Prognostic value of CYP3A4*1B polymorphism in patients with pulmonary tuberculosis

Abstract

Previously it was found that in slow metabolizers according to CYP3A4*1G genotype after completion of in-patient stage of anti-tuberculosis treatment, the level of cytolysis and toxicity indexes was much higher than in rapid metabolizers. The aim of the present research was to find the meaning of CYP3A4*1В polymorphism in tuberculosis (TB) patients for the level of isoniazid and rifampicin as well as for the outcome and toxicity development during in-patient TB treatment. Materials and methods. The medical records of 105 patients with pulmonary tuberculosis were examined. All these patients had primary pulmonary tuberculosis. They were receiving in-patient treatment at the Odesa Regional Center for Socially Significant Diseases (previously – the Odesa Regional Tuberculosis Dispensary) in 2012–2014. The study was conducted under the Declaration of Helsinki standards. Results. After in-patient treatment, the activity of cytolysis markers as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the cholestasis marker as gamma-glutathione transferase (GGT) in TB-patients with *AA genotype increased insignificantly by 7.0%, 9.3%, and 4.5% (p>0.05); in patients with the *AG genotype, the activity of ALT, AST and GGT, on the contrary, had a tendency for decreasing – by 18.7%, 3.0% and 9.0% (p>0.05); a similar trend was observed concerning the number of patients with increased activity of ALT, AST and GGT. At the end of treatment, the average activity of ALT in carriers of the *AA genotype was 1.8 times higher than in carriers of the *AG genotype (p=0.046; CI=-0.26...22.24). Conclusion. At the beginning of anti-tuberculosis chemotherapy, it is recommended to determine the CYP3A4*1B genotype in patients with pulmonary tuberculosis, which allow identifying the groups of patients with the *AG genotype, which is characterized by a greater risk of developing sub-therapeutic rifampicin concentrations in the blood during treatment and prove the usefulness of personalized choice of rifampicin dosage according to the CYP3A4*1B genotype.

Метою дослідження стало вивчення комплексного впливу поліморфізму локусу CYP3A4*1В на вміст найбільш ефективних протитуберкульозних препаратів, ефективність та токсичність протитуберкульозної терапії. Хворі з генотипом *AG локусу CYP3А4*1В через 2 і 6 год. після введення рифампіцину в 5 і 10 разів частіше мали субтерапевтичну концентрацію рифампіцину відповідно, ніж носії генотипу *АА (р<0.05); після стаціонарного лікування у носіїв генотипу *AG активність АлТ, АсТ і ГГТ дещо знизилась – на 18,7, 3,0 і 9,0% відповідно (р>0.05), водночас у носіїв генотипу *АА недостовірно зросла – на 7,0, 9,3 і 4,5% відповідно (р>0.05). Процес туберкульозного обсіменіння легеневої тканини у носіїв генотипу *AG зберігався втричі частіше, ніж у групі *AA (р<0.05). Таким чином, визначення генотипу CYP3A4*1В у хворих на туберкульоз легень на початку лікування дасть змогу індивідуально підбирати дозу рифампіцину.