1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  There is yet no established treatment for chronic hepatitis C patients non-responder to standard interferon and ribavirin.

Aim  To evaluate efficacy and safety of pegylated-interferon-α2a plus ribavirin with or without amantadine in such patients.

Methods  161 non-responders to standard interferon and ribavirin were randomized into two groups: 81 patients (Group 1) were given weekly Peg-IFN-α2a 180 μg plus ribavirin 1000–1200 mg/daily for 12 months, 80 patients (Group 2) received weekly Peg-IFN-α2a 180 μg plus ribavirin 1000–1200 mg/daily and amantadine 200 mg/daily for 12 months.

Results  At the end of follow-up, HCV-RNA was negative in 29.6% of Group 1 and in 21.2% of Group 2 patients (P = 0.22). Patients with genotypes 1 and 4 responded better to bi-therapy (21.7%) than to triple therapy (17.3%, P = 0.5) while among patients with genotypes 2 and 3 there was a trend towards a higher sustained virological response rate when retreated with triple treatment (80% vs. 75%, P = 0.82). On multivariate analysis, genotype 1 or 4, high body mass index and >20% reduction of Peg-interferon were associated with the treatment failure.

Conclusions  The addition of amantadine does not improve the overall SVR rate in non-responder patients retreated with Peg-IFN and ribavirin; however, about 30% of non-responders may achieve a sustained response, in particular patients with genotypes 2 and 3 show a high SVR (75%).


  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Since the introduction of the combined therapy (interferon + ribavirin; IFN + RBV) for hepatitis C, the issue of retreatment of non-responders has arisen. Most of the patients with unfavourable genotypes did not respond to standard combination therapy1, 2 and to date there is no therapeutic option for such patients. Preliminary results with pegylated (Peg)-IFN and RBV3 suggested that approximately 25–40% of non-responders to IFN monotherapy obtain a sustained virological response (SVR) but only 10–11% of non-responders to standard IFN–RBV combination therapy show a SVR when re-treated with Peg-IFN-based combination therapy. Recent studies4, 5 showed that response to retreatment with Peg-IFN and RBV is genotype-dependent, patients with favourable genotypes having a SVR rate of about 60%. Unfortunately, patients with genotype 1 are predominant among non-responder to previous therapies and SVR rate obtained in this population is very low, ranging from 14% to 19%.4–6 These disappointing results prompted many investigators to initiate randomized trials on a third potentially curative drug.

Amantadine (AMA), an oral anti-viral agent, has been proven to be of benefit in naive hepatitis C virus (HCV)-positive patients7 when associated with IFN and RBV, even though these results are not confirmed by some authors.8, 9 A recent meta-analysis9 has suggested that AMA may improve the efficacy of IFN plus RBV in the retreatment of HCV-positive patients not responding to a previous course of IFN monotherapy.

The role of AMA in the retreatment of non-responders to combined therapy is even more debated due to the low number of full reports on this topic.10, 11

In order to establish whether patients previously unresponsive to combined therapy with conventional IFN-based treatment regimens benefit from therapy with Peg-IFN/RBV-based regimens with or without AMA, we conducted a randomized-controlled trial; the study was designed to compare the efficacy and safety of Peg-IFN-α2a given at 180 μg dose once weekly plus RBV 1000–1200 mg/daily with or without AMA 200 mg given daily for 12 months.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Definition of non-response

In this study, we considered non-responders patients who had positive HCV-RNA serum test [by polymerase chain reaction (PCR)] after at least 24 weeks of full IFN therapy [3 million unit (MU) thrice weekly] plus RBV given at fixed dosage of 1000 mg/daily.

Sample size

For this protocol, a 20% SVR rate was assumed for the bi-therapy group and a 40% SVR rate was assumed for the triple-therapy group; based on these hypothesized rates, a total of 74 patients per arms would provide 80% power to detect a difference between the two regimens at the 5% significance level (two-sided). Allowing for a 10% dropout rate it was intended for 182 patients (81 per arm) to be recruited into this study. Because of a randomization error, only 80 patients were included in the triple-therapy group.

Definitions of response

Early virological response (EVR) was defined as a 2 log or greater decline in serum HCV-RNA level from the pretherapy baseline or the absence of detectable HCV-RNA in serum treatment at week 12. The end of treatment (EOT) virological response (ETR) was defined as the absence of serum HCV-RNA by PCR at the end of therapy. A SVR was defined as the HCV-RNA clearance (by PCR) 6 months after the ETR. A long-term virological response (LTR) was defined as the persistent HCV-RNA negativization 18 months after therapy withdrawal.

Selection of patients

The study was approved by the ethical committee and patients gave written informed consent for inclusion.

Between May 2001 and December 2002, 161 patients with chronic hepatitis C who fulfilled the definition of non-response were enrolled into the study.

Patients were eligible if they had the following inclusion criteria: age >18 and <65 years; positive results for HCV-RNA by PCR; chronic hepatitis C at liver biopsy performed within 1 year before entry; previous non-response to combined therapy; abnormal ALT levels (at least 1.5 times upper limit of normal; range: 0–40 IU). The exclusion criteria were previous course with PEG-IFN-based therapy; relapse after one or more IFN + RBV courses; a positive hepatitis B surface antigen test in serum; a positive test for antibody to the human immunodeficiency virus; alcoholic liver disease; haemochromatosis; Wilson's disease; drug-related liver disease; autoimmune hepatitis; haemoglobin level <10 g/dL, platelet count <70 000/mm3, white blood cell count <3000/mm3, or granulocyte count <1500/mm3; decompensated cirrhosis; intravenous drug abuse; abnormal serum uric acid level; presence of concomitant significant medical illness; history of haemolytic anaemia; α1-antitrypsin deficiency; obesity-induced liver disease; haemophilia; seizure disorders; ischaemic cardiovascular disease and severe mental depression. Pregnant women and patients unable to practice contraception during therapy and follow-up were also excluded.

Study design

All the patients underwent liver biopsies within 1 year before entry; each liver biopsy was reviewed blindly by one pathologist according to the Ishak's scoring system.12

Each patient was allocated through a concealed process, using a computerized program with block randomization at a central location, to receive one of the following treatment regimens.

  • 1
    Group 1 (81 patients): 180 μg once weekly of Peg-IFN-α2a plus RBV, either 1000 mg/day (body weight <75 kg) or 1200 mg/day (body weight >75 kg) for 12 months.
  • 2
    Group 2 (80 patients): 180 μg once weekly of Peg-IFN-α2a plus RBV, either 1000 mg/day (body weight <75 kg) or 1200 mg/day (body weight >75 kg) plus AMA 200 mg/daily for 12 months.

AMA was supplied as 100-mg capsules given orally in two divided doses of 200 mg/daily.

Patients were managed on an out-patient basis and clinical and biochemical assessments were conducted monthly during therapy and the 6-month follow-up; in order to exclude late relapses, patients showing SVR were followed up every 6 months for further 12 months. Patients not showing an EVR were suspended from treatment as well as patients with an EVR but HCV-RNA-positive at 24 weeks after starting treatment.

The primary efficacy end points were the rates of sustained virological responders and long-term responders.


All virological assessments were performed in one core laboratory.

At baseline, genotypes were identified using a line probe hybridization assay (Line Probe assay, LIPA HCV, Innogenetics, Zwijndrecht, Belgium). Immediately before the inclusion into the study, HCV-RNA was quantified by a branched-DNA assay (Quantiplex, Bayer Diagnostics, Tarrytown, NY, USA) with a lower limit of detection of 615 IU/mL. Serum samples below this cut-off were evaluated for HCV-RNA by the COBAS-AMPLICOR assay (Roche Diagnostic Systems, Branchburg, NJ, USA) which has a sensitivity of 50 IU/mL.

The COBAS-AMPLICOR assay was also used to test viraemia in each patient at the end of therapy and follow-up.

Statistical analysis

All the end points analysed were dichotomous variables and a Chi-square test was used for comparing the groups.

In order to adjust the comparison among the two groups and to asses the role of several prognostic factors we used multiple logistic regression models including demographic [age, sex, body mass index (BMI)], clinical (type of treatment, reduction of dosage), histological (staging) and virological (viraemia, genotype) variables. Results were expressed as odds ratio (OR) and 95% confidence intervals (CI).


  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The demographic, clinical, histological and virological characteristics of the patients are reported in Table 1. There were no major differences between the groups regarding age, gender distribution, BMI, number of previous treatment courses, ALT values, quantitative viraemia, genotypes and histology.

Table 1.   Characteristics of the patients
RegimenGroup 1 (Peg-IFN + ribavirin)Group 2 (Peg-IFN +  ribavirin + amantadine)
Mean age, years ± s.d. (range)50 ± 11 (27–65)50 ± 11 (22–65)
Sex (M/F)60/2159/21
Mean ALT, IU + s.d. (range)127 ± 84 (39–770)116 ± 85 (43–335)
BMI, ±s.d. (range)24.9 ± 3.5 (17.6–34.2)24.8 ± 3.4 (17.3–33)
 Mean (×106 genotype Eq/mL ± s.d.)1.8 ± 3.1 (0.07–18)2.1 ± 3.1 (0.01–19)
 ≥600 000 IU/mL22 (27%)20 (25%)
 <600 000 IU/mL59 (73%)60 (75%)
Genotype, n (%)
 166 (81)67 (84)
 2 9 (11) 4 (5)
 3 3 (4) 1 (1)
 4 3 (4) 8 (10)
 Grading, mean ± s.d. (range)5 ± 2.2 (1–10)5 ± 2.2 (1–9)
 Staging, mean ± s.d. (range)3 ± 1.5 (0–6)3 ± 1.5 (0–6)
 Cirrhosis, n (%)7 (8.6)11 (13.7)

Adverse events

Four patients showed severe adverse events during treatment: one patient of Group 1 died for myocardial infarction at week 16 of therapy; he was a 64-year-old male, with mild diabetes treated only with diet. His pretherapy ECG was normal and the latest RBC count performed 1 week before was not significantly abnormal (Hb = 12.2 g/dL, RBC = 4 122 000 mm3); he had already been treated with combination therapy for 6 months reporting no cardiac symptoms. Three other patients of Group 1 prematurely suspended treatment at weeks 14, 18 and 32, respectively, one for a diffuse dermatosis interpreted as RBV-induced toxycodermia, an another one for vascular hypoacusia and the latter for a severe non-haemolytic anaemia (Hb = 4.2 g/dL) because of bone marrow inhibition exerted by Peg-IFN. Two of them showed a complete remission after treatment discontinuation and supporter therapy with steroids (the former) and blood transfusions (the latter), while the other patient continue to show a persistent and severe hypoacusia during long-term follow-up.

Therapy was discontinued in further 22 patients because of side effects reported in Table 2. The most frequent reason for therapy withdrawal was mental depression, followed by influenza-like symptoms; seven patients (4.3%) prematurely suspended treatment for haematological disorders: three patients for neutropenia (<500 mm3), two for thrombocytopenia (<30 000 mm3) and two for anaemia (haemoglobin concentration <8.5 g/dL).

Table 2.   Side effects
Regimen Group 1 (Peg-IFN +  ribavirin; %)Group 2 (Peg-IFN +  ribavirin + amantadine; %)
Cause of discontinuation
Flu-like symptoms2.52.5
Neutropenia (<500 cells/mm3)2.52.5
Gastrointestinal disorders2.51.2
Platelet decrease (<40 000/mm3)1.21.2
Anaemia (<8.5 g/dL)1.21.2
Cause of drug reduction
Anaemia (≥10% decrease of baseline Hb)9.96.2
Flu-like symptoms7.43.7
Neutropenia (<750 cells/mm3)2.51.2
Gastrointestinal disorders2.50
Thyroid disease2.50
Platelet decrease (<80 000/mm3)1.21.2

Because of side effects, 15 (18.5%) of Group 1 patients and 10 (12.5%) of Group 2 patients reduced the dose of Peg-IFN from >80% to <60% of the target dose; dose reduction of RBV from >80% to <60% of the target dose occurred in 28 (34.5%) and 23 (28.7%) patients, respectively, of Groups 1 and 2. A 50% reduction of AMA dosage was observed in four (5%) patients of the triple-therapy arm. Dose reductions were usually observed during the first 24 weeks of treatment.

Virological response

Results were evaluated according to an intention-to-treat analysis and are reported in Table 3; analysis was based on the 161 patients who were randomized to treatment and received at least one dose of medicine.

Table 3.   HCV-RNA negativization at the end of the treatment and follow-up
RegimenGroup 1 (Peg-IFN +  ribavirin)Group 2 (Peg-IFN +  ribavirin + amantadine)P-value
Number of patients8180 
HCV-RNA clearance
End of therapy
 Responders (%)36 (44.4%)34 (42.5%)0.45
  Genotypes 1 and 439.1%41.3%0.51
  Genotypes 2 and 375.0%80%0.82
End of follow-up
 Responders (%)24 (29.6%)17 (21.2%)0.22
  Genotypes 1 and 421.7%17.3%0.50
  Genotypes 2 and 375.0%80%0.82

At the ETR, 36 (44.4%) of Group 1 patients and 34 (42.5%) of Group 2 patients had cleared HCV-RNA (P = 0.45); stratifying for genotype, ETR was 39.1% in Group 1 and 41.3% in Group 2 in patients with genotype 1 or 4 and 75% and 80%, respectively, in patients with favourable genotype. At the end of follow-up, HCV-RNA remained negative in 24 (29.6%) of Group 1 patients and in 17 (21.2%) of Group 2 patients (P = 0.22). A SVR was higher among patients with genotype 1 or 4 in Group 1 than in Group 2 (21.7% vs. 17.3%, P = 0.50) while a better SVR rate was observed for patients with genotypes 2 and 3 in Group 2 compared with Group 1 (80% vs. 75%, P = 0.82).

When the effect of reducing the dose of Peg-IFN or RBV on SVR was analysed, four of 25 (16%) patients who reduced Peg-IFN obtained a SVR compared with 37 of 136 (27.2%, P = 0.02) compliant patients; in contrast, reducing the dose of RBV did not appear to impact significantly the SVR rate (27.4% vs. 24.5%, P = N.S.).

Patients were also stratified according to their EVR pattern: after 12 weeks of treatment 47 (58%) of Group 1 patients showed an EVR compared with 44 (55%) of Group 2; 24 of 47 (51%) Group 1 patients showed a 2 log or greater decline in serum HCV-RNA level from the pre-treatment baseline, but were still HCV-RNA-positive by using PCR while the remaining 23 were HCV-RNA-negative.

Only eight of 24 (33.3%) patients showed a SVR compared with 16 of 23 (69.5%) patients with undetectable viraemia at week 12. A similar outcome was observed among Group 2 patients: three of 28 (10.7%) patients with a significant viraemic decline but persistent viraemia at week 12 were HCV-RNA-negative during the follow-up compared with 14 of 16 (87.5%) patients showing an early complete viral clearance.

Long-term follow-up

In order to exclude delayed virological relapses, all the patients with a SVR were followed up for further 12 months: no viraemic reappearances were observed in any patient.

Factors predictive of non-response

Sustained virological responders and non-responders/relapsers were stratified according to type of treatment, reduction of Peg-IFN dosage, gender, age, BMI, viraemia, genotype and histology.

Logistic regression analyses showed that treatment failure was significantly associated with HCV genotype 1 or 4, a >20% dose reduction of Peg-IFN and a baseline BMI higher than 25 (Table 4).

Table 4.   Results of multivariate logistic regression analysis correlating pre-treatment variables with treatment failure (non-response)
 Odds ratio (CI)P-value
Sex (female)0.583 (0.219–1.554)0.2810
Age (>45 years)1.030 (0.991–1.071)0.1355
BMI >253.328 (1.398–7.918)0.0066
Viraemia (≥600 000 IU/mL)1.087 (0.758–1.558)0.6506
Genotype (1 or 4)31.975 (6.960–146.908)<0.0001
Staging (≥3)1.938 (0.818–4.594)0.1327
Treatment (group 2)1.350 (0.572–3.185)0.4930
Peg-IFN reduction6.673 (1.261–35.307)0.0256


  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The advent of RBV in 19981, 2 has significantly reduced the proportion of HCV-positive naive patients not responding to anti-viral therapy. However, more than 50% of patients with genotype 1 or 4 who were treated with standard IFN plus RBV failed to respond and to date no satisfactory anti-viral rescue therapy has been reported for these patients; preliminary studies6, 13 suggested that approximately 12–18% of non-responders to standard IFN–RBV combination achieve an SVR with Peg-IFN-based combination therapy. Recent studies4, 5 showed that response to re-treatment with Peg-IFN plus RBV is based upon HCV genotypes. Patients with favourable genotypes (2 and 3) respond much better than patients with unfavourable genotype (1 or 4); these data strongly support the use of Peg-IFN plus RBV in this subset of patients. Unfortunately, the great majority of patients not responding to the standard combination therapy are genotype 1 carriers and in this particular population the SVR rate is not satisfactory.

To increase efficacy, a triple therapy (IFN + RBV + AMA) was evaluated in some studies; the low cost and absence of toxicity are reasons why this drug was widely used in the last years in both naive and non-responder patients. Results, however, are conflicting.7, 8, 10, 11, 14 A recent meta-analysis6 reported a significant effect of triple combination therapy with AMA in non-responders, but no effect upon naive patients or relapsers. However, most of the patients included in the meta-analysis had failed IFN monotherapy rather than IFN + RBV combination treatment and the definition of previous non-response was not homogeneous between studies.

In the great majority of the previous studies, AMA was prescribed in association with standard IFN and RBV. Only few published trials have added this anti-viral to Peg-IFN and RBV: in a recent controlled study15 comparing triple (Peg-IFN-α2b + RBV + AMA) with double (Peg-IFN-α2b + RBV) therapy in non-responders to standard IFN + RBV, the rates of SVR were disappointing in patients treated with either regimen (7% and 5%, respectively); the authors suggested that possible reasons for the poor response were the high proportion of cirrhotics and the 100% rate of unfavourable genotypes recruited in their study.

We confirm that the addition of AMA to double therapy is of no advantage; however, the SVR rates achieved in our study were low yet not so disappointing. Overall, the SVR rate varied between 21.2% and 29.6% in the two arms. Among patients with genotype 1 or 4, a SVR rate was observed in 21.7% of Group 1 and 17.3% of Group 2 while about 75% of patients with favourable genotypes showed a sustained response. Though superior, our data are comparable with those of Younossi et al.16 who found an overall SVR rate of 16.4%, with a significant difference between genotypes 1 and 2 or 3; the SVR discrepancy between the two studies may be related to the higher percentage of favourable genotypes and lower number of cirrhotics that were included in our study.

Recently, a French study5 adopting Peg-IFN-α2b plus RBV with or without AMA in non-responders to standard IFN plus RBV showed a higher SVR rate in the triple-therapy groups (24%) compared with the double-therapy group (16%), although the difference was not statistically significant. The trend for a beneficial effect of AMA was mainly present among genotypes 2 and 3 patients (SVR = 77.8% vs. 62.5%) like in our series. Interestingly, the SVR rate obtained by Maynard et al. among genotype 1 patients retreated with the triple therapy was identical to that observed in our genotype 1 patients (17%); at variance with their data, we found a higher SVR rate in genotypes 1 retreated with the double therapy (21.7% vs. 12.2%). The discrepancy may be explained by the different baseline characteristics of the patients.

To explain the apparent better results obtained in group 1, we focused on the higher number of patients with favourable genotype and the lesser number of cirrhotics included in this group despite randomization. Even though this difference is not statistically significant, it may account for the higher SVR rate observed among genotype 1 patients retreated with the double therapy.

Our data show that genotypes other than 1 and 4, a BMI <25 and adherence to therapy with Peg-IFN are strong predictive factors of sustained response. The influence of BMI on the outcome was unexpected as previous studies using Peg-IFN-α2a did not find a relationship between BMI and response to therapy.17, 18 However, those studies were conducted on naive patients and their results may not apply to non-responders.

The reduction of Peg-IFN within the first 24 weeks of therapy was also detrimental as it induced a significant decrease of SVR rate; the main reason for dosage reduction was the doctor-directed management of therapy-related adverse events. Side effects were common prompting discontinuation of treatment in about 14% of patients and adverse events were severe in four patients. The fatal outcome in a patient with mild diabetes suggests that pretherapy screening should be more thorough in this subset of patients: a normal ECG may not be sufficient to exclude an asymptomatic cardiac ischaemic disease.

Finally, our study confirms the importance of the EVR pattern in predicting the outcome;19, 20 however, the SVR rate was strikingly higher in patients with no detectable HCV-RNA within the first 12 weeks of therapy than in patients who achieved a 2 log viraemic decline but remained HCV-RNA-positive. This difference was particularly evident in Group 2 where only 10.7% of HCV-RNA-positive patients showed a SVR compared with 87.5% of HCV-RNA− patients.

In conclusion, the findings of this study indicate that the addition of AMA to Peg-IFN and RBV is not effective in improving the SVR rate in non-responders to previous therapy with standard IFN and RBV; however, our data and the results of three recent combination studies from the US4, 6, 13 confirm that the response to Peg-IFN and RBV in previous non-responders with genotypes 2 and 3 is comparable with the SVR rates seen in previously untreated patients, suggesting that combination therapy with Peg-IFN and RBV represents a viable treatment option in such subset of non-responders.


  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

No external funding was received for this study.


  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339: 148592.
  • 2
    Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks vs. interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352: 142632.
  • 3
    Shiffman ML. Retreatment of patients with chronic hepatitis C. Hepatology 2002; 36: S12834.
  • 4
    Taliani G, Gemignani G, Ferrari C, et al. Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients. Gastroenterology 2006; 130: 1098106.
  • 5
    Maynard M, Pradat P, Bailly F, et al. Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI). J Hepatol 2006; 44: 48490.
  • 6
    Shiffman ML, Di Bisceglie AM, Lindsay KL, et al. Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004; 126: 101523.
  • 7
    Mangia A, Ricci GL, Persico M, et al. A randomized controlled trial of pegylated interferon alfa2a (40 KD) or interferon alfa2a plus ribavirin and amantadine vs. interferon alfa2a and ribavirin in treatment-naive patients with chronic hepatitis C. J Viral Hepat 2005; 12: 2929.
  • 8
    Thuluvath PJ, Maheshwari A, Mehdi J, et al. Randomised, double blind, placebo controlled trial of interferon, ribavirin, and amantadine vs. interferon, ribavirin and placebo in treatment naive patients with chronic hepatitis C. Gut 2004; 53: 1305.
  • 9
    Deltenre P, Henrion J, Canva V, et al. Evaluation of amantadine in chronic hepatitis C: a meta-analysis. J Hepatol 2004; 41: 46273.
  • 10
    Thuluvath PJ, Pande H, Maygers J. Combination therapy with interferon-alfa2b, ribavirin, and amantadine in chronic hepatitis C non-responders to interferon and ribavirin. Dig Dis Sci 2003; 48: 5947.
  • 11
    Teuber G, Pascu M, Berg T, et al. Randomized, controlled trial with IFN-alfa combined with ribavirin with and without amantadine sulphate in non-responders with chronic hepatitis C. J Hepatol 2003; 39: 60613.
  • 12
    Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 6969.
  • 13
    Krawitt EL, Ashikaga T, Gordon SR, et al. Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C. J Hepatol 2005; 43: 2439.
  • 14
    Berg T, Kronenberger B, Hinrichsen H, et al. Triple therapy with amantadine in treatment-naive patients with chronic hepatitis C: a placebo-controlled trial. Hepatology 2003; 37: 135967.
  • 15
    Hasan F, Al-Khaldi J, Asker A, et al. Peginterferon alpha-2b plus ribavirin with or without amantadine for the treatment of non-responders to standard interferon and ribavirin. Antiviral Ther 2004; 9: 499503.
  • 16
    Younossi ZM, McCullough AC, Barnes DS, et al. Pegylated interferon alfa-2b, ribavirin and amantadine for chronic hepatitis C. Dig Dis Sci 2005; 50: 9705.
  • 17
    Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975.
  • 18
    Hadziyannis SJ, Sette H Jr, Morgan TR, et al. PEGASYS International Study Group. Peginterferon-alfa2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346.
  • 19
    Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38: 645.
  • 20
    Wong JB, Davis GL, McHutchison JG, Manns MP, Albrecht JK; International Hepatitis Interventional Therapy Group. Economic and clinical effects of evaluating rapid viral response to peginterferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C. Am J Gastroenterol 2003; 98: 2354.
    Direct Link: