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Dawson R.,University of Cape Town | Diacon A.H.,Stellenbosch University | Everitt D.,Stellenbosch University | Van Niekerk C.,Global Alliance for TB Drug Development | And 18 more authors.
The Lancet | Year: 2015

Background New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment. Methods We did this phase 2b study of bactericidal activity - defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis - at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419. Findings Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0-56 (0·155, 95% Bayesian credibility interval 0·133-0·178) was significantly greater than for HRZE (n=54, 0·112, 0·093-0·131). DRMPa200Z (n=9) had bactericidal activity of 0·117 (0·070-0·174). The bactericidal activity on days 7-14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen. Interpretation The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment. Funding Global Alliance for TB Drug Development. © 2015 Elsevier Ltd. Source


Robb M.L.,U.S. Army | Robb M.L.,National Institute of Allergy and Infectious Diseases | Eller L.A.,U.S. Army | Eller L.A.,National Institute of Allergy and Infectious Diseases | And 37 more authors.
New England Journal of Medicine | Year: 2016

BACKGROUND: Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure. METHODS: We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of im-munophenotyping of lymphocytes were obtained twice weekly. RESULTS: Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits. CONCLUSIONS: The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. Copyright © 2016 Massachusetts Medical Society. Source


Honeyborne I.,University College London | Mtafya B.,Mbeya Medical Research Center | Phillips P.P.J.,University College London | Hoelscher M.,Ludwig Maximilians University of Munich | And 9 more authors.
Journal of Clinical Microbiology | Year: 2014

We evaluated the use of the molecular bacterial load (MBL) assay, for measuring viable Mycobacterium tuberculosis in sputum, in comparison with solid agar and liquid culture. The MBL assay provides early information on the rate of decline in bacterial load and has technical advantages over culture in either form. Copyright © 2014, American Society for Microbiology. All Rights Reserved. Source


Bowness R.,University of St. Andrews | Boeree M.J.,Radboud University Nijmegen | Aarnoutse R.,Radboud University Nijmegen | Dawson R.,University of Cape Town | And 13 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2015

Objectives: The relationship between cfu and Mycobacterial Growth Indicator Tube (MGIT) time to positivity (TTP) is uncertain. We attempted to understand this relationship and create a mathematical model to relate these two methods of determining mycobacterial load. Methods: Sequential bacteriological load data from clinical trials determined by MGIT and cfu were collected and mathematical models derived. All model fittings were conducted in the R statistical software environment (version 3.0.2), using the lm and nls functions. Results: TTP showed a negative correlation with log10 cfu on all 14 days of the study. There was an increasing gradient of the regression line and y-intercept as treatment progressed. There was also a trend towards an increasing gradient with higher doses of rifampicin. Conclusions: These data suggest that there is a population of mycobacterial cells that are more numerous when detected in liquid than on solid medium. Increasing doses of rifampicin differentially kill this group of organisms. These findings support the idea that increased doses of rifampicin are more effective. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Source


Huber J.,Ludwig Maximilians University of Munich | Bauer D.,Ludwig Maximilians University of Munich | Hoelscher M.,Ludwig Maximilians University of Munich | Hoelscher M.,German Center for Infection Research | And 11 more authors.
Journal of Evaluation in Clinical Practice | Year: 2014

Rationale, aims and objectives In the field of global health, research capacity strengthening is becoming a common concept for defining and improving research competencies on individual, organizational, national and supranational level. However, HRCS activities often lack evaluation procedures to measure their impact and to ensure their quality. The aim of this study was to develop and validate a short questionnaire to evaluate trainings in the field of health research capacity strengthening (HRCS). Method The questionnaire was developed by an interdisciplinary research team and tested in four different training settings at the Mbeya Medical Research Center and Mbeya Referral Hospital, Tanzania. Construct validity of the questionnaire was tested based on 97 responses of the participants of four trainings. Results Iterative checking of Cronbach's alpha of the subscales and exploratory factor analysis revealed a four-factor solution that differed from the original structure and subscales of the questionnaire. The instrument was adapted accordingly and consists now of four subscales with 19 items, three global impression items, and open questions for participants' comments and recommendations. Conclusions The result of the study is a short, validated questionnaire for the evaluation of HRCS trainings on the individual level. The tool can be applied both to measure the short-term effects of international health research capacity trainings and to ensure their quality. In the future, after collecting larger sample sizes, a confirmatory factor analysis should be done to further support the four factors. © 2014 John Wiley & Sons, Ltd. Source

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