UCSF

Though efavirenz is an effective antiretroviral therapy for the treatment of HIV, its use is associated with pronounced interindividual variability in plasma concentration (exposure) and toxicity, increasing the risk of adverse events or therapy failure. Both genetic and non-genetic factors contribute to efavirenz exposure variability. This dissertation research contributes to our understanding of this phenomenon by modeling the influence of genetic and non-genetic factors on efavirenz exposure and describing a broad spectrum of symptoms and side effects and their association with genotypes that influence efavirenz exposure. A total of 182 SNPs and 45 haplotypes in 9 genes were analyzed with previously identified non-genetic factors in relationship to efavirenz drug exposure in 111 women on efavirenz who had undergone 24-hour blood sampling following a witnessed dose under routine conditions. Area-under-the-time curves (AUC) were calculated. We observed three alleles from two genes associated with an increase in efavirenz exposure: CYP2B6 (rs3745274); CYP2B6 (rs28399499), ABCB1 Haplotype A1 (rs27779562 and rs4148745). Of all the non-genetic factors assessed only orange juice consumption and increases in alanine aminotransferase remained statistically significant when genetic factors were included in the final multivariate model. CYP2B6 rs3745274 and rs28399499 can be combined into the CYP2B6 Metabolizer diplotype. Metabolizer diplotype was associated with an increase in efavirenz exposure for both slow and intermediate metabolizers. Risk alleles associated with increased efavirenz exposure were evaluated for associations with a broad spectrum of symptoms and side effects. Variation in CYP2B6 rs28399499 was associated with a perceived change in the amount of fat in the buttocks and change in buttock fat. Variability in CYP2B6 rs3745274 was associated with report of dietary changes to influence body shape. SNPs in the ADME pathway are associated not only with efavirenz exposure but also side effects. Pharmacogenetic testing may improve efavirenz outcomes and reduce symptoms and side effects associated with efavirenz exposure variability.

Key Words: ADME pharmacogenetics, adverse events, antiretroviral therapy, ATP-binding cassette (ABC) B1 haplotype, body habitus changes, cytochrome P450 (CYP) 2B6 single nucleotide polymorphisms (SNPs), CYP2B6 metabolizer diplotype, drug exposure, efavirenz, gene variations, HIV, plasma concentration, side effects and symptoms.