Associations between efavirenz concentrations, pharmacogenetics and neurocognitive performance in people living with HIV in Nigeria

Abstract

Objective: Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance. Design: Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected. Methods: Participants ( N = 93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography–tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning. Results: Strong correlation ( r = 0.66, P < 0.001) was observed between plasma and hair EFV concentrations. The median (interquartile range) hair EFV concentration was 6.85 ng/mg (4.56–10.93). CYP2B6 516G>T, ( P < 0.001) and CYP2B6 983T>C ( P = 0.001) were each associated with hair EFV concentrations. Similarly, 516G>T ( P < 0.001) and 983T>C ( P = 0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations ( r = 0.23, P = 0.043) and 983T>C genotype ( r = 0.38, P < 0.0005). Conclusion: This study demonstrated approximately three-fold and two-fold higher EFV plasma and hair concentrations, respectively, among CYP2B6 516TT compared with 516GG. Higher EFV concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.

Nevirapine hair and plasma concentrations and HIV-1 viral suppression among HIV infected ante-partum and post-partum women attended in a mother and child prevention program in Maputo city, Mozambique

“…The CYP2B6 NPSs rates in Mozambique and others countries support the likelihood of influence of CYP2B6 SNPs on NVP/EFV metabolism and HIV-1RNA response among our study population [ 27 , 43 , 52 ]. Nevertheless, this hypothesis needs further investigations.…”

“…A Mozambican study found the frequency of CYP2B6 SNPs (516T/785G of (34.7% and 42.6%) and 516T associated to high NVP toxicity among HIV/AIDS patients [ 48 , 49 ]. Likewise, carriers of CYP2B6 516G>T SNPs under NVP based ART had significantly higher NVP plasma concentration particularly the homozygotes CYP2B6 c.516T/T [ 41 – 44 , 50 ] Additionally, over threefold increase on EFV exposure in hair (long) and plasma (short) was reported among African American women [ 27 , 51 ] Nigerian patients [ 52 ] carrier of CYP2B6 516TT genotype. However, the role of CYP2B6 NPSs on low viral suppression still not clear [ 27 ].…”

Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up

“…Regarding CYP2B6, a higher risk of infection was observed in patients with a CYP2B6 metabolizer gene variant (rs2279343 GA). Although the G variant in rs2279343 has been previously correlated with efavirenz [34], methadone, bupropion, nicotine and others [35], no previous studies reported an association with immunosuppressant drugs. We do not know the reasons that could justify its association with infections.…”

Comparison of efavirenz levels in blood and hair with pharmacy refills as measures of adherence and predictors of viral suppression among people living with HIV in Nigeria

“…For DBS, venous blood was collected from each participant and spotted on to Whatmann 903 protein saver cards (50 µl per spot). The procedure used has been previously reported [ 22 ].…”

“…Analysis of efavirenz concentrations in DBS was carried out at the Liverpool Bio-analytical Facility (BAF), Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool using validated liquid chromatography tandem mass spectrometry (LC–MS/MS)-based methods [ 25 ]. Details of the laboratory methods used in this study have been reported previously [ 22 ].…”