Pharmacogenetics and Clinical Biomarkers for Subtherapeutic Plasma Efavirenz Concentration in HIV-1 Infected Thai Adults

Abstract

The aim of this study was to assess the influence of host genetic variations and clinical factors in relation to efavirenz level in HIV-1 infected Thai adults. A total of 100 HIV-infected subjects treated with efavirenz/lamivudine/tenofivir were prospectively enrolled. The panel of CYP2A6, CYP2B6 and CYP3A4/5 polymorphisms was genotyped. At steady state, plasma efavirenz concentrations were measured using high performance liquid chromatography. The relationship between host genetic and clinical factors in terms of efavirenz pharmacokinetics in HIV-1 infected Thai adults was analyzed. The minor allele frequency for CYP2A6 -48T>G, CYP2B6 g.18492T>C, CYP3A4*1B c.-392A>G, CYP3A4*18 c.878T>C and CYP3A5*3 c.6986A>G was 0.14, 0.27, 0.01, 0.03 and 0.38, respectively. Univariant and multivariant analysis indicated associations for CYP2B6 g.18492T>C (p < 0.001 and p = 0.001), aspartate aminotransferase (AST; p = 0.001 and p = 0.006) and blood urea nitrogen (BUN; p = 0.011 and p = 0.016) with plasma efavirenz concentration. However, CYP2A6 -48T>G, CYP3A4*1B c.-392A>G, CYP3A4*18 c.878T>C and CYP3A5*3 c.6986A>G had no significant impact on plasma efavirenz concentration in HIV-1 infected Thai adults. The CYP2B6 g.18492T>C polymorphism, AST and BUN were significantly associated with low efavirenz concentrations. The results from this study can be used to improve the prediction of efavirenz plasma concentration and to optimize its dose in antiretroviral therapy.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz‐Containing Antiretroviral Therapy

“…Another CYP2B6 SNP, rs2279345 (g.18492T>C), has been associated with slightly decreased plasma efavirenz concentrations . This SNP is not part of any defined (*) alleles.…”

“…Another CYP2B6 SNP, rs2279345 (g.18492T>C), has been associated with slightly decreased plasma efavirenz concentrations. [5][6][7][8][9] This SNP is not part of any defined (*) alleles. The presence of this SNP together with coadministration of a strong CYP inducer may increase the likelihood of subtherapeutic plasma efavirenz concentrations.…”

A Pharmacist’s Role in the Individualization of Treatment of HIV Patients

“…The most relevant polymorphisms CYP3A4*1B (-392 A>G), CYP3A5*3 (6986 A>G) and CYP3A5*6 (14690 G>A) and their relationships with the PKs of efavirenz (EFV), nelfinavir (NFV), IDV, SQV and lopinavir/RTV have been evaluated in various studies. Studies to date have not yet demonstrated a significant effect of these polymorphisms on the PKs of EFV or NFV [71,72]. However, an association between CYP3A5*3 and a decrease in the urinary excretion of SQV has been found but additional studies are needed to confirm this effect [73].…”

PharmGKB summary

“…As compared to CYP2B6, CYP2A6 is a minor player in EFV metabolism and associations between CYP2A6 polymorphisms and EFV PK parameters may be dependent on a patient’s underlying CYP2B6 genotype. For example, in Thai patients with the CYP2B6 * 1/ * 1 genotype (excluding patients with variant alleles at positions CYP2B6 rs8192709, rs3826711, rs3745274, rs2279343, rs3211369, rs3211371, rs8192719), CYP2A6 rs28399433 genotypes were not significantly associated with EFV plasma concentrations [12]. This was confirmed in a separate genomewide association study (GWAS) in 856 individuals that found no association between rs28399433 and estimated plasma trough concentrations of EFV [39].…”

“…In patients with the CYP2B6 * 1/ * 1 genotype (excluding patients with variant alleles at positions CYP2B6 rs8192709, rs3826711, rs3745274, rs2279343, rs3211369, rs3211371, rs8192719), rs776746 ( CYP3A5 ), rs28371759 ( CYP3A4 ) or rs2740574 (CYP3A4 ) genotypes were not found to be significantly associated with EFV plasma concentrations in 100 Thai HIV patients [12]. …”