See article in J. Gastroenterol. Hepatol. 2005; 20: 727–732
Hepatitis B virus (HBV) and hepatitis C virus (HCV) share several modes of transmission; not surprisingly, coinfection by the two viruses is not uncommon, particularly in areas where the two viruses are endemic and among subjects with a high risk of parenteral infection. Seroprevalence studies have shown that approximately 3–18% of patients with chronic HBV infection are also infected with HCV.1–7 In addition, HBV/HCV coinfection is of clinical relevance because it is associated with severe chronic liver diseases poorly sensitive to interferon (IFN) treatment and with a high risk of hepatocellular carcinoma (HCC) development.8–11 The virologic profiles of HBV and HCV and their interplay in coinfection are still largely undefined because most studies of the natural and post-therapeutic course of chronic hepatitis C have, among the main exclusion criteria, coexisting HBV infection and vice versa. These patients may show different virologic profiles: they may be either hepatitis B e antigen (HBeAg) or anti-HBe positive; they may have low HBV-DNA levels with high levels of HCV-RNA, and vice versa low or high levels for both viruses.12,13 However, all these data come from cross-sectional studies and, consequently, we do not know whether the levels of viremia of the two viruses represent a constant feature or only temporary changes in complex kinetics evolving with respect to diagnosis and therapy in patients with HBV/HCV coinfection.14
In most patients, HBV replication is suppressed while HCV replication remains active. However, the opposite has also been observed. In an Italian multicenter study, 837 hepatitis B surface antigen (HBsAg) positive patients were evaluated. Anti-HCV antibodies were present in 59 cases (7%). Independent predictors of dual infection were age >42 years, history of intravenous drug use, blood transfusion and residence in the south of the country. Of 36 HBV/HCV coinfected patients, 16 (44%) had only HBV-DNA in serum, five (14%) had both HBV-DNA and HCV-RNA, nine (25%) had HCV-RNA alone and six (17%) tested negative for both. In this series of unselected HBsAg positive patients, 89% of all the cases were HBeAg negative/anti-HBe positive and 100% of the patients with dual HBV/HCV infection were positive for anti-HBe. This virologic profile reflects the profound modifications in the epidemiological and clinical profile of HBV infection in southern Europe, and other developed countries that have emerged in the last decade. A spontaneous downtrend in the infection rate coupled with the vaccination campaign against HBV have caused a progressive reduction in newly acquired HBV infections. As a consequence, the proportion of chronic HBeAg positive infections has rapidly decreased over time, while in the aging cohort of HBV carriers, HBeAg-negative mutants are increasingly selected.7
Persons with dual HBV and HCV infection are difficult-to-treat patients. They respond poorly to IFN alpha monotherapy.8,15–17 IFN alpha monotherapy was more effective in clearing HBV infection than HCV infection16 and when investigators used higher doses of IFN α (9 million units [MU] instead of 6 MU three times weekly).17
In a pilot study by Liu et al., 21 HBV-DNA and HCV–RNA positive patients were treated for 24 weeks with a combination of ribavirin (1200 mg daily) and IFN alpha-2a (6 MU thrice weekly for 12 weeks, followed by 3 MU thrice weekly for the subsequent 12 weeks). They reported that combination therapy could achieve a similar HCV clearance rate in dual infection cases, comparable with HCV infection alone.18
In this issue of the Journal, Hung et al.19 add strong evidence to this notion. They treated 36 patients, all HBsAg, anti-HCV and HCV RNA positive with 18 of these HBV-DNA positive by Amplicor (Cobas Amplicor Monitor, Roche Diagnostics, Branchburg, NJ, USA), with a combination of IFN alpha-2b and ribavirin. Thirteen patients received 3 MU and 23 patients received 5 MU IFN thrice weekly for 24 weeks. Ribavirin was given at a daily dose of 800–1200 mg according to the weight of the patients. The sustained virologic response (SVR) was evaluated 48 weeks after discontinuation of the treatment. Another 72 patients with HCV infection alone served as controls. The study demonstrated that combination therapy induced a similar response against HCV in patients with dual HBV/HCV infection or HCV single infection (69%vs 71% of SVR). There was no significant difference in sustained HCV clearance between the 3 MU group and the 5 MU group (85%vs 61%).
At the end of 48 weeks follow-up, only two (11%) of 18 pretreatment viremic patients had negative serum HBV-DNA (< 200 copies/mL). This shows that such therapy was not sufficient to obtain satisfactory efficacy in clearing HBV viremia.
The bad news from this study is the reappearance of HBV-DNA in the serum of two (13%), six (40%) and eight (53%) of 15 patients without pretreatment HBV viremia at the end of treatment, and at the 24 and 48 weeks of follow-up, respectively. All these eight patients had negative HCV-RNA in serum at the end of treatment. The authors found the reappearance of both HBV-DNA and HCV-RNA in two patients at post-treatment week 48. The remaining six patients with reactivation of HBV infection achieved sustained clearance of HCV replication. IFN alpha therapy did not induce a severe HBV reactivation following suppression of HCV during and after the treatment course. The results of this study are in accordance with a previous report that HBV reactivation might develop following a decrease in HCV replication with IFN alpha therapy in a patient with positive HCV-RNA, anti-HBe and low serum HBV level.20
In conclusion, combination therapy with IFN alpha and ribavirin can be efficient for sustained clearance of HCV replication in a significant proportion of patients with dual HBV/HCV infection, and the HCV clearance rate in these patients is comparable with those infected with HCV alone. The influence of this treatment on HBV replication is lower. The danger and significance of reactivation of HBV infection after a decrease of HCV replication needs to be evaluated in longitudinal studies. At present, majority of patients with chronic hepatitis C are treated with a combination of pegylated IFN alpha and ribavirin. This combination is more efficient and better tolerated in patients with chronic HCV infection alone. It is very probable that it will be the same in patients with HBV/HCV coinfection but it is necessary to confirm this hypothesis in clinical trials.