Optimization of the TB Treatment Regimen Cascade

Grade 3-4 Liver Toxicity following NIH common toxicity criteria (CTC), including transaminase increases to \>5-20 ULN (grade 3), or \> 20 ULN (grade 4)

Time frame: until month eight

Population: One participant was allocated to double rifampicin arm but received standard TB treatment, and was analysed in the standard TB treatment arm.Two participants were deleted from analysis because they had grade 3 liver toxicity at baseline and 6 participants were deleted because they did not have any follow-up ALT values.

Following current WHO guidelines, an adverse treatment outcome is defined as any occurrence of the following: * Relapse: Cured previously from TB or completed treatment for TB and now having bacteriologically positive sputum for TB (at 12 months follow-up or at an earlier time point) * Default: The patient whose treatment was interrupted for ≥ 2 consecutive months. * Failure: Sputum positive for TB at 5 months or later during treatment. In line with current WHO recommendations, patients detected with MDR-TB or rifampicin resistance before this or another outcome applies and switched to the MDR-TB regimen will be excluded from the outcome analysis.18 Failure will also be declared if the regimen has to be changed for at least 2 drugs due to adverse events. * Death: All-cause mortality between case registration and end of TB treatment (related or not to TB or TB treatment)

Time frame: 12 months after end of treatment

Population: Intention-to-treat analysis. Additional 4 subjects were removed from the ITT analysis because they switched to MDR regimen (3 in control arm, 1 in intervention arm). 4 subjects (intervention arm) were removed from the ITT analysis because they were enrolled twice.

Area under the ROC curve (AUC) to predict adverse treatment outcome. The X-axis represents the 1-specificity, the Y-axis represents sensitivity. The AUC is estimated with 95% confidence interval.

Time frame: Auramine/FDA at 2 weeks and adverse treatment outcome 1 year after treatment completion

Comparison of fever resolution after 2 weeks of treatment between both treatment arms.

Time frame: after 2 weeks of treatment

Population: Total of participants with fever at baseline.

To assess whether the study regimen also cures high-level rifampicin resistant TB. Adverse treatment outcomes will be described and compared among treatment groups in subgroups defined by initial rifampicin resistance mutations (performed in all patients) detected.

Time frame: 12 months after end of TB treatment

Population: ITT analysis population. Compared to analysis population of primary objective - TB treatment outcome, 24 subjects were excluded from this analysis due to missing or negative sequencing results (8 in control group, 16 in intervention group).

To assess the effectiveness of FDA vital staining versus fever screening for early switch of non-responding rifampicin resistant TB to MDR-TB treatment

Time frame: at two weeks of treatment

Population: 7 initial resistant cases (5 in control group and 2 in intervention group).

number of failure / relapse cases without mutation detected at diagnosis as the denominator and comparing intervention and control arms.

Time frame: 12 months after end of TB treatment

Population: ITT analysis. This analysis only includes failure / relapse cases without mutation detected at diagnosis

The Negative Predictive value (and 95% CI) of conversion in the intervention arm will be estimated as the % of relapses among those with a minimum 1 log decline in the number of AFB, or who are already negative or only scanty positive on AFB smear (auramine or FDA).

Time frame: at 2 weeks of treatment

Population: ITT analysis. This analysis only includes participants in the intervention arm who are negative on auramine smear resp. FDA smear at 2 weeks.

Weight gain from baseline until end-of-treatment comparison between both treatment arms.

Time frame: until end of treatment (month eight)