Association of Genetic Variation with Efavirenz and Nevirapine Drug Resistance in HIV-1 Patients from Botswana.

PURPOSE

CYP2B6 liver enzyme metabolizes the two non-nucleoside reverse transcriptase inhibitors Efavirenz (EFV) and Nevirapine (NVP) used in the antiretroviral therapy (ART) regimens for HIV-infected individuals. Polymorphisms of the gene influence drug levels in plasma and possibly virological outcomes. The aim of this study was to explore the potential impact of genotype and haplotype variation on the risk of developing EFV/NVP drug resistance mutations (DRMs) in HIV-1 patients receiving EFV-/NVP-containing regimens in Botswana.

PATIENTS AND METHODS

Participants were a sub-sample of a larger study (Tshepo study) conducted in Gaborone, Botswana, among HIV-infected individuals taking EFV/NVP containing ART. Study samples were retrieved and assigned to cases (with DRMs) and controls (without DRMs). Four single-nucleotide polymorphisms (SNPs) in the gene (-82T>C; 516G>T; 785A>G; 983T>C) were genotyped, the haplotypes reconstructed, and the metabolic score assigned. The possible association between drug resistance and several independent factors (baseline characteristics and genotypes) was assessed by Binary Logistic Regression (BLR) analysis. EFV/NVP resistance status and haplotypes were also analyzed using Z-test, chi-square and Fisher's exact test statistics.

RESULTS

Two hundred and twenty-seven samples were analysed (40 with DRMs, 187 without DRMs). BLR analysis showed an association between EFV/NVP resistance and 516G allele (OR: 2.26; 95% CI: 1.27-4.01; =0.005). Moreover, haplotype analysis revealed that the proportion of EFV/NVP-resistant infections was higher among fast than extensive/slow metabolizers (30.8% vs 16.8%; 0.035), with the 516G allele more represented in the haplotypes of fast than extensive/slow metabolizers (100.0% vs 53.8%; <0.001).

CONCLUSION

We demonstrated that the 516G allele, and even more when combined in fast metabolic haplotypes, is associated with the presence of EFV/NVP resistance, strengthening the need to assess the genetic profiles in HIV-infected patients in order to improve the virologic outcomes of NNRTI containing ART.