Exposure to the four first-line anti-tuberculosis drugs and treatment outcomes: a target trial emulation study in...

Tuberculosis (TB) treatment outcomes in sub-Saharan Africa remain suboptimal despite high adherence to first-line therapy. Variability in drug pharmacokinetics, resulting in subtherapeutic plasma concentrations, may contribute to treatment failure and the development of resistance. This study estimated the causal effect of subtherapeutic plasma concentrations of first-line anti-TB drugs on treatment failure or death among individuals with drug-susceptible pulmonary TB in Ghana.

We conducted a prospective cohort study of 164 adults receiving standard WHO weight-band dosing at five Ghanaian hospitals. Peak plasma concentrations (C_max) of rifampicin, isoniazid, pyrazinamide, and ethambutol were measured at months 1-2 using validated LC-MS/MS. We emulated a target trial comparing two static strategies: (1) therapeutic C_max of at least one first-line drug versus (2) subtherapeutic C_max of all four drugs. Using the clone-censor-weight approach, we estimated the per-protocol analogue risk difference (RD) and risk ratio (RR) for treatment failure (smear positive at months 5 or 6) or death by month 6. Models were adjusted for baseline covariates using inverse probability of censoring weighting. Sensitivity analyses included inverse probability weighting with regression adjustment, plain inverse probability weighting, and E-values.

Of 164 participants, 120 had complete pharmacokinetic and outcome data; 20.0% (24/120) had subtherapeutic concentrations of all four drugs. The 6-month risk of treatment failure or death was 33.3% under the low-exposure strategy versus 4.2% under the adequate-exposure strategy (crude RD: 29.1% points). In weighted analyses, low drug exposure was associated with a 23.6%-point increase in absolute risk of treatment failure or death (95% CI: 2.6-44.7; p = 0.028) and a 7-fold higher relative risk (95% CI: 1.83-26.9; p = 0.004), corresponding to approximately one additional poor outcome for every four patients with subtherapeutic levels. Sensitivity analyses were consistent (ATE: 19.9%, 95% CI: 2.3-37.5). The E-value was 15.5 (lower bound 5.0).

Subtherapeutic exposure to all four first-line drugs was associated with increased risk of treatment failure or death among patients who survived into the intensive phase. Preventing multidrug subtherapeutic exposure through therapeutic drug monitoring or optimized dosing warrants randomized evaluation in high-burden settings.

Clinical trial number: not applicable.