For example, patients with a platelet count <100,000/mm3 were PI3K inhibitor 11-fold more likely to experience a decompensation event and 14-fold more likely to die a liver-related death or undergo liver transplantation, compared with subjects with a baseline platelet count ≥200,000/mm3. Rates of outcomes were also evaluated according to baseline body mass index, ALT activity, and serum HCV RNA. The annualized rate of cirrhosis was 8.9% for nonobese subjects versus 11.3% for obese subjects (P = 0.07); 8.2% for ALT <90 IU/L versus 12.2% for ALT ≥90 IU/L

(P = 0.001); and 11.1% for HCV RNA <6.5 log10 IU/mL versus 9.0% for HCV RNA ≥6.5 log10 IU/mL (P = 0.046). Rate of any clinical outcome was not associated with baseline obesity or with ALT activity (P ≥ 0.30) but was associated with lower HCV RNA level (P < 0.0001). The association of outcomes with HCV Akt inhibitor RNA level was not adjusted for stage of fibrosis,

which was strongly and inversely associated with HCV RNA level (P < 0.0001). Understanding the natural history of advanced hepatitis C has been challenging. Limitations in study design or execution of most, if not all, prior studies could have led to inaccurate results. No prior study had the rigor of the histological evaluation of the HALT-C Trial, in which three liver biopsies were performed and each biopsy was assessed by a team of 11 expert liver histopathologists who were masked to all patient information.11, 12 Additionally, few if any prior studies had uniform monitoring of patients at regular intervals and predefined case definitions, whereas patients in the HALT-C Trial were evaluated every 3-6 months throughout the study, and all outcomes were reviewed independently by experienced hepatologists. Furthermore, all patients in the HALT-C Trial had failed to clear HCV during peginterferon and ribavirin therapy, whereas in several other studies, progression was evaluated in patient cohorts, only subsets of whom were treated, and in whom selection for therapy was not based on uniform criteria. For the HALT-C Trial, our hypothesis was that 3.5 years of maintenance, low-dose (90 μg/week) peginterferon therapy would retard the

progression of chronic hepatitis C in patients with advanced fibrosis; unfortunately, maintenance therapy was found to be ineffective. MCE Because clinical outcome rates were either indistinguishable between treated and control patients or were inconsistently different (higher mortality among treated patients with noncirrhotic fibrosis and lower incidence of HCC among treated patients with cirrhosis), we pooled the two groups for an analysis of the rate of progression of chronic hepatitis C. We followed the combined cohort of >1,000 patients with clinically compensated advanced fibrosis or cirrhosis, both during the randomized (maintenance versus control) phase and the postrandomization phase for up to 8 years (median, 5.6 years).