PATIENTS AND METHODS Study design. Fourteen patients selleck inhibitor with CHC with liver fibrosis and active viral infection were included in the Hospital Cl��nic of Barcelona in an uncontrolled open-label study. Inclusion criteria were as follows: 1) age between 35 and 65 yr; 2) chronic elevation of serum aminotransferases for more than 6 mo and positive RNA-HCV; 3) significant liver fibrosis (��F2 in METAVIR score); 4) no previous response and/or contraindications to antiviral therapy. Exclusion criteria were 1) existence of other cause of chronic liver disease; 2) past history of hepatic decompensations or hepatocellular carcinoma; 3) alcohol consumption (>20 g/day); 4) arterial hypertension; 5) serum creatinine >1.5 mg/dl; 6) treatment with AT1 receptor blockers, angiotensin converting enzyme inhibitors, or interferon in the preceding 12 mo; and 7) contraindications to oral losartan.

Patients were treated for 18 mo with oral losartan 50 mg/day (Cozaar, MSD, Wilmington, DE). In all patients, two liver biopsies were performed: the first one within a 24-h period before the initiation of treatment and the second one on the day following the last dose of losartan. Liver biopsies were performed in the right lobe of the liver with a Tru-Cut 14-gauge needle (20 mm length). The protocol was approved by the Ethics Committee of the Hospital Cl��nic of Barcelona and the Agencia Espa?ola del Medicamento as a phase IV trial (ARAHEPC 02-0491), and registered into the protocol registration system (NCT00298714). An untreated control group undergoing paired liver biopsies was not included because of ethical concerns.

All patients gave written, informed consent. Measurements. Patients’ visits were every week the first month, every month the following 5 mo, and every 3 mo thereafter. At these time points, arterial pressure and standard serum liver tests were measured. At baseline and at the end of treatment quantitative HCV-RNA determinations were performed by use of Amplicor HCV-RNA (Roche Diagnostic Systems, Basel, Switzerland). The activity of the systemic RAS was assessed by measuring plasma renin activity (PRA) and serum angiotensin II levels at baseline, day 7, day 30, day 120, day 270, and the end of treatment (1). Treatment compliance was evaluated monthly by pill count and it was defined as an intake of more than 90% of monthly dose. Liver histological analysis.

Liver specimens were divided into two fragments: 2/3 were formalin fixed and paraffin embedded for standard histological GSK-3 analysis and 1/3 was immediately frozen in liquid nitrogen for RNA isolation. Paraffin-embedded samples were stained with hematoxylin-eosin and Masson’s trichrome. The degree of fibrosis and inflammation in liver specimens was blindly evaluated by the same pathologist (M. Bruguera) using the METAVIR scoring system (7).