Pharmacogenetic markers in the treatment of patients with multidrug-resistant tuberculosis

Background. Treatment of patients with tuberculosis (TB) with multidrug-resistant (MDR) causative agent is often complicated by adverse reactions (AR) with forced drug discontinuation, its effectiveness is far from the target indicators and depends on a number of factors, including the patient's genetic characteristics. Pharmacogenetic markers of MDR-TB have not been studied; it is expected that their identification will improve the results of treatment based on a personalized approach.

Objective. to determine the pharmacogenetic markers associated with the efficacy and safety of treatment of patients with MDR TB.

Methods. A prospective cohort study included 40 patients with MDR-TB without HIV infection who received therapy with bedaquiline, linezolid, and a fluoroquinolone in 2023–2024. All patients had 3–5 ml of venous blood collected once, regardless of the duration of therapy. Real-time PCR was used to determine the presence of single-nucleotide polymorphisms in the genes for cytochromes (CYP3A4, CYP3A5), P-glycoprotein (ABCB1), the membranebound ATP-binding cassette transporter (ABCG2), and the organic anion transporter (SLCO1B1), which were selected based on literature analysis and the PharmGKB database. The relationship between these indicators and the effectiveness and safety of treatment was assessed using univariate analysis, with the calculation of the odds ratio (OR) and its 95 % confidence interval (CI).

The results. Target polymorphisms were identified: SLCO1B1 (rs4149056 — in 25.8 %), ABCB1 (rs1045642 — in 75.0 %, rs2032582 — 72.2 %, rs1128503 — 77.8 %), ABCG2 (rs2231142 — in 24.3 %), CYP3A4 (rs2740574 — in 8.1 %), CYP3A5 (rs776746 — in 10.8 %). The treatment efficacy based on the criterion of cessation of bacteriosis was 89.3 % (95 % CI 72.0–97.1 %); the incidence of adverse events was 70 % (95 % CI 54.5–82.0 %), with neurotoxic reactions prevailing (in 11 of 40 patients, 27.5 %). The AA genotypes of the CYP3A5 rs776746 gene and the AA genotypes of the ABCG2 rs2231142 gene were associated with a minimum frequency of cessation of bacterial shedding: respectively, in 33 % and 0% of individuals with each variant, compared to 100% in the rest, p < 0.01; OR 0.021 (95 % CI 0.001–0.77) and 0.083 (95% CI 0.01–0.98). The risk of neurotoxic reactions was higher in the presence of the "wild" variant (genotype GG) of the ABCB1 rs2032582 gene (55.6 % vs. 16.0 % in patients with allelic polymorphisms, p = 0.034; OR 6.3; 95 % CI 1.2–33.3); gastrointestinal reactions — in the presence of the TT genotype of the ABCB1 rs1128503 gene (50.0 % vs. 10.0 %, p = 0.045; OR=9.0; 95 % CI 1.22–66.2 %).

Conclusion. Polymorphisms of CYP3A5 (rs776746, AA genotype) and ABCG2 (rs2231142, AA genotype) genes were revealed, associated with unfavorable results of treatment of patients with MDR-TB. Genetic predictors of neurotoxic and gastrointestinal reactions during treatment of patients with MDR of the pathogen were determined.

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