September 2017 Newsletter

1. The TB Portals: An open-access, web-based platform for global drug-resistant tuberculosis data sharing and analysis.
J Clin Microbiol. 2017 Sep 13. pii: JCM.01013-17. doi: 10.1128/JCM.01013-17. [Epub ahead of print]
Rosenthal A(1), Gabrielian A(2), Engle E(2), Hurt DE(2), Alexandru S(3), Crudu V(3), Sergueev E(4), Kirichenko V(4), Lapitskii V(4), Snezhko E(4), Kovalev V(4), Astrovko A(5), Skrahina A(5), Taaffe J(2), Harris M(2), Long A(2), Wollenberg K(2), Akhundova I(6), Ismayilova S(6), Skrahin A(7), Mammadbayov E(6), Gadirova H(6), Abuzarov R(6), Seyfaddinova M(6), Avaliani Z(6), Strambu I(8), Zaharia D(8), Muntean A(8), Ghita E(8), Bogdan M(8), Mindru R(8), Spinu V(8), Sora A(8), Ene C(8), Vashakidze S(9), Shubladze N(9), Nanava U(9), Tuzikov A(4), Tartakovsky M(2).

ABSTRACT: The TB Portals Program is an international consortium of physicians, radiologists, and microbiologists from countries with a heavy burden of drug-resistant tuberculosis working with data scientists and IT professionals. Together, we have built the TB Portals, a repository of socioeconomic/geographic, clinical, laboratory, radiological, and genomic data from patient cases of drug-resistant tuberculosis and backed by shareable, physical samples. Currently, there are 1,299 total cases from five country sites (Azerbaijan, Belarus, Moldova, Georgia, and Romania), of which 976 (75.1%) are multi- or extensively drug resistant, and 38.2%, 51.9%, and 36.3% of cases contain X-ray, CT scan, and  genomic data, respectively. The top Mycobacterium tuberculosis lineages represented among collected samples are Beijing, T1, and H3, and SNPs that confer resistance to isoniazid, rifampicin, ofloxacin, and moxifloxacin occur the most frequently. These data and samples have promoted drug discovery efforts and research into genomics and quantitative image analysis to improve diagnostics, while also serving as a valuable resource for researchers and clinical providers. The TB Portals database and associated projects are continually growing, and we invite new partners and collaborations in our initiative. The TB Portals data and their associated analytical and statistical tools are freely available at:

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2. Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis.
N Engl J Med. 2017 Sep 14;377(11):1043-1054. doi: 10.1056/NEJMoa1614915.
Xie YL(1), Chakravorty S(1), Armstrong DT(1), Hall SL(1), Via LE(1), Song T(1), Yuan X(1), Mo X(1), Zhu H(1), Xu P(1), Gao Q(1), Lee M(1), Lee J(1), Smith LE(1), Chen RY(1), Joh JS(1), Cho Y(1), Liu X(1), Ruan X(1), Liang L(1), Dharan N(1), Cho SN(1), Barry CE 3rd(1), Ellner JJ(1), Dorman SE(1), Alland D(1).

BACKGROUND: Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid.
METHODS: We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M.tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions.
RESULTS: Among the 308 participants who were culture-positive for M.tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 μg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 μg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 μg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater.
CONCLUSIONS: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; number, NCT02251327).

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3. Scaling-up the Xpert MTB/RIF assay for the detection of tuberculosis and rifampicin resistance in India: An economic analysis.
PLoS One. 2017 Sep 7;12(9):e0184270. doi: 10.1371/journal.pone.0184270. eCollection 2017.
Khaparde S(1), Raizada N(2), Nair SA(3), Denkinger C(4), Sachdeva KS(1), Paramasivan CN(2), Salhotra VS(5), Vassall A(6)(7), Hoog AV(6).

BACKGROUND: India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India.
METHODS: Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients.
RESULTS: The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US $1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert-for-all scenario (US$ 11,099).
CONCLUSIONS: The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care.

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4.Treatment outcomes for isoniazid-resistant tuberculosis under program conditions in British Columbia, Canada.
BMC Infect Dis. 2017 Sep 4;17(1):604. doi: 10.1186/s12879-017-2706-0.
Romanowski K(1), Chiang LY(1), Roth DZ(1), Krajden M(2), Tang P(2)(3), Cook VJ(1)(4), Johnston JC(5)(6).

BACKGROUND: Every year, over 1 million people develop isoniazid (INH) resistant tuberculosis (TB). Yet, the optimal treatment regimen remains unclear. Given increasing prevalence, the clinical efficacy of regimens used by physicians is of interest. This study aims to examine treatment outcomes of INH resistant TB patients, treated under programmatic conditions in British Columbia, Canada.
METHODS: Medical charts were retrospectively reviewed for cases of culture-confirmed INH mono-resistant TB reported to the BC Centre for Disease Control (BCCDC) from 2002 to 2014. Treatment regimens, patient and strain characteristics, and clinical outcomes were analysed.
RESULTS: One hundred sixty five cases of INH mono-resistant TB were included in analysis and over 30 different treatment regimens were prescribed. Median treatment duration was 10.5 months (IQR 9-12 months) and treatment was extended beyond 12 months for 26 patients (15.8%). Fifty six patients (22.6%) experienced an adverse event that resulted in a drug regimen modification. Overall, 140 patients (84.8%) had a successful treatment outcome while 12 (7.2%) had an unsuccessful treatment outcome of failure (n = 2; 1.2%), relapse (n = 4; 2.4%) or all cause mortality (n = 6; 3.6%).
CONCLUSION: Our treatment outcomes, while consistent with findings reported from other studies in high resource settings, raise concerns about current recommendations for INH resistant TB treatment. Only a small proportion of patients completed the recommended treatment regimens. High quality studies to confirm the effectiveness of standardized regimens are urgently needed, with special consideration given to trials utilizing fluoroquinolones.

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