Ritonavir Greatly Impairs CYP3A Activity in HIV Infection With Chronic Viral Hepatitis

PURPOSE: Ritonavir is a powerful inhibitor of cytochrome P450 3A (CYP3A) that metabolizes many antiretrovirals. We examined the effect of ritonavir and of chronic viral hepatitis (CVH) status on CYP3A activity. METHODS: Twenty-six HIV-positive men (13 with CVH, 16 on chronic ritonavir-based highly active antiretroviral therapy) received oral and intravenous midazolam, a probe for CYP3A phenotypic activity. RESULTS: CYP3A activity was expressed as oral clearance of the midazolam probe. In HIV-positive subjects not on ritonavir, CYP3A activity (mean +/- SD) did not differ between subjects by CVH (no CVH, controls: 28.5 +/- 9.0 vs. CVH+: 23.2 +/- 6.2 mL/min/kg, not significant). In those on ritonavir (R), CYP3A activity was 7% of controls (R: 2.1 +/- 0.8 vs. no R 28.5 +/- 9.0 mL/min/kg, P < 0.0004). CYP3A activity in subjects on ritonavir and with CVH was further reduced to 4% of controls (no CVH, R+ 2.1 +/- 0.8 vs. R+, CVH+ 1.0 +/- 0.4 mL/min/kg, P < 0.006). CONCLUSIONS: Ritonavir markedly decreases CYP3A activity. In the presence of CVH, ritonavir-based therapy further reduces CYP3A activity by half. Coinfection with CVH impairs CYP3A activity in the presence of the CYP3A inhibitor ritonavir.