The Food and Drug Administration and European Medicines Agency approval of first generation directly acting antivirals NS3 protease inhibitors boceprevir and telaprevir opens a new era in the treatment of patients with chronic hepatitis C virus genotype 1 infection. Indeed telaprevir and boceprevir registration trials clearly showed a substantial improvement in rates of sustained virological response both in naive and in treatment-experienced patients, with the possibility of shortened regimens in a consistent subset of patients, through the optimization of treatment algorithms. Phases 2 and 3 studies also provided the basis for the management of side effects in order to maximize the safety profile of directly acting antivirals. However, the entry of triple therapy in current clinical practice comes with some unresolved topics, such as relevance of IL28B genetic testing and other pretreatment predictors in patient selection, use of the 4-week pretreatment lead-in phase with dual therapy, safety of triple therapy in some high-risk patient categories and specific management of directly acting antivirals-induced anaemia. As a consequence of these open issues, clinical practice guidelines on triple therapy released by American and European associations provide slightly different recommendations, effectively leaving these " grey" areas wide open for individual interpretation in everyday clinical practice.
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