Abstract
Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide.
Highlights
Three recent international randomized phase 3 trials evaluating 4-month fluoroquinolone-containing regimens in adults with pulmonary, drug-susceptible tuberculosis failed to achieve non-inferiority compared with the standard 6-month control regimen (OFLOTUB1, ClinicalTrials.gov number NCT00216385; REMoxTB2, ClinicalTrials.gov number NCT00864383; RIFAQUIN3, ISRCTN number 44153044)
In this pooled analysis of individual participant datasets from these high-quality, contemporary trials, we sought to identify characteristics of those participants who were cured with 4-month regimens and, of those with hard-to-treat phenotypes of tuberculosis, who might require longer treatment durations
A total of 3,411 study participants treated for drug-susceptible tuberculosis with one of four fluoroquinolonecontaining 4-month regimens (n =2,001) or the standard 6-month regimen (n =1,404) were included in the modified intent-to-treat
Summary
Three recent international randomized phase 3 trials evaluating 4-month fluoroquinolone-containing regimens in adults with pulmonary, drug-susceptible tuberculosis failed to achieve non-inferiority compared with the standard 6-month control regimen (OFLOTUB1, ClinicalTrials.gov number NCT00216385; REMoxTB2, ClinicalTrials.gov number NCT00864383; RIFAQUIN3, ISRCTN number 44153044). Current tuberculosis regimen development efforts are aimed at using new drugs with increased potency to identify shorter treatments for all patients, regardless of severity of disease This approach places otherwise efficacious drugs and regimens at risk of being abandoned, impeding the identification of new tuberculosis regimens that would be curative if used with greater precision. In this pooled analysis of individual participant datasets from these high-quality, contemporary trials, we sought to identify characteristics of those participants who were cured with 4-month regimens and, of those with hard-to-treat phenotypes of tuberculosis, who might require longer treatment durations. We evaluated both baseline characteristics and on-treatment markers of risk, including dosing frequency and adherence, for their ability to stratify the study population into easy- or hard-to-treat phenotypes of tuberculosis
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