A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis

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.

Fig. 1. Analysis and validation populations.

Individual participant data from three trials were pooled for analysis. The original results were published in ref. (OFLOTUB), ref. (REMoxTB) and ref. (RIFAQUIN). Data from a fourth trial, DMID 01-009, were used for external validation and previously published in ref. . The modified intent-to-treat population was used for the analysis. ^aFor the validation dataset, the time-to-event analysis population in the original publication was used. ^bREMoxTB included two 4-month experimental groups.

Fig. 2. Multivariate HRs for unfavorable outcomes.

a, Multivariate analysis for experimental group with baseline predictors (top) and baseline and on-treatment predictors (bottom). b, Multivariate analysis for control group with baseline predictors (top) and baseline and on-treatment predictors (bottom). All analyses were adjusted for country, and effect sizes are available in Supplementary Tables 4 and 5. HRs with 95% Wald CIs are reported. The size of the square denotes the relative sample size according to variable. ^aAge <30 years, 179/916 (20%) unfavorable outcomes and age ≥30 years, 237/927 (26%) unfavorable outcomes. ^bAge <30 years, 136/830 (16%) unfavorable outcomes and age ≥30 years, 181/838 (22%) unfavorable outcomes; BMI ≥17 kg m⁻², 226/1,247 (18%) unfavorable outcomes and BMI <17 kg m⁻², 91/421 (22%) unfavorable outcomes. ^cAge <30 years, 92/657 (14%) unfavorable outcomes and age ≥30 years, 121/654 (19%) unfavorable outcomes; BMI ≥17 kg m⁻², 156/989 (16%) unfavorable outcomes and BMI <17 kg m⁻², 57/322 (18%) unfavorable outcomes. ^dBMI ≥17 kg m⁻², 102/901 (11%) unfavorable outcomes and BMI <17 kg m⁻², 36/285 (13%) unfavorable outcomes.

Fig. 3. Difference in percentage of unfavorable outcomes between the experimental group and the control group, overall and according to subgroups.

a, Non-inferiority tests based on analysis dataset. b, Validation of non-inferiority tests in a based on an independent validation dataset. The 90% CIs of the differences in percentage of unfavorable outcomes were determined by bootstrapping 500 samples. Red squares denote experimental subgroups that were non-inferior to the control subgroups, and blue squares denote subgroups that did not show non-inferiority. Study participants in the validation dataset were HIV-uninfected adults with non-cavitary disease and month 2 culture-negative status.

Fig. 4. Analysis of 7/7 and 6/7 dosing strategies and impact of adherence in the control group.

a, Kaplan–Meier estimates for fully adherent study participants (n = 996) after treatment with 7/7 or 6/7 dosing strategies. b, Multivariate analysis with total number of doses taken for study participants who took at least 4 months of treatment under 7/7 dosing strategies for 26 weeks (REMoxTB and RIFAQUIN trials), after adjustment for country and treatment duration. c, Multivariate analysis with total number of doses taken for study participants who took at least 4 months of treatment under 6/7 dosing strategies for 24 weeks (OFLOTUB trial), after adjustment for country and treatment duration. Effect sizes for country are available in Supplementary Table 7. In b and c, the HRs with 95% Wald CI are reported. ^aHazard ratio with 95% Wald CI for 6/7 dosing strategy relative to 7/7 dosing strategy for fully adherent population after adjustment for country and treatment duration. ^bTreatment duration <182 days, 21/110 (19%) unfavorable outcomes and treatment duration ≥182 days, 40/577 (7%) unfavorable outcomes. ^cTreatment duration <169 days, 21/155 (14%) unfavorable outcomes and treatment duration ≥169 days, 42/443 (9%) unfavorable outcomes.