Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana

Abstract

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics are dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p=0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after one month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

Association of CYP2B6 Genetic Variation with Efavirenz and Nevirapine Drug Resistance in HIV-1 Patients from Botswana

“…Genotype and allele frequencies for the four CYP2B6 SNPs analysed in this study were in line with literature, including most if not all studies from Botswana ( Table 6). The only discrepancy was represented by a study 41 conducted in the same area as the present research that indicated an allele frequency for CYP2B6 785G of 6%, well outside the accepted range of 35.2-52.8% for Southern Africa (Table 6). Finally, the two groups (with and without EFV/NVP-resistant HIV infections) into which we subdivided our study population appeared to be in panmixia, therefore offering an ideal situation for the comparison.…”

“…CYP2B6 genotype and haplotype information was translated into a measure of phenotype using the metabolic score (MS) system, 49 already adopted as "activity score" for CYP2A6, 50 CYP2C19, 51 CYP2D6, 52 and also consistent with Vujkovic et al, 41 for CYP2B6. The MS translates composite genotype and/or haplotype information into a qualitative measure of phenotype.…”

“…Study results concerning the association of CYP2B6 slow metabolizer profiles (defined by the presence of 516T and/or 983C alleles) and EFV and NVP-related adverse events and/or toxicity are also conflicting, with some showing an association 15 , 36–39 and others not. 18–20 , 30 , 31 , 40 , 41 Notably, due to the complexity of the CYP2B6 polymorphisms and the highest frequency of slow/intermediate genotypes among individuals of African ancestry, it is likely that haplotypes rather than a single polymorphism are better predictors of EFV/NVP plasma concentrations, 14 as well as of toxicity, in which polymorphisms in genes other than the CYP450 system may also play a role. 42 , 43 …”

“…Study results concerning the association of CYP2B6 slow metabolizer profiles (defined by the presence of 516T and/or 983C alleles) and EFV and NVP-related adverse events and/ or toxicity are also conflicting, with some showing an association 15,[36][37][38][39] and others not. [18][19][20]30,31,40,41 Notably, due to the complexity of the CYP2B6 polymorphisms and the highest frequency of slow/intermediate genotypes among individuals of African ancestry, it is likely that haplotypes rather than a single polymorphism are better predictors of EFV/NVP plasma concentrations, 14 as well as of toxicity, in which polymorphisms in genes other than the CYP450 system may also play a role. 42,43 Efavirenz and NVP have a long half-life (estimated at 40-115 and 25-164hrs, respectively), a low genetic barrier for HIV drug resistance, and complex pharmacogenetics, which raises the possibility of sub-therapeutic drug concentration in plasma, especially among CYP2B6 fast metabolizers, an aspect that has not been fully studied.…”

Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial

“…Although two-way messaging has been shown to be effective in treatment-naive individuals, treatment-experienced individuals pose a potentially greater challenge. Although treatment failure can be due to drug stockouts, 12 drug-drug interactions, 13 drug metabolism, 14,15 and pre-existing viral resistance, 16,17 populations with repeated treatment failures are likely to have a high number of individuals with repeated non-adherence. 18 Therefore, we aimed to find out if an intervention consisting of a two-way messaging system, with offers of local adherence support for individuals who requested help or who were not engaged with the system, would result in better HIV treatment outcomes than standard- of-care adherence support.…”