Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Supported by the European and Developing Country Clinical Trials Partnership (grant IP.2007.32011.011) and the Global Alliance for TB Drug Development, with support from the Bill & Melinda Gates Foundation, US Agency for International Development, UK Department for International Development, Directorate-General for International Cooperation of the Netherlands, Irish Aid and Australian Department of Foreign Affairs and Trade.Background Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Methods Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Results Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Conclusions Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.Publisher PDFPeer reviewe

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Supported by the European and Developing Country Clinical Trials Partnership (grant IP.2007.32011.011) and the Global Alliance for TB Drug Development, with support from the Bill & Melinda Gates Foundation, US Agency for International Development, UK Department for International Development, Directorate-General for International Cooperation of the Netherlands, Irish Aid and Australian Department of Foreign Affairs and Trade.Background Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Methods Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Results Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Conclusions Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.Publisher PDFPeer reviewe

Long-term spatially-replicated data show no physical cost to a benefactor species in a facilitative plant-plant interaction

DATA AVAILABILITY STATEMENT : Data are available from the Dryad Digital Repository: https://doi.org/10.5061/dryad.34tmpg4pp (Raath-Krüger et al. 2022).Facilitation is an interaction where one species (the benefactor) positively impacts another (the beneficiary). However, the reciprocal effects of beneficiaries on their benefactors are typically only documented using short-term datasets. We use Azorella selago, a cushion plant species and benefactor, and a co-occurring grass species, Agrostis magellanica, on sub-Antarctic Marion Island, comparing cushion plants and the grasses growing on them over a 13-year period using a correlative approach. We additionally compare the feedback effect of A. magellanica on A. selago identified using our long-term dataset with data collected from a single time period. We hypothesized that A. selago size and vitality would be negatively affected by A. magellanica cover and that the effect of A. magellanica on A. selago would become more negative with increasing beneficiary cover and abiotic-severity, due to, e.g. more intense competition for resources. We additionally hypothesized that A. magellanica cover would increase more on cushion plants with greater dead stem cover, since dead stems do not inhibit grass colonization or growth. The relationship between A. magellanica cover and A. selago size and vitality was not significant in the long-term dataset, and the feedback effect of A. magellanica on A. selago did not vary significantly with altitude or aspect; however, data from a single time period did not consistently identify this same lack of correlation. Moreover, A. selago dead stem cover was not significantly related to an increase in A. magellanica cover over the long term; however, we observed contrasting results from short-term datasets. Long-term datasets may, therefore, be more robust (and practical) for assessing beneficiary feedback effects than conventional approaches, particularly when benefactors are slow-growing. For the first time using a long-term dataset, we show a lack of physical cost to a benefactor species in a facilitative interaction, in contrast to the majority of short-term studies.The South African National Antarctic Program, the National Research Foundation of South Africa and the Swiss National Science Foundation.http://www.oikosjournal.orghj2024Plant Production and Soil ScienceStatisticsNon

Long-term spatially-replicated data show no physical cost to a benefactor species in a facilitative plant-plant interaction

Facilitation is an interaction where one species (the benefactor) positively impacts another (the beneficiary). However, the reciprocal effects of beneficiaries on their benefactors are typically only documented using short-term datasets. We use Azorella selago, a cushion plant species and benefactor, and a co-occurring grass species, Agrostis magellanica, on sub-Antarctic Marion Island, comparing cushion plants and the grasses growing on them over a 13-year period using a correlative approach. We additionally compare the feedback effect of A. magellanica on A. selago identified using our long-term dataset with data collected from a single time period. We hypothesized that A. selago size and vitality would be negatively affected by A. magellanica cover and that the effect of A. magellanica on A. selago would become more negative with increasing beneficiary cover and abiotic-severity, due to, e.g. more intense competition for resources. We additionally hypothesized that A. magellanica cover would increase more on cushion plants with greater dead stem cover, since dead stems do not inhibit grass colonization or growth. The relationship between A. magellanica cover and A. selago size and vitality was not significant in the long-term dataset, and the feedback effect of A. magellanica on A. selago did not vary significantly with altitude or aspect; however, data from a single time period did not consistently identify this same lack of correlation. Moreover, A. selago dead stem cover was not significantly related to an increase in A. magellanica cover over the long term; however, we observed contrasting results from short-term datasets. Long-term datasets may, therefore, be more robust (and practical) for assessing beneficiary feedback effects than conventional approaches, particularly when benefactors are slow-growing. For the first time using a long-term dataset, we show a lack of physical cost to a benefactor species in a facilitative interaction, in contrast to the majority of short-term studies.ISSN:0030-1299ISSN:1600-070

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

BackgroundDespite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials.MethodsUsing data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome.ResultsTime to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p &lt;0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP.ConclusionsCulture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

BackgroundDespite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials.MethodsUsing data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome.ResultsTime to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p &lt;0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP.ConclusionsCulture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383

Erratum to: Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

BackgroundDespite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials.MethodsUsing data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome.ResultsTime to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP.ConclusionsCulture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383