Updated Treatment of Dual Chronic Hepatitis C and B

In areas where hepatitis B virus (HBV) infection is endemic, a substantial number of patients are infected with both hepatitis C and B. Moreover, patients who are dually infected with hepatitis C virus (HCV) and HBV have been reported to carry a significantly higher risk of developing fulminant hepatic failure, liver cirrhosis, and hepatocellular carcinoma than those with HCV or HBV infection alone. Thus HCV and HBV dually infected patients need careful medical attention and effective treatment. Ideally, effective antiviral therapy for dually infected patients should eradicate both viruses. Alternatively, the treatment may be given against the virus most likely responsible for the liver injury. Dually infected hepatitis patients generally can be classified into two groups according to the dominant viral activity: the first in which hepatitis C dominates over hepatitis B (hepatitis C/B); the second in which hepatitis B dominates over hepatitis C (hepatitis B/C). Their natural histories may differ and require distinct treatments. Sporadic studies showed that IFN alone was not effective in clearing HCV or HBV in patients dually infected with hepatitis B and C. A recent study reported that dose augmentation of IFN to 9 MU thrice weekly for 6 months cleared HCV in 31% of the patients. This efficacy, however, was still not adequate. Because combining IFN with ribavirin has been shown to yield much better results in the treatment of chronic hepatitis C than IFN alone, the combination therapy might also be more effective in treating dual hepatitis B and C patients. To test this hypothesis, we conducted a pilot study using conventional IFN alfa plus ribavirin to treat 24 patients infected with both HCV and HBV [3]. The 24-week combination regimen with IFN and ribavirin cleared HCV in 43% (9/21) of these patients. This result was comparable to that in patients with chronic hepatitis C monoinfection. In addition, we found that the clearance of HCV RNA was sustained much less commonly in those infected by HCV genotype 1b compared with those infected with genotype 2a or 2b (21% vs. 86%, P<0.05). Two recent studies from southern Taiwan demonstrated similar results [4,5]. More interestingly, with long term (≥2 year post-treatment) follow-up, we found that a significant portion (21%) of responsive patients also cleared HBsAg. Based on these findings, we suggested that comparable efficacy of combination therapy using IFN plus ribavirin on the clearance of serum HCV RNA can be achieved in patients with HBV and HCV dual infection versus HCV monoinfection. Despite its comparable efficacy in clearing HCV RNA, we noted that for the hepatitis B/C patients, the IFN and ribavirin therapy appeared less effective in clearing either virus. This suggests different regimens may be needed for hepatitis B/C patients and hepatitis C/B patients. Combination therapy using pegylated IFNs has been shown to have a superior efficacy compared to conventional IFN alone in the treatment of chronic hepatitis C monoinfection. We anticipate that this efficacy may also be enhanced by pegylated IFN, and therefore propose that pegylated IFN plus ribavirin be used to treat dually infected patients with HCV genotype 1. Accordingly, we are conducting a multicenter clinical trial in Taiwan to examine the potential of this treatment for hepatitis C patients dually infected with HBV [6]. Eligible patients with active HCV with (n=161) or without (n=160) co-existence of hepatitis B surface antigen were consecutively enrolled. Patients infected with HCV genotype 1 received 48 weeks of combination therapy with peginterferon alfa-2a 180 mcg weekly plus daily 1000-1200 mg ribavirin. Patients with HCV genotype non-1 received 24 weeks of combination therapy with peginterferon alfa- 2a 180 mcg weekly plus daily 800 mg ribavirin. The primary efficacy endpoint was sustained HCV RNA clearance at 24 weeks post-treatment. By the end of March 2006, 21 (6.5%) patients were withdrawn prematurely from the study. The causes of withdrawal were skin lesions (n=8), non-compliance (n=7), constitutional symptoms (n=3), and dyspnea or cough (n=3). A total of 162 patients have completed treatment and follow-up, with the remainder still undergoing therapy. Interim results by intention-to-treat analysis are shown in Table 1. Our preliminary results suggested that combination therapy using peginterferon alfa-2a with ribavirin appears safe and effective for patients dually infected with HCV and HBV. For hepatitis B/C patients, different treatment strategy should be considered. A recent case series demonstrated that using IFN plus lamivudine combination therapy, HBeAg seroconversion and clearance of serum HBV DNA could be achieved in 13% and 38% of patients, respectively. Further large clinical trial should be conducted for this group. Finally, the long-term outcome after anti-viral treatment for dual HBV and HCV infection is still unknown. Therefore, until these problems are resolved, it is suggested that antiviral therapy for these patients should be given as part of well-designed clinical trials.