ABSTRACT
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are associated with a favorable increase in high-density lipoprotein cholesterol (HDL-c) level. Isolated studies have found a direct correlation between efavirenz (EFV) exposure and HDL-c level changes. Here we explore the impact that drug disposition variants associated with EFV exposure have on changes in HDL-c level. Seventy-six patients on first-line EFV-based regimens were genotyped for CYP2B6 516G>T and ABCB1 3435C>T. There was a 37% increase (+0.32 mmol/l, P < 0.001) in mean HDL-c level over 48 weeks, and this was univariately associated with gender (male +0.26 mmol/l, female +0.55 mmol/l; P = 0.03), ABCB1 3435C>T (CC +0.26 mmol/l, CT +0.16 mmol/l, TT +0.54 mmol/l; P(ANOVA) = 0.003) and CYP2B6 516 G>T (GG +0.27 mmol/l, GT +0.29 mmol/l, TT +0.72 mmol/l; P(ANOVA) = 0.08). There was a significant association between the cumulative number of predictive genotypes (CYP2B6 516TT or ABCB1 3435TT) and mean HDL-c level change: (group 0 +0.20 mmol/l, group 1 +0.47 mmol/l, group 2 +1.00 mmol/l; P(ANOVA) < 0.0001). These findings need to be validated in independent cohorts.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Anti-HIV Agents/pharmacology , Aryl Hydrocarbon Hydroxylases/genetics , Benzoxazines/pharmacology , Cholesterol, HDL/blood , HIV Infections/blood , HIV Infections/drug therapy , Oxidoreductases, N-Demethylating/genetics , Polymorphism, Single Nucleotide , Reverse Transcriptase Inhibitors/pharmacology , ATP Binding Cassette Transporter, Subfamily B , Adult , Alkynes , Anti-HIV Agents/blood , Anti-HIV Agents/therapeutic use , Benzoxazines/blood , Benzoxazines/therapeutic use , Cyclopropanes , Cytochrome P-450 CYP2B6 , Female , Genotype , HIV Infections/ethnology , Humans , Male , Middle Aged , Multivariate Analysis , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/therapeutic use , Sex Factors , Time FactorsABSTRACT
The use of highly active antiretroviral therapy in the treatment of HIV infection has resulted in significant reductions in mortality and morbidity worldwide. However, there is considerable interindividual variability in patient outcomes in terms of drug disposition, drug efficacy and adverse events. The basis of these differences is multifactorial, but host genetics are believed to play a significant part. To date, most attempts to explain this variability have focused on isolated single nucleotide polymorphisms. The most exciting development to date is the discovery of human leukocyte antigen subtype B*5701 (HLA B*5701) as a strong predictor of the abacavir hypersensitivity reaction. There is a gradual move away from single candidate gene analyses towards a high throughput whole genome approach. These studies must be performed on well characterized cohorts and reported associations must be validated in independent, ethnically diverse populations.
