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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:
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/ 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/
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, 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.
© 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:
DOI: 10.1093/jac/dkaa550
PMID: 33378452

HIV infection and multidrug resistant tuberculosis: a systematic review and

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
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:
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
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
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

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.
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.
© 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:
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