January 2019 Newsletter

NEWS AND ANNOUNCEMENTS

FIND WEBINAR SERIES 2019
FIND, the World Health Organization, the New Diagnostics Working Group and MSF Access Campaign are co-organizing a four-part webinar series on the use and implementation of next-generation sequencing (NGS) for drug-resistant TB (DR-TB). The series will take place on 5, 12, 19, and 26 February 2019. More information about these webinars and their specific times can be found here.

PUBLICATIONS

1. Ambient air pollution exposures and risk of drug-resistant tuberculosis.
Environ Int. 2019 Jan 11;124:161-169. doi: 10.1016/j.envint.2019.01.013. [Epub ahead of print]
Yao L, LiangLiang C, JinYue L, WanMei S, Lili S, YiFan L, HuaiChen L.

BACKGROUND: Few epidemiological studies have explored the effects of air pollution on the risk of drug-resistant tuberculosis (DR-TB).
OBJECTIVE: To investigate the short and long term residential concentrations of ambient air pollutants (particulate matter <10 μm in diameter (PM10) and particulate matter≤2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO)) in relation to the risk of DR-TB in a typical air pollution city, Jinan city, China.
METHODS: A total of 752 new culture-confirmed TB cases reported in TB prevention and control institutions of Jinan from January 1, 2014 to December 31, 2015 were included. Average individual-level concentrations of air pollution for 5 different exposure windows, vary from 90 days to 720 days to diagnosis were estimated using measurements from monitor closest to the patient home addresses. Logistic regression model adjusted for potential confounders was employed to evaluate correlation between air pollution and DR-TB risk at different five exposure windows individually.
RESULTS: There were substantially increased mono-drug resistance and poly-drug resistance risks for ambient PM2.5, PM10, O3, and CO exposures. High exposure to PM2.5, PM10, and CO was also significantly associated with increased incidence of multi-drug resistance (MDR) both in the single- and multi-pollutants regression models. The dominant positive associations for PM2.5was observed at 540 days exposure, for O3 was observed at 180 days exposure, and for PM10 and CO was observed from 90 days to 540 days exposures.
CONCLUSIONS: Our finding suggest that exposure to ambient air pollution (PM2.5, PM10, O3, and CO) are associated with increased risk of DR-TB. We provided epidemiological evidence of association between pollution exposure and mono-, poly- and multi-drug resistance.

This article is available for open access here.

2. Interventions to improve retention-in-care and treatment adherence among patients with drug-resistant tuberculosis: a systematic review.
Eur Respir J. 2019 Jan 10;53(1). pii: 1801030. doi: 10.1183/13993003.01030-2018.
Print 2019 Jan.
Law S, Daftary A, O’Donnell M, Padayatchi N, Calzavara L, Menzies D.

ABSTRACT: The global loss to follow-up (LTFU) rate among drug-resistant tuberculosis (DR-TB) patients remains high at 15%. We conducted a systematic review to explore interventions to reduce LTFU during DR-TB treatment.We searched for studies published between January 2000 and December 2017 that provided any form of psychosocial or material support for patients with DR-TB. We estimated point estimates and 95% confidence intervals of the proportion LTFU. We performed subgroup analyses and pooled estimates using an exact binomial likelihood approach.We included 35 DR-TB cohorts from 25 studies, with a pooled proportion LTFU of 17 (12-23)%.  Cohorts that received any form of psychosocial or material support had lower LTFU rates than those that received standard care. Psychosocial support throughout treatment, via counselling sessions or home visits, was associated with lower LTFU rates compared to when support was provided through a limited number of visits or not at all.Our review suggests that psychosocial support should be provided throughout DR-TB treatment in order to reduce treatment LTFU. Future studies should explore the potential of providing self-administered therapy complemented with psychosocial support during the continuation phase.

This article is available for open access here.

3. Such a long journey: What health seeking pathways of patients with drug resistant tuberculosis in Mumbai tell us.
PLoS One. 2019 Jan 17;14(1):e0209924. doi: 10.1371/journal.pone.0209924. eCollection 2019.
Bhattacharya Chakravarty A, Rangan S, Dholakia Y, Rai S, Kamble S, Raste T, Shah S, Shah S, Mistry N.

INTRODUCTION: The Indian Tuberculosis (TB) Programme currently faces the dual challenges of tackling increasing numbers of drug resistant (DR) TB cases and regulating practices of a pluralistic private sector catering to TB patients. A study of health seeking behaviour of DR-TB patients in such a situation, offers an opportunity to understand the problems patients face while interacting with health systems.
METHODOLOGY: Forty-six DR-TB patients drawn from 15 high TB burden wards in Mumbai were interviewed using an open ended interview tool. Interviews were audio recorded and transcribed. Pathway schematics developed from analysis of patient records, were linked to transcripts. Open coding was used to analyse these units and themes were derived after collating the codes.
RESULTS AND DISCUSSION: The paper presents themes interwoven with narratives in the discussions. These include awareness-action gap among patients, role of neighbourhood providers, responsiveness of health systems, the not-such a ‘merry go round’ that patients go/are made to go on while seeking care, costs of diagnostics and treatment, and how DR-TB is viewed as the ‘big TB’.
CONCLUSION: The recommendations are based on a preventative ethos which is sustainable, compared to interventions with top-down approaches, which get piloted, but fail to sustain impact when scaled up.

This article is available for open access here.

4. Pharmacokinetics, safety, and dosing of novel pediatric levofloxacin dispersible  tablets in children with multidrug-resistant tuberculosis exposure.
Antimicrob Agents Chemother. 2019 Jan 22. pii: AAC.01865-18. doi: 10.1128/AAC.01865-18. [Epub ahead of print]
Garcia-Prats AJ, Purchase SE, Osman M, Draper HR, Schaaf HS, Wiesner L, Denti P, Hesseling AC.

ABSTRACT: This study characterized the pharmacokinetics of novel 100 mg levofloxacin dispersible tablets in 24 children aged <5 years with household MDR-TB exposure. Data was pooled with previously published data from children (n=109) with MDR-TB receiving adult (250 mg) levofloxacin tablets, using nonlinear mixed-effect modelling. The adult 250 mg tablets had 41% lower bioavailability compared to thenovel dispersible tablets, resulting in much higher exposures with the dispersible tablets with the same mg/kg dose.

This article is available for open access here.

5. Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial.
Lancet Respir Med. 2019 Jan 7. pii: S2213-2600(18)30426-0. doi: 10.1016/S2213-2600(18)30426-0. [Epub ahead of print]
von Groote-Bidlingmaier F, Patientia R, Sanchez E, Balanag V Jr, Ticona E, Segura P, Cadena E, Yu C, Cirule A, Lizarbe V, Davidaviciene E, Domente L, Variava E, Caoili J, Danilovits M, Bielskiene V, Staples S, Hittel N, Petersen C, Wells C, Hafkin J, Geiter LJ, Gupta R.

BACKGROUND: Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment.

METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia,  Lithuania, Moldova, Peru, the Philippines, and South Africa). We enrolled eligible adults (>18 years) with pulmonary multidrug-resistant tuberculosis to receive, in combination with an optimised background regimen developed according to WHO and national guidelines, either oral delamanid (100 mg twice daily) for 2 months followed by 200 mg once daily for 4 months or placebo (same regimen). Patients were centrally randomised (2:1) and stratified by risk category for delayed sputum culture conversion. Primary outcomes were the time to sputum culture conversion over 6 months and the difference in the distribution of time to sputum culture conversion over 6 months between the two groups, as assessed in the modified intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424670.                FINDINGS: Between Sept 2, 2011, and Nov 27, 2013, we screened 714 patients, of whom 511 were randomly assigned (341 to delamanid plus optimised background regimen [delamanid group] and 170 to placebo plus optimised background regimen
[placebo group]) and formed the safety analysis population. 327 patients were culture-positive for multidrug-resistant tuberculosis at baseline and comprised the efficacy analysis population (226 in the delamanid group and 101 in the
placebo group). Median time to sputum culture conversion did not differ between the two groups (p=0·0562; modified Peto-Peto), with 51 days (IQR 29-98) in the delamanid group and 57 days (43-85) in the placebo group; the hazard ratio was 1·17 (95% CI 0·91-1·51, p=0·2157). 501 (98·0%) of 511 patients had at least one treatment-emergent adverse event. 136 (26·6%) of 511 patients had at least one
serious treatment-emergent adverse event; the incidence was similar between treatment groups (89 [26·1%] of 341 patients for delamanid and 47 [27·6%] of 170 for placebo). Deaths related to treatment-emergent adverse events were similar between groups (15 [4·4%] of 341 for delamanid and six [3·5%] of 170 for placebo). No deaths were considered to be related to delamanid.
INTERPRETATION: The reduction in median time to sputum culture conversion over 6 months was not significant in the primary analysis. Delamanid was well tolerated with a highly characterised safety profile. Further evaluation of delamanid is needed to determine its role in a rapidly evolving standard of care.
FUNDING: Otsuka Pharmaceutical.

This article is not available for open access.

6. Compassionate use of delamanid in combination with bedaquiline for the treatment of multidrug-resistant tuberculosis.
Eur Respir J. 2019 Jan 10;53(1). pii: 1801154. doi: 10.1183/13993003.01154-2018. Print 2019 Jan. Hafkin J, Hittel N, Martin A, Gupta R.

SUMMARY: Updated data from the Otsuka compassionate use program show that regimens combining delamanid and bedaquiline appear effective in MDR-TB cases with limited treatment options.This article is available here

Webinar: Introduction of the ICN/Curry Center Nursing guide for managing side effects to drug-resistant TB treatment (RECORDING AVAILABLE)

On January 16th, RESIST-TB and The Union’s Nurses and Allied Professionals Sub-Section (NAPS) hosted a webinar to discuss the ICN/CITC Nursing Guide for Management of Side Effects of DR-TB Treatment. Nurses are often the first to hear of a patient’s side effects during TB treatment, making them well positioned to intervene. The information presented in this guide, which is the topic of this webinar, was developed to help nurses assess for and respond appropriately to side effects related to anti-TB medications.

The ICN/CITC Nursing Guide for Management of Side Effects of DR-TB Treatment is available in English, Chinese and Russian.

For those of you who were unable to join the webinar, below is a recording. The slides used can be found here.

Key speakers: Bob Horsburgh, Carrie Tudor, Linette McElroy

*Speaking first is Bob Horsburgh (RESIST-TB), who introduces the key presenter Carrie Tudor (ICN)

Revamped WHO Civil Society Task Force

The World Health Organization has revamped its Civil Society Task Force on TB to strengthen collaboration for accelerating progress towards ending TB. As countries are beginning to ramp up efforts to end TB following commitments made by Heads of State at the first-ever UN High-Level Meeting on TB (UN HLM) in September 2018, the role of civil society in driving action and accountability is more important than ever.

Find the full article here.

December 2018 Newsletter

NEWS AND ANNOUNCEMENTS

 

Upcoming Webinar

Managing Side Effects to Drug-resistant TB Treatment – Hosted by RESIST-TB and The Union’s NAPS
On January 16th at 08:30 EST (14:30 CET, 15:30 SAST), RESIST-TB and The Union’s Nurses and Allied Professionals Sub-Section (NAPS) will be hosting a webinar to discuss the ICN/CITC Nursing Guide for Management of Side Effects of DR-TB Treatment. Nurses are often the first to hear of a patient’s side effects during TB treatment, making them well positioned to intervene. The information presented in this guide, which will be the topic of this webinar, was developed to help nurses assess for and respond appropriately to side effects related to anti-TB medications.

For more information on how to join the webinar, continue to check our website.

 

PUBLICATIONS

1. Acceptability of a Novel Levofloxacin Dispersible Tablet Formulation in Young Children Exposed to Multidrug-Resistant Tuberculosis.
Pediatr Infect Dis J. 2018 Dec 13. doi: 10.1097/INF.0000000000002268. [Epub ahead of print]
Purchase SE, Garcia-Prats AJ, De Koker P, Draper HR, Osman M, Seddon JA, Schaaf HS, Hesseling AC.

ABSTRACT: 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.

This article is can be found here.

2. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment.
Clin Infect Dis. 2018 Nov 28;67(suppl_3):S327-S335. doi: 10.1093/cid/ciy625
Bolhuis MS, Akkerman OW, Sturkenboom MGG,  Ghimire S, Srivastava S, Gumbo T, Alffenaar JC.

ABSTRACT: Linezolid has been successfully used for treatment of multidrug-resistant tuberculosis (MDR-TB). However, dose- and duration-related toxicity limit its use. Here, our aim was to search relevant pharmacokinetics (PK)/pharmacodynamics (PD) literature to identify the effective PK/PD index and to define the optimal daily dose and dosing frequency of linezolid in MDR-TB regimens. The systematic search resulted in 8 studies that met inclusion criteria. A significant PK variability was observed. Efficacy of linezolid seems to be driven by area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC). Literature is inconclusive about the preferred administration of a daily dose of 600 mg. To prevent development of drug resistance, an AUC/MIC ratio of 100 in the presence of a companion drug at relevant exposure is required. A daily dose of 600 mg seems appropriate to balance between efficacy and toxicity. Being a drug with a very narrow therapeutic window, linezolid treatment may benefit from a more personalized approach, that is, measuring actual MIC values and therapeutic drug monitoring.

This article is can be found here.

3. Minimum inhibitory concentrations of fluoroquinolones and pyrazinamide susceptibility correlate to clinical improvement in MDR-TB patients – a nationwide Swedish cohort study over two decades.
Clin Infect Dis. 2018 Dec 18. doi: 10.1093/cid/ciy1068. [Epub ahead of print]
Davies Forsman L, Jonsson J, Wagrell C, Werngren J, Mansjö
M, Wijkander M, Groenheit R, Hammar U, Giske CG, Schön T,
Bruchfeld J.

INTRODUCTION: Minimum inhibitory concentration (MIC) testing, unlike routine drug susceptibility testing (DST) at a single critical concentration, quantifies drug resistance. The association of MICs and treatment outcome in multidrug-resistant
tuberculosis (MDR-TB) patients is unclear. Therefore, we correlated MICs of first-and second-line TB drugs with time to sputum culture conversion (tSCC) and treatment outcome in MDR-TB patients.
MATERIALS/METHODS: Clinical and demographic data of MDR-TB patients in Sweden 1992-2014 including DST results were retrieved from medical records. MIC determinations were performed retrospectively for the stored individual Mtb isolates using broth microdilution in Middlebrook 7H9. We fitted Cox proportional hazard models correlating MICs, DST results and clinical variables to tSCC and treatment outcome.                                                                                                                                                                                                                             RESULTS: Successful treatment outcome was observed in 83.5% (132/158) of MDR-TB patients. Increasing MICs of fluoroquinolones, diabetes and age > 40 years were significantly associated with unsuccessful treatment outcome. Patients treated with PZA had a significantly shorter tSCC compared to patients were not (median difference 27 days).
CONCLUSION: Increasing MICs of fluoroquinolones were correlated to unsuccessful treatment outcome in MDR-TB patients. Further studies, including MIC testing and clinical outcome data to define clinical Mtb breakpoints, are warranted. PZA treatmentwas associated with shorter tSCC, highlighting the importance of PZA DST.

This article can be found here.

4. Transmission of drug-resistant tuberculosis in HIV-endemic settings
Lancet Infect Dis. 2018 Dec 13. pii: S1473-3099(18)30537-1. doi: 10.1016/S1473-3099(18)30537-1. [Epub ahead of print]
Khan PY, Yates TA, Osman M, Warren RM, van der Heijden Y, Padayatchi N, Nardell EA, Moore D, Mathema B, Gandhi N, Eldholm V, Dheda K, Hesseling AC, Mizrahi V, Rustomjee R, Pym A.

ABSTRACT: The emergence and expansion of the multidrug-resistant tuberculosis epidemic is a threat to the global control of tuberculosis. Multidrug-resistant tuberculosis is the result of the selection of resistance-conferring mutations during inadequate antituberculosis treatment. However, HIV has a profound effect on the natural history of tuberculosis, manifesting in an increased rate of disease progression, leading to increased transmission and amplification of multidrug-resistant tuberculosis. Interventions specific to HIV-endemic areas are urgently needed to block tuberculosis transmission. These interventions should include a combination of rapid molecular diagnostics and improved chemotherapy to shorten the duration of infectiousness, implementation of infection control measures, and activescreening of multidrug-resistant tuberculosis contacts, with prophylactic regimens for individuals without evidence of disease. Development and improvement of the efficacy of interventions will require a greater understanding of the factors affecting the transmission of multidrug-resistant tuberculosis in HIV-endemic settings, including population-based molecular epidemiology studies. In this Series article, we review what we know about the transmission of multidrug-resistant tuberculosis in settings with high burdens of HIV and define the research priorities required to develop more effective interventions, to diminish ongoing transmission and the amplification of drug resistance.

This article can be accessed for free here. (With a registered Lancet account, also free)

Science-based Dosing of Second Line Antituberculosis Agents for TB Programs – IDSA Clinical Infectious Disease Volume 67, Supplement 3 

1.Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

2. Gatifloxacin Pharmacokinetics/Pharmacodynamics–based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis

3. Artificial intelligence–derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis

4. Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis

5. Amikacin Dosing for MDR Tuberculosis: A Systematic Review to Establish or Revise the Current Recommended Dose for Tuberculosis Treatment

6. D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

7. Ethionamide Pharmacokinetics/Pharmacodynamics-derived Dose, the Role of MICs in Clinical Outcome, and the Resistance Arrow of Time in Multidrug-resistant Tuberculosis

8. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment

9.  The Sterilizing Effect of Intermittent Tedizolid for Pulmonary Tuberculosis

10. Multiparameter Responses to Tedizolid Monotherapy and Moxifloxacin Combination Therapy Models of Children With Intracellular Tuberculosis

11. Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration From Preclinical Models to Patients With Tuberculosis: Translating From Apples to Oranges

12.  Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!

13. The Role of Novel Approaches and New Findings in the Pharmacology of Tuberculosis Medicines in Improving Treatment Outcomes

*The above links provide abstracts to the articles

Nursing Guide for Managing Side Effects to Drug-resistant TB Treatment

This guide was developed by nurses with experience in the clinical care and programmatic management of TB and DR-TB in both high- and low-resource settings. Nursing and DR-TB literature were reviewed to establish best practice nursing assessment and intervention guidance. Nurses caring for patients with DR-TB field tested the job aid and provided feedback which was used to inform final content and format. A link to this guide online can be found here.

Citation: International Council of Nurses and Curry International Tuberculosis Center. Nursing guide for managing side effects to drug-resistant TB treatment. Geneva. 2018.

November 2018 Newsletter

NEWS AND ANNOUNCEMENTS

 

NEW: Simple KNCV stool test breakthrough for Childhood TB

A simple stool-based diagnosis that was developed by KNCV Tuberculosis Foundation could be a global lifesaver by enabling millions more children at risk from TB and MDR-TB to be tested. This breakthrough was announced during the Union World Conference and could drastically reduce the numbers of children under five dying from TB. Currently, an estimated 239,000 children die every year from TB. Children with TB rarely die when they receive standard treatment for the disease, but 90 percent of children who die from TB worldwide went untreated. Read more here.

NEW: Tuberculosis Research Funding Trends 2005-2017

In this report, Treatment Action Group (TAG) presents their data on TB research funding trends for the 13 years from 2005 to 2017. Although there have been spurts of notable growth, particularly in 2009 and again in 2016 and 2017, funding for TB research has lagged far behind internationally agreed-upon targets and has remained dependent on a few large funders. This extreme reliance on a handful of major funders makes the progress we have seen over the last decade precarious. In addition, when adjusted for inflation, funding for TB research has not increased from where it was a decade ago. This report, in full, can be found here.

UPCOMING WEBINAR: Hosted by TREAT TB

On December 6, 2018, at 7AM EST, TREAT TB will host a capacity building webinar on community engagement in MDR-TB clinical trials.

It will feature a presentation from Ezio Tavora dos Santos Filho, STREAM Community Engagement Coordinator from REDE-TB, followed by a question and answer session.

The presentation will highlight the importance and objectives of community engagement in clinical research, how to implement community engagement before a trial begins, as well as how to bring community engagement into an existing trial. To join the webinar, click here. To join by phone, please dial +1 855 880 1246 US Toll-free or +1 877 853 5257 US Toll-free. For international numbers, click here. Meeting ID: 912 316 884

A recording of the webinar and slides will be available on the TREAT TB website approximately one week after the webinar.

TREAT TB’s MDR-TB clinical trial capacity building webinar series will continue over the coming months, with webinars scheduled for January, March, and May 2019. Future topics to be addressed include regulatory requirements, institutional review boards and ethics approval, as well as laboratory strengthening.

 

PUBLICATIONS

 

1. Evaluation of carbapenems for multi/extensive-drug resistant Mycobacterium tuberculosis treatment.

Antimicrob Agents Chemother. 2018 Nov 19. pii: AAC.01489-18. doi: 10.1128/AAC.01489-18. [Epub ahead of print]
van Rijn SP(1), Zuur MA(1), Anthony R(2), Wilffert B(1)(3), van Altena R(4)(5), Akkerman OW(4)(5), de Lange WCM(4)(5), van der Werf TS(5)(6), Kosterink, JGW(1)(3), Alffenaar JC(7).

M/XDR-TB has become an increasing threat in high burden countries but also in affluent regions due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of M.tuberculosis To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo and clinical data on carbapenems in the treatment of M. tuberculosis and detection of knowledge gaps, in order to target future research. In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and lab strains of M. tuberculosis, are consistent. In vitro the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore is it practically impossible to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, one prospective, two observational and seven retrospective clinical studies to assess effectiveness, safety and tolerability of three different carbapenems (imipenem, meropenem and ertapenem). Presently we found no clear evidence to select one particular carbapenem among the different candidate compounds, to design an effective M/XDR-TB regimen. Therefore more clinical evidence and dose optimization substantiated by hollow fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.
This article does not have open access.

 

2. Relationship between chest radiographic characteristics, sputum bacterial load, and treatment outcomes in patients with extensively drug-resistant tuberculosis.

Int J Infect Dis. 2018 Nov 2. pii: S1201-9712(18)34574-0. doi: 10.1016/j.ijid.2018.10.026. [Epub ahead of print]
Te Riele JB(1), Buser V(2), Calligaro G(3), Esmail A(4), Theron G(5), Lesosky M(6), Dheda K(7).

BACKGROUND: Data about the relationship between chest radiographs and sputum bacillary load, with treatment outcomes, in patients with extensively drug-resistant tuberculosis (XDR-TB) from HIV/TB endemic settings are limited.
METHODS: Available chest radiographs from 97 South African XDR-TB patients, at the time of diagnosis, were evaluated by two independent readers using a validated scoring system. Chest radiograph findings were correlated with baseline sputum bacillary load (smear-grade and culture time-to-positive in MGIT), and prospectively ascertained clinical outcomes (culture conversion and all-cause mortality).
RESULTS: Radiographic bilateral lung disease was present in 75/97 (77%). In the multivariate analysis only a higher total radiographic score (95% CI) was associated with higher likelihood of death [1.16 (1.05-1.28) p=0.003], and failure to culture convert [0.85 (0.74-0.97) p=0.02]. However, when restricting analyses to HIV-infected patients, disease extent, cavitation, and total radiographic scores were not associated with mortality or culture-conversion. Finally, cavitary, disease extent, and total radiographic scores all positively correlated with bacterial load (culture time-to-positive).
CONCLUSIONS: In endemic settings, XDR-TB radiological disease extent scores are associated with adverse clinical outcomes, including mortality, in HIV uninfected persons. These data may have implications for clinical and programmatic decision-making and for evaluation of new regimens in clinical trials.

This article can be found here.

 

3. Compassionate Use of Delamanid in Combination with Bedaquiline for the Treatment of MDR-TB.

Eur Respir J. 2018 Oct 25. pii: 1801154. doi: 10.1183/13993003.01154-2018. [Epub ahead of print]
Hafkin J(1), Hittel N(2), Martin A(2), Gupta R(1).

Patients with multidrug-resistant tuberculosis (MDR-TB), in particular those with pre-extensively drug resistant (Pre-XDR) and extensively drug-resistant (XDR)-TB, and those that fail standard second-line therapy, are difficult to treat and have poor long-term outcomes [1].  To address this unmet medical need, there is strong interest in exploring the combined use of delamanid and bedaquiline, the only two anti-TB drugs approved for the treatment of pulmonary MDR-TB in the last 40 years, as their novel mechanisms of action may offer treatment alternatives for patients who have developed resistance or non-tolerability to existing anti-TB drugs [2, 3]. Despite the initial regulatory approvals of bedaquiline and delamanid in 2012 and 2014, respectively, global usage of both drugs in combination with one another remains limited in part due to the uncertainty around the safety and efficacy of such a combination regimen. Hence, there is an urgent need for programmatic data to better understand the “real-world” use of these two medicines used together in MDR-TB patients.

As part of a global access initiative, Otsuka Pharmaceutical Co., Ltd. in coordination with the European Respiratory Society (ERS) / WHO TB Consilium, and Médecins Sans Frontières / Partners in Health (MSF PIH) established its first Compassionate Use (CU) program in 2014 to provide access to delamanid, at no cost, for patients with limited treatment options [4]. In 2016, the program was modified to allow for the combined use of delamanid plus bedaquiline under specific conditions. We present here the early safety and efficacy outcomes of patients enrolled in this program receiving delamanid and bedaquiline concomitantly along with other anti-TB drugs for the treatment of MDR-TB.

This article does not have open access.

 

4. Bedaquiline and Repurposed Drugs for Fluoroquinolone-Resistant Multidrug-Resistant Tuberculosis: How Much Better Are They?

Am J Respir Crit Care Med. 2018 Nov 1;198(9):1228-1231. doi: 10.1164/rccm.201801-0019LE.
Bastard M(1), Guglielmetti L(2)(3)(4), Huerga H(1), Hayrapetyan A(5), Khachatryan N(6), Yegiazaryan L(5), Faqirzai J(6), Hovhannisyan L(6), Varaine F(2), Hewison C(2).

Treatment outcomes of conventional multidrug-resistant tuberculosis (MDR-TB) treatments are overall unsatisfactory, particularly for fluoroquinolone-resistant MDR-TB (1). In addition, long-term follow-up studies have shown that patients who have experienced previous treatment failure contribute importantly to ongoing transmission in the community (2). The introduction of two new drugs, bedaquiline and delamanid, has been reported to improve treatment outcomes for MDR/extensively drug-resistant (XDR)-TB (3, 4). In addition, there is growing evidence that repurposed drugs such as linezolid, clofazimine, and carbapenems with amoxicillin/clavulanate also have a role to play in MDR/XDR-TB treatment (5, 6). However, few reports have assessed new regimens rather than the addition of a single new or repurposed drug to a regimen (3, 4, 6).

In Armenia, Médecins Sans Frontières (MSF) has supported the National Tuberculosis Program for the treatment of MDR-TB patients since 2005. In 2013, bedaquiline was introduced into clinical practice through a compassionate use (CU) mechanism. At the same time, the repurposed drugs linezolid and imipenem/cilastatin became available for the first time. Clofazimine was already available. The objective of this study was to assess the clinical impact of regimens containing bedaquiline, linezolid, and/or imipenem/cilastatin.

This article does not have open access.

ACTIVISTS URGE NATIONAL TB PROGRAMS AND TREATMENT PROVIDERS TO DISCONTINUE USE OF HARMFUL INJECTABLE AGENTS IN TB TREATMENT

Activists from around the world called on National TB Programs to discontinue routine use of harmful injectable agents in treatment regimens for drug-resistant tuberculosis, in favor of newer, safer World Health Organization (WHO)-recommended treatments. Second-line injectable agents (kanamycin, capreomycin, and amikacin)—previously considered essential medicines for the treatment of multidrug-resistant TB (MDR-TB)—have poor efficacy against TB and high toxicity, including irreversible hearing loss. Giving these medicines to people with MDR-TB exposes them to unnecessary pain and risk of disability—in the case of kanamycin and capreomycin, without any benefit.

The full article can be accessed and read here.

Has compassionate use ever sunk a drug?

Click here to read a recent International Union Against Tuberculosis and Lung Disease Editorial by RESIST-TB members, Sarah McAnaw, Carole Mitnick, and Bob Horsburgh.

“New treatments for a serious disease generate understandable excitement among patients with life-threatening conditions. As pharmaceutical companies consider compassionate use of experimental drugs, one factor is commonly cited as a barrier to such use: fear that adverse events incurred by patients during Compassionate Use/Expanded Access (CU/EA) will impede regulatory approval of the drug. Such concerns stem from the obligation to report adverse events—that are serious, unexpected, and suspected to be related to the investigational drug— experienced by patients during treatment under CU/ EA programs.1 Such reports, it is feared, will damage the future of the drug, particularly since adverse events may not be related to the experimental drug and patients taking such drugs are typically sicker than the average patient.2 Existing evidence, however, does not support the notion that such events jeopardize regulatory approval.” Click here to read the article in full. 

Unitaid extends key research grant as part of a strong counterattack on tuberculosis

Unitaid is intensifying its commitment to fighting tuberculosis with a US$ 21 million investment in extending endTB, a global research project that is improving treatment regimens for patients with multidrug-resistant tuberculosis (MDR-TB). This project has been piloting bedaquiline and delamanid in 17 countries with the goal of providing countries and funding agencies with effective drugs to tackle MDR-TB on a large scale. 

Long-used treatments for MDR-TB can take up to two years, succeed in only about half the cases, and can cause major side effects. With endTB’s extension, a new clinical trial will be added to develop a treatment regimen for patients with fluoroquinolone-resistant MDR-TB. These regimens have the potential to cure 119,000 more patients, save 56,000 more lives and avert 239,000 drug-resistant infections from 2019 to 2027.

The endTB project’s original term was 2015-2019 and its budget US$ 60 million, but with the extension it will run through the end of 2022, with Unitaid support of up to US$ 81 million. 

To read the full article, click here.

TREAT TB Clinical Trial Capacity Building Webinar Series

RESIST-TB invites you to join TREAT TB for the second webinar in its series to promote capacity building for high quality clinical trials for MDR-TB.

On September 28th at 8 AM EST, Dr. Jan Komrska, senior pharmacist at Vital Strategies, will present a webinar on supply chain management for MDR-TB trials.

Connection details below.

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For more information about connection details and future webinars, click here.

To join the webinar from a PC, Mac, Linux, iOS or Android, click here.

To join by phone, please dial: US (toll free):  +1 855 880 1246 (Toll Free) or +1 877 853 5257 (Toll Free).

For international numbers, click here.

Meeting ID: 912 316 884