18-20 months) all-oral, individualised treatment regimen may be used. In addition, the review of new data in 2019 allowed the WHO to conclude that there are no major safety concerns on the use of bedaquiline for >6 months' duration, the use of delamanid and bedaquiline together and the use of bedaquiline during pregnancy, although formal recommendations were not made on these topics.The 2020 revision has highlighted the ongoing need for high-quality evidence and has reiterated the need for clinical trials and other research studies to contribute to the development of evidence-based policy.
 
Copyright ©The authors 2021.
 
DOI: 10.1183/13993003.03300-2020
PMCID: PMC8176349
PMID: 33243847


Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts.
 
Int J Tuberc Lung Dis. 2021 Jun 1;25(6):453-460. doi: 10.5588/ijtld.21.0035.
 
Oelofse S(1), Esmail A(1), Diacon AH(2), Conradie F(3), Olayanju O(1), Ngubane N(4), Howell P(3), Everitt D(5), Crook AM(6), Mendel CM(5), Wills GH(6), Olugbosi M(7), Del Parigi A(5), Sun E(5), Calatroni A(8), Spigelman M(5), Dheda K(9).
 
BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).
METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.
RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.
CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.
 
DOI: 10.5588/ijtld.21.0035
PMCID: PMC8171246
PMID: 34049607

 
Prisons as ecological drivers of fitness-compensated multidrug-resistant Mycobacterium tuberculosis.
 
Nat Med. 2021 May 24. doi: 10.1038/s41591-021-01358-x. Online ahead of print.
 
Gygli SM(#)(1)(2), Loiseau C(#)(1)(2), Jugheli L(1)(2)(3), Adamia N(3), Trauner A(1)(2), Reinhard M(1)(2), Ross A(1)(2), Borrell S(1)(2), Aspindzelashvili R(3), Maghradze N(1)(2)(3), Reither K(1)(2), Beisel C(4), Tukvadze N(1)(2)(3), Avaliani Z(3), Gagneux S(5)(6).
 
Multidrug-resistant tuberculosis (MDR-TB) accounts for one third of the annual deaths due to antimicrobial resistance1. Drug resistance-conferring mutations frequently cause fitness costs in bacteria2-5. Experimental work indicates that these drug resistance-related fitness costs might be mitigated by compensatory mutations6-10. However, the clinical relevance of compensatory evolution remains poorly understood. Here we show that, in the country of Georgia, during a 6-year nationwide study, 63% of MDR-TB was due to patient-to-patient transmission. Compensatory mutations and patient incarceration were independently associated with transmission. Furthermore, compensatory mutations were overrepresented among isolates from incarcerated individuals that also frequently spilled over into the non-incarcerated population. As a result, up to 31% of MDR-TB in Georgia was directly or indirectly linked to prisons. We conclude that prisons fuel the epidemic of MDR-TB in Georgia by acting as ecological drivers of fitness-compensated strains with high transmission potential.
 
DOI: 10.1038/s41591-021-01358-x
PMID: 34031604

All-oral longer regimens are effective for the management of multidrug resistant tuberculosis in high burden settings.
 
Eur Respir J. 2021 Jun 17:2004345. doi: 10.1183/13993003.04345-2020. Online ahead of print.
 
Khan PY(1)(2)(3), Franke MF(4)(5)(3), Hewison C(6), Seung KJ(4)(7), Huerga H(8), Atwood S(7), Ahmed S(9), Khan M(10), Sultana T(11), Manzur-Ul-Alam M(11), Vo LNQ(12)(13), Lecca L(14), Yae K(15), Kozhabekov S(16), Tamirat M(17), Gelin A(18), Vilbrun SC(19), Kikvidze M(20), Faqirzai J(21), Kadyrov A(22), Skrahina A(23), Mesic A(24), Avagyan N(6), Bastard M(8), Rich ML(4)(7), Khan U(12)(3), Mitnick CD(4)(5)(3).
 
BACKGROUND: Recent World Health Organisation guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline- and/or delamanid as part of their multidrug regimen.
METHODS: Patients with a positive baseline culture were included. Six-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods.
RESULTS: Culture conversion was observed in 83.8% (526/628) of patients receiving an all-oral regimen and 85.5% (425/497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95%CI: 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients.
CONCLUSIONS: Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.
 
Copyright ©The authors 2021. For reproduction rights and permissions contact 
permissions@ersnet.org.
 
DOI: 10.1183/13993003.04345-2020
PMID: 34140298

From Our May 2021 Newsletter

 

Multidrug-resistant tuberculosis imported into low-incidence countries-a GeoSentinel analysis, 2008-2020.

J Travel Med. 2021 May 12:taab069. doi: 10.1093/jtm/taab069. Online ahead of 
print.
 
Eimer J(1), Patimeteeporn C(2), Jensenius M(3), Gkrania-Klotsas E(4), Duvignaud 
A(5), Barnett ED(6), Hochberg NS(7), Chen LH(8), Trigo-Esteban E(9), Gertler 
M(10), Greenaway C(11), Grobusch MP(12)(13), Angelo KM(2), Hamer DH(7)(14), 
Caumes E(15)(16), Asgeirsson H(1)(17).
 
BACKGROUND: Early detection of imported multidrug-resistant tuberculosis (MDR-TB) is crucial, but knowledge gaps remain about migration- and travel-associated MDR-TB epidemiology. The aim was to describe epidemiologic characteristics among international travelers and migrants with MDR-TB. METHODS: Clinician-determined and microbiologically confirmed MDR-TB diagnoses deemed to be related to travel or migration were extracted from GeoSentinel, a global surveillance network of travel and tropical medicine clinics, from January 2008 through December 2020. MDR-TB was defined as resistance to both isoniazid and rifampicin. Additional resistance to either a fluoroquinolone or a second-line injectable drug was categorized as pre-extensively drug-resistant (pre-XDR) TB, and as extensively drug-resistant (XDR) TB when resistance was detected for both. Sub-analyses were performed based on degree of resistance and country of origin.
RESULTS: Of 201 patients, 136 had MDR-TB (67.7%), 25 had XDR-TB (12.4%), 23 had pre-XDR TB (11.4%), and 17 had unspecified MDR- or XDR-TB (8.5%); 196 (97.5%) were immigrants, of which 92 (45.8%) originated from the former Soviet Union. The median interval from arrival to presentation was 154 days (interquartile range [IQR]: 10-751 days); 34.3% of patients presented within 1 month after immigration, 30.9% between 1 and 12 months, and 34.9% after ≥1 year. Pre-XDR- and XDR-TB patients from the former Soviet Union other than Georgia presented earlier than those with MDR-TB (26 days [IQR: 8-522] vs. 369 days [IQR: 84-827]) while patients from Georgia presented very early, irrespectively of the level of resistance (8 days [IQR: 2-18] vs. 2 days [IQR: 1-17]). 
CONCLUSIONS: MDR-TB is uncommon in traditional travellers. Purposeful medical migration may partly explain differences in time to presentation among different groups. Public health resources are needed to better understand factors contributing to cross-border MDR-TB spread and to develop strategies to optimize care of TB-infected patients in their home countries before migration.
 
© International Society of Travel Medicine 2021. Published by Oxford University 
Press. All rights reserved. For Permissions, please e-mail: 
journals.permissions@oup.com.
 
DOI: 10.1093/jtm/taab069
PMID: 33987682


Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study.
 
Clin Microbiol Infect. 2021 Apr 23:S1198-743X(21)00169-5. doi: 
10.1016/j.cmi.2021.04.001. Online ahead of print.
 
Hu Y(1), Zheng X(1), Davies Forsman L(2), Ning Z(3), Chen C(4), Gao Y(1), Zhang 
Z(3), Lu W(4), Werngren J(5), Bruchfeld J(2), Hoffner S(6), Xu B(7).
 
OBJECTIVES: Little is known about how additional second-line drug resistance emerges during multidrug resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the 
recommended 2-year MDR-TB treatment. 
METHODS: Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. 
RESULTS: Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51-4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03-5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22-7.21) were independent risk factors associated with the development of additional second-line drug resistance. CONCLUSIONS: A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.
 
Copyright © 2021 European Society of Clinical Microbiology and Infectious 
Diseases. Published by Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/j.cmi.2021.04.001
PMID: 33895338


Tuberculosis, COVID-19 and hospital admission: Consensus on pros and cons based on a review of the evidence.
 
Pulmonology. 2021 May-Jun;27(3):248-256. doi: 10.1016/j.pulmoe.2020.12.016. Epub 
2021 Jan 28.
 
Migliori GB(1), Visca D(2), van den Boom M(3), Tiberi S(4), Silva DR(5), Centis 

R(6), D'Ambrosio L(7), Thomas T(8), Pontali E(9), Saderi L(10), Schaaf HS(11), 

Sotgiu G(10); contributing members of the Global Tuberculosis Network.
 
The scientific debate on the criteria guiding hospitalization of tuberculosis (TB) and COVID-19 patients is ongoing. The aim of this review is to present the available evidence on admission for TB and TB/COVID-19 patients and discuss the criteria guiding hospitalization. Furthermore, recommendations are made as derived from recently published World Health Organization documents, based on Global Tuberculosis Network (GTN) expert opinion. The core published documents and guidelines on the topic have been reviewed. The proportion of new TB cases admitted to hospital ranges between 50% and 100% while for multidrug-resistant (MDR) TB patients it ranges between 85 and 100% globally. For TB patients with COVID-19 the proportion of cases admitted is 58%, probably reflecting different scenarios related to the diagnosis of COVID-19 before, after or at the same time of the active TB episode. The hospital length of stay for drug-susceptible TB ranges from 20 to 60 days in most of countries, ranging from a mean of 10 days (USA) to around 90 days in the Russian Federation. Hospitalization is longer for MDR-TB (50-180 days). The most frequently stated reasons for recommending hospital admission include: severe TB, infection control concerns, co-morbidities and drug adverse events which cannot be managed at out-patient level. The review also provides suggestions on hospital requirements for safe admissions as well as patient discharge criteria, while underlining the relevance of patient-centred care through community/home-based care.
 
Copyright © 2021 Sociedade Portuguesa de Pneumologia. Published by Elsevier 
España, S.L.U. All rights reserved.
 
DOI: 10.1016/j.pulmoe.2020.12.016
PMCID: PMC7843149
PMID: 33547028 [Indexed for MEDLINE]


Diagnostic accuracy of the FluoroType MTB and MTBDR VER 2.0 assays for the centralised high throughput detection of Mycobacterium tuberculosis complex DNA and isoniazid and rifampicin resistance.

Clin Microbiol Infect. 2021 Apr 29:S1198-743X(21)00209-3. doi: 
10.1016/j.cmi.2021.04.022. Online ahead of print.
 
Dippenaar A(1), Derendinger B(1), Dolby T(2), Beylis N(3), van Helden PD(1), 
Theron G(1), Warren RM(1), de Vos M(4).
 
OBJECTIVES: To evaluate the accuracy of two new molecular diagnostic tests for the detection of drug resistant tuberculosis, the FluoroType MTB and MTBDR VER 2.0 assays, in combination with manual and automated DNA extraction methods.
METHODS: Sputa from 360 Xpert Ultra Mycobacterium tuberculosis complex (MTBC)-positive patients and 250 Xpert Ultra MTBC-negative patients were tested. GenoType MTBDRplus served as reference for MTBC and drug resistance detection. Sanger sequencing was used to resolve discrepancies.
RESULTS: FluoroType MTB VER 2.0 showed similar MTBC sensitivity compared to FluoroType MTBDR VER 2.0 [manual DNA extraction: 91.6% (294/321) vs. 89.8% (291/324) (p=0.4); automated DNA extraction: 92.1% (305/331) vs 87.7% (291/332) (p=0.05)]. FluoroType MTBDR VER2.0 showed comparable diagnostic accuracy to FluoroType MTBDR VER1.0 as previously reported for the detection of MTBC and rifampicin and isoniazid resistance.
CONCLUSIONS: The FluoroType MTB and MTBDR VER 2.0 assays together with an automated DNA extraction and PCR set-up platform may improve laboratory operational efficiency for the diagnosis of MTBC and resistance to rifampicin and isoniazid and show promise for the implementation in a centralised molecular drug susceptibility testing model.
 
Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/j.cmi.2021.04.022
PMID: 33933566
 
Rapid Tuberculosis Diagnostics Including Molecular First- and Second-Line Resistance Testing Based on a Novel Microfluidic DNA Extraction Cartridge.
 
J Mol Diagn. 2021 May;23(5):643-650. doi: 10.1016/j.jmoldx.2021.02.004. Epub 
2021 Feb 23.
 
Beutler M(1), Homann AR(2), Mihalic M(3), Plesnik S(3), Niebling L(2), Eckart 
M(4), Allerheiligen V(4), Czurratis D(5), Maharjan B(6), Shrestha B(6), Parpieva 
N(7), Turaev L(7), Sayfutdinov Z(7), Hofmann-Thiel S(8), Grasse W(9), 
Metzger-Boddien C(9), Paust N(2), Hoffmann H(10).
 
Xpert MTB/RIF testing has improved tuberculosis (TB) diagnostics and rifampicin (Rif) resistance testing worldwide. However, it has weaknesses, such as its restriction to Rif resistance testing and the inability to use extracted DNA for further testing. Herein, a holistic diagnostic workflow, including TB detection 
and resistance testing toward Rif, isoniazid, and important second-line drugs (SLDs), based on a novel microfluidic DNA extraction cartridge (TB-Disk), is presented. DNA from 73 precharacterized sputum samples was extracted with TB-Disk, including 45 clinical and bacteriologically confirmed TB samples, nine TB-negative samples, and 19 sputum samples spiked with twofold dilutions of TB bacteria. The extracted DNA was subjected to further testing with FluoroType MTB (FT-MTB), GenoType MTBDRplus (GT-plus), and GenoType MTBDRsl. A total of 100% (20/20) and 72% (18/25) of smear-positive and smear-negative TB samples were identified as Mycobacterium tuberculosis complex positive. A total of 79% (33/42) of subsequently GT-plus tested samples yielded a valid result. Eight samples were identified as multidrug-resistant TB by GT-plus and further tested for resistance toward SLDs using GenoType MTBDRsl, yielding 75% (6/8) valid results. FT-MTB with cartridge-based DNA extraction (Disk-DNA) and DNA extracted with FluoroLyse yielded similar analytical sensitivities. FT-MTB with Disk-DNA was 100% specific. TB-Disk in combination with FT-MTB enables sensitive TB detection. The Disk-DNA can be further  used for screening resistance toward first-line drugs and SLDs.
 
Copyright © 2021 Association for Molecular Pathology and American Society for 
Investigative Pathology. Published by Elsevier Inc. All rights reserved.
 
DOI: 10.1016/j.jmoldx.2021.02.004
PMID: 33636391

From Our April 2021 Newsletter

 Dynamic needs and challenges of people with drug-resistant tuberculosis and HIV  in South Africa: a qualitative study.
 
Lancet Glob Health. 2021 Apr;9(4):e479-e488. doi: 10.1016/S2214-109X(20)30548-9.
 
Daftary A(1), Mondal S(2), Zelnick J(3), Friedland G(4), Seepamore B(5), Boodhram R(6), Amico KR(7), Padayatchi N(6), O'Donnell MR(8).
 
BACKGROUND: There is little evidence of patient acceptability for drug-resistant tuberculosis (DRTB) care in the context of new treatment regimens and HIV co-infection. We aim to describe experiences of DRTB-HIV care among patients in KwaZulu-Natal province, South Africa.
METHODS: In this qualitative study using Bury's framework for chronic illness, we conducted 13 focus groups at a tertiary hospital with 55 patients co-infected with DRTB and HIV (28 women, 27 men) who were receiving new bedaquiline-based treatment for DRTB, concurrent with antiretroviral therapy. Eligible patients were consenting adults (aged >18 years) with confirmed DRTB and HIV who were enrolled into the PRAXIS study within 2 weeks of initiating bedaquiline-based treatment for DRTB. Participants were recruited from the PRAXIS cohort to participate in a focus group based on their time in DRTB treatment: early (2-6 weeks after treatment initiation), middle (2-6 months after discharge or treatment initiation if never hospitalised), and late (>6 months after treatment initiation). Focus groups were carried out in isiZulu language, audio recorded, and translated to English within 4 weeks. Participants were asked about their experiences of DRTB and HIV care and treatment, and qualitative data were coded and thematically analysed.
FINDINGS: From March, 2017, to June, 2018, distinctive patient challenges were identified at four critical stages of DRTB care: diagnosis, marked by centralised hospitalisation, renunciation from routine life, systemic stigmatisation and, for patients with longstanding HIV, renewed destabilisation; treatment initiation, marked by side-effects, isolation, and social disconnectedness; discharge, marked by brief respite and resurgent therapeutic and social disruption; and continuity, marked by deepening socioeconomic challenges despite clinical recovery. The periods of diagnosis and discharge into the community were particularly difficult. Treatment information and agency in decision making was a persistent gap. Sources of stigmatisation shifted with movement between the hospital and community. Resilience was built by connecting to peers, self-isolating, financial and material security, and a focus on recovery.
INTERPRETATION: People with DRTB and HIV undergo disruptive, life-altering experiences. The lack of information, agency, and social protections in DRTB care and treatment causes wider-reaching challenges for patients compared with HIV. Decentralised, community, peer-support, and differentiated care models for DRTB might be ameliorative and help to maximise the promise of new regimens.
FUNDING: US National Institutes of Health.
TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.
 
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/S2214-109X(20)30548-9
PMCID: PMC8009302
PMID: 33740409 [Indexed for MEDLINE]

Outcomes of multidrug-resistant tuberculosis treated with bedaquiline or delamanid.
 
Clin Infect Dis. 2021 Apr 10:ciab304. doi: 10.1093/cid/ciab304. Online ahead of print.
 
Hwang H(1), Kang H(2), Kwon YS(3), Jeon D(4), Shim TS(5), Yim JJ(1).
 
BACKGROUND: Since September 1, 2016, bedaquiline and delamanid have been administered for treatment of patients with multidrug-resistant/rifampicin-resistant tuberculosis after the official approval in South Korea. This study aimed to assess and compare the final treatment outcomes of patients who received bedaquiline with those of patients who received delamanid.
METHODS: This is a nationwide cohort study of patients with multidrug-resistant/rifampicin-resistant tuberculosis in whom bedaquiline or delamanid was administered from September 1, 2016, to February 28, 2018, after receiving the official approval in South Korea. Patients were classified into the bedaquiline and delamanid group according to the first used drug. We evaluated and compared the final treatment outcomes between the groups.
RESULTS: During the study period, 284 patients with multidrug-resistant/rifampicin-resistant tuberculosis were approved to use bedaquiline or delamanid and 260 were included in the final analysis; 119 (45.8%) and 141 patients (54.2%) were classified into bedaquiline and delamanid groups, respectively. Among them, 30 patients (11.5%) exhibited additional resistance to second-line injectable drugs, 94 patients (36.2%) had additional resistance to fluoroquinolones, and 37 patients (14.2%) had resistance to both drugs. The overall treatment success rate was 79.2%. Initiation of bedaquiline rather than delamanid was not associated with treatment success (adjusted odds ratio = 0.671, 95% confidence interval = 0.350-1.285).Frequencies of adverse events were not significantly different between the two groups.
CONCLUSIONS: Initial choice of bedaquiline or delamanid did not make any significant difference in the final treatment outcome or the frequencies of adverse events among patients with multidrug-resistant/rifampicin-resistant tuberculosis.
 
© The Author(s) 2021. 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/ciab304
PMID: 33837767

 Patients' perceptions regarding multidrug-resistant tuberculosis and barriers to seeking care in a priority city in Brazil during COVID-19 pandemic: A  qualitative study.
 
PLoS One. 2021 Apr 9;16(4):e0249822. doi: 10.1371/journal.pone.0249822. eCollection 2021.
 
Santos FLD(1), Souza LLL(1), Bruce ATI(1), Crispim JA(1), Arroyo LH(1), Ramos ACV(1), Berra TZ(1), Alves YM(1), Scholze AR(1), Costa FBPD(1), Martoreli Júnior JF(1), Moncaio ACS(2), Pinto IC(1), Arcêncio RA(1).
 
This study aimed to analyze the discourses of patients who were diagnosed with multidrug-resistant tuberculosis, the perception of why they acquired this health condition and barriers to seeking care in a priority city in Brazil during the COVID-19 pandemic. This was an exploratory qualitative study, which used the theoretical-methodological framework of the Discourse Analysis of French matrix, guided by the Consolidated Criteria for Reporting Qualitative Research. The study was conducted in Ribeirão Preto, São Paulo, Brazil. Seven participants were interviewed who were undergoing treatment at the time of the interview. The analysis of the participants' discourses allowed the emergence of four discursive blocks (1) impact of the social determinants in the development of multidrug-resistant tuberculosis, (2) barriers to seeking care and difficulties accessing health services, (3) perceptions of the side effects and their impact on multidrug-resistant tuberculosis treatment, and (4) tuberculosis and COVID-19: a necessary dialogue. Through discursive formations, these revealed the determinants of multidrug-resistant tuberculosis. Considering the complexity involved in the dynamics of multidrug-resistant tuberculosis, advancing in terms of equity in health, that is, in reducing unjust differences, is a challenge for public policies, especially at the current moment in Brazil, which is of accentuated economic, political and social crisis. The importance of psychosocial stressors and the lack of social support should also be highlighted as intermediary determinants of health. The study has also shown the situation of COVID-19, which consists of an important barrier for patients seeking care. Many patients reported fear, insecurity and worry with regard to returning to medical appointments, which might contribute to the worsening of tuberculosis in the scenario under study.
 
DOI: 10.1371/journal.pone.0249822
PMCID: PMC8034748
PMID: 33836024 [Indexed for MEDLINE]

 Culture conversion at six months in patients receiving bedaquiline- and  delamanid-containing regimens for the treatment of multidrug-resistant  tuberculosis.
 
Int J Infect Dis. 2021 Apr 3:S1201-9712(21)00293-9. doi: 10.1016/j.ijid.2021.03.075. Online ahead of print.
 
Maretbayeva SM(1), Rakisheva AS(2), Adenov MM(3), Yeraliyeva LT(3), Algozhin YZ(1), Stambekova AT(1), Berikova EA(3), Yedilbayev A(4), Rich ML(5), Seung KJ(5), Issayeva AM(6).
 
Rifampicin-resistant/multidrug-resistant (RR/MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis (TB) are serious public health problem in Kazakhstan. In 2012 and 2013, stringent regulatory authorities approved the first new TB drugs in fifty years, bedaquiline and delamanid, offering hope for more effective and less toxic MDR-TB treatment. The endTB Observational Study is a multi-country study that enrolled patients receiving a bedaquiline- or delamanid-containing regimen for RR/MDR-TB between 01 April 2015 and 30 September 2018. In Kazakhstan, 675 patients participated in the study; all had at least 6-months or longer of follow-up after the start of treatment. The present analysis focuses on endTB Observational Study patients living in Kazakhstan who had a positive baseline sputum culture (220 patients) and initiated a bedaquiline- or delamanid-containing regimen between February 1, 2016 and March 31, 2018. Of them, 195 (89%) of patients experienced culture conversion within six months.
 
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/j.ijid.2021.03.075
PMID: 33823277

From Our March 2021 Newsletter

Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with multidrug-resistant tuberculosis.
 
J Antimicrob Chemother. 2021 Mar 12;76(4):1019-1024. doi: 10.1093/jac/dkaa550.
 
Alghamdi WA(1), Al-Shaer MH(2), Kipiani M(3), Barbakadze K(3), Mikiashvili L(3), Kempker RR(4), Peloquin CA(2).
 
BACKGROUND: Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
OBJECTIVES: To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
METHODS: A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
RESULTS: Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
CONCLUSIONS: We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.
 
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
 
DOI: 10.1093/jac/dkaa550
PMCID: PMC7953320
PMID: 33378452

Dynamic needs and challenges of people with drug-resistant tuberculosis and HIV  in South Africa: a qualitative study.
 
Lancet Glob Health. 2021 Apr;9(4):e479-e488. doi: 10.1016/S2214-109X(20)30548-9.
 
Daftary A(1), Mondal S(2), Zelnick J(3), Friedland G(4), Seepamore B(5), Boodhram R(6), Amico KR(7), Padayatchi N(6), O'Donnell MR(8).
 
BACKGROUND: There is little evidence of patient acceptability for drug-resistant tuberculosis (DRTB) care in the context of new treatment regimens and HIV co-infection. We aim to describe experiences of DRTB-HIV care among patients in KwaZulu-Natal province, South Africa.
METHODS: In this qualitative study using Bury's framework for chronic illness, we conducted 13 focus groups at a tertiary hospital with 55 patients co-infected with DRTB and HIV (28 women, 27 men) who were receiving new bedaquiline-based treatment for DRTB, concurrent with antiretroviral therapy. Eligible patients were consenting adults (aged >18 years) with confirmed DRTB and HIV who were enrolled into the PRAXIS study within 2 weeks of initiating bedaquiline-based treatment for DRTB. Participants were recruited from the PRAXIS cohort to participate in a focus group based on their time in DRTB treatment: early (2-6 weeks after treatment initiation), middle (2-6 months after discharge or treatment initiation if never hospitalised), and late (>6 months after treatment initiation). Focus groups were carried out in isiZulu language, audio recorded, and translated to English within 4 weeks. Participants were asked about their experiences of DRTB and HIV care and treatment, and qualitative data were coded and thematically analysed.
FINDINGS: From March, 2017, to June, 2018, distinctive patient challenges were identified at four critical stages of DRTB care: diagnosis, marked by centralised hospitalisation, renunciation from routine life, systemic stigmatisation and, for patients with longstanding HIV, renewed destabilisation; treatment initiation, marked by side-effects, isolation, and social disconnectedness; discharge, marked by brief respite and resurgent therapeutic and social disruption; and continuity, marked by deepening socioeconomic challenges despite clinical recovery. The periods of diagnosis and discharge into the community were particularly difficult. Treatment information and agency in decision making was a persistent gap. Sources of stigmatisation shifted with movement between the hospital and community. Resilience was built by connecting to peers, self-isolating, financial and material security, and a focus on recovery.
INTERPRETATION: People with DRTB and HIV undergo disruptive, life-altering experiences. The lack of information, agency, and social protections in DRTB care and treatment causes wider-reaching challenges for patients compared with HIV. Decentralised, community, peer-support, and differentiated care models for DRTB might be ameliorative and help to maximise the promise of new regimens. FUNDING: US National Institutes of Health. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.
 
Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.
 
DOI: 10.1016/S2214-109X(20)30548-9
PMID: 33740409

Neuropsychiatric toxicity and cycloserine concentrations during treatment for  multidrug-resistant tuberculosis.
 
Int J Infect Dis. 2021 Mar 5:S1201-9712(21)00206-X. doi: 10.1016/j.ijid.2021.03.001. Online ahead of print.
 
Court R(1), Centner CM(2), Chirehwa M(3), Wiesner L(4), Denti P(5), de Vries N(6), Harding J(7), Gumbo T(8), Maartens G(9), McIlleron H(10).
 
BACKGROUND: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). There are limited prospective clinical data on the incidence and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine.
METHOD: We prospectively evaluated neuropsychiatric toxicity using validated screening tools in patients with multi-drug resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma.
RESULTS: We recruited 144 participants: 78 men; median age 35.2 years; 91 (63%) HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance (aHR:0.34, p:0.03) and high-dose pyridoxine (200 mg vs. 150 mg daily).
CONCLUSION: We observed a high incidence of early neuropsychiatric toxicity in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.
 
Copyright © 2021. Published by Elsevier Ltd.
 
DOI: 10.1016/j.ijid.2021.03.001
PMID: 33684562


Drug susceptibility patterns of Mycobacterium tuberculosis from adults with  multidrug-resistant tuberculosis and implications for a household contact  preventive therapy trial.
 
BMC Infect Dis. 2021 Feb 24;21(1):205. doi: 10.1186/s12879-021-05884-4.
 
Demers AM(1), Kim S(2), McCallum S(3), Eisenach K(4), Hughes M(3), Naini L(5), Mendoza-Ticona A(6), Pradhan N(7), Narunsky K(8), Poongulali S(9), Badal-Faesen S(10), Upton C(11), Smith E(12), Shah NS(13), Churchyard G(14)(15), Gupta A(7)(16), Hesseling A(1), Swindells S(17); ACTG A5300/IMPAACT I2003 PHOENIx Feasibility study team.
 
BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs).
METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability.
RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens.
CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.
 
DOI: 10.1186/s12879-021-05884-4
PMCID: PMC7903693
PMID: 33627075 [Indexed for MEDLINE]



Targeted next generation sequencing directly from sputum for comprehensive  genetic information on drug resistant Mycobacterium tuberculosis.
 
Tuberculosis (Edinb). 2021 Mar;127:102051. doi: 10.1016/j.tube.2021.102051. Epub 2021 Jan 8.
 
Kambli P(1), Ajbani K(2), Kazi M(3), Sadani M(4), Naik S(5), Shetty A(6), Tornheim JA(7), Singh H(8), Rodrigues C(9).
 
BACKGROUND: Timely drug resistance detection is essential to global tuberculosis management. Unfortunately, rapid molecular tests assess resistance to only a few drugs, with culture required for comprehensive susceptibility test results.
METHODS: We evaluated targeted next generation sequencing (tNGS) for tuberculosis on 40 uncultured sputum samples. Resistance profiles from tNGS were compared with profiles from Xpert MTB/RIF, line probe assay (LPA), pyrosequencing (PSQ), and phenotypic testing. Concordance, sensitivity, specificity, and overall test agreement were compared across assays.
RESULTS: tNGS provided results for 39 of 40 samples (97.5%) with faster turnaround than phenotypic testing (median 3 vs. 21 days, p = 0.0068). Most samples were isoniazid and rifampin resistant (N = 31, 79.5%), 21 (53.8%) were fluoroquinolone resistant, and 3 (7.7%) were also resistant to Kanamycin. Half were of the Beijing lineage (N = 20, 51.3%). tNGS from uncultured sputum identified all resistance to isoniazid, rifampin, fluoroquinolones, and second-line injectable drugs that was identified by other methods. Agreement between tNGS and existing assays was excellent for isoniazid, rifampin, and SLDs, very good for levofloxacin, and good for moxifloxacin.
CONCLUSION: tNGS can rapidly identify tuberculosis, lineage, and drug resistance with faster turnaround than phenotypic testing. tNGS is a potential alternative to phenotypic testing in high-burden settings.
 
Copyright © 2021 Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/j.tube.2021.102051
PMID: 33450448

 Effectiveness of Preventive Therapy for Persons Exposed at Home to  Drug-Resistant Tuberculosis, Karachi, Pakistan.
 
Emerg Infect Dis. 2021 Mar;27(3):805-812. doi: 10.3201/eid2703.203916.
 
Malik AA, Gandhi NR, Lash TL, Cranmer LM, Omer SB, Ahmed JF, Siddiqui S, Amanullah F, Khan AJ, Keshavjee S, Hussain H, Becerra MC.
 
In Karachi, Pakistan, a South Asian megacity with a high prevalence of tuberculosis (TB) and low HIV prevalence, we assessed the effectiveness of fluoroquinolone-based preventive therapy for drug-resistant (DR) TB exposure. During February 2016–March 2017, high-risk household contacts of DR TB patients began a 6-month course of preventive therapy with a fluoroquinolone-based, 2-drug regimen. We assessed effectiveness in this cohort by comparing the rate and risk for TB disease over 2 years to the rates and risks reported in the literature. Of 172 participants, TB occurred in 2 persons over 336 person-years of observation. TB disease incidence rate observed in the cohort was 6.0/1,000 person-years. The incidence rate ratio ranged from 0.29 (95% CI 0.04–1.3) to 0.50 (95% CI 0.06–2.8), with a pooled estimate of 0.35 (95% CI 0.14–0.87). Overall, fluoroquinolone-based preventive therapy for DR TB exposure reduced risk for TB disease by 65%.
 
Fluoroquinolone-based preventive therapy reduced risk for tuberculosis disease by 65%.
 
DOI: 10.3201/eid2703.203916
PMCID: PMC7920671
PMID: 33624580

From Our February 2021 Newsletter

QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial.

Lancet Infect Dis. 2021 Feb 12:S1473-3099(20)30770-2. doi: 10.1016/S1473-3099(20)30770-2. Online ahead of print.

Dooley KE(1), Rosenkranz SL(2), Conradie F(3), Moran L(4), Hafner R(5), von Groote-Bidlingmaier F(6), Lama JR(7), Shenje J(8), De Los Rios J(7), Comins K(6), Morganroth J(9), Diacon AH(10), Cramer YS(2), Donahue K(11), Maartens G(12); AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team.

Collaborators: Alli O, Gottesman J, Guevara M, Hikuam C, Hovind L, Karlsson M, McClaren J, McIlleron H, Murtaugh W, Rolls B, Shahkolahi A, Stone L, Tegha G, Tenai J, Upton C, Wimbish C.

BACKGROUND: Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy.
METHODS: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.
FINDINGS: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks.
INTERPRETATION: Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values.
FUNDING: Division of AIDS, National Institutes of Health.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30770-2
PMID: 33587897


Multidrug-resistant tuberculosis in children and adolescents: current strategies for prevention and treatment.
 
Expert Rev Respir Med. 2021 Feb;15(2):221-237. doi: 10.1080/17476348.2021.1828069. Epub 2020 Oct 10.
 
Seddon JA(1)(2), Johnson S(1)(2), Palmer M(1), van der Zalm MM(1), Lopez-Varela E(1)(3), Hughes J(1), Schaaf HS(1).
 
INTRODUCTION: An estimated 30,000 children develop multidrug-resistant (MDR) tuberculosis (TB) each year, with only a small proportion diagnosed and treated. This field has historically been neglected due to the perception that children with MDR-TB are challenging to diagnose and treat. Diagnostic and therapeutic developments in adults have improved pediatric management, yet further pediatric-specific research and wider implementation of evidence-based practices are required.
AREAS COVERED: This review combines the most recent data with expert opinion to highlight best practice in the evaluation, diagnosis, treatment, and support of children and adolescents with MDR-TB disease. A literature search of PubMed was carried out on topics related to MDR-TB in children. This review provides practical advice on MDR-TB prevention and gives updates on new regimens and novel treatments. The review also addresses host-directed therapy, comorbid conditions, special populations, psychosocial support, and post-TB morbidity, as well as identifying outstanding research questions.
EXPERT OPINION: Increased availability of molecular diagnostics has the potential to aid with the diagnosis of MDR-TB in children. Shorter MDR-TB disease treatment regimens have made therapy safer and shorter and further developments with novel agents and repurposed drugs should lead to additional improvements. The evidence base for MDR-TB preventive therapy is increasing.
 
DOI: 10.1080/17476348.2021.1828069
PMID: 32965141


Systematic Review of Mutations Associated with Isoniazid Resistance Points to  Continuing Evolution and Subsequent Evasion of Molecular Detection, and  Potential for Emergence of Multidrug Resistance in Clinical Strains of  Mycobacterium tuberculosis.
 
Antimicrob Agents Chemother. 2021 Feb 17;65(3):e02091-20. doi:
10.1128/AAC.02091-20. Print 2021 Feb 17.
 
Valafar SJ(1).
 
Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms and undermine our ability to contain outbreaks. This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes katG, inhA, and fabG1, and the intergenic region oxyR'-ahpC were considered in this review. Fifty-two articles were included that described 9,306 clinical isolates (5,804 INH resistant [INHr] and 3,502 INH susceptible [INHs]) from 31 countries. The three most frequently mutated loci continue to be locus 315 of katG (katG315; n = 4,271), locus -15 of inhA (inhA-15; n = 787), and locus -8 of inhA (inhA-8; 106). However, the diagnostic value of inhA-8 is far lower than previously thought, as it only appears in 25 (0.4%) of the INHr isolates lacking the first two mutations. I catalogued 45 new loci (29 katG, nine inhA, and seven ahpC) associated with INH resistance and identified 59 loci (common to this and previous reviews) as a reliable basis for molecular diagnostics. Including all observed mutations provides a cumulative sensitivity of 85.6%. In 14.4% of resistant isolates, no mechanism of resistance was detected, making them likely to escape molecular detection, and in the case of INH monoresistance, likely to convert to multidrug-resistant TB (MDR-TB). Integrating the information cataloged in this study into current diagnostic tools is essential for combating the emergence of MDR-TB, and its exclusion can lead to an unintended selection against common mechanisms and to diversifying evolution. Observation of many low-frequency resistance-conferring mutations points to an advantage of whole-genome sequencing (WGS) for diagnostics. Finally, I provide five recommendations for future diagnostic platforms.
 
Copyright © 2021 American Society for Microbiology.
 
DOI: 10.1128/AAC.02091-20
PMID: 33361298


4. Evaluating Integrated Care for People Living With HIV and Multidrug-Resistant  Tuberculosis in South Africa: A Case-Based Approach Using the Chronic Care Model.
 
J Assoc Nurses AIDS Care. 2021 Feb 15. doi: 10.1097/JNC.0000000000000242. Online ahead of print.
 
Geiger K(1), Bergman A, Farley JE.
 
In South Africa, tuberculosis (TB) and multidrug-resistant TB (MDR-TB) frequently occur in people living with HIV. World Health Organization guidelines recommend the integration of MDR-TB and HIV care but, in practice, fully integrated care is difficult to achieve. In this article, we use five elements of the Chronic Care Model as a framework for evaluating a case of integrated. MDR-TB/HIV care and to highlight opportunities for nurses to improve care delivery and patient outcomes. We apply the Chronic Care Model framework to a concrete example by examining the case of a 33-year-old man who developed MDR-TB treatment failure while concurrently taking a powerful new MDR-TB antiretroviral therapy regimen for his HIV.
 
Copyright © 2021 Association of Nurses in AIDS Care.
 
DOI: 10.1097/JNC.0000000000000242
PMID: 33595985


5. Should treatment of low-level rifampicin mono-resistant tuberculosis be different?
 
J Clin Tuberc Other Mycobact Dis. 2021 Jan 29;23:100222. doi:
10.1016/j.jctube.2021.100222. eCollection 2021 May.
 
Gopie FA(1)(2), Commiesie E(3), Baldi S(4), Kamst M(5), Kaur D(6), de Lange WCM(7), Pinas PS(4), Stijnberg D(3), Wongsokarijo M(4), Zijlmans CWR(2), de Zwaan R(5), van Soolingen D(5), Vreden SGS(1), de Vries G(8).
 
BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) was frequently detected in Suriname after the introduction of Xpert MTB/RIF in 2012. Subsequent phenotypic drug-susceptibility testing (DST) was not conclusive at that moment, while RR-TB patients treated with first-line tuberculostatics had good treatment outcome. In our study, we analysed this interesting observation.
METHODS: We collected demographic and clinical characteristics and treatment outcome of TB patients from May 2012-December 2018 and performed a univariate and multivariate analysis to assess possible associations with resistance to rifampicin. Secondly, we conducted whole genome sequencing on all available Mycobacterium tuberculosis isolates that had a rifampicin resistance in the Xpert MTB/RIF test and performed phenotypic DST on selected isolates.
FINDINGS: RR-TB was detected in 59 (9.6%) patients confirmed by Xpert. These patients were treated with rifampicin-containing regimens in most (88%) of the cases. In all 32 samples examined, a D435Y mutation in the rpoB gene was identified; only one isolate revealed an additional isoniazid mutation. Phenotypic DST indicated low-level rifampicin resistance. In multivariate analysis, the Creole ethnicity was a factor associated with rifampicin resistance (aOR 3.5; 95%CI 1.9-6.4). The treatment success rate for patients with RR-TB (78.0%) was comparable to the treatment outcome in non-RR-TB patients 77.8%.
INTERPRETATION: This study confirms a low-level rifampicin mono-resistance in TB patients of Suriname. These patients could benefit from a first-line regimen with high dose rifampicin (or rifabutin), rather than from the lengthy treatment. regimens for rifampicin-resistant and multi-drug resistant TB, a concept of stratified medicine also advocated for the treatment of TB.
FUNDING: None.
 
© 2021 The Authors. Published by Elsevier Ltd.
 
DOI: 10.1016/j.jctube.2021.100222
PMCID: PMC7869001
PMID: 33598570

From Our January 2021 Newsletter

 Pharmacokinetics of bedaquiline, delamanid and clofazimine in patients with
multidrug-resistant tuberculosis.

 
J Antimicrob Chemother. 2020 Dec 30:dkaa550. doi: 10.1093/jac/dkaa550. Online ahead of print.
 
Alghamdi WA(1), Al-Shaer MH(2), Kipiani M(3), Barbakadze K(3), Mikiashvili L(3), Kempker RR(4), Peloquin CA(2).
 
BACKGROUND: Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
OBJECTIVES: To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
METHODS: A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
RESULTS: Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
CONCLUSIONS: We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.
 
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
 
DOI: 10.1093/jac/dkaa550
PMID: 33378452

HIV infection and multidrug resistant tuberculosis: a systematic review and
meta-analysis.

 
BMC Infect Dis. 2021 Jan 11;21(1):51. doi: 10.1186/s12879-020-05749-2.
 
Sultana ZZ(1), Hoque FU(2), Beyene J(3), Akhlak-Ul-Islam M(4), Khan MHR(5), Ahmed S(6), Hawlader DH(7), Hossain A(8)(9)(10).
 
Erratum in BMC Infect Dis. 2021 Jan 20;21(1):86.
 
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) in HIV infected individuals is a serious threat to global efforts to combat tuberculosis. Inconsistent findings on the association between HIV infection and MDR-TB were present in many studies. We aimed to review existing data on the relationship
between HIV infection and MDR-TB systematically to assess the contribution of HIV on MDR-TB worldwide. We also investigated the patterns of MDR-TB by age, country-wise income, study designs, and global regions.
METHODS: We utilized PubMed, Google Scholar, and ScienceDirect databases to select eligible studies for meta-analysis that were published between January 12,010, and July 30, 2020. The random-effects model was used to obtain the pooled odds ratio of the crude association between HIV and MDR-TB with a 95%
confidence interval. We investigated the potential publication-bias by checking funnel plot asymmetry and using the Egger's test. Moreover, we assessed the heterogeneity using the I2 statistic. Sensitivity analysis was performed based on sample size and adjustment factors. The protocol was registered with PROSPERO-CRD42019132752.
RESULTS: We identified 1603 studies through a database search, and after subsequent eliminations we selected 54 studies including 430,534 TB patients. The pooled odds of MDR-TB was 1.42 times higher in HIV-positive patients than HIV-negative patients (OR=1.42,CI=1.17-1.71, I2=75.8%). Subgroup analysis revealed that the estimated pooled odds for South-East Asian countries was 1.86, which is the highest in WHO regions (OR=1.86,CI=1.30-2.67, I2=0.00%), followed by Europe and Africa. The effect estimate was found to be higher for primary MDR-TB (OR=2.76,CI=1.70-4.46, I2=0.00%). There was also a trend towards increased odds of MDR-TB for HIV patients older than 40 years (OR=1.56,CI=1.17-2.06). The association was found to be significant in high-burden TB countries (OR=1.75, CI=1.39-2.19) and in high-income countries
(OR=1.55, CI=1.06-2.27).
CONCLUSION: Such findings indicate that HIV infection raises the risk of MDR-TB, and after contrasting it with the results of the earlier pooled study, it appeared to be an upward risk trend. Moreover, we found that the risk is the highest in the South-East Asian region. A balanced allocation of resources is needed to halt both primary and secondary MDR-TB, particularly in HIV infected people with 40 years of age and older.
 
DOI: 10.1186/s12879-020-05749-2
PMCID: PMC7802168
PMID: 33430786 [Indexed for MEDLINE]

"Take the treatment and be brave": Care experiences of pregnant women with
rifampicin-resistant tuberculosis.

 
PLoS One. 2020 Dec 21;15(12):e0242604. doi: 10.1371/journal.pone.0242604.
eCollection 2020.
 
Loveday M(1)(2), Hlangu S(1), Furin J(3).
 
BACKGROUND: There are few data on the on the care experiences of pregnant women with rifampicin-resistant TB.
OBJECTIVE: To describe the treatment journeys of pregnant women with RR-TB-including how their care experiences shape their identities-and identify areas in which tailored interventions are needed.
METHODS: In this qualitative study in-depth interviews were conducted among a convenience sample from a population of pregnant women receiving treatment for RR-TB. This paper follows COREQ guidelines. A thematic network analysis using an inductive approach was performed to analyze the interview transcripts and notes. The analysis was iterative and a coding system developed which focused on the
care experiences of the women and how these experiences affected their perceptions of themselves, their children, and the health care system in which treatment was received.
RESULTS: Seventeen women were interviewed. The women described multiple challenges in their treatment journeys which required them to demonstrate sustained resilience (i.e. to "be brave"). Care experiences required them to negotiate seemingly contradictory identities as both new mothers-"givers of
life"-and RR-TB patients facing a complicated and potentially deadly disease. In terms of their "pregnancy identity" and "RR-TB patient identity" that emerged as part of their care experiences, four key themes were identified that appeared to have elements that were contradictory to one another (contradictory areas).
These included: 1) the experience of physical symptoms or changes; 2) the experience of the "mothering" and "patient" roles; 3) the experience of the care they received for their pregnancy and their RR-TB; and 4) the experience of community engagement. There were also three areas that overlapped with both
roles and during which identity was negotiated/reinforced and they included: 1) faith; 2) socioeconomic issues; and 3) long-term concerns over the child's health. At times, the health care system exacerbated these challenges as the women were not given the support they needed by health care providers who were
ill-informed or angry and treated the women in a discriminatory fashion. Left to
negotiate this confusing time period, the women turned to faith, their own mothers, and the fathers of their unborn children.
CONCLUSION: The care experiences of the women who participated in this study highlight several gaps in the current health care system that must be better addressed in both TB and perinatal services in order to improve the therapeutic journeys for pregnant women with RR-TB and their children. Suggestions for
optimizing care include the provision of integrated services, including specialized counseling as well as training for health care providers; engagement of peer support networks; provision of socioeconomic support; long-term medical care/follow-up for children born to women who were treated for RR-TB; and inclusion of faith-based services in the provision of care.
 
DOI: 10.1371/journal.pone.0242604
PMCID: PMC7751874
PMID: 33347448 [Indexed for MEDLINE]

Lesion Heterogeneity Coincides With Long-Term Heteroresistance in MDR-TB.
 
J Infect Dis. 2021 Jan 12:jiab011. doi: 10.1093/infdis/jiab011. Online ahead of
print.
 
Chen Y(1)(2), Ji L(2), Liu Q(1)(3), Li J(2), Hong C(2), Jiang Q(1)(2), Gan M(4), Takiff HE(5)(6)(7), Yu W(2), Tan W(2), Gao Q(1)(2).
 
Tuberculosis (TB) heteroresistance, in which only a fraction of the bacteria in a TB patient contains drug-resistant mutations, has been a rising concern. However, its origins and prevalence remain elusive. Here, whole-genome sequencing was performed on 83 serial isolates from 31 MDR-TB patients and heteroresistance was detected in isolates from 21 (67.74%) patients. Heteroresistance persisted in the host for long periods, spanning months to years, and was associated with having multiple tubercular lesions. Our findings indicate that heteroresistance is common and persistent in MDR-TB patients and
may affect the success of their treatment regimens.
 
© The Author(s) 2021. 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/infdis/jiab011
PMID: 33433601

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A
Prospective Multicountry Study.

 
Am J Respir Crit Care Med. 2021 Jan 1;203(1):111-119. doi: 10.1164/rccm.202001-0135OC.
 
Franke MF(1)(2), Khan P(3), Hewison C(4), Khan U(3), Huerga H(5), Seung KJ(2)(6), Rich ML(2)(6), Zarli K(7), Samieva N(8), Oyewusi L(9), Nair P(10), Mudassar M(3), Melikyan N(5), Lenggogeni P(11), Lecca L(12), Kumsa A(13), Khan M(14), Islam S(15), Hussein K(16), Docteur W(17), Chumburidze N(18), Berikova
E(19), Atshemyan H(20), Atwood S(6), Alam M(15), Ahmed S(3), Bastard M(5), Mitnick CD(1)(2)(6).
 
Comment in Am J Respir Crit Care Med. 2021 Jan 1;203(1):11-13.
 
Rationale: Bedaquiline and delamanid offer the possibility of more effective and less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). 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 TB or MDR-TB treated in routine care with delamanid- and/or bedaquiline-containing regimens according to World Health Organization guidance.Objectives: We report the frequency of sputum culture conversion within 6 months of treatment initiation and the risk factors for
nonconversion.
Methods: We included patients with a positive baseline culture who initiated a first endTB regimen before April 2018. Two consecutive negative cultures collected 15 days or more apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups.Measurements and Main Results: A total of 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture
conversion within 6 months. In adjusted analyses, patients with HIV had a lower probability of conversion (0.73; 95% confidence interval [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 or glucose intolerance, and baseline resistance were not associated with
conversion.
Conclusions: Frequent sputum conversion in patients with rifampin-resistant TB or 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
PMCID: PMC7781121
PMID: 32706644