MOLECULAR GENETIC ANALYSIS OF HUMAN IMMUNODEFICIENCY VIRUS ANTIRETROVIRAL THERAPY RESPONSE IN SOUTH AFRICA - A PHARMACOGENETICS STUDY

The results of pharmacotherapy can vary both within and between different populations and ethnic groups. Although numerous factors are believed responsible for observed discrepancies in drug response, genetic differences, most often in the form of single nucleotide polymorphisms (SNPs), between individuals and ethnic groups are an important and at times predominant factor. The response to antiretroviral (ARV) drugs for the treatment of human immunodeficiency virus (HIV)-infection is not dissimilar. Marked variations in both ARV efficacy and occurrence of adverse drug reactions (ADRs) have been observed on both an individual and ethnic group level, which are largely attributed to polymorphisms within genes involved in the metabolism and transport of these compounds – such genes include the CYP2B6 and CYP3A4 genes, both members of the cytochrome P450 (CYP) gene superfamily, and the multidrug-resistance 1 (MDR1) gene encoding an efflux transporter protein, phosphoglycoprotein (PGP). An improved understanding of the genetic influences on ARV drug response could lead to improved therapies with fewer side-effects and minimised drug resistance. The main aim of this study was thus to investigate the genetic basis of observed differences in ARV therapy (ART) response in South African ethnic groups. Deoxyribonucleic acid (DNA) samples were collected from 206 HIV-positive individuals of Mixed-Ancestry and Xhosa ethnicity that were currently or prospectively receiving ART. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was employed to screen the A-392G SNP in CYP3A4, the G516T and A785G SNPs in CYP2B6, and the T-129C, C1236T, G2677T/A and C3435T SNPs in MDR1. Hardy-Weinberg equilibrium (HWE) and haplotype analyses were subsequently performed on the resultant SNP genotype and allele frequencies. The possible effects of ethnicity on ART response were examined by means of univariate two-way analysis of variables (ANOVA) testing. Univariate one-way ANOVA testing of the change in cluster of differentiation 4 (CD4)-cell count after six months of ART was used to analyse the possible effects of the seven polymorphisms on immune recovery. All seven SNPs were found to be in HWE in both the Mixed-Ancestry and Xhosa ethnic groups. An extremely high level of linkage disequilibrium (LD) between the 516 and 785 loci in CYP2B6 was detected in both the Mixed-Ancestry (r = 0.97; logarithm of the odds (LOD) score = 24.84) and Xhosa (r = 0.98; LOD score = 41.31) ethnic groups. LD was also detected between the 1236, 2677 and 3435 loci in MDR1 in the Mixed-Ancestry population, although none was found between any of the examined MDR1 SNPs in the Xhosa population. Univariate two-way ANOVA testing found no apparent effect of ethnicity on immune recovery in response to ART. Univariate one-way ANOVA testing detected a discernible effect of genotype on immune recovery in the cases of the T-129C (p = 0.03) and G2677A (p < 0.01) polymorphisms in the MDR1 gene. Therefore, this study identified no effect of ethnicity on ART response but did detect an association between the T-129C and G2677A SNPs in MDR1 and the level of immune response to ART. These findings suggest that MDR1 polymorphisms can be predictive of immune recovery after initiation of ART. This study thus represents an important step towards improved ART drug regimens in South African populations.