#Global #burden of #latent #MDR #tuberculosis: #trends and #estimates based on mathematical modelling (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling

Gwenan M Knight, PhD, C Finn McQuaid, PhD, Peter J Dodd, PhD †, Rein M G J Houben, PhD †

Open Access / Published: July 04, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30307-X

 

Summary

Background

To end the global tuberculosis epidemic, latent tuberculosis infection needs to be addressed. All standard treatments for latent tuberculosis contain drugs to which multidrug-resistant (MDR) Mycobacterium tuberculosis is resistant. We aimed to estimate the global burden of multidrug-resistant latent tuberculosis infection to inform tuberculosis elimination policy.

Methods

By fitting a flexible statistical model to tuberculosis drug resistance surveillance and survey data collated by WHO, we estimated national trends in the proportion of new tuberculosis cases that were caused by MDR strains. We used these data as a proxy for the proportion of new infections caused by MDR M tuberculosis and multiplied trends in annual risk of infection from previous estimates of the burden of latent tuberculosis to generate trends in the annual risk of infection with MDR M tuberculosis. These estimates were used in a cohort model to estimate changes in the global and national prevalence of latent infection with MDR M tuberculosis. We also estimated recent infection levels (ie, in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis in 2035 and 2050.

Findings

19·1 million (95% uncertainty interval [UI] 16·4 million–21·7 million) people were latently infected with MDR tuberculosis in 2014—a global prevalence of 0·3% (95% UI 0·2–0·3). MDR strains accounted for 1·2% (95% UI 1·0–1·4) of the total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6–3·1) of the burden among children younger than 15 years (risk ratio for those younger than 15 years vsthose aged 15 years or older 2·65 [95% UI 2·11–3·25]). Recent latent infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million–2·3 million) people globally were at high risk of active MDR tuberculosis in 2015.

Interpretation

We estimate that three in every 1000 people globally carry latent MDR tuberculosis infection, and prevalence is around ten times higher among those younger than 15 years. If current trends continue, the proportion of latent tuberculosis caused by MDR strains will increase, which will pose serious challenges for management of latent tuberculosis—a cornerstone of tuberculosis elimination strategies.

Funding

UK Medical Research Council, Bill & Melinda Gates Foundation, and European Research Council.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; Worldwide.

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Extensive #global #movement of #MDR M. #tuberculosis strains revealed by whole-genome analysis (Thorax, abstract)

[Source: Thorax, full page: (LINK). Abstract, edited.]

Extensive global movement of multidrug-resistant M. tuberculosisstrains revealed by whole-genome analysis

Keira A Cohen 1, Abigail L Manson 2, Thomas Abeel 2,3, Christopher A Desjardins 2, Sinead B Chapman 2, Sven Hoffner 4, Bruce W Birren 2, Ashlee M Earl 2

Author affiliations: 1 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 2 Broad Institute of Harvard and M.I.T, Cambridge, Massachusetts, USA; 3 Delft Bioinformatics Lab, Technische Universiteit Delft Faculteit Technische Natuurwetenschappen, Delft, Netherlands; 4 Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden

Correspondence to Dr Ashlee M Earl, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; aearl@broadinstitute.org

 

Abstract

Background 

While the international spread of multidrug-resistant (MDR) Mycobacterium tuberculosis strains is an acknowledged public health threat, a broad and more comprehensive examination of the global spread of MDR-tuberculosis (TB) using whole-genome sequencing has not yet been performed.

Methods 

In a global dataset of 5310 M. tuberculosis whole-genome sequences isolated from five continents, we performed a phylogenetic analysis to identify and characterise clades of MDR-TB with respect to geographic dispersion.

Results 

Extensive international dissemination of MDR-TB was observed, with identification of 32 migrant MDR-TB clades with descendants isolated in 17 unique countries. Relatively recent movement of strains from both Beijing and non-Beijing lineages indicated successful global spread of varied genetic backgrounds. Migrant MDR-TB clade members shared relatively recent common ancestry, with a median estimate of divergence of 13–27 years. Migrant extensively drug-resistant (XDR)-TB clades were not observed, although development of XDR-TB within migratory MDR-TB clades was common.

Conclusions 

Application of genomic techniques to investigate global MDR migration patterns revealed extensive global spread of MDR clades between countries of varying TB burden. Further expansion of genomic studies to incorporate isolates from diverse global settings into a single analysis, as well as data sharing platforms that facilitate genomic data sharing across country lines, may allow for future epidemiological analyses to monitor for international transmission of MDR-TB. In addition, efforts to perform routine whole-genome sequencing on all newly identified M. tuberculosis, like in England, will serve to better our understanding of the transmission dynamics of MDR-TB globally.

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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

DOI: http://dx.doi.org/10.1136/thoraxjnl-2018-211616

Keywords: Antibiotics; Drugs Resistance; MDR-TB; Tuberculosis.

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#Outcomes of #Bedaquiline #Treatment in Patients with #MDR #Tuberculosis (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 5—May 2019 / Research

Outcomes of Bedaquiline Treatment in Patients with Multidrug-Resistant Tuberculosis

Lawrence Mbuagbaw  , Lorenzo Guglielmetti, Catherine Hewison, Nyasha Bakare, Mathieu Bastard, Eric Caumes, Mathilde Fréchet-Jachym, Jérôme Robert, Nicolas Veziris, Naira Khachatryan, Tinatin Kotrikadze, Armen Hayrapetyan, Zaza Avaliani, Holger J. Schünemann, and Christian Lienhardt

Author affiliations: St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada (L. Mbuagbaw); Centre for the Development of Best Practices in Health, Yaoundé, Cameroon (L. Mbuagbaw); McMaster University, Hamilton (L. Mbuagbaw, H.J. Schünnemann); Centre d’Immunologie et des Maladies Infectieuses, INSERM, Paris (L. Guglielmetti, E. Caumes, J. Robert, N. Veziris); Centre Hospitalier de Bligny, Bris-sous-Forges, France (L. Guglielmetti, M. Frechet-Jachym); Sorbonne Université, Paris, France (L. Guglielmetti, J. Robert, N. Veziris); Médecins Sans Frontières, Paris (C. Hewison); Janssen Research & Development, LLC, Titusville, New Jersey, USA (N. Bakere); Epicentre, Paris (M. Bastard); Hôpitaux Universitaires de l’Est Parisien, Paris (N. Veziris); Médecins Sans Frontières, Yerevan, Armenia (N. Khachatryan); Médecins Sans Frontières, Tbilisi, Georgia (T. Kotrikadze); National Tuberculosis Control Centre, Yerevan (A. Hayrapetyan); National Centre for Tuberculosis and Lung Disease, Tbilisi (Z. Avaliani); World Health Organization, Geneva, Switzerland (C. Lienhardt); Université de Montpellier, Montpellier, France (C. Lienhardt)

 

Abstract

Bedaquiline is recommended by the World Health Organization for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). We pooled data from 5 cohorts of patients treated with bedaquiline in France, Georgia, Armenia, and South Africa and in a multicountry study. The rate of culture conversion to negative at 6 months (by the end of 6 months of treatment) was 78% (95% CI 73.5%–81.9%), and the treatment success rate was 65.8% (95% CI 59.9%–71.3%). Death rate was 11.7% (95% CI 7.0%–19.1%). Up to 91.1% (95% CI 82.2%–95.8%) of the patients experienced >1 adverse event, and 11.2% (95% CI 5.0%–23.2%) experienced a serious adverse event. Lung cavitations were consistently associated with unfavorable outcomes. The use of bedaquiline in MDR and XDR TB treatment regimens appears to be effective and safe across different settings, although the certainty of evidence was assessed as very low.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; MDR-TB; XDR-TB; Bedaquiline.

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#Drug susceptibility #testing and #mortality in patients treated for #tuberculosis in high-burden countries: a multicentre cohort study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries: a multicentre cohort study

Kathrin Zürcher, MSc *, Marie Ballif, PhD *, Prof Lukas Fenner, MD, Sonia Borrell, PhD, Peter M Keller, MD, Joachim Gnokoro, MD, Olivier Marcy, MD, Prof Marcel Yotebieng, MD, Lameck Diero, MD, Prof E Jane Carter, MD, Neesha Rockwood, PhD, Prof Robert J Wilkinson, PhD, Prof Helen Cox, PhD, Nicholas Ezati, MSc, Prof Alash’le G Abimiku, PhD, Jimena Collantes, MSc, Anchalee Avihingsanon, MD, Kamon Kawkitinarong, MD, Miriam Reinhard, Rico Hömke, Robin Huebner, PhD, Prof Sebastien Gagneux, PhD *, Prof Erik C Böttger, MD *, Prof Matthias Egger, MD  * on behalf of theInternational epidemiology Databases to Evaluate AIDS (IeDEA) consortium †

Published: February 07, 2019 / DOI: https://doi.org/10.1016/S1473-3099(18)30673-X

 

Summary

Background

Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and in a reference laboratory.

Methods

This multicentre cohort study was done in Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand. We collected Mycobacterium tuberculosis isolates and clinical data from adult patients aged 16 years or older. Patients were stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing was done locally and at the Swiss National Center for Mycobacteria, Zurich, Switzerland. We examined mortality during treatment according to drug susceptibility test results and treatment adequacy in multivariable logistic regression models adjusting for sex, age, sputum microscopy, and HIV status.

Findings

We obtained M tuberculosis isolates from 871 patients diagnosed between 2013 and 2016. After exclusion of 237 patients, 634 patients with tuberculosis were included in this analysis; the median age was 33·2 years (IQR 26·9–42·5), 239 (38%) were women, 272 (43%) were HIV-positive, and 69 (11%) patients died. Based on the reference laboratory drug susceptibility test, 394 (62%) strains were pan-susceptible, 45 (7%) monoresistant, 163 (26%) multidrug-resistant (MDR), and 30 (5%) had pre-extensively or extensively drug resistant (pre-XDR or XDR) tuberculosis. Results of reference and local laboratories were concordant for 513 (81%) of 634 patients and discordant for 121 (19%) of 634. Overall, sensitivity to detect any resistance was 90·8% (95% CI 86·5–94·2) and specificity 84·3% (80·3–87·7). Mortality ranged from 6% (20 of 336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57% (eight of 14) in patients with resistant strains who were under-treated. In logistic regression models, compared with concordant drug susceptibility test results, the adjusted odds ratio of death was 7·33 (95% CI 2·70–19·95) for patients with discordant results potentially leading to under-treatment.

Interpretation

Inaccurate drug susceptibility testing by comparison with a reference standard leads to under-treatment of drug-resistant tuberculosis and increased mortality. Rapid molecular drug susceptibility test of first-line and second-line drugs at diagnosis is required to improve outcomes in patients with MDR tuberculosis and pre-XDR or XDR tuberculosis.

Funding

National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, Swiss National Center for Mycobacteria.

Keywords: Mycobacterium tuberculosis; Antibiotics; Drugs Resistance.

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#Outbreak of #MDR #TB in [#ZA] South Africa undetected by #WHO-endorsed commercial #tests: an observational study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study

Ndivhuho A Makhado, MSc, Edith Matabane, MSc, Mauro Faccin, PhD, Claire Pinçon, PhD, Agathe Jouet, PhD, Fairouz Boutachkourt, BSc, Léonie Goeminne, BSc, Cyril Gaudin, PhD, Gugu Maphalala, MSc, Patrick Beckert, PhD, Stefan Niemann, PhD, Jean-Charles Delvenne, PhD, Michel Delmée, MD, Lufuno Razwiedani, MD, Maphoshane Nchabeleng, MD, Philip Supply, PhD †, Bouke C de Jong, MD †, Emmanuel André, MD  †

Published: October 17, 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30496-1

 

Summary

Background

Global roll-out of rapid molecular assays is revolutionising the diagnosis of rifampicin resistance, predictive of multidrug-resistance, in tuberculosis. However, 30% of the multidrug-resistant (MDR) strains in an eSwatini study harboured the Ile491Phe mutation in the rpoB gene, which is associated with poor rifampicin-based treatment outcomes but is missed by commercial molecular assays or scored as susceptible by phenotypic drug-susceptibility testing deployed in South Africa. We evaluated the presence of Ile491Phe among South African tuberculosis isolates reported as isoniazid-monoresistant according to current national testing algorithms.

Methods

We screened records of 37 644 Mycobacterium tuberculosis positive cultures from four South African provinces, diagnosed at the National Health Laboratory Service–Dr George Mukhari Tertiary Laboratory, to identify isolates with rifampicin sensitivity and isoniazid resistance according to Xpert MTB/RIF, GenoType MTBDRplus, and BACTEC MGIT 960. Of 1823 isolates that met these criteria, 277 were randomly selected and screened for Ile491Phe with multiplex allele-specific PCR and Sanger sequencing of rpoB. Ile491Phe-positive strains (as well as 17 Ile491Phe-bearing isolates from the eSwatini study) were then tested by Deeplex-MycTB deep sequencing and whole-genome sequencing to evaluate their patterns of extensive resistance, transmission, and evolution.

Findings

Ile491Phe was identified in 37 (15%) of 249 samples with valid multiplex allele-specific PCR and sequencing results, thus reclassifying them as MDR. All 37 isolates were additionally identified as genotypically resistant to all first-line drugs by Deeplex-MycTB. Six of the South African isolates harboured four distinct mutations potentially associated with decreased bedaquiline sensitivity. Consistent with Deeplex-MycTB genotypic profiles, whole-genome sequencing revealed concurrent silent spread in South Africa of a MDR tuberculosis strain lineage extending from the eSwatini outbreak and at least another independently emerged Ile491Phe-bearing lineage. Whole-genome sequencing further suggested acquisition of mechanisms compensating for the Ile491Phe fitness cost, and of additional bedaquiline resistance following the introduction of this drug in South Africa.

Interpretation

A substantial number of MDR tuberculosis cases harbouring the Ile491Phe mutation in the rpoB gene in South Africa are missed by current diagnostic strategies, resulting in ineffective first-line treatment, continued amplification of drug resistance, and concurrent silent spread in the community.

Funding

VLIR-UOS, National Research Foundation (South Africa), and INNOVIRIS.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; South Africa.

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#Prevalence of drug- #resistant #tuberculosis and imputed burden in #SouthAfrica: a national and sub-national cross-sectional survey (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Prevalence of drug-resistant tuberculosis and imputed burden in South Africa: a national and sub-national cross-sectional survey

Nazir Ahmed Ismail, FCPath, Lindiwe Mvusi, MBChB, Ananta Nanoo, MSc, Andries Dreyer, FCPath, Shaheed V Omar, PhD, Sanni Babatunde, PhD, Thabo Molebatsi, MPH, Martie van der Walt, PhD, Adeboye Adelekan, PhD, Varough Deyde, PhD, Chikwe Ihekweazu, FFPH†, Prof Shabir A Madhi, PhD†

† Contributed equally

Published: 20 April 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30222-6

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We sought to estimate the prevalence of resistance to tuberculosis drugs in newly diagnosed and retreated patients with tuberculosis provincially and nationally, and compared these with the 2001–02 estimates.

Methods

A cross-sectional survey was done between June 15, 2012–June 14, 2014, using population proportionate randomised cluster sampling in the nine provinces in South Africa. 343 clusters were included, ranging between 31 and 48 per province. A patient was eligible for inclusion in the survey if he or she presented as a presumptive case during the intake period at a drug resistance survey enrolling facility. Consenting participants (≥18 years old) completed a questionnaire and had a sputum sample tested for resistance to first-line and second-line drugs. Analysis was by logistic regression with robust SEs, inverse probability weighted against routine data, and estimates were derived using a random effects model.

Findings

101 422 participants were tested in 2012–14. Nationally, the prevalence of MDR tuberculosis was 2·1% (95% CI 1·5–2·7) among new tuberculosis cases and 4·6% (3·2–6·0) among retreatment cases. The provincial point prevalence of MDR tuberculosis ranged between 1·6% (95% CI 0·9–2·9) and 5·1% (3·7–7·0). Overall, the prevalence of rifampicin-resistant tuberculosis (4·6%, 95% CI 3·5–5·7) was higher than the prevalence of MDR tuberculosis (2·8%, 2·0–3·6; p=0·01). Comparing the current survey with the previous (2001–02) survey, the overall MDR tuberculosis prevalence was 2·8% versus 2·9% and prevalance of rifampicin-resistant tuberculosis was 3·4% versus 1·8%, respectively. The prevalence of isoniazid mono-resistant tuberculosis was above 5% in all provinces. The prevalence of ethionamide and pyrazinamide resistance among MDR tuberculosis cases was 44·7% (95% CI 25·9–63·6) and 59·1% (49·0–69·1), respectively. The prevalence of XDR tuberculosis was 4·9% (95% CI 1·0–8·8). Nationally, the estimated numbers of cases of rifampicin-resistant tuberculosis, MDR tuberculosis, and isoniazid mono-resistant tuberculosis for 2014 were 13 551, 8249, and 17 970, respectively.

Interpretation

The overall prevalence of MDR tuberculosis in South Africa in 2012–14 was similar to that in 2001–02; however, prevalence of rifampicin-resistant tuberculosis almost doubled among new cases. Furthermore, the high prevalence of isoniazid mono-resistant tuberculosis, not routinely screened for, and resistance to second-line drugs has implications for empirical management.

Funding

President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention under the terms of 1U19GH000571.

Keywords: South Africa; Tuberculosis; Antibiotics; Drugs Resistance; MDR-TB; Rifampicin; Isoniazid.

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#Tuberculosis: #progress and #advances in development of new #drugs, #treatment regimens, and host-directed therapies (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Simon Tiberi, MD, Nelita du Plessis, PhD, Prof Gerhard Walzl, FRCP, Michael J Vjecha, MD, Martin Rao, PhD, Prof Francine Ntoumi, FRCP, Prof Sayoki Mfinanga, PhD, Nathan Kapata, MPH, Prof Peter Mwaba, FRCP, Prof Timothy D McHugh, PhD, Prof Giuseppe Ippolito, FRCP, Prof Giovanni Battista Migliori, FRCP, Prof Markus J Maeurer, FRCP, Prof Alimuddin Zumla, FRCP

Published: 23 March 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30110-5

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Tuberculosis remains the world’s leading cause of death from an infectious disease, responsible for an estimated 1 674 000 deaths annually. WHO estimated 600 000 cases of rifampicin-resistant tuberculosis in 2016—of which 490 000 were multidrug resistant (MDR), with less than 50% survival after receiving recommended treatment regimens. Concerted efforts of stakeholders, advocates, and researchers are advancing further development of shorter course, more effective, safer, and better tolerated treatment regimens. We review the developmental pipeline and landscape of new and repurposed tuberculosis drugs, treatment regimens, and host-directed therapies (HDTs) for drug-sensitive and drug-resistant tuberculosis. 14 candidate drugs for drug-susceptible, drug-resistant, and latent tuberculosis are in clinical stages of drug development; nine are novel in phase 1 and 2 trials, and three new drugs are in advanced stages of development for MDR tuberculosis. Specific updates are provided on clinical trials of bedaquiline, delamanid, pretomanid, and other licensed or repurposed drugs that are undergoing investigation, including trials aimed at shortening duration of tuberculosis treatment, improving treatment outcomes and patient adherence, and reducing toxic effects. Ongoing clinical trials for shortening tuberculosis treatment duration, improving treatment outcomes in MDR tuberculosis, and preventing disease in people with latent tuberculosis infection are reviewed. A range of HDTs and immune-based treatments are under investigation as adjunctive therapy for shortening duration of therapy, preventing permanent lung injury, and improving treatment outcomes of MDR tuberculosis. We discuss the HDT development pipeline, ongoing clinical trials, and translational research efforts for adjunct tuberculosis treatment.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; MDR-TB.

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