Meta-Analysis of Clinical Studies Supports the Pharmacokinetic Variability Hypothesis for Acquired Drug Resistance and Failure of Antituberculosis Therapy

(See the Editorial Commentary by Egelund and Peloquin, on pages 178–9.) Tuberculosis has ravaged humans since antiquity. Fortunately, the development of short-course chemotherapy regimens comprised of isoniazid, rifampin, and pyrazinamide has led to considerable success in treating tuberculosis [1]. Although program-defined measures such as completion of therapy are said to be about 95% successful, the microbiological success is only 50%–60% in many high-burden countries such as those in Africa [2–5]. In addition, acquired drug resistance (ADR) continues to be a major problem despite the use of the directly observed therapy, short course (DOTS) program [6]. The DOTS program was developed to improve outcomes such as microbiological failure, relapse, and ADR, with a focus on ensuring adherence; it was formally adopted by all countries that were being served by the World Health Organization at the end of the 1990s. We recently examined the effect of adherence in hollow-fiber studies in which degrees of noncompliance were varied from missing 0% of doses to missing 100% of doses [7]. Microbiological failure was only encountered when nonadherence was >60%. Even more surprising was the fact that no ADR emerged with any extent of nonadherence. In addition, common factors such as pharmacokinetic mismatching of isoniazid and rifampin have also been found not to account for ADR [8]. However, pharmacokinetic mismatch seen with intermittent regimens using isoniazid and long half-life rifamycin has yet to be studied. We then used computer-aided clinical trial simulations to examine other reasons for therapy failure and ADR [7]. Pharmacokinetic variability was most commonly responsible for ADR and microbiological failure in the in silico analysis. Nevertheless, this has been properly identified as a Gedanken experiment that allows for generation of a hypothesis but still needs to be confirmed by clinical studies [9]. The first step in isoniazid metabolism is hepatic acetylation by N-acetyl transferase 2 (NAT2) [10]; NAT2 has several alleles associated with rapid and slow acetylation, which are associated with 88% of all variability in isoniazid systemic clearance [11]. It is known that the microbial kill and drug-resistance suppression of isoniazid best correlate with the ratios of both the 24-hour area under the concentration time curve (AUC) and the peak concentration to minimum inhibitory concentration across many animal species and in patients [12–14]. Because AUC is proportional to dose divided by clearance, variability in isoniazid clearance could lead to rapid acetylators with decreased sputum conversion rates, poorer microbiological outcomes, and increased ADR. Nevertheless, it is widely believed that acetylation status does not affect efficacy of isoniazid in modern combination therapy regimens [1, 15]. Here, we tested this pharmacokinetic variability hypothesis for isoniazid alone in a meta-analysis of prospective clinical studies that compared outcomes in patients with different acetylation statuses.