The relationship between nevirapine plasma concentrations and abnormal liver function tests

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 gamma-glutamyl transferase (gammaGT). 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 gammaGT). 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 (r(2) = 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 Ctrough and ALT elevations. Significantly higher NVP total and unbound C-trough were observed in patients with increased gammaGT ( > 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 (chi(2) = 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.