Effect of ribavirin and amantadine on early hepatitis C virus RNA rebound and clearance in serum during daily high-dose interferon

The early rebound in serum HCV RNA during HCV dynamic studies with high-dose interferon may be due to de novo infection with interferon escape quasispecies. We simultaneously measured serum alanine aminotransferase (ALT) and HCV RNA at rapid intervals in chronic HCV liver disease patients during interferon therapy alone or in combination with ribavirin and amantadine. HCV RNA declined rapidly between 0 and 48 hr in all patients (phase 1). Ribavirin and amantadine significantly increased this phase 1 decline. In all four monotherapy patients with viral rebound, the increasing levels of HCV RNA were associated with a parallel increase in serum ALT, consistent with a hepatitis flare or de novo infection. By contrast, in the four monotherapy patients without viral rebound, and all eight patients receiving combination therapy, the slow progressive phase two decay was associated with declining serum ALT levels. Ribavirin or ribavirin and amantadine significantly and incrementally increased the phase two HCV RNA clearance. Dynamic sequencing in the HVR1 region in one rebound patient confirmed the potential for rapid evolutionary changes during interferon therapy. These preliminary data suggest that early viral rebound might be associated with de novo infection with interferon escape HCV variants, which in turn are attenuated by ribavirin and amantadine.     

Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin

To assess the efficacy and safety of maintenance therapy with ribavirin alone in chronic hepatitis C, 108 patients were treated with the combination of interferon alfa and ribavirin for 24 weeks; those who failed to have a virologic response were offered enrollment in a randomized, double-blind, controlled trial of ribavirin (1,000-1,200 mg daily) versus placebo for the subsequent 48 weeks. Patients were monitored at regular intervals with symptom questionnaires, serum aminotransferase levels, hepatitis C virus (HCV) RNA levels, and complete blood counts and underwent liver biopsy at the completion of therapy. Among 108 patients, 50 were still HCV RNA positive after 24 weeks of treatment, of whom 34 agreed to be randomized to continue either ribavirin monotherapy or placebo. Among 17 patients who received placebo, there was no overall improvement in symptoms, serum alanine aminotransferase (ALT) levels, HCV RNA levels, or hepatic histology. Among the 17 patients who received ribavirin, serum ALT levels and necroinflammatory features of liver histology were improved, whereas symptoms, HCV RNA levels, and hepatic fibrosis scores were not changed significantly from baseline. Responses to ribavirin seemed to be categorical, such that 8 patients (47%) had definite improvement in liver histology. Patients with improved histology had improvements in serum ALT levels both on combination therapy and after switching to ribavirin monotherapy. In conclusion, continuation of ribavirin monotherapy may maintain serum biochemical improvements that occur during interferon-ribavirin combination therapy in some patients and that these improvements are often associated with decreases in necroinflammatory changes in the liver. Whether these improvements will ultimately result in prevention of progression of hepatitis C requires further study.     

Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy

BACKGROUND AND AIMS: Addition of ribavirin to interferon alfa treatment has substantially increased sustained virologic response rates in patients with chronic hepatitis C (CHC). Ribavirin acts as an RNA virus mutagen in vitro, thereby leading to error catastrophe. However, data in CHC are controversial. METHODS: The nonstructural (NS) 5B quasi-species heterogeneity was analyzed in Huh7 cells harboring a subgenomic hepatitis C virus (HCV) replicon system treated with ribavirin or levovirin. Accordingly, NS5B quasi-species were studied in 14 patients with CHC who received ribavirin alone or combined with pegylated interferon alfa both at baseline and during the first weeks of therapy. Analysis of NS3 quasi-species served as control. RESULTS: Cultivation of HCV replicon cells with ribavirin led to higher NS5B mutational frequencies compared with levovirin-treated or untreated cells (P < .05). Patients receiving ribavirin monotherapy showed higher overall mutational frequencies within NS3 and NS5B during therapy as compared with baseline (P < .01). Proportions of ribavirin-specific G-to-A and C-to-T transitions increased (P < .01). Paired analysis confirmed significant mean increases of mutational frequencies of approximately 5%. Ribavirin serum concentrations were positively correlated with mutational frequency changes (P < .05). In patients receiving combination therapy, a decrease of NS5B mutational frequencies ( approximately 10%) and lower proportions of G-to-A and T-to-C mutations (P < .01) were detectable. CONCLUSIONS: Ribavirin, but not its L-enantiomer levovirin, is a mutagen in HCV replicon cells. In patients with CHC, ribavirin monotherapy exhibits a moderate mutagenic effect early during therapy that is not detectable in combination with pegylated interferon alfa.     

Antiviral effect of ribavirin in early non-responders to interferon monotherapy assessed by kinetics of hepatitis C virus RNA and hepatitis C virus core antigen

BACKGROUND/AIMS: To evaluate the efficacy of ribavirin, given in second intention in non-responders to interferon alone, by studying viral kinetics. METHODS: We conducted a trial including 203 patients with chronic hepatitis C, na?ve of treatment. Patients were treated with interferon three times a week with or without ribavirin and amantadine according to response. Viral kinetics were assessed by serial measurements of HCV RNA (bDNA 3.0 and Monitor 2.0) and a new assay, trak-C, able to quantify total Hepatitis C virus (HCV) core antigen. RESULTS: A significant initial drop in HCV RNA or HCV core antigen, under interferon alone, was associated with response to therapy, -4.85+/-1.33 log for HCV RNA in sustained responders versus -1.86+/-1.53 log for others groups, P<0.001. In patients receiving ribavirin in second intention, we also observed a similar drop in HCV RNA and HCV core antigen, predictive of sustained response, -2.67+/-1.26 log for HCV RNA in sustained responders versus -0.44+/-0.49 log in non-responders, P<0.001. CONCLUSIONS: Ribavirin has probably an additional antiviral effect in interferon treated patients. Kinetics of HCV RNA and HCV core antigen under treatment are highly predictive of a sustained virological response.     

Daily or three times per week interferon alpha-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C not responding to previous interferon alone

BACKGROUND/AIMS: We compared the efficacy and safety of the combined therapy of daily interferon alpha-2b and ribavirin with those of interferon alpha-2b three times per week alone or in combination with ribavirin in non-responder patients with hepatitis C virus (HCV) infection.METHODS: A total of 376 patients were randomly assigned to receive interferon alpha-2b (6 MU three times per week for 24 weeks followed by 3 MU three times per week for 24 weeks) alone (group A) or in combination with ribavirin for 48 weeks (group B), or daily interferon alpha-2b (3 MU per day for 24 weeks followed by 3 MU three times per week for 24 weeks) and ribavirin (group C).RESULTS: After 24 weeks of therapy, HCV RNA was undetectable in 11.7, 24.0, and 37.8% for groups A, B, and C, respectively. Sustained virological response was more frequent in patients who received combination therapy with three times weekly interferon (20.9%) or daily interferon (26.0%) than in patients who received interferon alone (5.8%) (P<0.001). The predictive HCV parameters for sustained response were a low viral load on day 7 and a negative HCV RNA on week 12.CONCLUSIONS: In conclusion, in non-responder patients with chronic hepatitis C, virological response with daily interferon and ribavirin, compared to interferon monotherapy, was significantly improved during treatment, although sustained virological response was similar for both combination therapies with ribavirin and three times a week or daily interferon.     

Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin

BACKGROUND & AIMS: Pegylated interferon alfa-ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of ribavirin in HCV clearance during therapy and to evaluate the consequences of ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. METHODS: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 microg/wk, plus ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. RESULTS: Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of ribavirin may not be needed when HCV RNA is undetectable at week 2. CONCLUSIONS: We made 3 conclusions from this study. First, ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, ribavirin must be administered for the full treatment duration in most genotype 1-infected patients who respond; third, baseline parameters may help identify patients who could discontinue ribavirin or reduce the dose without losing their chance of success.     

A potent antiviral effect on hepatitis C viral dynamics in serum and peripheral blood mononuclear cells during combination therapy with high-dose daily interferon alfa plus ribavirin and intravenous twice-daily treatment with interferon beta

Hepatitis C virus (HCV) is known to infect and replicate within peripheral blood mononuclear cells (PBMC), thereby enabling the direct evaluation of antiviral mechanisms by analyzing HCV dynamics in PBMC. To address potential molecular differences associated with distinct antiviral regimens, we studied HCV dynamics in both serum and PBMC in 44 patients with HCV genotype 1b and high viral load who were randomly assigned to the following 4 different treatment groups: 1) combination therapy with 6 MU daily of interferon alfa 2b (IFN-alpha2b) plus 800 mg of ribavirin; 2) monotherapy with 6 MU daily of IFN-alpha2b; 3) monotherapy with twice-daily intravenous administration with 3MU of IFN-beta; and 4) monotherapy with daily intravenous administration with 6 MU of IFN-beta. HCV-RNA levels were measured serially using highly sensitive real-time detection polymerase chain reaction (PCR). HCV dynamics in both the serum and PBMC showed a "biphasic" pattern. The exponential decay slopes of the second phase were significantly higher in the combination or twice-daily dosing regimen groups compared with groups 2 or 4 (0.10 +/- 0.08 vs. 0.02 +/- 0.09 or 0.16 +/- 0.09 vs. 0.02 +/- 0.04 day(-1); P <.05 or P <.0005, respectively). Moreover, the viral half-lives in the second phase were significantly shorter in these groups (73.2 +/- 42.5 vs. 240.1 +/- 120.7 or 56.0 +/- 44.6 vs. 361.6 +/- 293.5 hours; P <.05 or P <.05, respectively). Additionally, the slope of HCV decline in PBMC tended to be higher in the combination regimens, as compared with monotherapy. Taken together, our data on HCV dynamics provide molecular insight into utilization of combination or twice-daily dosing regimens to increase rates of sustained viral eradication of HCV.     

Hepatitis C virus free-virion and immune-complex dynamics during interferon therapy with and without ribavirin in genotype-1b chronic hepatitis C patients

The Synergistic effect of interferon (IFN) and ribavirin for patients with chronic hepatitis C has been demonstrated, but ribavirin has no apparent direct antiviral effect against hepatitis C virus (HCV) when used as monotherapy. To elucidate the mechanism of ribavirin on enhanced HCV eradication when used in combination therapy, we investigated the serum HCV dynamics of free-virions (FV) and immune-complexes (IC) in genotype-1b infected patients treated with IFN-alpha2b alone (n = 11) or in combination with ribavirin (n = 15). Serum FV- and IC-HCV RNA were separated by immunoprecipitation using anti-human immunoglobulin and quantified serially using real-time detection polymerase chain reaction. At the first phase (day 0-2), the decline of FV- and IC-HCV RNA was similar between the two treatment groups. At the second phase (day 2-28), the decline of IC was significantly faster in patients treated with IFN plus ribavirin compared with IFN alone [exponential decay slope = 0.079 +/- 0.036 vs 0.048 +/- 0.027 log10/day, P = 0.0248; half-life = 81.1 +/- 21.4 vs 135.1 +/- 61.4 h, P = 0.0053], although the second phase FV-decline was not significantly different between the two treatment groups. The fast second phase decline of IC was associated with sustained virological response to therapy. These results suggest that ribavirin may modulate the humoral immune response against HCV and trigger a favourable response to IFN. In conclusion, analysis of early IC-HCV dynamics is useful for predicting the response to therapy and for understanding the mechanism of action of antiviral drugs in chronic hepatitis C patients.     

Daily or three times per week interferon α-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C not responding to previous interferon alone

Background/Aims: We compared the efficacy and safety of the combined therapy of daily interferon α-2b and ribavirin with those of interferon α-2b three times per week alone or in combination with ribavirin in non-responder patients with hepatitis C virus (HCV) infection.Methods: A total of 376 patients were randomly assigned to receive interferon α-2b (6 MU three times per week for 24 weeks followed by 3 MU three times per week for 24 weeks) alone (group A) or in combination with ribavirin for 48 weeks (group B), or daily interferon α-2b (3 MU per day for 24 weeks followed by 3 MU three times per week for 24 weeks) and ribavirin (group C).Results: After 24 weeks of therapy, HCV RNA was undetectable in 11.7, 24.0, and 37.8% for groups A, B, and C, respectively. Sustained virological response was more frequent in patients who received combination therapy with three times weekly interferon (20.9%) or daily interferon (26.0%) than in patients who received interferon alone (5.8%) (P<0.001). The predictive HCV parameters for sustained response were a low viral load on day 7 and a negative HCV RNA on week 12.Conclusions: In conclusion, in non-responder patients with chronic hepatitis C, virological response with daily interferon and ribavirin, compared to interferon monotherapy, was significantly improved during treatment, although sustained virological response was similar for both combination therapies with ribavirin and three times a week or daily interferon.     

In vivo interferon system assessed by 2′‐5′ oligoadenylate synthetase activity in chronic hepatitis C virus patients treated with pegylated interferon and ribavirin

Aim: 2′,5′ oligoadenylate synthetase (2‐5AS), an enzyme induced by interferon, is an accurate indicator of the antiviral effect of interferon. We measured it during pegylated interferon based therapies in patients with chronic hepatitis C virus (HCV) in order to determine the dynamics of antiviral status in vivo and the relationship between the response to exogenous interferon and the outcome of therapy. Methods: A total of 160 patients with chronic HCV were treated with pegylated interferon alfa 2a or 2b or non‐pegylated interferon, with or without ribavirin. Serum 2‐5AS activity was measured by radioimmunoassay assay kits every 2 weeks. Results: In 60 patients treated with pegylated interferon alfa 2a or 2b, 2‐5AS levels increased to 7–40 times (average 235 pmol/dL) above the pretreatment levels (30 pmol/dL), which were significantly higher than the levels during non‐pegylated interferon therapy. Ribavirin did not enhance 2‐5AS levels. 2‐5AS levels between sustained virological response (SVR) and non‐SVR, including null responders to pegylated interferon plus ribavirin therapy were not significantly different. Conclusion: 2‐5AS levels were significantly higher in patients treated with pegylated interferon than in those treated with non‐pegylated interferon, suggesting that pegylated interferon is more potent at inducing interferon response genes resulting in an improved antiviral effect. Ribavirin did not appear to be related to interferon response gene induction.     

Antiviral action of ribavirin in chronic hepatitis C

BACKGROUND & AIMS: In the patients with chronic hepatitis C, the addition of ribavirin to interferon (IFN)-alpha significantly increases the virologic responses. Our aim was to assess the antiviral action of ribavirin on hepatitis C virus (HCV) as a function of ribavirin pharmacokinetics and to evaluate the influence of this antiviral effect on IFN-alpha efficacy. METHODS: Forty-five patients with chronic hepatitis C (genotype 1b) received various schedules of IFN-alpha and/or ribavirin administration. Frequent blood sampling was performed for HCV RNA kinetics and ribavirin pharmacokinetics assessment. RESULTS: Ribavirin monotherapy induced a significant, moderate, early, and transient viral load decrease in approximately half of the patients. The occurrence of this effect was associated with longer ribavirin clearance half-lives and higher serum ribavirin concentrations. Ribavirin antiviral effect partly reduced the rebound preceding the second IFN-alpha injection in patients receiving standard IFN-alpha 3 times per week plus ribavirin. The magnitude of the rebound was inversely related to ribavirin concentrations. These patients subsequently experienced a slow, but significant, second slope of viral decrease and cleared HCV RNA. The addition of ribavirin to daily IFN-alpha monotherapy did not have any impact on the second phase of viral decline. CONCLUSIONS: Ribavirin exerts a significant, moderate, and transient antiviral effect in a significant proportion of patients with chronic hepatitis C. The antiviral effect of ribavirin correlates with ribavirin pharmacokinetics and is partly responsible for the improved efficacy of the combination of standard IFN-alpha and ribavirin compared with IFN-alpha monotherapy by increasing the incidence of the initial response.     

SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders

BACKGROUND & AIMS: SCH 503034 is a novel and potent oral hepatitis C virus (HCV) protease inhibitor. In this phase Ib study, we assessed safety parameters and virologic response of combination of SCH 503034 plus pegylated (PEG) interferon (IFN) alpha-2b in patients with HCV genotype 1 infections who were previously nonresponders to PEG-IFN-alpha-2b +/- ribavirin therapy. METHODS: This was a multicenter, open-label, 2-dose level, 3-way crossover, randomized (to crossover sequence) study carried out in 3 medical centers in Europe. Adult patients received SCH 503034 200 mg (n = 14) or 400 mg (n = 12) 3 times daily orally and PEG-IFN-alpha-2b 1.5 microg/kg subcutaneously once each week. Patients received SCH 503034 as monotherapy for 1 week, PEG-IFN-alpha-2b as monotherapy for 2 weeks, and combination therapy for 2 weeks with washout periods between each treatment period. RESULTS: Combination therapy with SCH 503034 and PEG-IFN-alpha-2b was well tolerated, with no clinically significant changes in safety parameters. Mean maximum log(10) changes in HCV RNA were -2.45 +/- 0.22 and -2.88 +/- 0.22 for PEG-IFN-alpha-2b plus 200 mg and 400 mg SCH 503034, respectively, compared with -1.08 +/- 0.22 and -1.61 +/- 0.21 for SCH 503034 200 mg and 400 mg, respectively, and -1.08 +/- 0.22 and -1.26 +/- 0.20 for PEG-IFN-alpha-2b alone in the 200 mg and 400 mg SCH 503034 groups, respectively. CONCLUSIONS: SCH 503034 plus PEG-IFN-alpha-2b was well tolerated in patients with HCV genotype 1 nonresponders to PEG-IFN-alpha-2b +/- ribavirin. These preliminary results of antiviral activity of the combination suggest a potential new therapeutic option for this hard-to-treat, nonresponder patient population.     

Treatment of hepatitis C virus genotype 4-related cirrhosis: ribavirin and interferon combination compared with interferon alone

BACKGROUND: Response to treatment with interferon alfa, with or without concomitant ribavirin, varies with the viral genotype and the degree of fibrosis in patients with chronic hepatitis C virus (HCV). GOALS: To determine the response of HCV type 4-related cirrhosis to interferon and ribavirin combination treatment compared with interferon alone. STUDY: Patients living in Kuwait were assigned to take either interferon alone at a dosage of 5 million units thrice weekly (26 patients) or interferon 5 million units thrice weekly combined with ribavirin 1,000 mg/d (21 patients) for 24 weeks. Biochemical response was defined as normal alanine aminotransferase (ALT) at end of therapy. Sustained biochemical response was defined as normal ALT 6 months after the end of therapy. Sustained virologic response was defined as negative serum HCV RNA 6 months after the end of therapy. RESULTS: Only 2 (8%) of 26 patients showed biochemical response after interferon alone, whereas 11 (52%) of 21 showed biochemical response after interferon combined with ribavirin (p < 0.01). Only 2 (8%) of 26 patients showed sustained biochemical response after interferon alone, whereas 5 (23%) of 21 showed sustained biochemical response after interferon combined with ribavirin (not significant, p > 0.1). None of the 26 patients showed virologic response after interferon alone, whereas 3 (14%) of 21 showed sustained virologic response after interferon combined with ribavirin (not significant, p > 0.1). CONCLUSION: These results suggest that patients with cirrhosis caused by HCV type 4 show no response to interferon alone and only slightly better response to 24 weeks of interferon combined with ribavirin.     

Interferon versus ribavirin plus interferon in chronic hepatitis C previously resistant to interferon: a randomized trial.

BACKGROUND: More than 70% of patients with chronic hepatitis C are resistant to interferon therapy. Ribavirin, in association with interferon, has been demonstrated as effective, at a dose of 800-1200 mg/day, but the efficacy of a lower dose has not been established. METHODS: We assessed the effectiveness of the combination of 600 mg/day of ribavirin plus 3 MU of interferon over a period of 6 months, in a group of patients previously resistant to interferon. Sixty-two patients with chronic hepatitis C with serum and hepatic HCV RNA relapsers or non-responders to interferon, were randomly divided into two groups: group A received 3 MU of interferon alpha-2b, three times a week for 6 months; group B was given the same dose plus 600 mg per day of ribavirin for 6 months. Two patients from each group dropped from therapy. One patient from group A and two from group B withdrew from treatment because of adverse effects. RESULTS: Mean alanine aminotransferase levels were similar in both groups throughout the study. A sustained response was observed in 7% and 7.4% of groups A and B with short-term response in 39% and 59%, and no response in 54% and 34% from both groups respectively (non-significant). At 12 months, 4 and 7 patients from groups A and B respectively, cleared serum HCV RNA however, only one sustained responder from each group cleared HCV RNA from peripheral blood mononuclear cells. At 18 months, 3 patients remained serum HCV RNA negative. Adverse effects were similar. Only haemoglobin values were lower in group B in the first month of therapy (p<0.05). CONCLUSION: In conclusion, the combination of 3 MU of interferon plus 600 mg of ribavirin is not effective in chronic hepatitis C resistant to interferon.     

Mycophenolate mofetil in combination with recombinant interferon alfa-2a in interferon-nonresponder patients with chronic hepatitis C

BACKGROUND/AIMS: Since ribavirin was able to improve the antiviral efficacy of interferon alfa in patients with chronic hepatitis C, several other adjuncts have been studied. It has been shown that mycophenolate mofetil (MMF) is a more potent inhibitor of the inosine 5'-monophosphate-dehydrogenase (IMPDH) than ribavirin. The present study is a pilot study evaluating the efficacy and safety of combination therapy with interferon alfa-2a and MMF in interferon alfa nonresponder patients. METHODS: Thirty-eight adult patients with chronic hepatitis C who did not respond to a previous interferon alfa monotherapy were enrolled to receive 6 million units of interferon alfa-2a tiw in combination with MMF (1 week 500 mg/day, 1 week 1000 mg/day, 22 weeks 2000 mg/day). RESULTS: An interim analysis of 29 patients after 12 weeks of therapy showed that only one patient had negative hepatitis C virus-RNA at this time point. There was no significant reduction of the viral load during therapy. Due to inefficacy the study was discontinued. CONCLUSIONS: Combination therapy of interferon alfa-2a and MMF is ineffective in improving virological response rates in nonresponder patients with chronic hepatitis C. These data suggest that inhibition of the IMPDH seems not to be the major mechanism of ribavirin in enhancing the antiviral effect of interferon alfa in chronic hepatitis C.     

Utility of early testing for HCV viremia as predictive factor of sustained response during interferon or interferon plus ribavirin treatment

BACKGROUND/AIM: To evaluate the utility of early testing for hepatitis C viremia as a predictor of treatment outcome during interferon or combination therapy. METHODS: We studied 184 patients with chronic hepatitis C who received interferon and were monitored for HCV RNA. Sixty-two patients received interferon alone for 12 months and 122 patients, who were still HCV RNA positive at 2 months, received an additional 12-month course of interferon and ribavirin combination therapy. RESULTS: Using this strategy, sustained response occurred in a total of 34 patients (18.5%). Independent variables associated with sustained response were HCV genotype (p=0.06), viral load < or = 5.1 logs/ml (p= 0.005) and negative HCV RNA at 1 month (p<0.0001) in the interferon group, and female sex (p=0.04), genotype (p=0.03), viral load < or = 5.5 logs/ml (p=0.01), normal ALT (p=0.001) and decline in viral load > or = 1.2 logs/ml after 2 months of interferon monotherapy (p<0.001) and negative viremia at 5 months of ribavirin onset (p<0.0001) in the combination therapy group. Persistence of viremia at 1 month of interferon monotherapy and at 5 months of combination therapy were the strongest predictors of non-response (negative predictive value of 100% and 99%, respectively). CONCLUSIONS: Qualitative assessment of HCV RNA during treatment is the strongest predictor of sustained response during interferon or combination therapy for chronic hepatitis C.     

A pilot study of interferon alfa and ribavirin combination in liver transplant recipients with recurrent hepatitis C

Although interferon alfa (IFN-alpha) and ribavirin are widely used in the treatment of hepatitis C, their role in the transplant recipient is unclear. We conducted a pilot study to determine the efficacy and safety of this therapy in transplant recipients with recurrent hepatitis C. Patients at least 6 months posttransplantation were treated with IFN-alpha 3 million units 3 times a week subcutaneously and ribavirin 800 mg daily by mouth for 48 weeks followed by ribavirin monotherapy for 24 weeks. The primary end point was sustained virologic response, and secondary end points included biochemical, virologic, and histologic responses at the end of combination treatment. Thirty-eight patients initiated therapy but 16 withdrew due to adverse effects, including 2 with myocardial infarction. Median age was 50 years; 74% were men, and 91% had genotype 1. The median interval between transplantation and enrollment was 23 months. On an intention-to-treat basis, 7 patients (18%) had a biochemical and 5 (13%) had a virologic response at the end of combination treatment. Inflammatory activity did not change, but fibrosis worsened in virologic nonresponders. Ribavirin maintenance caused a further decrease in serum alanine aminotransferase levels, but hepatitis C virus (HCV) RNA levels increased. Only 2 of the 38 patients (5%) had a sustained virologic response. Several patients required treatment with erythropoietin for anemia. In conclusion, IFN-alpha and ribavirin are effective in a small proportion of liver allograft recipients with recurrent hepatitis C. Adverse effects occur commonly, requiring dose reductions and treatment withdrawal.     

Firstline treatment for hepatitis C: combination interferon/ribavirin versus interferon monotherapy

In the initial treatment of chronic hepatitis C, interferon‐alfa (IFN‐α) monotherapy for 24–48 weeks induces sustained response rates of only 10–20%. Combination therapy with IFN‐α plus ribavirin induces a sustained response in 40–50% of patients, and can be now recommended as the firstline therapy for chronic hepatitis C. Stopping therapy at week 12 because of persistent viraemia is unnecessary with the combination therapy because later clearance of HCV RNA can still occur with a sustained response. Patients with HCV genotype 1 should receive 48 weeks of combination therapy, in contrast to 24 weeks for patients with genotypes 2 or 3. For patients who cannot tolerate the side effects of ribavirin, such as anaemia, IFN‐α at 3 MU three times weekly for 48 weeks is preferred as the initial therapy. The long‐acting pegylated IFN can be expected to enhance the efficacy of combination therapy in the treatment of chronic hepatitis C and appears to be much more potent as monotherapy. Further studies are needed to improve the current ‘half‐full’ status of chronic hepatitis C treatment.     

Triple combination of interferon alpha-2b,ribavirin, and amantadine for treatment of chronic hepatitis C

Retreatment of interferon-resistant chronic hepatitis C represents a significant clinical challenge. In an open-label, pilot study, the safety and efficacy of interferon alpha-2b, ribavirin, and amantadine were assessed. Twenty patients with chronic hepatitis C who had previously failed to respond to a course of interferon monotherapy followed by a course of combination therapy (10 patients received interferon alpha-2b [3 million units three times a week] plus ribavirin [800 mg/d] and 10 patients received interferon alpha-2b [3 million units three times a week] plus amantadine [200 mg/d]) were enrolled in this retreatment protocol. One month after discontinuation of their last regimen, patients started treatment with interferon alpha-2b (3 million units three times a week), ribavirin (1,000-1,200 mg/d), and amantadine (200 mg/d). Biochemical and virologic end points were monitored. Patients with hepatitis C virus (HCV) RNA levels of <100 copies/mL at the end of 24 weeks of therapy completed a 48-week course of interferon alpha-2b, ribavirin, and amantadine treatment. Of the enrolled subjects, 60% were male, 85% were white, 85% had HCV genotype 1, and 20% had histologic cirrhosis. The mean age +/- SD of the patients was 44.1 +/- 4.9 years, the mean baseline HCV RNA level +/- SD was 1,845,150 +/- 1,279,069 copies/mL, and the mean baseline alanine aminotransferase level +/- SD was 130 +/- 100 U/L. Five patients (25%) became HCV RNA negative (<100 copies/mL) after 24 weeks of treatment, with only three patients (15%) remaining HCV RNA negative at the end of 48 weeks of treatment. This end of treatment response was sustained 6 months after the discontinuation of treatment in only two patients (10%). In this interferon-resistant group, a treatment regimen of interferon alpha-2b, ribavirin, and amantadine was associated with only a 10% sustained viral eradication rate.     

Effect of ribavirin on dynamics of hepatitis C viremia in interferon alpha-treated patiens with response or no response

Combination therapy with interferon-alpha (IFN alpha) plus Ribavirin has been shown to improve the response rate in patients with chronic hepatitis C as compared to IFN alpha alone. However, the mode of anti-viral action of Ribavirin is still unknown. To prove, whether Ribavirin has any additional effect on the decline of hepatitis C viremia during the first weeks of treatment patients with and without combination therapy were compared. Kinetic studies were performed in patients who either responded to IFN alpha alone or IFN alpha plus Ribavirin combination as well as in nonresponders to both forms of therapeutic approaches. 64 IFN alpha naive patients with histologically proven chronic hepatitis C were included in the study. Patients were randomized to receive either IFN alpha-2a (Hoffmann-La Roche) 6 MU thrice weekly or IFN alpha 6 MU tiw plus Ribavirin (Meduna) 14 mg/kg/day for 12 weeks. 37 patients (58%) became HCV RNA-negative (= responders; 17 [46%] with IFN alpha alone, and 20 [54%] with combination therapy). 27 patients remained HCV RNA-positive (= non-responders; 13 [48%] with IFN alpha alone, and 14 [52%] with combination therapy). HCV RNA concentrations were measured in all patients at baseline as well as 1, 2, 4, and 12 weeks after the start of treatment (bDNA assay, Chiron). Using nonradioactive single-stranded conformation (SSCP)-analysis of the HCV hypervariable region 1 we investigated further whether initial viral decline is correlated with changes in viral quasispecies distribution. In primary responders, ribavirin did not influence hepatitis C viremia decline which was of biphasic nature. Also in nonresponders HCV RNA levels decreased after one week of treatment irrespectively of the mode of therapy (mean 10.0 +/- 2.3 to 5.5 +/- 1.1) (phase 1). In the following weeks, however, 2 types of HCV dynamics could be observed (phase 2). In patients with combination therapy, a further reduction of viremia level could be observed, whereas viremia levels in patients with IFN alpha alone slightly increased (week 12: 3.0 +/- 0.5 MEq/mL [combination, n = 15] vs. 7.5 +/- 2.9 MEq/mL [IFN alpha-mono, n = 12]). The individual response of these nonresponder patients showed, however, marked differences (range percentage decline after 4 weeks, 0-98%). Changes in the viral population (quasispecies distribution) as cause of these differences could be excluded by SSCP-analysis of PCR products of the HCV hypervariable region 1. Ribavirin in combination with IFN alpha exerts an additional anti-viral/immunmodulatory effect which manifests itself in phase 2 of hepatitis C viremia decline. The biphasic decline of hepatitis C viremia also observed in IFN alpha-nonresponders can not be explained by the selection of primary IFN alpha-resistant viral variants. The individual differences in the dynamic of hepatitis C viremia observed in the so called "nonresponders" imply that the term "nonresponder" should be redefined, considering our observation that a marked viral decline can occur in these patients.