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Monday, 27 March 2017 07:25

Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline:A Model-Based Analysis

Amber Kunkel, Frank G. Cobelens, Ted Cohen





New drugs for the treatment of tuberculosis (TB) are becoming available for the first time in over 40 y. Optimal strategies for introducing these drugs have not yet been established. The objective of this study was to compare different strategies for introducing the new TB drug bedaquiline based on patients' resistance patterns.



We created a Markov decision model to follow a hypothetical cohort of multidrug-resistant (MDR) TB patients under different bedaquiline use strategies. The explored strategies included making bedaquiline available to all patients with MDR TB, restricting bedaquiline usage to patients with MDR plus additional resistance and withholding bedaquiline introduction completely. We compared these strategies according to life expectancy, risks of acquired resistance, and the expected number and health outcomes of secondary cases. For our simulated cohort, the mean (2.5th, 97.5th percentile) life expectancy from time of initiation of MDR TB treatment at age 30 was 36.0 y (33.5, 38.7) assuming all patients with MDR TB received bedaquiline, 35.1 y (34.4, 35.8) assuming patients with pre-extensively drug-resistant (PreXDR) and extensively drug-resistant (XDR) TB received bedaquiline, and 34.9 y (34.6, 35.2) assuming only patients with XDR TB received bedaquiline. Although providing bedaquiline to all MDR patients resulted in the highest life expectancy for our initial cohort averaged across all parameter sets, for parameter sets in which bedaquiline conferred high risks of added mortality and only small reductions in median time to culture conversion, the optimal strategy would be to withhold use even from patients with the most extensive resistance. Across all parameter sets, the most liberal bedaquiline use strategies consistently increased the risk of bedaquiline resistance but decreased the risk of resistance to other MDR drugs. In almost all cases, more liberal bedaquiline use strategies reduced the expected number of secondary cases and resulting life years lost. The generalizability of our results is limited by the lack of available data about drug effects among individuals with HIV co-infection, drug interactions, and other sources of heterogeneity, as well as changing recommendations for MDR TB treatment.



If mortality benefits can be empirically verified, our results provide support for expanding bedaquiline access to all patients with MDR TB. Such expansion could improve patients' health, protect background MDR TB drugs, and decrease transmission, but would likely result in greater resistance to bedaquiline.



Comment from Frank van Leth:

The paper describes the results of a mathematical model assessing the effect of different strategies for bedaquiline use on life expectancy, transmission, and acquired resistance.

The rational foer the study is the reported mortality increase with bedaquiline use in the phase IIb study. Despite this observation, the drug was approved for use based on these results in a rather restrictive patient group (those without other treatment options).

The authors model the effect for adding bedaquiline to all patients with MDR, those with pre-XDR or XDR, or only those with XDR.

The authors conclude that a more liberal use of the drug in all patients with MDR is warranted if the unexplained mortality finding in the phase IIb trail can be refuted.


The study lacks real-life data and is subjective to input parameters, as with every modeling study. Despite this major drawback, studies like this identify research priorities and areas of uncertainty. It is up to us to react to these challenges




Thursday, 02 February 2017 11:36

Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon γ release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial

Published Online January 31, 2017

Morten Ruhwald, Henrik Aggerbeck, Rafael Vázquez Gallardo, Søren T Hoff, José I Villate, Bettine Borregaard, José A Martinez, Ingrid Kromann, Antón Penas, Luis L Anibarro, Maria Luiza de Souza-Galvão, Francisca Sánchez, Jose Ángel Rodrigo-Pendás, Antoni Noguera-Julian, Xavier Martínez-Lacasa, Maria Victoria Tuñez, Virginia Leiro Fernández, Joan P Millet, Antonio Moreno, Nazaret Cobos, José M Miró, Llanos Roldan, Angels Orcau, Peter Andersen, Joan A Caylá, TESEC Working Group



Background Targeted screening and treatment of Mycobacterium tuberculosis infection substantially reduces the risk of developing active tuberculosis. C-Tb (Statens Serum Institute, Copenhagen, Denmark) is a novel specific skin test based on ESAT-6 and CFP10 antigens. We investigated the safety and diagnostic potential of C-Tb compared with established tests in the contact-tracing setting.



Negative controls, close contacts, occasional contacts, and patients with active pulmonary tuberculosis were enrolled at 13 centres in Spain. We compared C-Tb with the QuantiFERON-TB Gold In-Tube ([QFT] Qiagen, Hilden, Germany) interferon γ release assay (IGRA) and the purified protein derivative (PPD) RT 23 tuberculin skin test ([TST] Statens Serum Institute). All participants older than 5 years were tested with QFT. Some participants in the negative control group received C-Tb without the TST to test for potential interactions between C-Tb and PPD RT 23. The rest were randomly assigned in blocks of ten and tested with both C-Tb and TST, with five in each block receiving injection of C-Tb in the right arm and the TST in the left arm and five vice versa. The primary and safety analyses were done in all participants randomly assigned to a group who received any test. This trial is registered with ClinicalTrials.gov, number NCT01631266, and with EudraCT, number 2011-005617-36.



From July 24, 2012, to Oct 2, 2014, 979 participants were enrolled, of whom 263 were negative controls, 299 were occasional contacts, 316 were close contacts, and 101 were patients with tuberculosis. 970 (99%) participants completed the trial. Induration sizes were similar for C-Tb and TST, but TST positivity was affected by BCG vaccination status. We found a strong positive trend towards C-Tb test positivity with increasing risk of infection, from 3% in negative controls to 16% in occasional contacts, to 43% in close contacts. C-Tb and QFT results were concordant in 785 (94%) of 834 participants aged 5 years and older, and results did not differ significantly between exposure groups. The safety profile of C-Tb was similar to that for the TST.



C-Tb delivered IGRA-like results in a field-friendly format. Being unaffected by BCG vaccination status, the C-Tb skin test might provide more accurate treatment guidance in settings where the TST is commonly used.



Statens Serum Institut.



Wednesday, 21 December 2016 13:22


Transmission of multidrug-resistant Mycobacterium tuberculosis in Shanghai, China: a retrospective observational study using whole-genome sequencing and epidemiological investigation.

Yang C, Luo T, Shen X, Wu J, Gan M, Xu P, Wu Z, Lin S, Tian J, Liu Q, Yuan Z, Mei J, DeRiemer K, Gao Q.


Lancet Infect Dis. 2016 Dec 2. pii: S1473-3099(16)30418-2. doi: 10.1016/S1473-3099(16)30418-2. [Epub ahead of print]






Multidrug-resistance is a substantial threat to global elimination of tuberculosis. Understanding transmission patterns is crucial for control of the disease. We used a genomic and epidemiological approach to assess recent transmission of multidrug-resistant (MDR) tuberculosis and identify potential risk factors for transmission.



We did a population-based, retrospective study of patients who tested positive for tuberculosis between Jan 1, 2009, and Dec 31, 2012, in Shanghai, China. We did variable-number-of-tandem-repeat genotyping and whole-genome sequencing of isolates. We measured strain diversity within and between genomically clustered isolates. Genomic and epidemiological data were combined to construct transmission networks.



367 (5%) of 7982 patients with tuberculosis had MDR tuberculosis and 324 (88%) of these had isolates available for genomic analysis. 103 (32%) of the 324 MDR strains were in 38 genomic clusters that differed by 12 or fewer single nucleotide polymorphisms (SNPs), indicating recent transmission of MDR strains. Patients who had delayed diagnosis or were older than 45 years had high risk of recent transmission. 235 (73%) patients with MDR tuberculosis probably had transmission of MDR strains. Transmission network analysis showed that 33 (87%) of the 38 clusters accumulated additional drug-resistance mutations through emergence or fixation of mutations during transmission. 68 (66%) of 103 clustered MDR strains had compensatory mutations of rifampicin resistance.



Recent transmission of MDR tuberculosis strains, with increasing drug-resistance, drives the MDR tuberculosis epidemic in Shanghai, China. Whole-genome sequencing can measure of the heterogeneity of drug-resistant mutations within and between hosts and help to determine the transmission patterns of MDR tuberculosis.



National Science and Technology Major Project, National Natural Science Foundation of China, and US National Insitutes of Health.



Thursday, 24 November 2016 09:34


Submit your image of TB and win an iPad!

TBnet calls for a photograph related to TB for a photoexhibition and book. 

Submit your images of TB by March 3st 2017 to cehlers@fz-borstel.de. Photos will be judged by an international jury.





Submit up to 3 photos, a title and a description for the TBnet photoproject and explain what you wish to improve in TB treatment

The photographer of the best image will be awarded



·    Tuberculosis (TB)is a curable contagious infectious disease

·    TBbacilli are transmitted through the air

·    TB is one of the 10 leading causes of deaths worldwide

·    Patients withTB face a longstanding treatment with a combination of antibiotics

·    Emerging drug-resistanceof TBbacilli challenges the success of TB therapy

·    Patients with TB experience isolation and fear to be the source of infection to family and other contacts


Submit your image of TB and win an iPad! Deadline: March 31st 2017


·    TBnet calls for a photograph related to TBfor a photoexhibition and book

·    Submit your images of TB by March 31st 2017 to cehlers@fz-borstel.de

·    Submit up to 3 photos, a title and a description for the TBnet photoproject

·    Explain what you wish to improve in TB treatment

·    Photos will be judged by an international jury

·    The photographer of the best image will be awarded


 Find submission details here.


TBnet Photo Contest Forms - please fill both and send back with email












Wednesday, 23 November 2016 11:13

High-dose rifampicin, moxifl oxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial


Martin J Boeree*, Norbert Heinrich*, Rob Aarnoutse, Andreas H Diacon, Rodney Dawson, Sunita Rehal, Gibson S Kibiki, Gavin Churchyard, Ian Sanne, Nyanda E Ntinginya, Lilian T Minja, Robert D Hunt, Salome Charalambous, Madeleine Hanekom, Hadija H Semvua, Stellah G Mpagama, Christina Manyama, Bariki Mtafya, Klaus Reither, Robert S Wallis, Amour Venter, Kim Narunsky, Anka Mekota, Sonja Henne, Angela Colbers, Georgette Plemper van Balen, Stephen H Gillespie, Patrick P J Phillips, Michael Hoelscher, on behalf of the PanACEA consortium‡



Background Tuberculosis is the world’s leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. Methods. We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional hazards regression model and adjusted for minimisation variables. 



Wednesday, 23 November 2016 11:04

Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease


Kenneth N. Olivier, David E. Griffith, Gina Eagle, John P. McGinnis II, Liza Micioni, Keith Liu, Charles L. Daley, Kevin L. Winthrop, Stephen Ruoss, Doreen J. Addrizzo-Harris,  Patrick A. Flume, Daniel Dorgan, Matthias Salathe, Barbara A. Brown-Elliott, Renu Gupta, Richard J. Wallace, Jr.


Scientific Knowledge on the Subject

At a Glance Commentary: Management of pulmonary nontuberculous mycobacterial (PNTM) disease is limited by lengthy multi-drug regimens, drug toxicity and/or intolerance, and poor drug efficacy. Liposomes are taken up by lung macrophages, allowing intracellular delivery of high levels of amikacin into nontuberculous mycobacteria (NTM)–infected cells, and inhalation allows localized drug delivery. In select patients with treatment-refractory PNTM disease, liposomal amikacin for inhalation (LAI) added to guidelines-based therapy may be able to achieve early and sustained negative sputum cultures with limited systemic toxicity. What This Study Adds to the Field


This multi-center clinical trial assessed the novel drug formulation LAI in patients with persistently positive NTM cultures despite having received guidelines-based treatment for at least 6 months prior to screening. Although the primary end point was not achieved, more patients receiving LAI treatment than patients receiving placebo had a negative NTM sputum culture at Day 84 (32% [14/44] vs. 9% [4/45]; P = 0.006). Most of these patients (n=14/18) also had a negative culture at 28 days after LAI discontinuation. Culture conversion, used in tuberculosis trials to predict lasting mycobacterial eradication, occurred mainly in non-cystic fibrosis patients with Mycobacterium avium complex infection. Results of this study indicate that in select patients with treatment-refractory PNTM disease, LAI added to guidelines-based therapy can achieve early and sustained negative sputum cultures. Further, culture conversion in response to treatment with LAI may be associated with improvements in functional capacity and relative to treatment with parenteral amikacin, limited systemic toxicity.



Thursday, 27 October 2016 08:45

Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure


Stephanus T Malherbe, Shubhada Shenai, Katharina Ronacher, Andre G Loxton, Gregory Dolganov, Magdalena Kriel, Tran Van, Ray Y Chen, James Warwick, Laura E Via, Taeksun Song, Myungsun Lee, Gary Schoolnik, Gerard Tromp, David Alland, Clifton E Barry III, Jill Winter, Gerhard Walzl, the Catalysis TB–Biomarker Consortium, Lance Lucas, Gian van der Spuy, Kim Stanley, Lani Theart, Bronwyn Smith, Nelita Du Plessis et al.


Nature Medicine 22, 1094–1100 (2016) doi:10.1038/nm.4177

Received 18 December 2015 Accepted 29 July 2016 Published online 05 September 2016 Corrected online 19 October 2016



The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET–CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET–CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.



Thursday, 27 October 2016 08:42

Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-D-glucose positron emission and computed tomography

Hanif Esmail, Rachel P Lai, Maia Lesosky, Katalin A Wilkinson, Christine M Graham, Anna K Coussens, Tolu Oni, James M Warwick, Qonita Said-Hartley, Coenraad F Koegelenberg, Gerhard Walzl, JoAnne L Flynn, Douglas B Young, Clifton E Barry III, Anne O'Garra & Robert J Wilkinson


Nature Medicine 22, 1090–1093 (2016) doi:10.1038/nm.4161

Received 08 February 2016 Accepted 08 July 2016 Published online 05 September 2016


Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.



Thursday, 15 September 2016 12:11

Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection

Vidhya R. Nair, Luis H. Franco, Vineetha M. Zacharia, Haaris S. Khan, Chelsea E. Stamm, Wu You, Denise K. Marciano, Hideo Yagita, Beth Levine, Michael U. Shiloh, http://dx.doi.org/10.1016/j.celrep.2016.06.080




•Mtb translocates across model M cells in vitro in an active, transcellular process

•Depletion of airway M cells in mice reduces Mtb dissemination via NALT

•M cells contribute to Mtb dissemination from the airway mucosa

•Airway M cell depletion in mice prior to aerosol Mtb infection improves survival




The prevailing paradigm is that tuberculosis infection is initiated when patrolling alveolar macrophages and dendritic cells within the terminal alveolus ingest inhaled Mycobacterium tuberculosis (Mtb). However, definitive data for this model are lacking. Among the epithelial cells of the upper airway, a specialized epithelial cell known as a microfold cell (M cell) overlies various components of mucosa-associated lymphatic tissue. Here, using multiple mouse models, we show that Mtb invades via M cells to initiate infection. Intranasal Mtb infection in mice lacking M cells either genetically or by antibody depletion resulted in reduced invasion and dissemination to draining lymph nodes. M cell-depleted mice infected via aerosol also had delayed dissemination to lymph nodes and reduced mortality. Translocation of Mtb across two M cell transwell models was rapid and transcellular. Thus, M cell translocation is a vital entry mechanism that contributes to the pathogenesis of Mtb.


Full article here.

Wednesday, 07 September 2016 08:27

A) Comment on: Delamanid susceptibility testing of Mycobacterium tuberculosis using the resazurin microtitre assay and the BACTEC™ MGIT™ 960 system


Comment by Graham Bothamley: Drug sensitivity testing for delaminid meets unexpected problems.  The manufacturers of delaminid, and coincidentally sponsors of the European Respiratory Society’s TB consilium, are called to account regarding drug sensitivity testing for delaminid.



B) Bacterial Loads Measured by the Xpert MTB/RIF Assay as Markers of Culture Conversion and Bacteriological Cure in Pulmonary TB.

Shenai S1, Ronacher K2, Malherbe S2, Stanley K2, Kriel M2, Winter J3, Peppard T4, Barry CE5, Wang J6, Dodd LE7, Via LE8,9, Barry CE 3rd8,9, Walzl G2, Alland D1.



Biomarkers are needed to monitor tuberculosis (TB) treatment and predict treatment outcomes. We evaluated the Xpert MTB/RIF (Xpert) assay as a biomarker for TB treatment during and at the end of the 24 weeks therapy.


Sputum from 108 HIV-negative, culture-positive pulmonary TB patients was analyzed using Xpert at time points before and during anti-TB therapy. Results were compared against culture. Direct Xpert cycle-threshold (Ct), a change in the Ct (delta Ct), or a novel "percent closing of baseline Ct deficit" (percent closing) were evaluated as classifiers of same-day and end-of-treatment culture and therapeutic outcomes.


Xpert was positive in 29/95 (30.5%) of subjects at week 24; and positive one year after treatment in 8/64 (12.5%) successfully-treated patients who remained free of tuberculosis. We identified a relationship between initial bacterial load measured by baseline Xpert Ct and time to culture conversion (hazard ratio 1.06, p = 0.0023), and to the likelihood of being among the 8 treatment failures at week 24 (AUC = 72.8%). Xpert Ct was even more strongly associated with culture conversion on the day the test was performed with AUCs 96.7%, 99.2%, 86.0% and 90.2%, at Day 7, Week 4, 8 and 24, respectively. Compared to baseline Ct measures alone, a combined measure of baseline Ct plus either Delta Ct or percent closing improved the classification of treatment failure status to a 75% sensitivity and 88.9% specificity.


Genome loads measured by Xpert provide a potentially-useful biomarker for classifying same day culture status and predicting response to therapy.


Comment by Graham Bothamley: Cycle threshold in Xpert MTB/RIF at the level of detection (25 to 40 Ct) are suggested to monitor treatment.  At the end of successful treatment, 31% remain positive (Ct >40), and 12.5% remain positive a year after successful treatment has been completed.