Genetic Polymorphisms of N-acetyl Transferase 2 and the Risk of Hepatotoxicity in Patients on Isoniazid Preventive Therapy at Kenyatta National Hospital

Abstract

BACKGROUND Isoniazid preventive therapy (IPT) is an important intervention to prevent activation of latent tuberculosis (TB) infection. Genetic variations associated with N-acetyl transferase (NAT2) are closely associated with isoniazid-induced hepatotoxicity in IPT. This occurs as a result of the patient's unique acetylation phenotype, which can affect clinical outcomes of patients on IPT therapy. OBJECTIVES The main objective was to characterize the distribution of selected single nucleotide polymorphisms (SNPs) of NAT2 in patients on IPT at the Comprehensive Care Centre (CCC) of Kenyatta National Hospital (KNH) and to investigate for a relationship between acetylator status and isoniazid induced hepatotoxicity as indicated by elevated alanine amino transferase (ALT) levels. METHODS This was a cross-sectional study of human immunodeficiency virus (HIV) patients on IPT at KNH CCC. Convenient sampling was employed during routine patient visits at the CCC, following which inclusion and exclusion criteria were applied to recruit patients. Data was extracted from patient records using a data collection form. Blood samples were taken from patients. The QIAamp ® DNA Mini-Kit was used at the University of Nairobi's Institute of Tropical Infectious Diseases (UNITID) for DNA extraction and purification of genomic DNA, followed by DNA sequencing. Data analysis included both descriptive and inferential statistical methods which were used to summarize the data, this was done in SPSS version 25. RESULTS Output data were summarized as follows: Mean, BMI (basal metabolic index) and age were 25.75 kg/m2 and 46.7 years, respectively. As a proxy indicator for hepatotoxicity, the cut-off for ALT levels was 40 UI/L (units per liter). The median ALT level was 22 UI/L and the mean CD4 level was 492 cells/mm3. The prevalence of the homozygous NAT2 genotype was 19% and that of the heterozygous genotype was 50%. The proportion of the population with slow acetylator alleles was 56% and the proportion of fast acetylator alleles was 44%. Fisher's exact test showed no significant association between ALT levels and NAT2 genotype (P = 0.330). Similarly, NAT2 genotype and ethnolinguistic group (P = 1.0), alcohol consumption (P = 0.577), smoking status (P = 0.751), comorbidities (P = 0.127), and gender (P = 0.346). NAT2*5 and NAT2*6 alleles were more frequent in this population compared to NAT2*7 and NAT2*14. On multivariate regression analysis, the independent predictors. Smoking status, alcohol status, comorbidities, and gender were not significant in predicting elevated ALT levels (P > 0.05). CONCLUSION The study found no significant association between NAT2 genotypes and ALT levels (P = 0.33). However it found that there was a high frequency of NAT2*5 and NAT2*6 alleles compared to NAT2*7 and NAT2*14 alleles among the 41 genotyped sequences in this study population. In addition, the study also found that, there was no significant differences in the distribution of NAT2 genotypes and the Ethno-linguistic groups (P = 1.00). Similarly, there was no association between ALT levels and factors such as age, BMI, smoking status, alcohol status, gender and comorbidities. More studies on the effect of NAT2 genotypes on Anti-tuberculosis drug induced hepatoxicity in the Kenyan population with a larger sample size is recommended