Department of Medicine, Gastorenterology Division 1, AM and A Migliavacca Center for the Study of Liver Disease, Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy.
Advanced liver fibrosis is a recognized barrier to both access and response to triple therapy with protease inhibitors Boceprevir and Telaprevir, and is associated with an increased risk of severe treatment-related adverse events. While not properly addressed by registration trials enrolling highly selected populations, this nuance of protease inhibitors triple therapy for hepatitis C virus genotype 1 was highlighted by the observational study CUPIC conducted in France. The study enrolled a large number of patients, beyond the safety criteria of registration trials, thereby ending in worrisome safety profiles of protease inhibitors regimens in patients with severe liver impairment who in the past had safely, but unsuccessfully, been exposed to dual therapy with interferon and ribavirin. Indeed, protease inhibitors therapy led to alarming rates of infection and clinical decompensation, particularly in patients with reduced hepatic reserve as predicted by the low platelets and albumin levels. Ultimately antiviral therapy resulted in a death rate of up to 2% and a treatment discontinuation rate of 26%, not to mention the increased need of bone marrow stimulating factors and blood transfusions. The 16-week interim report of the HEP3002 trial expanded the access program to Telaprevir, enrolling patients with advanced fibrosis who fulfilled the safety criteria of registration trials only, and offered an unbiased evaluation of Telaprevir tolerability and safety in this most in-need population, since the rates of treatment discontinuation due to adverse events were up to 14%.