Background
Hepatitis C virus (HCV) is the major etiologic agent in parenterally transmitted non-A non-B hepatitis and frequently causes persistent infection leading to chronic liver disease and primary hepatocellular carcinoma (HCC)[
1,
2]. Interferon-alpha (IFN-α) was the first approved therapy in the 1980s but resulted in a sustained virological response in only 8–20% of chronic hepatitis C patients treated with a standard regimen of IFN-α monotherapy, 3 million units (MU) thrice weekly for 24 weeks [
3‐
8]. A number of factors have been considered in terms of their potential to predict the response to IFN-α therapy. These include infection with non-genotype 1b, lower levels of viremia and the absence of cirrhosis, which have been currently reported to be associated with a better response[
2,
9,
10]. Several studies in Japan and Western countries have shown that higher dose (5–10 MU) of IFN could improve the efficacy on chronic hepatitis C[
5,
9,
11]. Reviewing the Medline, however, only one limited study on the efficacy of IFN therapy for naïve patients of chronic hepatitis C has been reported before 1997 in Taiwan[
4]. Furthermore, the dose effect, tolerability and durability of high-dose IFN therapy for naïve Taiwanese chronic hepatitis C patients have never been reported.
Since 1992, we have treated a number of Taiwanese patients with chronic hepatitis C with a standard IFN regimen, 3 MU thrice weekly for 24 weeks, and since 1995, with 6 MU thrice weekly for 24 weeks. We have followed these patients closely for 5–10 years, and we report herein the end-of-treatment and sustained response, and results of long-term follow-up to both regimens, as well as the dose effect, tolerability and durability of high-dose IFN therapy.
Discussion
In the present study, we have investigated the dose effect of IFN-α therapy on a group of Taiwanese patients with chronic hepatitis C in a 10-year follow-up. Our results demonstrated that 6 MU IFN-α, thrice weekly for 24 weeks, had better efficacy (2.3-fold) than 3 MU, thrice weekly for 24 weeks, in both virological and histological responses. Improved efficacy was mainly seen in subgroups of patients with one of the two unfavorable virologic factors, the medium-risk group, in the current study. The 6-MU regimen was as tolerable as standard 3-MU regimen for Taiwanese patients. Both regimens had good durability of SVR.
Treatment with IFN-α was the first approved therapy but a SVR could be achieved in only 8–20% of chronic hepatitis C patients treated with a standard regimen of IFN-α monotherapy (3 MU thrice weekly for 24 weeks) [
3‐
8]. Therefore, how to improve the efficacy of IFN-α therapy is the concern of many studies. Until recently, 48 weeks of IFN-α, 3 MU thrice weekly was recommended for the treatment of chronic hepatitis C[
5]. Concerning the suffering from long-term IFN therapy, we conducted higher dose of IFN regimen, 6 MU thrice weekly for 24 weeks, which total dosage was equal to that of 3 MU, thrice weekly for 48 weeks. In the present study, 6-MU regimen was observed to achieve significantly higher rates of ETVR and SVR than 3-MU regimen, but had no benefit on reducing the relapse rate. In contrast to the duration effect on improvement of SVR by reducing the relapse rate after end-of-treatment, our results implicated the dose effect on the initial response of HCV to IFN therapy[
5,
7,
8]. High dose regimen as well as induction therapy could result in early clearance of HCV viremia, which is very important in the prediction of IFN response[
10,
15,
16].
In the present study, the incidence of discontinuation and most of the major adverse events were similar between standard dose and higher dose of IFN therapy, despite that the higher dose of IFN regimen had significantly higher incidence of psychological manifestations. However, the psychological manifestations, mainly presented as irritability, could be controlled well with minor tranquillizers.
Consistent with previous reports[
2,
3,
9,
10,
14], we confirmed the associations of pretreatment serum HCV RNA levels, HCV genotype 1b and presence of cirrhosis with response to IFN-α treatment in chronic hepatitis C patients by using stepwise logistic regression model. According to previous studies for Taiwanese patients, we divided our patients into three virological risk groups based on the presence/absence of HCV genotype 1b and the baseline viral loads greater than the cut-off point, 0.65 Meq/mL, or not[
14]. As observed in the present study, 6-MU regimen could achieve significantly higher rate of ETVR but could not decrease the relapse rate in all of the three risk groups. Although our logistic regression model predicted a 2.3-times increase in probability for a SVR to occur in the 6-MU regimen versus the 3-MU regimen, the significantly better efficacy of 6-MU regimen on SVR was only observed in patients with one virological risk factor. Therefore, how to enhance the ETVR for the medium- and high-risk groups and to reduce the relapse rates for all of the three risk groups will be the key to improve SVR. Extended therapy and/or combination with ribavirin might be considered to overcome the unfavorable virological risk factors[
16,
17]. Since the unfavorable virological risk factors are unchangeable, tailored regimens of IFN with or without ribavirin combination therapy according to the virological status are the only way to improve the efficiency of HCV eradication, as recommended in recent consensus on management of chronic hepatitis C[
18,
19].
In accordance with previous studies [
20‐
22], a significant decrease in necroinflammatory activity of liver histology was observed in the current study. However, our material was unable to show whether the IFN treatment resulted in cessation of fibrogenesis, regardless of IFN regimen and virological response (data not shown). Indeed, no firm conclusion can be drawn about whether the fibrosis remaining at long-term follow-up was irreversible and established or whether it will diminish with even longer follow-up[
22]. Further analysis of histological response, stratified by IFN regimen and SVR, we found that 6-MU regimen could achieve histological improvement not only in SVR but also in non-SVR. By contrast, most of non-SVR treated with 3-MU regimen had histological worsening. These results presumed the prominent benefit of high dose IFN on the treatment of chronic hepatitis C.
Similar to other reports[
23,
24], the long-term prognosis was excellent in this well-defined material of SVR. Serum HCV RNA was persistently undetectable in 63 of 64 patients with SVR. The only one patient, who had reappearance of serum HCV RNA concomitant with abnormal ALT level at the 57th month of follow-up, is a resident of an HCV hyperendemic area, Tzukuan[
25]. Whether this is reinfection[
26] or recurrence[
23,
24] of HCV remains to be clarified by phylogenetic analysis of viral genome. Also our results confirm that IFN therapy, when associated with response, reduces the incidence of LC and HCC among chronic hepatitis C patients[
27].
A greater efficacy in treatment of chronic hepatitis C was observed in combination with IFN-α and ribavirin[
24], which has been available in Taiwan since August 1998 and becomes to be the recommendations for chronic hepatitis C patients[
18,
19]. More recently, combination of pegylated IFN-α plus ribavirin shows more effective and convenient and may replace the current standard of IFN-α plus ribavirin[
28,
29]. The results of current study could provide decision-making information for future therapeutic strategies of individualizing dose and duration of standard or pegylated IFN-α treatment in combination with ribavirin according to the baseline virological predictors to improve the efficiency of HCV eradication. However, pegylated IFN-α and ribavirin combination therapy is expensive and might carry potential side effects. The present higher dose regimen of IFN monotherapy might be suggested for patients who are contraindicated to ribavirin and/or pegylated IFN-α therapy[
30].
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
MLY carried out the laboratory work and molecular virologic studies, participated in the collection and clinical evaluation of patients, performed the statistical analysis, and drafted the manuscript. CYD, SCC and LPL participated in the laboratory work and molecular virologic studies, and in the collection and clinical evaluation of patients. MYH, ZYL, MYH, JFT and LYW, participated in the collection and clinical evaluation of patients. WYC participated in the design of the study. WLC conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.