Pharmacogenetic Aspects of Anti-Tuberculosis Therapy in Latvian Population

Pharmacogenetics (PGx) plays a crucial role in personalised medicine by revealing how genetic variations influence drug response, guiding initial doses, and working in conjunction with therapeutic drug monitoring (TDM) to adjust dosing according to drug metabolism for each individual. Together, PGx and TDM work synergistically to optimise treatment, as using the patient’s PGx profile and up-to-date patient data on drug levels in the systemic circulation enables precision, effectiveness and safety of treatment, moving away from a one-size-fits-all approach to a more individualised strategy. Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which is transmitted between humans through the respiratory tract, most commonly affecting the lungs. TB is a major global public health challenge and social threat worldwide. With the increasing population mobility and travel, TB strains, including drug-resistant variants, are easily disseminated worldwide. The implementation of personalised medicine strategies may help to ensure the effectiveness of existing treatments, promptly identify those patients most likely to develop adverse drug reactions (ADRs), and reduce the likelihood of acquired drug resistance in Mtb, thus playing an important role in the global fight against TB. This Thesis describes the PGx aspects of TB treatment focusing on the Latvian population. Isoniazid (INH) is a cornerstone of the standard regimen for the treatment of drug-susceptible TB (DS-TB). However, the variability in pharmacokinetic (PK) parameters and drug plasma levels may affect drug response and lead to ADRs including a drug-induced hepatotoxicity (DIH). This Thesis primarily investigates the impact of changes in INH PK parameters due to genetic variability in three genes encoding INH-metabolising enzymes, together with a number of patient-related factors, on the response to anti-TB treatment and the risk of DIH in patients with DS-TB. In particular, the N-acetyltransferase 2 (NAT2) haplotype, referred to as acetylator status, and the genotype of glutathione S-transferase M1 class (GSTM1) were assessed in TB patients. Additionally, a new next-generation sequencing-based method for full-length cytochrome P450 family 2 subfamily E member 1 (CYP2E1) gene analysis was designed and evaluated to determine whether CYP2E1 gene variants are of clinical significance. Aminoglycosides (AGs) are potent, broad-spectrum antibiotics, which remain important drugs in the treatment of multidrug-resistant TB. AG-induced hearing loss (AIHL) is a well-recognised ADR with rapid, profound, and irreversible hearing loss that can occur in predisposed individuals. The MT-RNR1 gene, encoding the mitochondrial ribosomal 12S subunit, is particularly susceptible to gene variants associated with AIHL. In this Thesis, the prevalence of AIHL-related MT-RNR1 gene variants was investigated in the Baltic-speaking ethnic Latvian population in comparison to the general population worldwide in order to improve the accuracy and safety of treatment with AGs. This Thesis is presented as a comprehensive compilation of peer-reviewed publications, summarising advancements in personalised TB medicine. Specifically, it focuses on identifying and characterising the factors that contribute to variations in drug response and safety through comprehensive analysis of the PGx and PK data in TB patients. This approach could provide us with an opportunity to advance therapeutic decision-making. The inclusion of profiling of INH and its two main metabolites in clinical studies, together with PGx screening, could be beneficial in determining optimal dosing strategies, tailoring treatment regimens, and fostering a patient-centred healthcare approach for TB patients, challenging the current paradigm of modern public health.