Abstract
TB precision treatment, including optimised drug exposure in relation to drug susceptibility testing, may help end TB http://ow.ly/Utu2u
To the Editor:
We read with interest the recent Perspective paper by Lönnroth et al. [1] describing a framework for tuberculosis (TB) elimination. In our opinion, monitoring drug exposure by measuring blood concentrations over time (therapeutic drug monitoring (TDM)) may be helpful in contributing to TB elimination in low- and medium-burden setting.
Treatment with the four first-line drugs (isoniazid, rifampicin, pyrazinamide and ethambutol), though usually successful, is increasingly challenged by the emergence of drug resistance, toxicity, relapse and nonresponse.
For a drug to be effective, both its action at the site of the disease process (pharmacodynamics) and the drug concentration over time (pharmacokinetics) are equally important. For most TB drugs, the area under the curve (AUC) is the most important pharmacokinetics parameter [2]. Drug exposure may be influenced by several different factors, such as concomitant food intake, comorbidities, co-medication and intra-individual differences in pharmacokinetics. Patients prone to low drug exposures are those with malabsorption and gastro-intestinal disorders, patients who have drug–drug interactions, and patients with diabetes mellitus or HIV co-infection. More importantly, pharmacokinetic variability is the driver of drug resistance [2]. In these individuals, there is a rationale for TDM.
It is not only the above-mentioned external factors that are important; the first-line TB drugs themselves are also problematic. The variability of rifampin plasma drug concentrations over time are influenced by its auto-inducing capacity, lowering rifampin exposure by 40% after 40 days when the induction is maximised [3]. The variability of isoniazid exposure is further influenced by N-acetyltransferase 2 (NAT2), which metabolises it to non-hepatotoxic metabolites. Generally, slow acetylators exhibit higher isoniazid plasma concentrations than rapid acetylators [4]. In a randomised clinical trial, isoniazid dosing adjusted for the NAT2 genotype resulted in reduced toxicity and decreased treatment failure [5]. Clearance of isoniazid, rifampin and pyrazinamide is a metabolic process handled by liver enzymes. Altered or impaired hepatic function further complicates dosing of these drugs. As it is rather difficult to quantify the metabolising function of the liver, TDM is the only way to ascertain adequate dosing. Three of the first-line TB drugs (isoniazid, rifampin and pyrazinamide) are potentially hepatotoxic [6] and more so if plasma concentrations increase [7]. TDM may therefore also prevent toxicity if performed timely.
Poor treatment outcome has been associated with low TB drug exposure, with an almost nine-fold increase in treatment failure in patients with low drug exposure [8]. In order to achieve a favourable outcome, the AUC of pyrazinamide should be >363, rifampin should be >13 and isoniazid should be >52 mg·h·L−1. Low maximum concentration to minimum inhibitory concentration ratios preceded acquired drug resistance [8]. Clearly, these data call for TDM.
For TB treatment, the time has come to move away from a one-size-fits-all approach; we need individualised approaches with considerably more precision. In figure 1, a strategy to use TDM on top of regular care is shown. We realise that this statement is more of a hypothesis or viewpoint than a scientifically proven fact. Indeed, scientific evidence is limited at this point in time. A randomised clinical trial should therefore explore the potential benefit of TDM in TB treatment. Standard treatment should be compared with TDM-guided dosing in combination with minimum inhibitory concentration testing. The study should be powered to detect both clinically and epidemiologically meaningful differences in relapse rate, acquired drug resistance or toxicity. TDM implementation in TB treatment need not necessarily increase cost. Even in high TB-burdened, resource-poor countries, TDM may prove cost-effective. Local healthcare workers could be taught to take patient samples. Dried blood spot sampling has considerable logistic and financial advantages, involving easier sampling, storage and transportation, making TDM an attainable goal in remote, poorly resourced areas [9].
Once proven cost-effective, it seems logical to team up with the Global Laboratory Initiative (GLI) of the World Health Organization (WHO), whose aim is to strengthen and expand TB laboratory capacity [10].
For several TB drugs, physicians have used TDM in TB treatment if toxicity was suspected or if patients responded unfavourably. Indeed, TDM is “ready for prime time”. Instead of working in the dark, with a gunshot approach, clinicians should switch on the light provided by TDM and support their clinical decisions with current technologies to hit their target with much more precision.
Footnotes
Conflict of interest: None declared.
- Received July 20, 2015.
- Accepted August 29, 2015.
- Copyright ©ERS 2016