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Streicher E.M.,Stellenbosch University | Maharaj K.,University of KwaZulu - Natal | York T.,Stellenbosch University | Van Heerden C.,Stellenbosch University | And 10 more authors.
Journal of Clinical Microbiology | Year: 2014

We developed a pyrazinamidase gene DNA-sequencing method to rapidly identify pyrazinamide resistance-causing mutations in GenoLyse-treated, smear-positive sputum specimens. The sensitivity and specificity were 90.9 and 100%, respectively, compared to those of MGIT drug susceptibility testing, after the exclusion of synonymous mutations and nonsynonymous mutations previously associated with susceptibility to pyrazinamide. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Bunga C.,National Institute for Medical Research | Ferdous S.,center | Jonas A.,National Institute for Medical Research | Islam S.,center | And 8 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2014

OBJECTIVE: To estimate the costs incurred by patients during the intensive and continuation phases of the current 6-month tuberculosis (TB) regimen in Bangladesh and Tanzania, and thus identify potential benefits to patients of a shorter, 4-month treatment regimen. DESIGN: The validated Stop TB patient cost questionnaire was adapted and used in interviews with 190 patients in the continuation phase of treatment with current regimens. RESULTS: In both countries, overall patient costs were lower during 2 months of the continuation phase (US$74 in Tanzania and US$56 in Bangladesh) than during the 2 months of the intensive phase of treatment (US$150 and US$111, respectively). However, continuation phase patient costs still represented 89% and 77% of the 2-month average national income in the respective countries. Direct travel costs in some settings were kept low by local delivery system features such as community treatment observation. Lost productivity and costs for supplementary foods remained significant. CONCLUSIONS: Although it is not a straightforward exercise to determine the exact magnitude of likely savings, a shorter regimen would reduce out-of-pocket expenses incurred by patients in the most recent 2 months of the continuation phase and allow an earlier return to productive activities. © 2014 The Union.

Denkinger C.M.,Beth Israel Deaconess Medical Center | Dolinger D.,FIND | Schito M.,Foundation Medicine | Wells W.,TB Alliance | And 9 more authors.
The Journal of infectious diseases | Year: 2015

METHODS: A target product profile for a molecular drug-susceptibility test (DST) was developed on the basis of a collaborative effort that included opinions gathered from researchers, clinicians, policy makers, and test developers on optimal clinical and operational characteristics in settings of intended use. In addition, the current diagnostic ecosystem and the diagnostic development landscape were mapped.RESULTS: Molecular DSTs for detecting tuberculosis in microscopy centers should ideally evaluate for resistance to rifampin, fluoroquinolones, isoniazid, and pyrazinamide and enable the selection of the most appropriate treatment regimen. Performance characteristics of DSTs need to be optimized, but compromises can be made that depend on the trade-off between a false-positive result and a false-negative result. The operational requirements of a test will vary depending on the site of implementation. However, the most-important considerations pertain to quality control, maintenance and calibration, and the ability to export data.CONCLUSION: This target product profile defines the needs as perceived by the tuberculosis stakeholder community and attempts to provide a means of communication with test developers to ensure that fit-for-purpose DSTs are being developed.BACKGROUND: Current phenotypic testing for drug resistance in patients with tuberculosis is inadequate primarily with respect to turnaround time. Molecular tests hold the promise of an improved time to diagnosis. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Nachman S.,SUNY at Stony Brook | Ahmed A.,Levine Childrens Hospital at Carolinas Medical Center | Amanullah F.,Indus Hospital | Becerra M.C.,Harvard University | And 28 more authors.
The Lancet Infectious Diseases | Year: 2015

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained. © 2015 Elsevier Ltd.

Gillespie S.H.,University of St. Andrews | Crook A.M.,University College London | McHugh T.D.,University College London | Mendel C.M.,TB Alliance | And 5 more authors.
New England Journal of Medicine | Year: 2014

Background Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis.Methods We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization.Results Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-totreat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group.Conclusions The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.). Copyright © 2014 Massachusetts Medical Society. All rights reserved.

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