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RECENT PUBLICATIONS

From Our December 2020 Newsletter

Compassionate Use of Delamanid in Adults and Children for Drug-resistant TB:  5-year Update.
 
Eur Respir J. 2020 Nov 26:2002483. doi: 10.1183/13993003.02483-2020. Online ahead of print.
 
Ghosh S(1), Breitscheidel L(1), Lazarevic N(1), Martin A(1), Hafkin J(2), Hittel N(1).
 
BACKGROUND: Although delamanid has been approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in numerous regions, in areas where it is not yet registered, it can be accessed as part of salvage therapy-in particular, for those patients with limited treatment options-via the Otsuka Compassionate Use (CU) programme. Here we present the analysis of interim treatment outcomes by 24 weeks of more than 200 multidrug-resistant tuberculosis (MDR-TB) patients globally who received delamanid under the Otsuka CU programme.
METHODS: We evaluated the treatment efficacy, with respect to culture negativity at 24 weeks, and safety profile of delamanid in a MDR-TB cohort of patients treated under CU between 2014 and 2019.
RESULTS: Among patients who received delamanid as part of a multidrug regimen, 123/202 (61%) had extensively drug-resistant tuberculosis (XDR-TB), 66/202 (33%) had HIV co-infection, and 34/202 (17%) were children ages between 6 and 17 years. Of those patients who were culture positive at delamanid treatment initiation and completed 24 weeks of delamanid treatment in combination with other anti-TB drugs, culture negativity was achieved in 116/147 (79%). The corresponding rates of culture negativity for patients with XDR-TB, HIV co-infection, and the paediatric subgroup were 69/90 (77%), 44/48 (92%), and 20/25 (80%), respectively. QT interval prolongation was the most frequently observed serious adverse event (reported in 8% of patients receiving delamanid). Overall, treatment safety outcomes did not reveal any new or unidentified risks.
CONCLUSIONS: The use of delamanid combined with other active drugs has the potential to achieve high rates of culture negativity in difficult-to-treat drug-resistant tuberculosis cases, with a favourable safety profile.
 
Copyright ©ERS 2020.
 
DOI: 10.1183/13993003.02483-2020
PMID: 33243846

From Our November 2020 Newsletter

 Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB.

 
Int J Tuberc Lung Dis. 2020 Nov 1;24(11):1134-1144. doi: 10.5588/ijtld.20.0330.
 
Cox V(1), McKenna L(2), Acquah R(3), Reuter A(3), Wasserman S(4), Vambe D(5), Ustero P(6), Udwadia Z(7), Triviño-Duran L(8), Tommasi M(9), Skrahina A(10), Seddon JA(11), Rodolfo R(12), Rich M(13), Padanilam X(14), Oyewusi L(15), Ohler L(16), Lungu P(17), Loveday M(18), Khan U(19), Khan P(20), Hughes J(21), Hewison C(22), Guglielmetti L(22), Furin J(23).
 
Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second 'Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective,
we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.
 
DOI: 10.5588/ijtld.20.0330
PMID: 33172520


Population Pharmacokinetic Analysis of Delamanid in Patients with Pulmonary Multi-Drug Resistant Tuberculosis.

 
Antimicrob Agents Chemother. 2020 Oct 26:AAC.01202-20. doi: 10.1128/AAC.01202-20. Online ahead of print.
 
Wang X(1), Mallikaarjun S(2), Gibiansky E(3).
 
A population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK dataset contained 20,483 plasma samples from 744 patients with MDR-TB receiving an optimized background regimen (OBR). Delamanid PK was adequately described for all observed dosing regimens and subpopulations by a two-compartment model with first-order elimination and absorption, an absorption lag time, and decreased relative bioavailability with increasing dose. Relative bioavailabilities of 200 mg and higher doses (250 and 300 mg) were 76% and 58% of a 100 mg dose, respectively. Relative bioavailability was 26% higher after evening doses than morning doses and 9% higher in outpatient settings than inpatient settings. The rate of absorption was faster, and lag time shorter, following a morning dose compared to an evening dose. Relative bioavailabilities in patients in North-East Asian and South-East Asian regions were 53% and 40% higher, respectively, than patients in non-Asian regions. Apparent clearance was higher (to the power of -0.892) in patients with hypoalbuminemia (albumin < 3.4 g/dL). Co-administration of efavirenz in patients with HIV increased delamanid clearance by 35%. Delamanid exposure was not affected by age (18-64 years), mild/moderate renal impairment, anti-TB antibiotic resistance status, HIV status or markers of hepatic dysfunction; nor by concomitant administration of OBR, lamivudine, tenofovir, pyridoxine, CYP 3A4 inhibitors and inducers or antacids. Model evaluation suggested reasonable model fit and predictive power, indicating the model should prove reliable to derive PK metrics for subsequent PK/PD analyses.
 
Copyright © 2020 Wang et al.
 
DOI: 10.1128/AAC.01202-20
PMID: 33106258



Changes in treatment for multidrug-resistant tuberculosis according to national income.

Eur Respir J. 2020 Nov 5;56(5):2001394. doi: 10.1183/13993003.01394-2020. Print 2020 Nov.
 
Kwak N(1), Winters N(2), Campbell JR(2), Chan ED(3)(4), Gegia M(5), Lange C(6)(7)(8)(9), Lee M(10), Milanov V(11), Menzies D(2), Yim JJ(1).
 
The aim of this study was to analyse temporal changes in treatments for and outcomes of multidrug-resistant (MDR)/rifampin-resistant (RR)-tuberculosis (TB) in the context of national economic status.We analysed data collected by the Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB Treatment on MDR/RR-TB patients from 37 countries. The data were stratified by three national income levels (low-/lower-middle, upper-middle and high) and grouped by time of treatment initiation (2001-2003, 2004-2006, 2007-2009, 2010-2012 and 2013-2015). Temporal trends over the study period were analysed. The probability of treatment success in different income groups over time was calculated using generalised linear mixed models with random effects.In total, 9036 patients were included in the analysis. Over the study period, use of group
A drugs (levofloxacin/moxifloxacin, bedaquiline and linezolid) recommended by the World Health Organization increased and treatment outcomes improved in all income groups. Between 2001-2003 and 2013-2015, treatment success rates increased from 60% to 78% in low-/lower-middle-income countries, from 40% to 67%
in upper-middle-income countries, and from 73% to 81% in high-income countries. In earlier years, the probability of treatment success in upper-middle-income countries was lower than that in low-/lower-middle-income countries, but no difference was observed after 2010. However, high-income countries had persistently higher probability of treatment success compared to upper-middle income countries.Improved treatment outcomes and greater uptake of group A drugs were observed over time for patients with MDR/RR-TB at all income levels. However, treatment outcomes are still unsatisfactory, especially in
upper-middle-income countries.
 
Copyright ©ERS 2020.
 
DOI: 10.1183/13993003.01394-2020
PMID: 32586878



Molecular evaluation of fluoroquinolone resistance in serial Mycobacterium  tuberculosis isolates from individuals diagnosed with multidrug-resistant  tuberculosis.

 
Antimicrob Agents Chemother. 2020 Oct 26:AAC.01663-20. doi: 10.1128/AAC.01663-20. Online ahead of print.
 
Willby M(1), Chopra P(1), Lemmer D(2), Klein K(1), Dalton TL, Engelthaler DM(2), Cegielski P(3), Posey JE(4); Global PETTS Investigators.
 
Fluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Varying levels of resistance are associated with specific mutations within the Quinolone Resistance Determining Region (QRDR) of gyrA We sequenced the QRDR from serial isolates of MDR TB patients in the Preserving Effective TB Treatment Study (PETTS) with baseline (FQR) or acquired FQ resistance (FQACQR) using the IonTorrent™ Personal Genome Machine to a depth of 10,000x and reported single nucleotide polymorphisms in ≥1% of reads. FQR isolates harbored 15 distinct alleles with 1.3 (max=6) on average per isolate. Eighteen alleles were identified in FQACQR isolates with an average of 1.6 (max=9) per isolate. Isolates from 78% of FQACQR individuals had mutant alleles identified within 6 months of treatment initiation. Asp94Gly followed by
Ala90Val were the predominant alleles in initial FQ-resistant isolates. Seventy-seven percent (36/47) of FQACQR group patients had isolates with FQ resistance alleles prior to changes to the FQ component of their treatment. Unlike individuals treated initially with other FQs, none of the 21 individuals treated initially with levofloxacin developed genotypic or phenotypic FQ resistance, although, country of residence is likely a contributing factor since 69% of these individuals were from a single country. Initial detection of phenotypic and genotypic resistance occurred simultaneously for most; however, phenotypic resistance occurred earlier in isolates harboring mixtures of very low-abundance (<1% of reads) alleles while genotypic resistance often occurred earlier for low-level resistance-associated alleles. Understanding factors influencing acquisition and evolution of FQ resistance could reveal strategies for improved treatment success.
 
Copyright © 2020 American Society for Microbiology.
 
DOI: 10.1128/AAC.01663-20
PMID: 33106264

 

From Our October 2020 Newsletter

 Impacts of social support on the treatment outcomes of drug-resistant tuberculosis: a systematic review and meta-analysis.
 
BMJ Open. 2020 Oct 8;10(10):e036985. doi: 10.1136/bmjopen-2020-036985.
 
Wen S(1)(2), Yin J(3)(2), Sun Q(1)(2).
 
OBJECTIVE: To assess the effectiveness of social support on treatment success promotion or lost to follow-up (LTFU) reduction for patients with drug-resistant tuberculosis (DR-TB).
DESIGN: We searched Pubmed, Web of Science, Embase, Scopus and Medline databases until 18 June 2020 for interventional or mixed-method studies which reported social support and treatment outcomes of DR-TB patients. Two independent reviewers extracted data and disagreements were resolved by consensus with a third reviewer. Random-effects meta-analysis was performed to calculate the OR and 95% CI for the effects of social support on the improvement of treatment outcomes and the heterogeneity and risk of bias were assessed.
SETTING: Low-income and middle-income countries.
PARTICIPANTS: DR-TB patients.
OUTCOMES: Treatment success is defined as the combination of the cured and treatment completion, and LTFU is measured as treatment being interrupted for two consecutive months or more.
RESULTS: Among 173 articles selected for full-text review, 162 were excluded through independent review (kappa=0.87) and 10 studies enrolling 1621 DR-TB patients in eight countries were included for qualitative analysis. In these studies, the most frequently introduced social support was material support (10 studies), followed by informational (eight studies), emotional (seven studies) and companionship support (four studies). Seven studies that reported treatment outcomes in both intervention arm and control arm are qualified for meta-analysis. An encouraging improvement on treatment success rate (OR: 2.58; 95% CI: 1.80 to 3.69) was found when material support was integrated into social support packages and no heterogeneity was observed (I1 of 0%, Q test p=0.72). Reduction on LTFU rate (OR: 0.17; 95% CI: 0.05 to 0.55) was also noted when material support was available but substantial heterogeneity was found (I2 of 80%, Q test p=0.002).
CONCLUSION: Material support appeared feasible and effective to improve treatment success for DR-TB patients combined with other social support interventions.
PROSPERO REGISTRATION NUMBER: CRD42019140824.
 
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
 
DOI: 10.1136/bmjopen-2020-036985
PMCID: PMC7545632
PMID: 33033087


Multidrug-resistant tuberculosis during pregnancy and adverse birth outcomes: a  systematic review and meta-analysis.
 
BJOG. 2020 Oct 17. doi: 10.1111/1471-0528.16573. Online ahead of print.
 
Alene KA(1)(2)(3), Jegnie A(4), Adane AA(3)(5).
 
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a major global public health concern. However, there is a dearth of literature on whether MDR-TB and its medications impact maternal and perinatal outcomes, and when such evidence exists the findings are conflicting.
OBJECTIVES: This systematic review and meta-analysis aimed to examine the impact of MDR-TB and its medications during pregnancy on maternal and perinatal outcomes.
SEARCH STRATEGY: The PubMed, Scopus, and Web of Science databases were searched from earliest to February 2020.
SELECTION CRITERIA: Records were screened based on pre-defined selection criteria and assessed for quality by two independent reviewers.
DATA COLLECTION AND ANALYSIS: A meta-analysis was performed using the random-effects model to calculate pooled prevalence for each outcome. MAIN RESULTS: Of the 72 records identified, 12 included in the systematic review and meta-analysis, consisting of 174 pregnant women with MDR-TB and 110 adverse outcomes. Maternal death, pregnancy loss, preterm birth, and low birthweight were the most common maternal and perinatal adverse outcomes reported in the studies. The overall pooled prevalence was 7.5% (95% confidence interval (CI): 3.2, 12.8) for maternal death, 10.6% (95% CI: 6.0, 16.3) for pregnancy loss, 12.9% (95% CI: 0.0, 38.0) for preterm birth, and 23.7% (95% CI: 17.0, 31.0) for low birthweight.
CONCLUSIONS: The findings suggest that MDR-TB is associated with a high risk of adverse maternal and perinatal outcomes, but these should be interpreted cautiously as the evidence is largely preliminary. Adequately powered prospective cohort studies are urgently required to corroborate these findings.
 
This article is protected by copyright. All rights reserved.
 
DOI: 10.1111/1471-0528.16573
PMID: 33068306


Electronic dose monitoring identifies a high-risk subpopulation in the treatment  of drug-resistant tuberculosis and HIV.
 

Clin Infect Dis. 2020 Oct 14:ciaa1557. doi: 10.1093/cid/ciaa1557. Online ahead of print.
 
Zelnick JR(1), Daftary A(2)(3), Hwang C(4), Labar AS(5), Boodhram R(3), Maharaj B(3), Wolf AK(6), Mondal S(7), Amico KR(8), Orrell C(9), Seepamore B(10), Friedland G(11), Padayatchi N(3), O'Donnell MR(4)(3)(6).
 
BACKGROUND: In generalized drug-resistant tuberculosis (DR-TB) HIV epidemics, identifying subpopulations at high risk for treatment failure and loss to care is critically important to improve treatment outcomes and prevent amplification of drug resistance. We hypothesized that an electronic dose-monitoring (EDM) device could empirically identify adherence-challenged patients and that a mixed-methods approach would characterize treatment challenges.
METHODS: A prospective study of DR-TB HIV patients on antiretroviral therapy (ART) initiating bedaquiline-containing regimens in KwaZulu-Natal, South Africa. Separate EDM devices measured adherence for bedaquiline and ART. Patients with low adherence (<85%) to both bedaquiline and ART were identified as high-risk for poor outcomes. Baseline survey, study visit notes and focus group discussions characterized treatment challenges.
RESULTS: From December 2016-February 2018, 32 of 198 (16%) enrolled DR-TB HIV patients were identified as dual adherence-challenged. In a multivariate model
including baseline characteristics, only receiving a disability grant was significantly associated with dual non-adherence at 6-months. Mixed-methods identified treatment barriers including, alcohol abuse, family conflicts, and mental health issues. Compared to adherent patients, dual-adherence challenged patients struggled to prioritize treatment and lacked support, and dual adherence-challenged patients experienced higher rates of detectable HIV viral load and mortality compared to more adherent patients.
CONCLUSION: EDM empirically identified a subpopulation of DR-TB HIV patients
with dual adherence challenges early in treatment. Mixed-methods revealed intense psychosocial, behavioral, and structural barriers to care in this subpopulation. Our data supports developing differential, patient-centered, adherence support interventions focused on psychosocial and structural challenges for subpopulations of at-risk DR-TB HIV patients.
 
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
 
DOI: 10.1093/cid/ciaa1557
PMID: 33053186


Application of Targeted Next-Generation Sequencing Assay on a Portable  Sequencing Platform for Culture-Free Detection of Drug-Resistant Tuberculosis  from Clinical Samples.
 
J Clin Microbiol. 2020 Sep 22;58(10):e00632-20. doi: 10.1128/JCM.00632-20. Print
2020 Sep 22.
 
Cabibbe AM(1), Spitaleri A(1)(2), Battaglia S(1), Colman RE(3)(4), Suresh A(3), Uplekar S(3), Rodwell TC(# (3)(4), Cirillo DM(#)(5).
 
Targeted next-generation sequencing (tNGS) has emerged as a comprehensive alternative to existing methods for drug susceptibility testing (DST) of Mycobacterium tuberculosis from patient sputum samples for clinical diagnosis of drug-resistant tuberculosis (DR-TB). However, the complexity of sequencing platforms has limited their uptake in low-resource settings. The goal of this study was to evaluate the use of the tNGS-based DST solution Genoscreen Deeplex Myc-TB, for use on the compact, low-cost Oxford Nanopore Technologies MinION sequencer. One hundred four DNA samples extracted from smear-positive sputum sediments, previously sequenced using the Deeplex assay on an Illumina MiniSeq, were resequenced on MinION after applying a custom library preparation. MinION read quality, mapping statistics, and variant calling were computed using an in-house pipeline and compared to the reference MiniSeq data. The average percentage of MinION reads mapped to an H37RV reference genome was 90.8%, versus 99.5% on MiniSeq. The mean depths of coverage were 4,151× and 4,177× on MinION and MiniSeq, respectively, with heterogeneous distribution across targeted genes. Composite reference coverage breadth was >99% for both platforms. We observed full concordance between technologies in reporting the clinically relevant drug-resistant markers, including full gene deletions. In conclusion, we demonstrated that the workflow and sequencing data obtained from Deeplex on MinION are comparable to those for the MiniSeq, despite the higher raw error rates on MinION, with the added advantage of MinION's portability, versatility, and low capital costs. Targeted NGS on MinION is a promising DST solution for rapidly providing clinically relevant data to manage complex DR-TB cases.
 
Copyright © 2020 Cabibbe et al.
 
DOI: 10.1128/JCM.00632-20
PMCID: PMC7512157
PMID: 32727827


Therapeutic drug monitoring in patients with tuberculosis and concurrent medical  problems.
 
Expert Opin Drug Metab Toxicol. 2020 Oct 12. doi: 10.1080/17425255.2021.1836158. Online ahead of print.
 
Märtson AG(1), Burch G(2), Ghimire S(1), Alffenaar JC(1)(3)(4)(5), Peloquin CA(2).
 
INTRODUCTION: Therapeutic drug monitoring (TDM) has been recommended for treatment optimization in tuberculosis (TB) but is only is used in certain countries e.g. USA, Germany, the Netherlands, Sweden and Tanzania. Recently, new drugs have emerged and PK studies in TB are continuing, which contributes further evidence for TDM in TB. The aim of this review is to provide an update on drugs used in TB, treatment strategies for these drugs, and TDM to support broader implementation.
AREAS COVERED: This review describes the different drug classes used for TB, multidrug-resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB), along with their pharmacokinetics, dosing strategies, TDM and sampling strategies. Moreover, the review discusses TDM for patient TB and renal or liver
impairment, patients co-infected with HIV or hepatitis, and special patient populations - children and pregnant women.
EXPERT OPINION: TB treatment has a long history of using "one size fits all." This has contributed to treatment failures, treatment relapses, and the selection of drug-resistant isolates. While challenging in resource-limited circumstances, TDM offers the clinician the opportunity to individualize and optimize treatment early in treatment. This approach may help to refine treatment and thereby reduce adverse effects and poor treatment outcomes. Funding, training, and randomized controlled trials are needed to advance the use of TDM for patients with TB.
 
DOI: 10.1080/17425255.2021.1836158
PMID: 33040625


 One step forward: Successful end-of-treatment outcomes of drug-resistant TB  patients who received concomitant bedaquiline and delamanid in Mumbai, India.
 
Clin Infect Dis. 2020 Oct 20:ciaa1577. doi: 10.1093/cid/ciaa1577. Online ahead of print.
 
Das M(1), Dalal A(2), Laxmeshwar C(1), Ravi S(1), Mamnoon F(1), Meneguim AC(1), Paryani R(1), Mathur T(1), Singh P(1), Mansoor H(1), Kalon S(1), Hossain FN(1), Lachenal N(3), Coutisson S(3), Ferlazzo G(4), Isaakidis P(4).
 
BACKGROUND: Médecins Sans Frontières clinic in Mumbai, India has been providing concomitant Bedaquiline (BDQ) and Delamanid (DLM) in treatment regimen for patients with drug-resistant tuberculosis (DR-TB) and limited therapeutic options, referred from other healthcare institutions, since 2016. The study documents the end-of-treatment outcomes, culture-conversion rates, and serious adverse events (SAEs) during treatment.
METHODS: This was a retrospective cohort study based on routinely collected programme data. In clinic, treatment regimens are designed based on culture-drug sensitivity test patterns, previous drug-exposures and are provided for 20-22 months. The BDQ and DLM are extended beyond 24 weeks as off-label use. Patients who initiated DR-TB treatment including BDQ and DLM (concomitantly for at least 4 weeks) during February2016-February2018 were included.
RESULT: Of the 70 patients included, the median (IQR) age was 25(22-32) years and 56% were females. All except one were fluoroquinolone resistant. The median(IQR) duration of exposure to BDQ and DLM was 77(43-96) weeks. Thirty-nine episodes of serious-adverse-events(SAEs) were reported among 30(43%) patients, including five instances of QTc prolongation-assessed as possibly related to BDQ and/or DLM. Majority(69%) had culture conversion before 24 weeks of treatment. In 61(87%), use of BDQ and DLM was extended beyond 24 weeks. Successful end-of-treatment outcomes were reported in 49(70%) patients.
CONCLUSION: The successful treatment outcomes of this cohort show that regimens including concomitant bedaquiline and delamanid for longer than 24 weeks are effective and can be safely administered on ambulatory basis. National TB programmes globally should scale up access to life saving DR-TB regimens with new drugs.
 
© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America.
 
DOI: 10.1093/cid/ciaa1577
PMID: 33079176
 

Isoniazid Preventive Therapy in Contacts of Multidrug-Resistant Tuberculosis.
 
Am J Respir Crit Care Med. 2020 Oct 15;202(8):1159-1168. doi: 10.1164/rccm.201908-1576OC.
 
Huang CC(1)(2), Becerra MC(2), Calderon R(3), Contreras C(3), Galea J(4), Grandjean L(5)(6)(7), Lecca L(3), Yataco R(3), Zhang Z(1)(2), Murray M(1)(2).
 
Comment in Am J Respir Crit Care Med. 2020 Oct 15;202(8):1077-1078.
 
Rationale: The World Health Organization recommends the use of isoniazid (INH) alone or in combination with rifapentine to treat latent tuberculosis infections. The recent rise of drug-resistant tuberculosis has complicated the choice of treatment regimen for latent tuberculosis infection
Objectives: To evaluate the effects of INH preventive therapy on the contacts of patients with multidrug-resistant tuberculosis.Methods: In a prospective cohort study conducted between September 2009 and August 2012, we identified 4,500 index patients with tuberculosis and 14,044 tuberculosis-exposed household contacts who we followed for 1 year for the occurrence of incident tuberculosis disease. Although Peruvian national guidelines specify that INH preventive therapy should be provided to contacts aged 19 years old or younger, only half this group received INH preventive therapy.
Measurements and Main Results: Among 4,216 contacts under 19 years of age, 2,106 contacts (50%) initiated INH preventive therapy at enrollment. The protective effect of INH was more extreme in contacts exposed to drug-sensitive tuberculosis (adjusted hazard ratio, 0.30; 95% confidence interval, 0.18-0.48) and to multidrug-resistant tuberculosis (adjusted hazard ratio, 0.19; 95% confidence interval, 0.05-0.66) compared with those exposed to mono-INH-resistant tuberculosis (adjusted hazard ratio, 0.80; 95% confidence interval, 0.23-2.80). In the second independent study, tuberculosis occurred in none of the 76 household contacts who received INH preventive therapy compared with 3% (8 of 273) of those who did not.
Conclusions: Household contacts who received INH preventive therapy had a lower incidence of tuberculosis disease even when they had been exposed to an index patient with multidrug-resistant tuberculosis. INH may have a role in the management of latent multidrug-resistant tuberculosis infection.
 
DOI: 10.1164/rccm.201908-1576OC
PMCID: PMC7560814
PMID: 32551948

 From Our September 2020 Newsletter

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

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

 

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

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

 

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

Public investments in the clinical development of bedaquiline.

 

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

 From Our August 2020 Newsletter

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

(Article not publicly available)


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



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



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

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



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

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

From Our January 2020 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