High versus standard doses interferon-alpha in the treatment of naïve chronic hepatitis C patients in Taiwan: a 10-year cohort study
© Yu et al; licensee BioMed Central Ltd. 2005
Received: 25 November 2004
Accepted: 12 April 2005
Published: 12 April 2005
Interferon-alpha monotherapy is effective in less than one-third patients with chronic hepatitis C. The dose-effect, tolerability and durability of interferon-alpha treatment and its long-term effect on the prevention of cirrhosis and hepatocellular carcinoma in naïve Taiwanese patients with chronic hepatitis C have not been well investigated. We conducted the present cohort study treated with high and standard interferon-alpha to illustrate the issues.
We performed a long-term virologic and histological follow-up of 214 chronic hepatitis C patients treated with interferon-alpha, 3 million units (3-MU, n = 80) or 6-MU (n = 134) thrice weekly for 24 weeks, in Taiwan between 1992 and 2001.
There was no difference in the incidence of discontinuation between 3-MU and 6-MU groups (4/80, 5.0% versus 10/134. 7.5%). The 6-MU group had similar incidence of adverse events with the 3-MU group, except that 6-MU group had significantly higher incidence of psychological manifestations, mainly presented as irritability. The rates of sustained virological response (SVR) were significantly higher in 6-MU regimen (37.1%) than in 3-MU regimen (23.7%, p < 0.05) in per protocol analysis. Based on multivariate analysis, baseline viral load was strongly associated with SVR, followed by hepatitis C virus genotype, interferon-alpha regimen, and liver fibrosis. A histological improvement in necroinflammatory activity, but not in fibrosis was observed in the follow-up biopsy performed 0.5–5.5 years (mean: 1.9 years, n = 51) after end-of-treatment. Among patients without SVR, there was more activity improvement in 6-MU group. The durability of SVR was 100% (18/18) and 97.8% (45/46) for 3-MU and 6-MU group, respectively, in a mean follow-up period of 6.81 years (5.25–9.18 years). For 163 baseline non-cirrhotic patients, 9 of 84 (10.7%) non-responders and 3 of 79 (3.8%) sustained responders progressed to cirrhosis during a mean follow-up period of 5.52 and 5.74 years, respectively (p = 0.067, Kaplan-Meier survival analysis, log-rank test). For all 200 patients, hepatocellular carcinoma was detected in 12 of 113 (10.6%) non-responders and one of 87 (1.1%) sustained responders during a mean follow-up period of 5.67 and 5.73 years, respectively (p < 0.01, Kaplan-Meier survival analysis, log-rank test).
We confirm the dose effect of interferon-alpha in chronic hepatitis C. Six-MU regimen had better efficacy than 3-MU regimen in virologic and histological responses. Both regimens had good tolerability and durability in Taiwan. Sustained response could reduce the incidence of cirrhotic change and hepatocarcinogenesis.
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. 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.
Incidence of discontinuation and adverse events
3-MU group, No. (%)
6-MU group, No. (%)
Detection/quantification of serum HCV RNA and genotyping
Detection of serum HCV RNA was performed using a standardized automated qualitative reverse transcription polymerase chain reaction assay (RT-PCR, COBAS AMPLICOR Hepatitis C Virus Test, version 2.0; Roche, Branchburg, NJ, USA). The detection limit was 50 IU/mL. HCV genotypes 1a, 1b, 2a, 2b and 3a were determined by amplification of the core region using genotype-specific primers described by Okamoto et al. Serum HCV RNA levels were measured by using the branched DNA assay (Quantiplex HCV RNA 2.0, Bayer, Emeryville, CA), performed strictly in accordance with the manufacturer's instructions. The quantification range was 0.2 to 120 million equivalents (Meq) of HCV RNA per ml.
Frequency was compared between groups using the chi-square test with Yate's correction or Fisher's exact test. Group means were compared using the Student t-test. Serum HCV RNA levels were expressed as the mean ± standard deviation after logarithmic transformation of original values. Stepwise logistic regression was used to analyze factors associated with IFN-α response. Comparisons of paired liver histology were carried out with two-sample Wilcoxon's signed rank test. Preventive effects of antiviral therapy on progression of chronic HCV infection to liver cirrhosis (LC) and HCC were analyzed by using Kaplan-Meier survival analysis.
There was no difference of incidence of discontinuation of treatment between 3-MU and 6-MU groups (Table 1). The incidence of adverse events was similar between two groups in the presentation of flu-like symptoms, gastrointestinal and dermatological manifestations, and alopecia. However, patients in 6-MU group had significantly higher rate of psychological manifestation than those in 3-MU group did (74/134, 55.2% versus 34/80, 41.0%, p = 0.028, Table 1).
SVR and factors predicting SVR
Baseline demographic and clinical features of 200 chronic hepatitis C patients with interferon-alpha therapy
3-MU group† No. (%)
6-MU group‡ No. (%)
47.3 ± 10.4
45.3 ± 11.7
History of transfusion
Total score of necroinflammatory activity
4.48 ± 2.56
4.23 ± 2.46
Pretreatment ALT value (U/L)
117.4 ± 102.8
104.1 ± 95.4
Pretreatment HCV RNA level (log equivalent/mL)
5.97 ± 0.59
6.01 ± 0.68
Factors associated with sustained viral response to interferon-alpha therapy
Non-SVR† No. (%)
SVR† No. (%)
47.6 ± 10.0
44.2 ± 13.5
History of transfusion
Total score of necroinflammatory activity
4.10 ± 2.59
4.21 ± 2.31
Pretreatment ALT value (IU/L)
87.8 ± 86.5
143.5 ± 153.5
Pretreatment serum level of HCV RNA§
6.17 ± 0.61
5.62 ± 0.56
Multivariate logistic regression analysis of factors associated with sustained viral response to interferon-alpha therapy in chronic hepatitis C patients
Pretreatment HCV RNA level§
Per 1 log increase
1b = 1; non-1b = 0
6-MU = 1; 3-MU = 0¶
Stage of fibrosis
F3–4 = 1; F0–2 = 0
Dose effect on SVR according to virological risk factors
Dose effect of interferon-alpha in chronic hepatitis C patients Dose effect of interferon-alpha on end-of-treatment virological response, virological relapse, and sustained virological response in chronic hepatitis C patients with low-, medium-, and high- virological risk
Low-risk patients, n/N (%)†
Medium-risk patients, n/N (%)‡
High-risk patients, n/N (%)§
End-of-treatment virological response
Sustained virological response
Paired histological examination
Mean liver histological scores before and after interferon-alpha treatment in 51 Taiwanese chronic hepatitis C patients
1.25 ± 1.47
0.84 ± 1.27
1.02 ± 1.24
0.49 ± 0.92
1.88 ± 1.24
1.16 ± 1.32
Total necroinflammatory score
4.08 ± 2.86
2.51 ± 3.06
1.12 ± 1.09
1.10 ± 1.22
Long-term follow-up for viral status and the development of LC and HCC
During the follow-up period, reappearance of serum HCV RNA was found in one patient, who has achieved SVR in 6-MU group, at the 57th month. The durability of SVR was 100% and 97.8% for 3-MU and 6MU group, respectively, in a mean follow-up period of 6.81 years (5.25–9.18 years). The SVR remained similar among three IFN preparations at the end of the 10 years.
Of 136 non-responders in the present study, 50 received a second course of IFN-based treatment. Three of 11 (27.3%) with IFN-α monotherapy and 20 of 39 (51.3%) with IFN-α/ribavirin combination therapy achieved a second SVR. Clinical evaluation, liver biochemistry, α-fetoprotein, and abdominal sonography were performed every 3–6 months for patients without baseline cirrhosis, and every 2–3 months for those with baseline cirrhosis during the follow-up period.
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. 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. 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. 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. Whether this is reinfection 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.
A greater efficacy in treatment of chronic hepatitis C was observed in combination with IFN-α and ribavirin, 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.
We confirm the dose effect of IFN in chronic hepatitis C. Six-MU regimen had better efficacy than standard 3-MU regimen in both of virological and histological responses, and was as tolerable as 3-MU regimen. Nearly all sustained virological responders had a durable response and the sustained response had a preventive effect on the development of HCV-associated LC and HCC. Since the unfavorable predictors, high pretreatment HCV RNA levels, infected with genotype 1b, and presence of cirrhosis, are unchangeable, adjustment of IFN dose and duration according to the unfavorable factors is important to achieve a better efficacy/risk ratio. Our results 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 baseline predictors.
List of abbreviations
- Hepatitis C virus:
- million units:
- liver cirrhosis:
LC, hepatocellular carcinoma: HCC, end-of-treatment virologic responder: ETVR, sustained virologic responder: SVR
- reverse transcription polymerase chain reaction assay:
- million equivalent:
This study was supported by the Taiwan Liver Research Foundation.
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