Scholarlink

Background <p>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.</p> Methods <p>We conducted a prospective cohort study of 164 adults receiving standard WHO weight-band dosing at five Ghanaian hospitals. Peak plasma concentrations (C<sub>max</sub>) 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<sub>max</sub> of at least one first-line drug versus (2) subtherapeutic C<sub>max</sub> 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.</p> Results <p>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; <i>p</i> = 0.028) and a 7-fold higher relative risk (95% CI: 1.83–26.9; <i>p</i> = 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).</p> Conclusions <p>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.</p> Trial registration <p>Clinical trial number: not applicable.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月20日

查看全文
  • Michael Opoku-Mireku,
  • Awewura Kwara,
  • Margaret Y. M. Lartey,
  • Charles A. Peloquin,
  • Divine Aseye Yao Amenuke,
  • Kwasi Adjepong Twum,
  • Priscilla A. Nortey,
  • Alexander Ansah Manu,
  • Kwadwo Ansah Koram

摘要

Background

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.

Methods

We conducted a prospective cohort study of 164 adults receiving standard WHO weight-band dosing at five Ghanaian hospitals. Peak plasma concentrations (Cmax) 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 Cmax of at least one first-line drug versus (2) subtherapeutic Cmax 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.

Results

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).

Conclusions

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.

Trial registration

Clinical trial number: not applicable.