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.     

Daily or three times a week interferon alfa-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C

BACKGROUND/AIMS: Data on hepatitis C virus (HCV) viral dynamics and on the effect of interferon in blocking virion production have suggested a rationale for daily administration of interferon in patients with chronic hepatitis C infection. We compared the efficacy and safety of daily interferon alfa-2b in combination with ribavirin with those of interferon alfa-2b three times a week alone or in combination with ribavirin. METHODS: We randomly assigned 321 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin for 48 weeks or daily interferon alfa-2b (3 million units per day for 12 weeks then 3 million units three times per week for 24 weeks) and ribavirin (36 week treatment). RESULTS: The rate of sustained virologic response (defined as an undetectable serum HCV-RNA level 72 weeks after initiation of treatment) was higher in patients who received combination therapy with three times weekly interferon (51.7%) or daily interferon (46.1%) than in patients who received interferon alone (25%) (P=0.0001 and P=0.002, respectively). Independent predictive factors for sustained virologic response were combination therapy, weight, genotype and viral load. In conclusion, in patients with chronic hepatitis C, combination therapy with induction treatment (daily interferon for 12 weeks) and shorter duration of treatment was not different from combination therapy for 48 weeks without induction treatment. CONCLUSIONS: Induction treatment with interferon for 12 weeks and combination therapy for a total duration of 36 weeks could therefore be cost effective.     

Peginterferon alfa-2a plus ribavirin for treating chronic hepatitis C virus infection: analysis of Mexican patients included in a multicenter international clinical trial

Treatment with polyethylene glycol-modified interferon alfa-2a (peginterferon) alone produces significantly higher sustained antiviral responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. Thirty-two patients were randomly assigned to treatment, and received at least one dose of medication consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1,000 or 1,200 mg, depending on body weight) (n = 14), weekly peginterferon alfa-2a plus daily placebo (n = 6), or three million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks (n = 12). More patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than patients who received interferon alfa-2b plus ribavirin (7/14 vs. 4/12) or peginterferon alfa-2a plus placebo (0/6). The overall safety profiles of the three treatment regimens were similar. In conclusion, for patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained viral reduction compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.     

Economic and clinical effects of evaluating rapid viral response to peginterferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C

OBJECTIVES: Evaluation of 12-wk viral response to initial antiviral therapy for chronic hepatitis C has been recommended to minimize antiviral-associated morbidity and costs. The aim of this study was to examine the economic and clinical effects of evaluating rapid viral response during antiviral therapy for treatment naive chronic hepatitis C patients. METHODS: We applied viral response and drug dosage from an international randomized clinical trial of ribavirin plus peginterferon alfa-2b or ribavirin plus interferon alfa-2b to a previously published computer cohort simulation to project lifelong clinical and economic outcomes. Natural history and economic estimates were based on published literature, expert panel estimates, and actual variable and reimbursement cost data. RESULTS: The assessment of 12-wk rapid viral response reduced antiviral treatment duration by 40-44% and antiviral costs by 44-45% (savings of $15,116-16,268 for peginterferon plus ribavirin and $8300 for interferon plus ribavirin) compared to full 48-wk dosing. With the 12-wk evaluation, the marginal cost-effectiveness of peginterferon plus ribavirin versus interferon plus ribavirin was $13,600-22,800 compared with $14,600-25,000 per discounted quality adjusted life-year gained with the 24-wk evaluation. For genotype 1, hepatitis C infected patients, 12-wk testing for peginterferon plus ribavirin remaining preferred and cost-effective compared with interferon plus ribavirin. For genotype 2 or 3, hepatitis C infected patients, 12-wk testing yielded similar results to those of 24-wk treatment. CONCLUSIONS: Assessment of 12-wk viral response in genotype 1, hepatitis C infected patients should reduce peginterferon plus ribavirin morbidity and costs and improve its cost-effectiveness; however, for genotype 2 and 3, hepatitis C infected patients, 12-wk testing and 24-wk treatment have similar outcomes. Decisions regarding continuation of antiviral treatment should also consider the variability in the accuracy of quantitative viral assays as well as patient preferences and other potential benefits of the same treatments.     

Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C

AIM: To assess systematically the spectrum and extent of depressive symptoms comparing patient groups receiving peginterferon or conventional interferon. METHODS: Ninety-eight patients with chronic hepatitis C and interferon-based therapy (+ribavirin) were consecutively enrolled in a longitudinal study. Patients were treated with conventional interferon alfa-2b (48/98 patients; 5 MIU interferon alfa-2b thrice weekly) or peginterferon alfa-2b (50/98 patients; 80-150 μg peginterferon alfa-2b) in combination with weight-adapted ribavirin (800-1 200 mg/d). Repeated psychometric testing was performed before, three times during and once after antiviral therapy: Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS), anger/hostility by the Symptom Checklist-90 Items Revised (SCL-90-R). RESULTS: Therapy with pegylated interferon alfa-2b produces comparable scores for depression (ANOVA: P = 0.875) as compared to conventional interferon. Maximums of depression scores were even higher and cases of clinically relevant depression were frequent during therapy with peginterferon. Scores for anger/hostility were comparable for both therapy subgroups. CONCLUSION: Our findings suggest that the extent and frequency of depressive symptoms in total are not reduced by peginterferon. Monitoring and management of neuropsychiatric toxicity especially depression have to be considered as much as in antiviral therapy with unmodified interferon.     

Cost effectiveness of ribavirin/interferon alfa-2b after interferon relapse in chronic hepatitis C

PURPOSE: Many patients with chronic hepatitis C who are treated with interferon suffer a relapse after an initial response. About half of these patients have a sustained virological response to retreatment with the combination of ribavirin and interferon alfa-2b. The aim of this study was to estimate the cost effectiveness of retreatment with combination therapy versus interferon alone for patients who have previously relapsed after interferon. SUBJECTS AND METHODS: Data from a randomized trial among 345 relapsed patients that compared combination therapy with interferon alone were used to project lifelong clinical and economic outcomes. Natural history and economic estimates (discounted at 3% per year) were based upon published literature, expert panel estimates, and cost and reimbursement data. RESULTS: Compared with retreatment with interferon alone, combination therapy should prolong life expectancy by about 2 discounted quality-adjusted life years (3 life years, undiscounted) while increasing costs modestly. The results were robust, maintaining an advantage to combination therapy in sensitivity analysis for all subgroups and with reasonable variations in all model parameters. CONCLUSION: For patients with chronic hepatitis C who relapse after an initial response to interferon alone, retreatment with the combination of ribavirin and interferon alfa-2b should prolong life and be cost effective.     

Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study

BACKGROUND AND AIMS: Hepatitis C virus (HCV) reinfection after liver transplantation is frequent and leads to chronic hepatitis and cirrhosis. The use of antiviral therapy in this situation remains controversial. This study aimed to assess the safety and efficacy of interferon alfa-2b plus ribavirin for recurrent hepatitis C following liver transplantation. METHODS: Transplant recipients with recurrent chronic hepatitis C were randomized to receive either no treatment or therapy with interferon alfa-2b (3 MU 3 times a week) plus 1000-1200 mg/day ribavirin for 1 year. Patients were followed up for 6 months after the end of treatment. The primary end point was loss of HCV RNA 6 months after the end of treatment. RESULTS: Fifty-two patients were randomized (treatment, 28; placebo, 24). Sixteen patients were withdrawn from the study; 12 (43%) were from the treated group (mainly for anemia [7 patients]) and 4 (17%) from the control group. In the treated group, serum HCV RNA was undetectable in 9 patients (32%) at the end of treatment and 6 (21.4%) at the end of the follow-up period, whereas no patient in the control group lost HCV RNA at any point (P = 0.036 at the end of follow-up). However, there was no significant histologic improvement. CONCLUSIONS: The combination of interferon alfa-2b plus ribavirin induced a sustained virologic response in 21% of transplant recipients with recurrent hepatitis C. However, 43% discontinued therapy due to adverse events (primarily severe anemia). Strategies to enable treatment with lower doses of ribavirin need to be explored.     

Response to pegylated interferon alpha-2b and ribavirin in children with chronic hepatitis C

GOALS: The purpose of this communication is to report our observations on the treatment of a diverse group of adolescent patients who were chronically infected with hepatitis C and received pegylated interferon and ribavirin. BACKGROUND: The currently accepted optimal therapy for adults with chronic hepatitis C is weekly injections of pegylated interferon and twice daily oral ribavirin. Information on interferon alone or in combination with ribavirin for chronic hepatitis C in children is limited. There is no published information on pegylated interferon and ribavirin in pediatric patients who previously failed interferon therapy. REPORT: Ten patients 11 to 18 years old received weekly pegylated interferon and twice daily ribavirin for hepatitis C. Treatment continued for 48 weeks, except for 1 patient with hepatitis C virus type 3a who was treated for 24 weeks and 1 patient who did not complete the course of treatment. The period of observation continued from November 2002 to December 2004. Within this group were 3 pediatric patients who had previously failed interferon therapy for hepatitis C. RESULTS: All but 1 patient had a viral response (no detectable virus) at some time during or after the treatment. Three patients achieved sustained viral response (no detectable virus 6 mo after the therapy). One patient who previously failed interferon therapy was among the sustained responders. CONCLUSIONS: In response to treatment with pegylated interferon and ribavirin, children and adolescents with chronic hepatitis C achieve results similar to those seen in adults. Previous antiviral therapy does not preclude positive response to pegylated interferon and ribavirin.     

The impact of peginterferon alfa-2a plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C

BACKGROUND/AIMS: Peginterferon alfa-2a plus ribavirin improves sustained virological responses compared with interferon alfa-2b and ribavirin, or peginterferon alfa-2a alone in chronic hepatitis C. We examined the impact of these treatments on health related quality of life (HRQOL). METHODS: Patients (n=1121) were randomized to peginterferon alfa-2a weekly plus ribavirin or placebo, or interferon alfa-2b thrice weekly plus ribavirin. HRQOL was assessed with the SF-36 Health Survey and Fatigue Severity Scale (FSS). RESULTS: Patients receiving peginterferon alfa-2a plus ribavirin reported better HRQOL than those receiving interferon alfa-2b plus ribavirin. These differences were statistically significant for three SF-36 domains and both FSS scores (p<=0.05). Patients receiving peginterferon alfa-2a plus placebo had the least impairment; adding ribavirin significantly decreased five domains of the SF-36 and both FSS scores. Sustained virological response was associated with improvement at follow-up on all SF-36 and FSS scores. CONCLUSIONS: The effects of combination therapy on HRQOL and fatigue are less with peginterferon alfa-2a plus ribavirin than interferon alfa-2b plus ribavirin. Each medication in combination therapy with interferon and ribavirin, affects patients' quality of life differently. Understanding the relationship of specific therapeutic options to HRQOL may help physicians minimize the impact of therapy on HRQOL.     

High-dose vitamins E and C supplementation prevents ribavirin-induced hemolytic anemia in patients with chronic hepatitis C

Aim:  In combination therapy using interferon (IFN) and ribavirin for chronic hepatitis C, reduced doses should be used due to ribavirin-induced hemolytic anemia. The present study aimed to elucidate whether high-dose vitamins E and C supplementation attenuated ribavirin-induced hemolytic anemia.
Methods:  Twenty-one consecutive patients with chronic hepatitis C were enrolled in this study between July 2003 and December 2004, and received high-dose vitamins E (2000 mg) and C (2000 mg) supplementation, daily, in addition to IFN alfa-2b and ribavirin combination therapy (vitamins E/C group). Twenty-one sex- and age-matched patients who received a standard regimen of IFN alfa-2b and ribavirin for chronic hepatitis C between January 2001 and June 2003 were evaluated as the control group.
Results:  Decrease in hemoglobin level was significantly prevented in the vitamins E and C group compared to that in the control group ( P  =   0.029). Three (14.3%) patients in the control group discontinued treatment because of anemia, while no treated patient dropped out of the study due to anemia. Sustained virological response was not significantly different between the two groups.
Conclusion:  High-dose vitamins E and C supplementation prevented ribavirin-induced hemolytic anemia during combination therapy with ribavirin and IFN alfa-2b in patients with chronic hepatitis C.     

First-line therapy with daily versus thrice-weekly interferon alfa-2b plus ribavirin for chronic hepatitis C

OBJECTIVES: Combination therapy with interferon and ribavirin is the most effective treatment for chronic hepatitis C today. Before pegylated interferons became available, higher and more frequent doses of interferon were expected to be more effective than the standard regimen of three million units thrice weekly. In fact, daily dosing is still proposed for non-pegylated interferon. The aim of this study was to compare the efficacy and safety of daily versus thrice-weekly interferon alfa-2b in combination with ribavirin as first-line treatment of chronic hepatitis C. METHODS: A total of 116 treatment-naive patients were randomised to receive either interferon alfa-2b three million units daily or thrice-weekly in combination with ribavirin for 24 weeks. Patients with hepatitis C virus (HCV) genotype 1 who were HCV-RNA negative at 24 weeks continued treatment with thrice-weekly interferon plus ribavirin for another 24 weeks. Sustained virological response was defined as an undetectable HCV-RNA level 24 weeks after treatment was completed (end of follow-up). RESULTS: In an intention-to-treat analysis, HCV-RNA was undetectable at the end of treatment in 71% and 74% of patients treated with daily and thrice-weekly interferon, respectively. At the end of follow-up, HCV-RNA was undetectable in 47% and 57% of patients treated with daily and thrice-weekly interferon, respectively. Sustained virological response rates were almost twice as high in patients with genotypes 2 and 3 as in patients with genotype 1 but were not different between treatment groups. CONCLUSIONS: This study could not show any difference between daily and thrice-weekly standard interferon plus ribavirin in achieving end-of-treatment and sustained virological responses in chronic hepatitis C.     

Scientific rationale and study design of the individualized dosing efficacy vs flat dosing to assess optimal pegylated interferon therapy (IDEAL) trial: determining optimal dosing in patients with genotype 1 chronic hepatitis C

Summary.  Current standard-of-care antiviral treatment for patients with chronic hepatitis C is combination therapy with pegylated interferon (PEG-IFN) alfa plus ribavirin. Two large clinical trials determined that each PEG-IFN alfa compound, when given in combination with ribavirin, results in overall sustained virological response (SVR) rates of approximately 50%; SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 are typically lower (42–46%). Differences in study design, treatment regimens, and patient populations preclude comparison of the data across trials; therefore, the most effective use of PEG-IFN alfa in combination with ribavirin is unclear. The Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study is a phase 3b, randomized, parallel-group, US multicentre trial in treatment-naive genotype 1 patients with chronic hepatitis C. Initially, this study was undertaken to evaluate the efficacy and safety of weight-based ribavirin dosing (800–1400 mg / day) and PEG-IFN alfa-2b dosing (arm 1: PEG-IFN alfa-2b 1.5 μg / kg / week; arm 2: PEG-IFN alfa-2b 1.0 μg / kg / week). However, because a clinical trial directly comparing the efficacy and safety of PEG-IFN alfa-2a and alfa-2b in combination with weight-based ribavirin dosing has not been performed, an additional arm (arm 3: PEG-IFN alfa-2a 180 μg / week plus ribavirin 1000–1200 mg / day) was included to address this important issue. IDEAL is fully enrolled (>3000 patients) and complete study data, including SVR rates, are expected in early 2008. Herein, we present the scientific rationale and study design, discuss key data from other trials, and summarize our expectations of this study.     

High-dose interferon alfa-2b and ribavirin in patients previously treated with interferon: results of a prospective, randomized, controlled trial.

BACKGROUND: Kinetic studies have demonstrated a more rapid reduction in hepatitis C virus (HCV) RNA levels among patients taking high daily doses of interferon compared with those taking standard-dose interferon. GOALS: To compare the efficacy and safety of high-dose interferon alfa-2b and ribavirin with standard-dose interferon alfa-2b and ribavirin in chronic hepatitis C patients previously treated with interferon. STUDY: One hundred seven patients (30 interferon relapsers and 77 interferon nonresponders) were randomized to take either high-dose interferon alfa-2b in combination with ribavirin (group A) (consisting of 5 MU/d for 4 weeks, 5 MU three times weekly for 8 weeks, and then 3 MU three times weekly for 36 weeks) or standard-dose interferon alfa-2b and ribavirin (group B) for 48 weeks. Serum alanine transaminase (ALT), HCV RNA levels, and safety data were prospectively collected and compared during treatment and at week 24 of follow-up. RESULTS: The mean serum ALT and HCV RNA levels, as well as the proportion of patients with genotype 1 and cirrhosis and who were African American, were similar in the two treatment groups at study entry. The rates of suppression of HCV RNA to undetectable levels at weeks 4, 12, and 48 were similar. In addition, the sustained virologic response rates at week 24 of follow-up were similar in groups A and B (29% vs. 39%, respectively, p = 0.277). Clinical variables that correlated with a sustained virologic response included a history of relapse to previous interferon therapy and non-1 HCV genotype ( p < 0.01). CONCLUSIONS: Short-term, high-dose interferon alfa-2b and ribavirin failed to demonstrate a tangible benefit compared with standard-dose interferon alfa-2b and ribavirin. However, our study results and others suggest that standard-dose interferon and ribavirin for 48 weeks should be considered for selected patients who did not respond to previous interferon therapy.     

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.     

HLA class I B44 is associated with sustained response to interferon + ribavirin therapy in patients with chronic hepatitis C

OBJECTIVE: The aim of this study was to assess the influence of host genetic factors on response to combination therapy for chronic hepatitis C infection. METHODS: Patients with biopsy-proved chronic hepatitis C infection were treated with interferon alone (n = 143) or combined therapy of interferon + ribavarin (n = 105; 46 treatment na?ve, 59 relapsers). Human leukocyte antigen (HLA) class I was determined by microlymphocytotoxicity and class II by polymerase chain reaction-single specific oligonucleotide. The two biallelic tumor necrosis factor-alpha promoter polymorphisms were studied by a polymerase chain reaction-amplification refractory mutation system. Other variables measured were viral genotype, hepatitis C virus RNA load, liver function tests, and ferritin concentration. RESULTS: Univariate analysis indicated that patients bearing HLA B44+, DRB1*03, infected by genotype non-1, with higher concentrations of transaminases and shorter duration of infection showed a higher sustained response (SR) rate than those on combination therapy. HLA class II and TNF-alpha promoter polymorphisms were not related to SR. In multivariate analysis, non-1 genotype (OR 2.42, 95% CI 1.12-5.55, p = 0.026) and HLA B44+ (OR 4.84, 95% CI 1.3-17.8, p = 0.017) were the independent variables associated with SR. However, HLA B44+ was not associated with SR in patients treated with interferon alone. CONCLUSIONS: HLA class I B44 is related to a higher rate of SR in combination therapy but not in interferon monotherapy, whereas HLA class II, tumor necrosis factor-alpha -238A or -308A seem not to influence response to the antiviral therapy. These findings may be of value in therapy selection for hepatitis C-infected patients.     

Current therapy for hepatitis C: pegylated interferon and ribavirin

The combinations of peginterferon alfa-2a or peginterferon alfa-2b with ribavirin lead to significant improvement in sustained virological response when compared with standard interferon and ribavirin therapy. These newer agents represent the most effective treatments available for the initial therapy of patients with chronic hepatitis C. A review of the clinical trials to date suggests certain similarities and differences between the two preparations. For both regimens, however, it is apparent that information concerning the predictability of response and the importance of adherence to the treatment regimens will be of great value in the therapeutic management of chronic hepatitis C. Although viral load and genotype, gender, age, and absence of fibrosis have been shown consistently to be important predictors of response, identification of additional host immune and genetic factors involved in determining outcome of antiviral therapy are necessary.     

Combination of "low-dose" ribavirin and interferon alfa-2a therapy followed by interferon alfa-2a monotherapy in chronic HCV-infected non-responders and relapsers after interferon alfa-2a monotherapy

AIM: To report on the efficacy, safety and tolerability of interferon alfa-2a combined with a low dose of ribavirin for relapsers and non-responders to alpha interferon monotherapy. METHODS: Thirty four chronic hepatitis C virus-infected non responders to interferon alfa-2a monotherapy (a course of at least 3 months treatment) and 13 relapsers to interferon alfa-2a monotherapy (a dose of 3 to 6 million units three times per week for at least 20 weeks but not more than 18 months) were treated with the same dose of interferon alfa-2a used before (3 to 6 million units three times per week) and ribavirin (10mg/kg daily) for 6 months. In complete responders, interferon alfa-2a was administered for further 6 months at the same dose used before as monotherapy. RESULTS: Seven (20.6%) of 34 non responders stopped the combined therapy due to adverse events, including two patients with histological and clinical Child A cirrhosis. In 17/27 (63%) non responders, the combined therapy was stopped after three months because of non response. Ten of the 27 non responders completed the 12 month treatment course. At a mean follow up of 28 months (16-37 months) after the treatment, 4/10 (15%) previous non responders still remained complete responders. All 13 previous relapsers completed the 12-month treatment course. At a mean follow up of 22 months (9-36 months) after treatment, 6/13 (46%) the previous relapsers were still sustained complete responders. CONCLUSION: Our treatment schedule of the combined therapy for 6 months of interferon Alfa-2a with a low dose of ribavirin (10mg/kg/day) followed by 6 months of interferon Alfa-2a monotherapy is able to induce a sustained complete response rate in 15% of non responders and 46% of relapsers with chronic hepatitis C virus related liver diseases comparable to those obtained with the standard doses of ribavirin 1000-1200 mg/day. Randomized prospective controlled trials using lower total amounts of ribavirin in combination with interferon should be performed.     

Safety and efficacy of treatment with pegylated interferon alpha-2a with ribavirin in chronic hepatitis C genotype 4

The hepatitis C virus (HCV) genotype is an important predictive outcome parameter for pegylated interferon plus ribavirin therapy. Most published therapeutic trials to date have enrolled mainly patients with HCV genotypes 1, 2 and 3. Limited studies have focused on genotype 4 patients, who have had a poor representation in pivotal trials. Our aim was to evaluate the efficacy and safety of treatment with standard dose pegylated interferon alfa-2a in combination with weight-based ribavirin in patients with chronic hepatitis C genotype 4. In this prospective observational study, 198 patients with HCV-4 were included in this study from February 2004 to August 2005,188 patients who received at least 1 dose of drugs were included in the ITT analysis and they were treated with pegylated interferon alfa-2a and ribavirin for 48 weeks. Baseline and demographic characteristics, response to treatment at weeks 12, 48 and 72, and the nature and frequency of adverse effects were analyzed. Virological response at week 12 was achieved in 144 patients (76.6%). Virological response at the end of treatment was present in 110 patients (58.5%). At week 72, 99 patients presented SVR (52.7%). The reported adverse events were similar to those found in the literature for treatments of similar dose and duration. In conclusion, combined treatment with pegylated interferon alfa-2a and ribavirin was well tolerated and effective in chronic hepatitis C genotype 4, yielding response rates between those reported for genotype 1 and those of genotypes 2-3.     

Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence

BACKGROUND AND AIMS: A proportion of liver transplanted patients with recurrent chronic hepatitis have a sustained virological response to combination therapy with interferon plus ribavirin. However, the long term benefit of antiviral therapy with regard to hepatitis C virus (HCV) RNA clearance remains unknown in patients with HCV recurrence. This study examined the long term biochemical, virological, and histological outcome in transplanted patients with recurrent chronic hepatitis who had a sustained virological response to antiviral therapy. PATIENTS AND METHODS: Fifty four patients with recurrent hepatitis C were treated with antiviral therapy involving induction by combination therapy (interferon (IFN) plus ribavirin) for six months and maintenance ribavirin therapy for 12 months. Fourteen patients who had recurrent chronic hepatitis and sustained virological response to antiviral therapy were followed for three years after the end of antiviral therapy. Serum alanine aminotransferases were assessed every three months during the observation period. Serum hepatitis C RNA detected by polymerase chain reaction was evaluated every six months during follow up, and protocol biopsy procedures were performed routinely every year. Semiquantitative histopathological assessment of allograft hepatitis was performed using the Knodell score and HCV was also detected by polymerase chain reaction on frozen graft tissue samples. RESULTS: At the end of antiviral therapy, the sustained response rate was 26%. A complete response (normal serum alanine aminotransferase level and undetectable serum HCV RNA) was achieved in 13/14 (93%) patients three years after the end of treatment. A comparison of liver histology findings before and after a mean of three years after antiviral therapy showed a clear improvement in 12/14 (86%) patients. In 5/14 (36%) patients, the last biopsy showed normal or near normal histological findings. After three years of follow up, the total Knodell score was 3.2 (range 1-8) versus 8.3 (range 5-12) before treatment (p=0.001). Graft HCV RNA was detectable before treatment in all 14 patients and was undetectable at the end of follow up in 13/14 (93%) patients tested. CONCLUSION: In patients with biochemical and virological responses induced by ribavirin and interferon, a complete response was sustained in 93% for at least three years after cessation of therapy. This long term response was associated with absence of detectable intrahepatic hepatitis C RNA and marked histological improvement.     

Consensus Interferon and Ribavirin in Patients with Chronic Hepatitis C Who Were Nonresponders to Pegylated Interferon alfa-2b and Ribavirin

Recent studies suggest that consensus interferon and ribavirin is effective in retreating patients with chronic hepatitis C who failed therapy with interferon alfa and ribavirin. The objective of the present study was to assess the efficacy, safety, and tolerability of consensus interferon and ribavirin in patients who did not respond to pegylated interferon alfa-2b and ribavirin. We retrospectively identified 137 consecutive nonresponders to pegylated interferon alfa-2b and ribavirin and initiated patients on daily treatment with consensus interferon 15 mug subcutaneously and weight-based ribavirin for 48 weeks. If patients were HCV RNA negative at 12 weeks, the dose was reduced to 15 mug three times weekly for the remaining 36 weeks. The sustained virologic response rate was 37%. Daily consensus interferon therapy was safe and well tolerated in all patients. No dose reductions were required, and no patient discontinued therapy. Further studies of consensus interferon and ribavirin in nonresponders are warranted.