June 2019 Newsletter

News

FDA Antimicrobial Drugs Advisory Committee recommends approval of pretomanid

Investigational drug pretomanid is under regulatory review by FDA for treatment of XDR-TB and treatment-intolerant or non-responsive MDR-TB as part of a new investigational regimen. A decision regarding pretomanid approval is expected to be made by August of 2019.

Advocates call on TB Alliance to make public the pretomanid licensing agreement with Mylan

TB advocates sent an open letter to TB alliance requesting the organization toshare their recent agreement with Mylan.

Publications

1. TB Preventive Therapy for individuals exposed to drug-resistant tuberculosis: feasibility and safety of a community-based delivery of
fluoroquinolone-containing preventive regimen.
Clin Infect Dis. 2019 Jun 12. pii: ciz502. doi: 10.1093/cid/ciz502. [Epub ahead
of print]
Malik AA, Fuad J, Siddiqui S, Amanullah F, Jaswal M, Pmdcp ZB, Jabeen F, Fatima R, Yuen CM, Salahuddin N, Khan AJ, Keshavjee S, Becerra MC, Hussain H.

BACKGROUND: Observational studies have demonstrated the effectiveness of a
fluoroquinolone-based regimen to treat individuals exposed to or presumed to be
infected with drug-resistant (DR)-TB. We sought to assess the feasibility of this
approach in an urban setting in South Asia.
METHODS: From February 2016 until March 2017, all household contacts of DR-TB
patients enrolled at The Indus Hospital were screened for TB symptoms at home.
Children 0-17 years, symptomatic adults and those with an immunocompromising
condition (HIV, diabetes or malnutrition) were evaluated for TB disease. Contacts
diagnosed with TB disease were started on treatment. Contacts without TB disease
(i) younger than 5 years; (ii) between 5 and 17 years old with either a positive
TST or an immunocompromising condition; or (iii) 18 years and older with an
immunocompromising conditionwere offered six month treatment with a
fluoroquinolone.
RESULTS: One hundred households with 800 contacts were enrolled: 353 (44·1%)
individuals age 17 years or younger with a median age of 19 years (IQR: 10-32);
423 (52·9%) were males. In total, 737 (92·1%) individuals were screened, of which
eight were already on treatment for TB (1·1%), and another three (0·4%) contacts
were diagnosed with TB disease and started on treatment. Of 215 eligible for
infection treatment, 172 (80·0%) contacts initiated and 121 (70·3%) completed
treatment. No TB disease nor significant adverse events were observed during 12
months of follow up in any group.
CONCLUSIONS: Fluoroquinolone-based treatment for contacts with presumed DR-TB
infection is feasible and well tolerated in a high TB burden setting.

This article is not available via open access.

2. Direct detection of pyrazinamide resistance of Mycobacterium tuberculosis using pncA PCR Sequencing.
J Clin Microbiol. 2019 Jun 12. pii: JCM.00145-19. doi: 10.1128/JCM.00145-19.
[Epub ahead of print]
Tam KK, Leung KS, Siu GK, Chang KC, Wong SS, Ho PL, Leung EK, Yam WC.

An in-house-developed pncA sequencing for pyrazinamide (PZA) resistance was
evaluated using 162 archived Mycobacterium tuberculosis complex (MTBC) isolates
with well-defined phenotypic PZA susceptibility profile by BACTEC MGIT 960 PZA
kit and PZase activities. Preliminary results showed 100% concordance between
pncA sequencing and phenotypic PZA drug susceptibility test (DST) among archived
isolates. Meanwhile, 637 respiratory specimens were prospectively collected with
158 reported as MTBC-positive by Abbott Realtime MTB Assay (96.3% sensitivity
[95% Cl: 92.2-98.7%]; 100% specificity [95% CI: 99.2-100.0%]). Genotypic and
phenotypic PZA resistance profiles of these 158 MTBC-positive specimens were
analysed by pncA sequencing and BACTEC MGIT 960 PZA kit, respectively. For PZA
resistance, pncA sequencing detected pncA mutations in 5/5(100%) phenotypic PZA
resistant respiratory specimens within four working days. No pncA mutations were
detected among PZA susceptible specimens. Combining archived isolates with
prospective specimens, 27 were identified as phenotypic PZA resistant with pncA
mutation. Among these 27 samples, 6/27 (22.2%) phenotypic PZA resistant strains
carried novel pncA mutations without rpsA and panD mutations. These included 5
with mutations (Del383T, Del380-390, A-Ins at 127, A-Ins at 407 and G-Ins at 508)
in pncA structural gene, and 1 with mutation (T-12C) at pncA promoter region. All
these six strains had no or reduced PZase activities, indicating the novel
mutations might confer PZA resistance. Additionally, 25/27 phenotypic PZA
resistant strains were confirmed multidrug-resistant tuberculosis (MDR-TB). As
PZA is commonly used in MDR-TB treatment regimen, direct pncA sequencing will
rapidly detect PZA resistance and facilitate judicious use of PZA in treating
PZA-susceptible MDR-TB.

This article is not available via open access.

3. Surveillance of adverse events in the treatment of drug-resistant tuberculosis: A global feasibility study.
Int J Infect Dis. 2019 Jun;83:72-76. doi: 10.1016/j.ijid.2019.03.036. Epub 2019
Apr 3.
Members of the International Study Group on new anti-tuberculosis drugs and
adverse events monitoring.

The World Health Organization launched a global initiative, known as aDSM (active
TB drug safety monitoring and management) to better describe the safety profile
of new treatment regimens for drug-resistant tuberculosis (TB) in real-world
settings. However, comprehensive surveillance is difficult to implement in
several countries. The aim of the aDSM project is to demonstrate the feasibility
of implementing national aDSM registers and to describe the type and the
frequency of adverse events (AEs) associated with exposure to the new anti-TB
drugs. Following a pilot study carried out in 2016, official involvement of TB
reference centres/countries into the project was sought and cases treated with
bedaquiline- and/or delamanid-containing regimens were consecutively recruited.
AEs were prospectively collected ensuring potential attribution of the AE to a
specific drug based on its known safety profile. A total of 309 cases were fully
reported from 41 centres in 27 countries (65% males; 268 treated with
bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781
cases the participating countries had committed to report by the first quarter of
2019.

Read the article here.

4. Acceptability of a Novel Levofloxacin Dispersible Tablet Formulation in Young Children Exposed to Multidrug-resistant Tuberculosis.
Pediatr Infect Dis J. 2019 Jun;38(6):608-610. doi: 10.1097/INF.0000000000002268.
Purchase SE, Garcia-Prats AJ, De Koker P, Draper HR, Osman M, Seddon JA, Schaaf HS, Hesseling AC.

Levofloxacin is used for the treatment and prevention of multidrug-resistant
tuberculosis in children, but current adult formulations are poorly palatable. A
questionnaire administered to caregivers of 27 children taking a novel 100 mg
dispersible taste-masked levofloxacin tablet found the new formulation to be more
palatable (69%) and easier to prepare (81%) than the adult formulation. This
formulation may assist children to better adhere to anti-tuberculous therapy.

Read the article here.

Union Symposium Presentations (2017)

Presentation 1 by Elizabeth Schnaubelt, MD, Global Tuberculosis Branch Division of Global HIV and TB

Manufacturing XDR TB: Timing of Acquired Resistance to Fluoroquinolones and Second-line Injectable Drugs during MDR TB Treatment in 9 Countries, 2005–2010, Preserving Effective TB Treatment Study (PETTS)

To view this presentation click here.


Presentation 2 by Isaac Chikwanha, MD, TB/HIV/HCV advisor, Access Campaign, MSF Geneva

The Role of Policy Adoption and Implementation for Elimination of MDR-TB

To view this presentation click here.


Presentation 3 by Gavin Churchyard, (MBBCh, FCP (SA), FRCP (Edin), MMED, PhD) Co-Chair of PHOENIx Feasibility Study and Main Trial

Accessing MDR-TB exposed Households: the PHOENiX MDR-TB Feasibility Study

To view this presentation click here.


Presentation 4 by Emily A. Kendall, MD Assistant Professor, Infectious Diseases, Johns Hopkins University School of MedicineMDR-TB

Elimination: What will it cost?

To view this presentation click here.

New: MDR-TB Clinical Trials Landscape Supplement now online

The Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Supplement has been published in the International Journal of Tuberculosis and Lung Disease and is now available online! The supplement can be found in the December 2016 issue of the IJTDL – find a direct link to the issue and all included articles here.

A complete list of articles included in the Supplement is below:

Horsburgh, C. Robert; Rusen, I.D.; Mitnick, Carole D. 

Phillips, P.P.J.

Cellamare, M.; Milstein, M.; Ventz, S.; Baudin, E.; Trippa, L.; Mitnick, C.D.

Davies, G.R.; Wallis, R.S. 

Milstein, M.; Brzezinski, A.; Varaine, F.; Mitnick, C.D.

Dheda, K.; Esmail, A.; Limberis, J.; Maartens, G.

Gupta, R.; Wells, C.D.; Hittel, N.; Hafkin, J.; Geiter, L.J.

Murray, S.; Mendel, C.; Spigelman, M.

Sterling, T.R.

Nuermberger, E.

O’Donnell, M.R.; Padayatchi, N.; Metcalfe, J.Z.

 

Updated Research Agenda for the Programmatic Management of Drug-Resistant Tuberculosis

On May 25, PLoS One published an article by Dr. Carole Mitnick et al. on the updated research agenda for the programmatic management of drug-resistant tuberculosis (PMDT). The authors built upon previous PMDT publications by reviewing resources including guidelines, documents, websites and publications published between January 2008 and August 2013 that cited the last research agenda released in 2008. Resources reviewed spanned five main research categories: Laboratory Support, Epidemiology, Programmatically Relevant Research, Treatment Strategy, and Management of Contacts. Results showed that there was continuity around the priorities for research in PMDT that could help fill longstanding evidence gaps barring expanded treatment access.  Identified priorities specifically highlighted the importance of increased coordinated efforts to address questions regarding: shorter treatment regimens; knowledge of disease burden without representative data; and treatment for latent TB infection in household contacts of known drug-resistant (DR-TB) patients. Addressing such questions is essential to stem the epidemic of TB, including DR-TB.

Read the open-access article here.

Ambulatory multi-drug resistant tuberculosis treatment outcomes in a cohort of HIV-infected patients in a slum stting in Mumbai, India

Isaakidis P, Cox H, Varghese B, et al. PLoS One 2011; 6(12): e28066.

A study on the results of providing MDR-TB treatment to patients on an ambulatory basis and under directly observed therapy using a decentralized network of providers. Encouraging results were achieved, though authors warn that a rapid scale-up of both ART and second-line treatment for MDR-TB is needed to mitigate the growing epidemic.

More

A Phase IIa Trial of the New Tuberculosis Vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis-Infected Adults.

Scriba, T.J., Tameris, M., Smit, E., van der Merwe, L., et al. Am J Resp Crit Care Med 2012; 185(7): 769-78. Epub 2012 Jan 26. 

Novel TB vaccines should be safe and effective in populations infected with Mycobacterium tuberculosis (M.tb) and/or HIV for effective TB control. This study determined the safety and immunogenicity of MVA85A, a novel TB vaccine, among M.tb- and/or HIV-infected persons in a setting where TB and HIV are endemic. An open-label, phase IIa trial was conducted in 48 adults with M.tb and/or HIV infection. Safety and immunogenicity were analyzed up to 52 weeks after intradermal vaccination with 5 × 10(7) plaque-forming units of MVA85A. No significant effect of antiretroviral therapy on immunogenicity of MVA85A was observed. MVA85A was safe and immunogenic in persons with HIV and/or M.tb infection. These results support further evaluation of safety and efficacy of this vaccine for prevention of TB in these target populations.

More

A systematic review of the cost and cost effectiveness of treatment for multidrug-resistant tuberculosis

Fitzpatrick C, Floyd K. Pharmacoeconomics 2012; 30(1): 63-80.

The authors conducted a systematic review of the cost and cost effectiveness of treatment for MDR-TB and synthesized the available data. They concluded that treatment for MDR-TB can be cost effective in low- and middle-income countries. Evidence of the cost effectiveness of outpatient vs inpatient models of care are limited and more data is needed from Africa and Asia – though unless there is strong evidence that hospitalization is necessary to achieve high rates of adherence to treatment, patients with MDR-TB should be treated using mainly ambulatory care.

More

Daily 300 mg dose of linezolid for multidrug-resistant and extensively drug-resistant tuberculosis: updated analysis of 51 patients.

Koh WJ, Kang YR, Jeon K, Kwon OJ, Lyu J, Kim WS, Shim TS. J Antimicrob Chemother 2012;67(6):1503-7. Epub 2012 Mar 8.

The objective was to evaluate the efficacy, tolerability and adverse events of a 300 mg daily dose of linezolid in the treatment of MDR/XDR-TB. The study retrospectively reviewed the medical records of 51 MDR-TB patients, including 26 patients (51%) with XDR-TB, to evaluate the safety, tolerability and efficacy of therapy with 300 mg/day linezolid. All patients had failed previous treatments with second-line anti-TB drugs. The findings suggest that linezolid at a daily dose of 300 mg is effective against intractable MDR/XDR-TB, and may be associated with fewer neuropathic side effects than a daily dose of 600 or 1200 mg.

More

Editorial: Encouraging News for multidrug-resistant tuberculosis treatment

Mitnick C and Horsburgh CR. Am J Respir Crit Med 2010; 182: 1337-43.

This editorial highlights a report of a short, highly effective standardized MDR-TB treatment regimen published in an earlier issue of the journal. The report, published by Van Deun and colleagues, describes a 9-month regimen containing 7 drugs in the intensive phase that achieved a cure in 88% of patients with MDR-TB in Bangladesh. Though the authors of the editorial point out some potential limitations, they maintain that if the regimen could assure similar results in heterogenous populations, it could represent a major advance in MDR-TB treatment. They encourage further randomized, controlled trials of multidrug regimens for MDR-TB in order to further tailor their efficacy and tolerability.

Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment

Kurbatova EV, Gammino VM, Bayona J, et al. IJTLD 2011; 15(11): 1553-5.

A retrospective analysis of three alternative monitoring strategies in a cohort of MDR-TB patients in Estonia, Latvia, Philippines, Russia and Peru (2000-2004), which illustrates that less frequent testing delays confirmation of bacteriological conversion. The delay prolongs intensive treatment, hospitalization, and respiratory isolation, increasing cost and toxicity. After conversion, less frequent testing could delay diagnosis of possible treatment failure.

More