PREVIOUS LITERATURE IN DR-TB

From our June 2020 Newsletter

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

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

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

Ambulatory management of pre- and extensively drug resistant tuberculosis  patients with imipenem delivered through port-a-cath: A mixed methods study on  treatment outcomes and challenges.
 
PLoS One. 2020 Jun 16;15(6):e0234651. doi: 10.1371/journal.pone.0234651. eCollection 2020.
 
Chavan VV(1), Dalal A(2), Nagaraja S(3), Thekkur P(4)(5), Mansoor H(1), Meneguim A(1), Paryani R(1), Singh P(1), Kalon S(1), Das M(1), Ferlazzo G(6), Isaakidis P(6).
 
BACKGROUND: Imipenem, an intravenous antibiotic is recommended for use in drug resistant tuberculosis (DR-TB) when an effective regimen with combination of other second line drugs is not possible. Though the treatment success rates with carbapenems are promising, the twice daily injection of Imipenem usually requires patients to be hospitalized. The Médecins Sans Frontières independent clinic in Mumbai, India implemented ambulatory and home based management of patients receiving Imipenem through the use of port-a-cath.
OBJECTIVE: We aimed to describe the adverse events and treatment outcomes of ambulatory pre- and XDR-TB patients initiated on imipenem through port-a-cath between January 2015 and June 2018 and to explore the challenges with this regimen as perceived by healthcare providers and patients.
METHODS: A convergent mixed methods study with quantitative (longitudinal descriptive study using the routine data) and qualitative (descriptive study) part conducted concurrently. For the quantitative component, all XDR-TB and pre-XDR-TB initiated on imipenem containing regimen during January 2015-June 2018 were included. For qualitative component, interviews were carried out including patients who initiated on imipenem (n = 5) and healthcare providers (n = 7) involved in providing treatment. Treatment outcomes, culture conversion and adverse events during treatment were described. Thematic analysis was carried
out for qualitative component.
RESULTS: Of the 70 patients included, the mean age was 28.1 (standard deviation: 11.2) years and 36 (51.4%) were females. Fifty one (72.9%) had XDR-TB. All patients were resistant to fluoroquinilone, levofloxacin. Vomiting was reported by 55 (78.6%) patients and at least one episode of QTC prolongation (more than 500 msec by Fredrecia method) was detected in 25 (35.7%). Port-a-cath block and
infection was seen in 11 (15.7%) and 20 (28.6%) patients respectively. Favourable outcomes were seen in 43 (61.4%) patients. Mortality was seen in 22 (31.4%) patients, 2 (2.9%) were lost-to-follow-up and 3 (4.3%) were declared as treatment failure. The overarching theme of the qualitative analysis was: Challenges in delivering Imipenem via port-a-cath device in ambulatory care. Major challenges identified were difficulties in adhering to drug dose timelines, vomiting, restricted mobility due to port-a-cath, paucity of infection control and space constraints at patients' home for optimal care.
CONCLUSION: Administration of imipenem was feasible through port-a-cath. Though outcomes with ambulatory based imipenem containing regimens were promising, there were several challenges in providing care. The feasibility of infusion at day care facilities needs to explored to overcome challenges in infusion at
patients home.
 
DOI: 10.1371/journal.pone.0234651
PMCID: PMC7297304
PMID: 32544174


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

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

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


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

From our May 2020 Newsletter

Ambulatory management of pre- and extensively drug resistant tuberculosis  patients with imipenem delivered through port-a-cath: A mixed methods study on  treatment outcomes and challenges.
 
PLoS One. 2020 Jun 16;15(6):e0234651. doi: 10.1371/journal.pone.0234651. eCollection 2020.
 
Chavan VV(1), Dalal A(2), Nagaraja S(3), Thekkur P(4)(5), Mansoor H(1), Meneguim A(1), Paryani R(1), Singh P(1), Kalon S(1), Das M(1), Ferlazzo G(6), Isaakidis P(6).
 
BACKGROUND: Imipenem, an intravenous antibiotic is recommended for use in drug resistant tuberculosis (DR-TB) when an effective regimen with combination of other second line drugs is not possible. Though the treatment success rates with carbapenems are promising, the twice daily injection of Imipenem usually requires patients to be hospitalized. The Médecins Sans Frontières independent clinic in Mumbai, India implemented ambulatory and home based management of patients receiving Imipenem through the use of port-a-cath.
OBJECTIVE: We aimed to describe the adverse events and treatment outcomes of ambulatory pre- and XDR-TB patients initiated on imipenem through port-a-cath between January 2015 and June 2018 and to explore the challenges with this regimen as perceived by healthcare providers and patients.
METHODS: A convergent mixed methods study with quantitative (longitudinal descriptive study using the routine data) and qualitative (descriptive study) part conducted concurrently. For the quantitative component, all XDR-TB and pre-XDR-TB initiated on imipenem containing regimen during January 2015-June 2018 were included. For qualitative component, interviews were carried out including patients who initiated on imipenem (n = 5) and healthcare providers (n = 7) involved in providing treatment. Treatment outcomes, culture conversion and adverse events during treatment were described. Thematic analysis was carried
out for qualitative component.
RESULTS: Of the 70 patients included, the mean age was 28.1 (standard deviation: 11.2) years and 36 (51.4%) were females. Fifty one (72.9%) had XDR-TB. All patients were resistant to fluoroquinilone, levofloxacin. Vomiting was reported by 55 (78.6%) patients and at least one episode of QTC prolongation (more than 500 msec by Fredrecia method) was detected in 25 (35.7%). Port-a-cath block and
infection was seen in 11 (15.7%) and 20 (28.6%) patients respectively. Favourable outcomes were seen in 43 (61.4%) patients. Mortality was seen in 22 (31.4%) patients, 2 (2.9%) were lost-to-follow-up and 3 (4.3%) were declared as treatment failure. The overarching theme of the qualitative analysis was: Challenges in delivering Imipenem via port-a-cath device in ambulatory care. Major challenges identified were difficulties in adhering to drug dose timelines, vomiting, restricted mobility due to port-a-cath, paucity of infection control and space constraints at patients' home for optimal care.
CONCLUSION: Administration of imipenem was feasible through port-a-cath. Though outcomes with ambulatory based imipenem containing regimens were promising, there were several challenges in providing care. The feasibility of infusion at day care facilities needs to explored to overcome challenges in infusion at
patients home.
 
DOI: 10.1371/journal.pone.0234651
PMCID: PMC7297304
PMID: 32544174

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

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

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

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

From our April 2020 Newsletter

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

 

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

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

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

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

DOI: 10.1093/cid/ciaa327
PMID: 32266942

 

Read the full article here.

 

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

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

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

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

DOI: 10.3390/antibiotics9030133
PMID: 32209979

 

Read the full article here.

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

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

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

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

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

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

 

This article is not available via Open Access.

 

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

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

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

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

Copyright © 2020 Kaniga et al.

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

 

Read the full article here.

From our March 2020 Newsletter

Triumph and Tragedy of 21st Century Tuberculosis Drug Development.

 

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

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

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

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

 

This article is not available via open access. 

 

Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.

 

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

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

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

 

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

 

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

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

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

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

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

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

 

This article is not available via open access.

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

 

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

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

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

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

DOI: 10.1093/cid/ciaa254
PMID: 32166306

 

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


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

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

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

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

 

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

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

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

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

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

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

DOI: 10.1183/13993003.01467-2019
PMID: 31862767

 

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

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

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

DOI: 10.1080/14787210.2020.1756776
PMID: 32345064

 

 

 

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


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

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

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

 

 

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


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

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