Influence of SULT1A1*2 Polymorphism on Plasma Efavirenz Concentration in Thai HIV-1 Patients

Abstract

Plasma efavirenz (EFV) concentrations within therapeutic levels are essential to successfully treat patients suffering from human immunodeficiency virus (HIV) type 1. In addition to the drug-metabolizing enzyme CYP2B6, other phase II drug-metabolizing enzymes and transporters may have an important role in the pharmacokinetics of EFV. Thus, the influence of phase II drug-metabolizing enzymes and drug transporters on plasma EFV levels was investigated in Thai HIV patients receiving EFV. Patients and Methods: Genotyping was performed by TaqMan ® real-time PCR in 149 HIV-infected Thai adults, and plasma efavirenz concentration was measured by a validated high-performance liquid chromatography in 12 hours after dosing steady-state plasma samples at week 12 and 24. Results: Patients with three or more copies of SULT1A1 had significantly lower median plasma EFV concentrations than those carrying two copies at week 12 (p=0.046) and SULT1A1*2 (c.638G>A) carriers had significantly lower median plasma EFV concentrations compared to those not carrying the variant at week 24 (p=0.048). However, no significant association was found after adjusting for CYP2B6 genotype. Conclusion: Genetic variation in a combination of SULT1A1*2 and SULT1A1 copy number may contribute to variability in EFV metabolism and thereby may impact drug response. The influence of a combination between the SULT1A1 and CYP2B6 genotype on EFV pharmacokinetics should be further investigated in a larger study population.

Effects of rifampicin, CYP2B6 and ABCB1 polymorphisms on efavirenz plasma concentration in Chinese patients living with HIV and tuberculosis

“…WHO recommended efavirenz 400 mg might be administered during treatment of HIV-associated TB in Guidelines, 13 based on a pharmacokinetic study of 22 people with HIV but TB, which also indicated efavirenz exposure decreased when co-administered with rifampicin and further decreased along with time. 62 In consideration of reduction of efavirenz exposure by rifampicin, long cause of anti-TB therapy, and a high proportion of patients with a subtherapeutic concentration in HIV/TB co-infection patients, 63 especially in Southeast Asia (17.3% in current study, 8.3–10.4% in Thai), 43,64 co-administration with efavirenz 400 mg and rifampicin in HIV/TB patients might result in a higher proportion of patients with subtherapeutic concentration, thus an increased proportion of patients at risk of viral resistance or treatment failure. In contrast, however, the enzyme-inducing effect of rifampicin might be beneficial to patients at risk of adverse effects because of high efavirenz concentrations associated with low body weight or low metabolizer.…”

“…The efavirenz C 0 was consistent with the STRIDE study consisting of multiple ethnicities around the world, 10 slightly higher than 1.70 μg/ mL reported in Malay 41 and 1.58 μg/mL in Papua New Guinea population, 42 but lower than 2.32 μg/mL in Thai. 43 The gene polymorphism and different populations seemed to be the main reason. 19 As several previous studies reported, CYP2B6 genotypes (especially 516G>T and 785A>G) were significant predictors of efavirenz exposure, and highly polymorphic in different populations.…”

“…The efavirenz C 0 was consistent with the STRIDE study consisting of multiple ethnicities around the world, 10 slightly higher than 1.70 μg/mL reported in Malay 41 and 1.58 μg/mL in Papua New Guinea population, 42 but lower than 2.32 μg/mL in Thai. 43 The gene polymorphism and different populations seemed to be the main reason. 19…”

A comprehensive Thai pharmacogenomics database (TPGxD‐1): Phenotype prediction and variants identification in 942 whole‐genome sequencing data

“…The SULT1A1 diplotype definition was not reported in CPIC and PharmVar. However, previous studies reported that *2 was found to be associated with lower enzyme activity 12 , 44 …”

Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV

“…Sulfotransferase family 1A member 1 (SULT1A1) promotes HIV-1 infection of primary human monocyte-derived macrophages by regulating retroviral reverse transcription (Swann et al, 2016). Furthermore, increased copy counts of SULT1A1 may also be associated with reduced plasma concentrations of efavirenz, which is a common component of HAART (Chamnanphon et al, 2021). Translational regulatory lncRNA 1 (TRERNA1) is a long non-coding RNA that is associated with increasing diffuse large B cell lymphoma proliferation when N 6 -methyladenosine methylation levels are decreased in the transcript (Song et al, 2022).…”