Long Term Effects of Peginterferon Alfa-2a Plus Ribavirin for Chronic Hepatitis C/B Co-Infection and Chronic Hepatitis C
Long Term Effects of Peginterferon Alfa-2a Plus Ribavirin for Chronic Hepatitis C/B Co-Infection and Chronic Hepatitis C
Chronic hepatitis C may relapse in simple chronic hepatitis C patients who initially obtained
 sustained virologic responses. Although the HCV SVR could be maintained in around 90%, the
 remaining 10% of these patients may develop hepatitis C relapse during follow-up. Therefore,
 it is important to follow up the long-term of these patients with dual chronic hepatitis B
 and C.

 From another aspect, for the treatment of chronic hepatitis B, the virologic and serologic
 responses may also not be durable. Alternatively, previous studies suggested that the
 therapeutic efficacy might not be seen in the study period, and incremental response might
 occur during long-term follow-up. Therefore it is also important to clarify the long-term
 outcome of treatment in this dually infected population.

 Evaluation of the long term effects of treatment with peginterferon alfa-2a plus ribavirin
 for patients with chronic hepatitis C/ hepatitis B co-Infection and chronic hepatitis C in
 the original study ML17862 is important. This present protocol is thus to assess whether the
 HCV SVR is sustained and to assess the durability of the HBV virologic and serologic
 responses or any incremental response during a 5-year follow-up period, including six months
 after end of the therapy in the original study and an additional 4 and half years in this
 project (5 years overall follow-up after the end of treatment). Specifically, we wish to
 assess the (1) sustained virologic response (SVR) of HCV in both populations, (2) incidence
 of HBsAg loss and HBsAg seroconversion (HBsAg loss and appearance of anti-HBs) in dually
 infected population, (3) ALT normalization or flare off-treatment during both populations,
 (4) reductions of HCV RNA from the original baseline levels in the two patient populations,
 and (5) reduction of serum HBV DNA off-treatment in the dually infected population.
Pegylated IFNs (such as PEG-IFN alfa-2a, PEGASYS®) have been shown to possess a superior
 efficacy and convenience to conventional IFNs, either alone or in combination with RBV in
 patients with chronic hepatitis C only [Zeuzem et al, 2000; Heathcote et al, 2000; Fried et
 al, 2002; Hadziyannis et al, EASL 2002]. For patients with chronic hepatitis B, pilot study
 also revealed that the biochemical and virologic responses were better in HBeAg-positive
 patients receiving pegylated IFN than those receiving conventional IFN [24-week
 post-treatment combined virologic, HBeAg loss, and ALT normalization rate: 28% vs. 12%; Lai
 et al, APSAL 2002].

 The efficacy using a 24-week combination therapy in the sustained clearance of serum HCV RNA
 is equivalent to that using a 48-week combination therapy in patients with HCV genotype non-1
 [Hadziyannis et al, EASL 2002]. A 48-week course of pegylated IFN and RBV combination
 therapy, in contrast, has been shown to yield a better efficacy in the sustained clearance of
 serum HCV RNA in patients with HCV genotype 1 than a 24-week combination therapy in western
 countries [SVR: 40~51% vs. 29~41%, Table 1, Hadziyannis et al, EASL 2002; Poynard et al,
 1998]. Based on these findings, NIH Consensus Statement suggests that patients with genotype
 1 need 48 weeks of combination treatment and standard doses of RBV [NIH 2002]. Previous study
 revealed that a 12-week RBV therapy was not effective for patients with chronic hepatitis B
 [Kakumu et al, 1993]. Therefore, in this proposal, the treatment duration will be 24 weeks
 for HCV genotype 2/3, and will be 48 weeks for HCV genotype 1, in patients with monoinfected
 chronic hepatitis C and dual chronic hepatitis C and B.

 Increased RBV dosage has been considered as a contributory factor to the better efficacy in
 some previous studies. Recent studies suggested that using RBV 800 mg daily is adequate to
 treatment HCV genotype non-1 but standard dosage of RBV is required to treatment HCV genotype
 1 [NIH 2002]. We follow the recommendations and use RBV 800 mg daily for HCV genotype non-1,
 both in dually infected patients and in monoinfected chronic hepatitis C patients. RBV with
 1000-1200 mg daily will be used for HCV genotype 1 according the body weight of the patient,
 both in dually infected patients and in monoinfected chronic hepatitis C patients.

 Previous studies suggested that chronic hepatitis C may relapse in simple chronic hepatitis C
 patients who initially obtained sustained virologic responses at 6 months after end of the
 treatment [Chemello et al, 1996; Marcellin et al, 1997]. Although the HCV SVR could be
 maintained in around 90%, the remaining 10% of these patients may develop hepatitis C relapse
 during follow-up. Chemello et al followed up 107 patients with chronic hepatitis C who
 maintained normal aminotransferase levels as long as 12 months after interferon-alpha therapy
 [Chemello et al, 1996]. Hepatitis C virus RNA was detected in 27 (25%) patients with
 sustained biochemical response; 80 (75%) patients were negative for HCV RNA. Patients
 positive for HCV RNA were older (P < 0.001), had received a smaller interferon-alpha dose (P
 = 0.02), and were more frequently infected with HCV genotype 2 (P < 0.01). Liver histologic
 findings were active in 57% of patients positive for HCV RNA, despite normal alanine
 aminotransferase levels, compared with only 12% of patients who were negative for HCV RNA (P
 = 0.01). The estimated probability of hepatitis relapse by 4 years after therapy was 53% in
 viremic patients and 0% in patients negative for HCV RNA (P < 0.001). Marcellin et al
 followed up 80 patients who had chronic hepatitis C and received interferon-alpha therapy
 [Marcellin et al, 1997]. The 80 patients had follow-up 1 to 7.6 years (mean +/- SD, 4.0 +/-
 2.0 years) after interferon-alpha treatment. The follow-up period was 1, 2, 3, 4, 5, 6, and
 more than 6 years in 11, 13, 14, 18, 10, 12, and 2 patients, respectively, after the end of
 therapy. During the entire follow-up period, 93% (95% CI, 84% to 97%) of patients had
 persistently normal serum ALT levels. Serum HCV RNA remained undetectable in 96% (CI, 89% to
 99%) of patients. A comparison of liver histologic findings before and 1 to 6.2 years after
 interferon-alpha treatment showed a clear improvement in 94% (CI, 83% to 99%) of patients. In
 62% of patients, the last biopsy done showed normal or nearly normal histologic findings.
 Liver HCV RNA was detectable before treatment in all 13 patients tested and was undetectable
 1 to 5 years after treatment in all 27 patients tested. They thus concluded that in patients
 with chronic hepatitis C who have persistently normal serum ALT levels and no detectable
 serum HCV RNA 6 months after interferon-alpha therapy, long-term sustained biochemical and
 virologic response is generally seen. Similar finding was noted in one reported case with
 dual chronic hepatitis B and C [Yalcin et al, 2003]. To be noted, this dually infected
 patient had reactivation of hepatitis B accompanied by severe flare of hepatitis activity
 during treatment and had relapse of hepatitis C after end of the treatment. Therefore, it is
 important to follow up the long-term of these patients with dual chronic hepatitis B and C.

 From another aspect, for the treatment of chronic hepatitis B, the virologic and serologic
 responses may also not be durable [Liaw et al, 2005; Lok et al, 2004; Hadziyannis et al,
 2003; Janssen et al, 2005]. Alternatively, previous studies suggested that the therapeutic
 efficacy might not be seen in the study period, and incremental response might occur during
 long-term follow-up as learned from previous experiences of using antiviral agents including
 interferon for the treatment of chronic hepatitis B [Saruc et al, 2003; Carreno et al, 2001].
 Therefore it is also important to clarify the long-term outcome of treatment in this dually
 infected population.

 This present protocol is thus to assess whether the HCV SVR is sustained and to assess the
 durability of the HBV virologic and serologic responses or any incremental response during a
 5-year follow-up period, including six months after end of the therapy in the original study
 and an additional 4 and half years in this project (5 years overall follow-up after the end
 of treatment). Specifically, we wish to assess the (1) sustained virologic response (SVR) of
 HCV in both populations, (2) incidence of HBsAg loss and HBsAg seroconversion (HBsAg loss and
 appearance of anti-HBs) in dually infected population, (3) ALT normalization or flare
 off-treatment during both populations, (4) reductions of HCV RNA from the original baseline
 levels in the two patient populations, and (5) reduction of serum HBV DNA off-treatment in
 the dually infected population.
Inclusion Criteria:

 -  Patients who were randomized, treated and returned for follow up in the ML17862
 protocol will be eligible for inclusion in this protocol

 Exclusion Criteria:

 -  Patients unwilling to provide informed consent or abide by the requirements of the
 study.

 -  Patients who have already initiated anti-HCV or HBV treatment, approved or
 investigational since completion of the original protocol