Direct antiviral agents in hepatitis C virus related liver disease: Don't count the chickens before they're hatched

Since molecules with direct-acting antiviral (DAA) became available, the landscape of the treatment of hepatitis C virus (HCV) infection has completely changed. The new drugs are extremely effective in eradicating infection, and treatment is very well tolerated with a duration of 8-12 wk. This review aims to report the outstanding clinical benefits of DAA and to highlight their critical disadvantages, identifying some clinically relevant hot topics. First, do the rates of virological response remain as high when patients with more advanced cirrhosis are considered? Large studies have shown slightly lower but still satisfactory rates of response in these patients. Nevertheless, modified schedules with an extended treatment duration and use of ribavirin may be necessary. Second, does the treatment of HCV infection affect the risk of occurrence and recurrence of liver cancer? Incidence is reduced after viral eradication but remains high enough to warrant periodic surveillance for an early diagnosis. In contrast, the risk of recurrence seems to be unaffected by viral clearance; however, DAA treatment improves survival because of the reduced risk of progression of liver disease. Third, can HCV treatment also have favorable effects on major comorbidities? HCV eradication is associated with a reduced incidence of diabetes, an improvement in glycemic control and a decreased risk of cardiovascular events; nevertheless, a risk of hypoglycemia during DAA treatment has been reported. Finally, is it safe to treat patients with HCV/ hepatitis B virus (HBV) coinfection? In this setting, HCV is usually the main driver of viral activity, while HBV replication is suppressed. Because various studies have described HBV reactivation after HCV clearance, a baseline evaluation for HBV coinfection and a specific follow-up is mandatory.