Hepatitis C virus infection in patients with hemophilia in Korea: Is antiviral therapy effective and safe?

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Hepatitis C virus (HCV) infection is often observed in hemophilic patients who received a blood transfusion of clotting factor concentrates before the mid-1980s, and this increases comorbidity and mortality rates.1 About 80% of HCV-infected patients have chronic HCV infections, and at least 20% develop end-stage liver disease (ESLD).23

In Korea, anti-HCV positivity in 1999 was reported to be 49.1% and 47.9% for hemophilia A and B, respectively; since then, it has steadily decreased to 40.1% and 34.1% in 2005 and 33% and 23.8% in 2012.4 However, among hemophilic patients with anti-HCV positivity, about 31% were positive in HCV RNA testing, and about half remain untreated.5 A cross-sectional study on the prevalence of hepatitis C and the use of antiviral treatment among patients with hemophilia in the Netherlands showed that about 68% of patients remained untreated. The reasons for non-treatment included the fear of unpleasant side effects of antiviral treatment by the patients (46%), normal liver enzyme values (45%), and doctors' beliefs that the treatment was not very effective (35%).6

The response rate of hemophilic patients to interferon (IFN) monotherapy treatment was reported to be low, with a sustained virologic response (SVR) of about 20% (6.5-47.6%); combination therapy of IFN plus ribavirin showed a higher SVR than IFN monotherapy at about 36% (17.7-50.0%).17 Reasons for the low SVR with IFN monotherapy compared to non-hemophilic patients include a long duration of HCV infection, male gender, greater prevalence of HCV genotype 1, and high levels of viremia.7 In many studies, combination therapy of pegylated interferon (PegIFN) plus ribavirin resulted in variable treatment response rates due to differences in ethnicities and comorbidities in the patients enrolled. In those studies, the rate of SVR was generally high, at about 49-63% (33-51% in genotype 1/4, 71-86% in genotype 2/3) and showed no difference compared to non-hemophilic patients.13891011 Also, severe thrombocytopenia and bleeding tendency, side effects to be considered with the treatment, showed no difference in hemophilic patients compared to non-hemophilic patients11; major bleeding has not been reported in hemophilic patients.91012

Recently, Fransen van de Putte et al.13 compared patients with inherited bleeding disorders (including mainly hemophilia) who either did or did not receive antiviral therapy. The rates of developing ESLD were 0.6%, 1%, 16%, and 19% in the spontaneous clearance group, successful treatment group, never-treated group, and unsuccessful treatment group, respectively.3 In addition, when successful HCV treatment was carried out, hepatic fibrosis improved.13 In summary, the treatment effect and frequency of serious side effects, including bleeding, were not different between hemophilic patients and non-hemophilic patients receiving PegIFN plus ribavirin; furthermore, hepatic fibrosis improved, and the rate of developing ESLD was reduced in the treatment group. Accordingly, unless contraindicated, hemophilia patients with HCV infections must be treated with PegIFN and ribavirin.

The effect of HCV treatment in achieving SVR varies based on ethnicity and country; in the case of Korea, the response to PegIFN plus ribavirin is better than for the US or Europe. However, there have been no studies on IFN monotherapy or combination therapy in domestic hemophilic patients. This may be because interest in hemophilia in Korea is low due to the lack of hemophilic patients, with just 2,204 hemophilic patients, 600 anti-HCV-positive cases, and nearly 200 HCV PCR-positive cases.5 In this issue of Clinical and Molecular Hepatology, Yang et al. analyzed the treatment effect of PegIFN plus ribavirin in hemophilia patients with HCV infection as subjects. The results were very interesting and surprising. The majority (85.6%) of hemophilic patients demonstrated SVR, and when analyzed by genotype, the rates were 82.4% and 91.7% for genotype 1/6 and genotype 2/3, respectively. This indicates the rate of reaching SVR was higher than reported in other studies. The authors reported high compliance, more patients who were younger, few patients with human immunodeficiency virus (HIV) co-infection, and a favorable rate of IL28B polymorphism as the reasons for the high treatment success rate compared to other studies. Many studies have shown that the response to PegIFN plus ribavirin treatment is poorer with older age, HIV co-infection, high viral load, genotype 1, and failure to achieve rapid virologic response (RVR) or early virologic response (EVR).891014 Additionally, there is a report that Koreans with HCV infection have the IL28B polymorphism, which shows a favorable response to treatment.1415

This study showed that among factors important for achieving SVR, only achievement of RVR was significant upon multivariate analysis. In particular, the genotype, which is known as an important factor associated with SVR, was not statistically significant. However, this may be because the success rates of treatment in both groups were relatively similar and because there were few patients. In addition, the rates of severe thrombocytopenia or discontinuation of antiviral treatment due to thrombocytopenia noted in this study did not differ significantly compared with the results of previous studies on non-hemophilic patients. Additionally, severe bleeding was not reported in patients with hemophilia in this study. Although bleeding is the most worrisome complication in patients with hemophilia, the current findings suggest that it would not be problematic to treat patients with HCV infections who also have hemophilia, as long as the guidelines are carefully followed.

This study is significant in that treatment with PegIFN plus ribavirin was reported for HCV-infected patients with hemophilia for the first time in Korea; moreover, there were no severe adverse events compared to non-hemophilic patients. As studies on HCV infection including more than 100 hemophilic patients are rare, this study is expected to play an important role in the treatment of patients with hemophilia. Since a poorer treatment response has been reported for hemophilic patients with past treatment failure9 or HIV co-infection116 compared to those without such conditions, further studies are needed on these patients. Protease inhibitors (boceprevir, telaprevir, etc.) have been recently approved for the treatment of HCV genotype 1 infections; in combination with PegIFN plus ribavirin, these may be considered a triple combination therapy as an alternative for such patients.31417 In several recent case reports, successful results have been reported on protease inhibitor-based triple therapy for HCV infection treatment in patients with hemophilia.181920 Additionally, combining current approaches with other new direct acting antivirals, such as NS3/4A protease inhibitor, NS5A inhibitor, NS5B polymerase inhibitor, may shorten the treatment period. Furthermore, in the near future, treatment regimens without interferon will be available to patients for whom interferon therapy is contraindicated.