Risk factors of isoniazid-induced hepatotoxicity in Tunisian tuberculosis patients

Abstract

Previous studies have shown controversial results on whether acetylator status causes isoniazid-induced hepatotoxicity (IIH). Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear. The objectives of this study were (i) to assess the quantitative relationship between the level of isoniazid serum concentration and the incidence of IIH and (ii) to evaluate the extent of implication of the N-acetyltransferase-2 (NAT2) and CYP2E1 polymorphisms genes to induce this disorder. Seventy-one patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction. Three restriction enzymes, RsaI, PstI and DraI were used to detect CYP2E1 RFLP and four different restriction enzymes, KpnI, TaqI, BamHI and Ddel were used to determine NAT2 acetylator status. Therapeutic drug monitoring (TDM) of isoniazid (serum concentration performed 3 h after the morning dose: C3) was performed. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Receiver Operating Characteristics curve analysis was used to evaluate the relationship between risk factors and the incidence of IIH. Eleven (15.4%) patients have developed IIH. Demographic factors, including age, weight and gender were not associated with the incidence of hepatotoxicity. High serum concentration of isoniazid (C3) was found to be a risk factor of IIH (area under the curve: 0.74, P=0.007, 95% confidence interval (95% CI): 0.56-0.93), with a cutoff value at 3.69 mg l (odds ratio (OR): 13.2, P=0.0007, 95% CI: 2.9-59). Multivariate analysis showed that only a C3 over 3.69 mg l remains a risk factor of IIH. NAT2 and CYP2E1 variants were not found to increase the risk of IIH when analyzed separately. However, combined analysis of the NAT2/CYP2E1 gene polymorphisms showed that patients with both DraI C/D and slow acetylator have an increased risk of IIH compared with other combined NAT2/CYP2E1 genotype profiles (OR: 8.41, P=0.01, 95% CI: 1.54-45.76). Our results suggest that a serum concentration of isoniazid over 3.69 mg l and a combined genotype CYP2E1 DraI(C/D)/slow acetylator are major risk factors for IIH. Therefore, TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

“…Meanwhile, slow acetylation genotypes are more likely to lead to ATLI. It has been reported that 52%‐72% of Caucasians have slow acetylating phenotypes, while 34%‐61% of Africans carry slow acetylated phenotypes . In America, the rate of slow acetylation types ranges from 23% to 75%, while Asians only have 9%‐32% of the slow acetylation phenotype .…”

Limited sampling strategy for predicting isoniazid exposure in patients with extrapulmonary tuberculosis

“…Despite the paucity of studies regarding the added value of isoniazid TDM, most of the investigators have proved a large intra‐ and interindividual variability in isoniazid pharmacokinetics in tuberculosis patients . It was shown that some factors such as age, sex, gastrointestinal disorders and drug interactions affect the pharmacokinetics of isoniazid leading to response variation .…”

“…It was shown that some factors such as age, sex, gastrointestinal disorders and drug interactions affect the pharmacokinetics of isoniazid leading to response variation . Thus, a close TDM is required to ensure efficacy and avoid side effects, such as hepatotoxicity and neurotoxicity . Isoniazid pharmacokinetics has not been characterized in either Tunisian or in south Mediterranean patients.…”

“…Moreover, isoniazid has a narrow therapeutic index exposing patients to potential toxicity particularly hepatic and neurological ones. Consequently, the need for a concentration‐controlled dosing based on therapeutic drug monitoring (TDM) of isoniazid would be useful to optimize its efficacy and reduce its adverse effects …”

Predictors of Prolonged TB Treatment in a Dutch Outpatient Setting

“…Moreover, several studies evaluated the relation between drug concentrations, drug metabolizing enzymes and toxicity. Although findings were consistent, showing toxicity at higher concentrations, a randomized controlled trial showing that TDM reduces DILI has not been performed [36–38]. …”