From Our July 2019 Newsletter

Publications

1. Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.
Lancet Infect Dis. 2019 Jul 4. pii: S1473-3099(19)30307-X. doi:
10.1016/S1473-3099(19)30307-X. [Epub ahead of print]

Knight GM(1), McQuaid CF(2), Dodd PJ(3), Houben RMGJ(2).

BACKGROUND: To end the global tuberculosis epidemic, latent tuberculosis
infection needs to be addressed. All standard treatments for latent tuberculosis
contain drugs to which multidrug-resistant (MDR) Mycobacterium tuberculosis is
resistant. We aimed to estimate the global burden of multidrug-resistant latent
tuberculosis infection to inform tuberculosis elimination policy.
METHODS: By fitting a flexible statistical model to tuberculosis drug resistance
surveillance and survey data collated by WHO, we estimated national trends in the
proportion of new tuberculosis cases that were caused by MDR strains. We used
these data as a proxy for the proportion of new infections caused by MDR M
tuberculosis and multiplied trends in annual risk of infection from previous
estimates of the burden of latent tuberculosis to generate trends in the annual
risk of infection with MDR M tuberculosis. These estimates were used in a cohort
model to estimate changes in the global and national prevalence of latent
infection with MDR M tuberculosis. We also estimated recent infection levels (ie,
in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis
in 2035 and 2050.
FINDINGS: 19·1 million (95% uncertainty interval [UI] 16·4 million-21·7 million)
people were latently infected with MDR tuberculosis in 2014-a global prevalence
of 0·3% (95% UI 0·2-0·3). MDR strains accounted for 1·2% (95% UI 1·0-1·4) of the
total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6-3·1) of the
burden among children younger than 15 years (risk ratio for those younger than 15
years vs those aged 15 years or older 2·65 [95% UI 2·11-3·25]). Recent latent
infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million-2·3
million) people globally were at high risk of active MDR tuberculosis in 2015.
INTERPRETATION: We estimate that three in every 1000 people globally carry latent
MDR tuberculosis infection, and prevalence is around ten times higher among those
younger than 15 years. If current trends continue, the proportion of latent
tuberculosis caused by MDR strains will increase, which will pose serious
challenges for management of latent tuberculosis-a cornerstone of tuberculosis
elimination strategies.
FUNDING: UK Medical Research Council, Bill & Melinda Gates Foundation, and
European Research Council.

Read the article here.

2. Analysis of loss to follow-up in 4099 multidrug-resistant pulmonary tuberculosis
patients.
Eur Respir J. 2019 Jul 11;54(1). pii: 1800353. doi: 10.1183/13993003.00353-2018.
Print 2019 Jul.

Walker IF(1), Shi O(2)(3), Hicks JP(4), Elsey H(4), Wei X(2), Menzies D(5), Lan
Z(5), Falzon D(6), Migliori GB(7), Pérez-Guzmán C(8)(9), Vargas MH(9)(10),
García-García L(11), Sifuentes Osornio J(12), Ponce-De-León A(13), van der Walt
M(14), Newell JN(4).

Loss to follow-up (LFU) of ≥2 consecutive months contributes to the poor levels
of treatment success in multidrug-resistant tuberculosis (MDR-TB) reported by TB
programmes. We explored the timing of when LFU occurs by month of MDR-TB
treatment and identified patient-level risk factors associated with LFU.We
analysed a dataset of individual MDR-TB patient data (4099 patients from 22
countries). We used Kaplan-Meier survival curves to plot time to LFU and a Cox
proportional hazards model to explore the association of potential risk factors
with LFU.Around one-sixth (n=702) of patients were recorded as LFU. Median
(interquartile range) time to LFU was 7 (3-11) months. The majority of LFU
occurred in the initial phase of treatment (75% in the first 11 months). Major
risk factors associated with LFU were: age 36-50 years (HR 1.3, 95% CI 1.0-1.6;
p=0.04) compared with age 0-25 years, being HIV positive (HR 1.8, 95% CI 1.2-2.7;
p<0.01) compared with HIV negative, on an individualised treatment regimen (HR
0.7, 95% CI 0.6-1.0; p=0.03) compared with a standardised regimen and a recorded
serious adverse event (HR 0.5, 95% CI 0.4-0.6; p<0.01) compared with no serious
adverse event.Both patient- and regimen-related factors were associated with LFU,
which may guide interventions to improve treatment adherence, particularly in the
first 11 months.

Read the article here.

3. Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and
Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection.
Antimicrob Agents Chemother. 2019 Jun 24;63(7). pii: e00279-19. doi:
10.1128/AAC.00279-19. Print 2019 Jul.

Al-Shaer MH(1), Alghamdi WA(1)(2), Alsultan A(3), An G(4), Ahmed S(5), Alkabab
Y(6), Banu S(5), Barbakadze K(7), Houpt E(6), Kipiani M(7), Mikiashvili L(7),
Cegielski JP(8), Kempker RR(9), Heysell SK(6), Peloquin CA(10).

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare
the culture conversion between new-generation (levofloxacin and moxifloxacin) and
old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop
pharmacokinetic models, and calculate target attainment for levofloxacin and
moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted
between 1984 and 2015, infected with drug-resistant tuberculosis, and who had
received fluoroquinolones for ≥28 days were included. Demographics, sputum
cultures and susceptibility, treatment regimens, and serum concentrations were
collected. A time-to-event analysis was conducted, and Cox proportional hazards
model was used to compare the time to culture conversion. Using additional data
from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were
performed to assess target attainment for different doses. Overall, 124 patients
received fluoroquinolones. The median age was 40 years, and the median weight was
60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones.
New-generation fluoroquinolones showed a faster time to culture conversion
(median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and
clofazimine treatment, patients treated with new-generation fluoroquinolones were
more likely to have culture conversion (adjusted hazards ratio, 2.16 [95%
confidence interval, 1.28 to 3.64]). We included 178 patients in the
pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a
one-compartment model with first-order absorption and elimination. At least 1,500
to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill
at the current epidemiologic cutoff values. In summary, new-generation
fluoroquinolones showed faster time to culture conversion compared to the old
generation. For optimal target attainment at the current MIC values, higher doses
of levofloxacin and moxifloxacin may be needed.

Read the article here.

4. Characterization of linezolid-resistance-associated mutations in Mycobacterium
tuberculosis through WGS.

J Antimicrob Chemother. 2019 Jul 1;74(7):1795-1798. doi: 10.1093/jac/dkz150.

Pi R(1)(2), Liu Q(1)(2), Jiang Q(1)(2), Gao Q(1)(2).

OBJECTIVES: Linezolid is becoming an important antibiotic for treating MDR/XDR
TB, but the mutations conferring resistance to linezolid remain inadequately
characterized. Herein, we investigated the linezolid-resistance-associated
mutations on a whole-genome scale through parallel selections of resistant
isolates in vitro.
METHODS: Ten parallel Mycobacterium tuberculosis H37Rv cultures were subjected to
spontaneous mutant selection on 7H11 agar plates containing 2.5 mg/L linezolid.
The linezolid resistance of resulting colonies was confirmed by growth on a
second linezolid plate. WGS was then performed to identify mutations associated
with linezolid resistance.
RESULTS: Of 181 colonies appearing on the initial linezolid plates, 154 were
confirmed to be linezolid resistant. WGS showed that 88.3% (136/154) of these
isolates had a T460C mutation in rplC, resulting in a C154R substitution. The
other 18 isolates harboured a single mutation in the rrl gene, with G2814T and
G2270T mutations accounting for 7.8% (12/154) and 3.9% (6/154), respectively.
CONCLUSIONS: No mutations in novel genes were associated with linezolid
resistance in a whole-genome investigation of 154 linezolid-resistant isolates
selected in vitro. These results emphasize that rrl and rplC genes should be the
major targets for molecular detection of linezolid resistance.

This article is not available via open access.

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

Complete makeover in fight of MDR-TB

An international collaborative study led by Dr. Dick Menzies at McGill University has shown that several new medicines, including bedaquiline, linezolid, and the later generation fluoroquinolones, have produced consistently better cure rates for MDR-TB patients and have been proven to be more effective at treating XDR-TB than currently used treatments. 

The World Health Organization (WHO) has already responded to this study’s findings by announcing landmark changes in line with this MDR-TB regimen and, also, positioning fully oral regimens over injectable agents. “The guidelines committee simply erased the old treatment recommendations and started over. They gave the treatment guidelines a complete make-over,” says Dr. Menzies.

To read the full article, click here.

SimpliciTB clinical trial launched with first patients in Tbilisi, Georgia

TB Alliance has started a new, four month clinical trial, SimpliciTB, to test the efficacy of the BPaMZ treatment regimen consisting of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in people with drug-sensitive TB against the standard six-month treatment regimen. SimpliciTB is looking to see if this regimen can shorten the duration of treatment by one third. BPaMZ was previously studied in a Phase 2b study, NC-005, in which MDR-TB patients saw improvement three times faster than those enrolled on the standard treatment. SimpliciTB is currently enrolling patients in Tbilisi, Georgia at the at the National Center for Tuberculosis and Lung Disease. 150 of the total 450 patients that will be enrolled are expected to have MDR-TB across 26 centers in 10 countries. 

To read the full article, click here.

RESIST-TB Webinar

Please join RESIST-TB on September 6, 2018 from 8:30 – 9:30am EST for a special webinar on Adequate and Well – Controlled Studies in the TB Regimen Development: An FDA Perspective. Hosted by Dr. Carole Mitnick, this webinar will feature the expertise of FDA mathematical statistician, Karen Higgins.

Connection details below. 

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To join the webinar, please use the following link:
https://hms.webex.com/hms/onstage/g.php?t=a&d=711971099
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WHO Rapid Communication: Key Changes to Treatment of MDR/RR-TB

The World Health Organization (WHO) released a rapid communication ahead of updated, more detailed guidelines on treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) later in 2018. These improved guidelines are expected to lead to major improvements in treatment and quality of life of MDR-TB patients. The rapid communication announces a priority ranking for medicines available for treatment. This aims to improve access to more effective drugs in countries that currently have low treatment success rates. WHO also announced the forthcoming establishment of a multi-stakeholder Task Force to support national TB programs through the transition of the improved 2018 guidelines. 

Click here to read the full communication.