Impact of efavirenz pharmacokinetics and pharmacogenomics on neuropsychological performance in older HIV-infected patients

Background: Pharmacokinetics (PK) and pharmacodynamics of efavirenz and its 8-hydroxy metabolite (8-OHefavirenz) have not been robustly evaluated in older HIV-infected persons. Objectives: We investigated relationships between neuropsychological (NP) performance and efavirenz and 8-OH-efavirenz PK in HIV-infected individuals > 50 years of age. Methods: A cross-sectional study of HIV-infected adults on an efavirenz-containing regimen. The 12 and 18 h post-dose plasma efavirenz and 8-OH-efavirenz were quantified. CYP2B6 polymorphisms were investigated. Participants underwent neuropsychological tests; surveys were used for depression, sleep quality and anxiety. We investigated potential correlations of efavirenz and 8-OH-efavirenz plasma concentrations with NP performance, sleep, depression, anxiety and CYP2B6 polymorphisms. Results: Thirty participants (24 men and 6 women) with mean age 57 years (range 50-68). Plasma efavirenz concentrations did not correlate with NP performance; however, higher plasma 8-OH-efavirenz correlated with better learning (P=0.002), language (P=0.002) and total NP z-scores (P=0.003). No correlation was seen for efavirenz or 8-OH-efavirenz with sleep, anxiety or depression. Median 12 and 18 h efavirenz plasma concentrations were 1967 ng/mL (IQR 1476-2394) and 1676 ng/mL (IQR 1120-2062), respectively. Median 12 and 18 h 8-OH-efavirenz plasma concentrations were 378 ng/mL (IQR 223-589) and 384 ng/mL (IQR 216-621), respectively. CYP2B6 G516T was associated with significantly higher plasma efavirenz at 12 and 18 h (P=0.02) but not worse NP function. Conclusions: Better neurocognitive functioning was associated with higher 8-OH-efavirenz but not efavirenz plasma concentrations. No correlation was observed with sleep or depression. These findings point to a need for greater understanding of the metabolic profile of efavirenz and 8-OH-efavirenz in plasma and the CNS and relationships with antiviral effect and neurotoxicity.