Impact of pharmacogenetic markers of CYP2B6 and clinical factors on plasma efavirenz level in HIV/tuberculosis co‐infected Thai patients

Abstract

Purpose of studyPolymorphisms of CYP2B6 are associated with altered activity of cytochrome P450 2B6 which has an effect on plasma efavirenz level. The data of these polymorphisms and their effect, particularly in HIV/TB co‐infected patients, is still limited.MethodsA total of 150 HIV‐infected Thai adults with active tuberculosis (TB) and receiving rifampicin‐containing anti‐TB regimen were prospectively enrolled to receive a once‐daily regimen of efavirenz 600 mg/tenofovir/lamivudine. Nine single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped using real‐time PCR‐based allelic discrimination. At 12 weeks after ART, plasma efavirenz levels at 12 hours after dosing were measured by HPLC assay.Summary of resultsOf all, the median (IQR) CD4 count was 44 (17–113) cells/mm3 and median (IQR) plasma HIV‐1 RNA was 5.8 (5.4–6.3) log copies/mL. Eight (5.3%) patients discontinued efavirenz due to adverse events prior to measuring efavirenz level. Of 142 patients, the frequencies of wild type, heterozygous mutant, and homozygous mutant of each SNP were 64C>T (89%, 10%, 1%), 499C>G (99%, 1%, 0%), 516G>T (45%, 47%, 8%), 785A>G (36%, 54%, 10%), 1375A>G (100%, 0%, 0%), 1459C>T (97%, 3%, 0%), 3003C>T (29%, 44%, 27%), 18492T>C (55, 39%, 6%), and 21563C>T (38%, 57%, 5%). Median (IQR) plasma efavirenz level of 102 patients who were concurrently receiving efavirenz and rifampicin was 2.08 (1.33–3.51) mg/dL and those of 40 patients who did not received rifampicin was 2.72 (1.80–5.21) mg/dL. Of 102 patients, heterozygous/homozygous mutant vs. wild type of 5 SNPs associated with high mean efavirenz level were 516G>T (3.6 vs. 1.9 mg/dL, P<0.001), 785A>G (3.2 vs. 2.0 mg/dL, P=0.001), 3003C>T (4.0 vs. 2.4 mg/dL, P=0.012), 18492T>C (3.5 vs. 2.0, P<0.001), 21563C;>T (3.4 vs. 1.9 mg/dL, P<0.001). Three of 9 haplotypes identified, including *6/*6, *1/*6, and *4/*6, were associated with high efavirenz level. By multivariate analysis, factors associated with high efavirenz level included specific haplotype (P<0.001), low body weight (P=0.003), and receiving rifampicin (P=0.058).ConclusionsParticular SNPs and haplotype of CYP2B6, especially *6/*6, has the greatest impact on efavirenz level in HIV/TB co‐infected Thai patients whereas low body weight and concurrent receiving rifampicin have lesser effects.