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.