The Relationship between Nevirapine Plasma Concentrations and Abnormal Liver Function Tests

Abstract

Abnormal liver function tests are frequently observed in HIV-infected individuals receiving nevirapine (NVP). Here we investigate the relationship between total and unbound plasma concentrations of NVP and the liver enzymes alanine aminotransferase (ALT) and γ-glutamyl transferase (γGT). HIV-infected individuals [n = 85, 22 female, 34 hepatitis C or B virus (HCV or HBV⁺)] receiving NVP (200 mg bd; median duration 66 weeks, range 3–189) and two nucleoside reverse transcriptase inhibitors (NRTIs) were enrolled into this study. Blood samples were taken at C_trough (12 hr postdose) for measurement of NVP and liver function tests (ALT and γGT). Plasma protein bound and unbound drug was separated using ultrafiltration and NVP concentrations quantified using HPLC-MS/MS. A linear relationship was observed between total and unbound NVP C_trough (r² = 0.77, p < 0.0001). Patients with elevated ALT (>37 IU/liter; n = 31) had higher NVP unbound C_trough than those with ALT within the normal range (median 2268 vs. 1694 ng/ml, p = 0.04) but there was no difference in total C_trough. Logistic regression revealed no association between higher NVP C_trough and ALT elevations. Significantly higher NVP total and unbound C_trough were observed in patients with increased γGT (>40 IU/liter; n = 63; total 6747 vs. 4530 ng/ml, p = 0.001; unbound 2113 vs. 1557 ng/ml, p = 0.03). Significantly higher unbound NVP C_trough was observed in HCV/HBV⁺ (median 2275 vs. 1726 ng/ml, p = 0.02) and on bivariate analysis, higher NVP C_trough was associated with HCV/HBV coinfection (χ² = 4.228; p = 0.04). Overall we found no strong association between NVP concentrations and hepatotoxicity. Although in this study NVP was well tolerated in HCV/HBV coinfected patients, higher plasma concentrations were observed.