R. D’Ambrosio

Direct-acting antivirals: the endgame for hepatitis C?

Directly-acting antivirals (DAA) have finally allowed all patients to be potentially cured from chronic hepatitis C (HCV) infection. All-oral, Interferon (IFN)-free regimens are based upon the combination of molecules targeting different sites of the HCV replication process. Three classes of DAA exist: protease inhibitors (anti-NS3/4A), RNA-dependent polymerase inhibitors (anti-NS5B) and anti-NS5A inhibitors, which are characterized by different antiviral potency and barrier to resistance and therefore are usually combined in different treatment schedules. Treatment regimens are still largely dependent on HCV genotype and stage of liver disease, with duration ranging between 12 weeks and 24 weeks, while overall treatment efficacy has climbed to nearly 95% in most patient groups, including historically difficult-to-treat categories (HCV genotype 1, advanced liver disease). The elimination of IFN has allowed safe and efficacious treatment of patients formerly contraindicated to antiviral therapy, such as decompensated cirrhosis and solid organ transplant recipients. Availability of potent and safe antiviral drugs combined with improvement of worldwide access to treatment could finally lead to HCV elimination in the next decades.

Safety of direct antiviral agents in real life

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%.

Dual therapy with peg-interferon and ribavirin in thalassemia major patients with chronic HCV infection: Is there still an indication?

BACKGROUNDnIron overload and hepatitis C virus (HCV) infection together can lead to chronic liver damage in thalassemia major (TM) patients.nnnAIMSnWe investigated viral, genetic, and disease factors influencing sustained virological response (SVR) after peg-interferon and ribavirin therapy in TM patients with HCV infection.nnnMETHODSnWe analyzed 230 TM patients with HCV infection (mean age 36.0±6.3 years; 59.1% genotype 1; 32.2% genotype 2; 3.4% genotype 3; and 5.3% genotype 4; 28.7% carried CC allele of rs12979860 in IL28B locus; 79.6% had chronic hepatitis and 20.4% cirrhosis; 63.5% naive and 36.5% previously treated with interferon alone) treated in 14 Italian centers.nnnRESULTSnBy multivariate regression analysis SVR was independently associated with CC allele of IL28B SNP (OR 2.98; CI 95% 1.29-6.86; p=0.010) and rapid virologic response (OR 11.82; CI 95% 3.83-36.54; p<0.001) in 136 genotype 1 patients. Combining favorable variables the probability of SVR ranged from 31% to 93%. In genotype 2 patients, only RVR (OR 8.61; CI 95% 2.85-26.01; p<0.001) was associated with SVR higher than 80%. In 3 patients with cirrhosis a decompensation of liver or heart disease were observed. Over 50% of patients increased blood transfusions.nnnCONCLUSIONnDual therapy in TM patients with chronic HCV infection is efficacious in patients with the best virological, genetic and clinical predictors. Patients with cirrhosis have an increased risk of worsening liver or heart disease.

Treating hepatitis C in patients with hemoglobinopathies

Introduction: Patients with hemoglobinopathies and chronic hepatitis C virus (HCV) infection are at high risk of developing severe liver disease. Anti-HCV therapies represent an important tool to modify the survival of these patients, since their life expectancy has significantly increased following the availability of iron chelation therapy. IFN-based regimens represented the standard of care before the recent approval of new direct antiviral agents. In 2009, the combination of pegylated (Peg)-IFN with ribavirin (RBV) replaced IFN monotherapy, leading to an improvement of therapy efficacy. Areas covered: We reviewed the available data published on patients with hemoglobinopathies and HCV chronic infection. Studies are heterogeneous, since patients with hemoglobinopathies underwent different anti-HCV regimens. We analyzed both efficacy and safety data, focusing on anemia, which might be worsened by the use of combined IFN/RBV, requiring modifications in transfusional schedules and iron chelation therapy. Expert opinion: The recent approval of IFN-free regimens has rapidly changed the scenario, since they are associated with overall high rates of sustained virological response and negligible side effects. However, these new drugs are very expensive thus limiting their access. Therefore, IFN and RBV will probably remain an acceptable therapeutic option for many patients, especially in underdeveloped countries.