Retreatment with interferon and ribavirin vs interferon alone according to viraemia in interferon responder-relapser hepatitis C patients: a prospective multicentre randomized controlled study. Effect of retreatment with interferon alone or interferon plus ribavirin on hepatitis C virus quasispecies diversification in nonresponder patients with chronic hepatitis C. Efficacy of 5 MU of interferon in combination with ribavirin for naïve patients with chronic hepatitis C virus: a randomized controlled trial. The pattern of response to interferon alpha (alpha-IFN) predicts sustained response to a 6-month alpha-IFN and ribavirin retreatment for chronic hepatitis C. TVVH Study Group. Interferon-alpha-2b and ribavirin for retreatment of chronic hepatitis C. Combination treatment of interferon alpha-2b and ribavirin in comparison to interferon monotherapy in treatment of chronic hepatitis C genotype 4 patients. Reduction of relapse rates by 18-month treatment in chronic hepatitis C. A Benelux randomized trial in 300 patients. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT) Interferon-alpha alone versus interferon-alpha plus ribavirin in patients with chronic hepatitis C not responding to previous interferon-alpha treatment. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. A randomized trial of high-dose interferon alpha-2b, with or without ribavirin, in chronic hepatitis C patients who have not responded to standard dose interferon. Interferon alpha-2B and ribavirin in combination for patients with chronic hepatitis C who failed to respond to, or relapsed after, interferon alpha therapy: a randomized trial. Interferon-alpha (IFN alpha) daily dose versus IFN alpha plus ribavirin for treatment-naive chronic hepatitis c patients infected by genotype 1b. Interferon-alpha-2B and ribavirin in combination for chronic hepatitis C patients not responding to interferon-alpha alone: an Italian multicenter, randomized, controlled, clinical study. Interim analysis of a randomized controlled trial of combination of ribavirin and high dose interferon-alpha in interferon nonresponders with chronic hepatitis C. Peginterferon alpha-2a combination therapies in chronic hepatitis C patients who relapsed after or had a viral breakthrough on therapy with standard interferon alpha-2b plus ribavirin: a pilot study of efficacy and safety. Ribavirin and interferon-alpha combination therapy vs interferon-alpha alone in the retreatment of chronic hepatitis C: a randomized clinical trial. Evaluation of long-term efficacy of interferon alpha-2b and ribavirin in combination in naive patients with chronic hepatitis C: an Italian multicenter experience. Ribavirin-Interferon in Chronic Hepatitis Italian Group Investigators. Clinical comparison of high-dose interferon-alpha2b with or without ribavirin for treatment of interferon-relapsed chronic hepatitis C. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. Interferon versus ribavirin plus interferon in chronic hepatitis C previously resistant to interferon: a randomized trial. 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. Interferon-alpha2a/ribaviran versus interferon-alpha2a alone for the retreatment of hepatitis C patients who relapse after a standard course of interferon. Randomized trial of three different regimens for 24 weeks for re-treatment of chronic hepatitis C patients who failed to respond to interferon-alpha monotherapy in Taiwan. High rate of long-term virological response after a 1-year course of interferon +/- ribavirin in chronic hepatitis C relapsers. Results of a 191 patients randomized trial. Induction interferon and ribavirin for re-treatment of chronic hepatitis C patients unresponsive to interferon alone. The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C. Interferon-alpha2b induction treatment with or without ribavirin in chronic hepatitis C: a multicenter, randomized, controlled trial. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin. Treatment with interferon-alpha2a alone or interferon-alpha2a plus ribavirin in patients with chronic hepatitis C previously treated with interferon-alpha2a. CONSTRUCT Group. High sustained response rate in patients with histologically mild (low grade and stage) chronic hepatitis C infection. A randomized, double blind, placebo controlled trial of interferon alpha-2b with and without ribavirin. Retreatment of non-responder or relapser chronic hepatitis C patients with interferon plus ribavirin vs interferon alone. The safety and tolerability of daily infergen plus ribavirin in the treatment of naíïve chronic hepatitis C patients. Histological response in patients treated by interferon plus ribavirin for hepatitis C virus-related severe fibrosis. Interferon alpha plus ketoprofen or interferon alpha plus ribavirin in chronic hepatitis C non-responder to interferon alpha alone: results of a pilot study. Interferon-alpha plus ribavirin in chronic hepatitis C resistant to previous interferon-alpha course: results of a randomized multicenter trial. Combination of ribavirin and interferon-alfa surpasses high doses of interferon-alfa alone in patients with genotype-1b-related chronic hepatitis C. High-dose interferon plus ribavirin in chronic hepatitis C not responding to recombinant alpha-interferon. Sequential versus concomitant administration of ribavirin and interferon alfa-n3 in patients with chronic hepatitis C not responding to interferon alone: results of a randomized, controlled trial. A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. The Hepatitis C Intervention Therapy Group. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. A randomized trial of induction doses of interferon alone or in combination with ribavirin or ribavirin plus amantadine for treatment of nonresponder patients with chronic hepatitis C. 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. Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis. Peginterferon alpha-2a (40 KD) plus ribavirin for the treatment of chronic hepatitis C in Japanese patients. Treatment of chronic hepatitis C in patients who failed interferon monotherapy: effects of higher doses of interferon and ribavirin combination therapy. The Virginia Cooperative Hepatitis Treatment Group. Pilot study of a short course of ribavirin and alpha interferon in the treatment of chronic active hepatitis C not responding to alpha-interferon alone. Hepatitis C in adults and adolescents with hemophilia: a randomized, controlled trial of interferon alfa-2b and ribavirin. Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions.
Low pretreatment viral load has consistently been shown to be an independent predictor of sustained response (SR) in patients with chronic hepatitis C infection. We assessed the efficacy of interferon (IFN) plus ribavirin vs IFN alone in low viraemic patients (<2 millions copies/mL) who had relapsed to a previous course of IFN and the efficacy of 24 vs 48 week combination therapy in high viraemic patients. Two hundred and ninety-seven patients were randomly assigned to one of the four regimens after stratification on pretreatment viral load. All patients received IFN-alpha2b (6 million units thrice weekly for 24 weeks and 3 million units thrice weekly for 24 weeks). Patients with low viraemia received either IFN-alpha2b alone for 48 weeks (R1: 42 patients) or IFN-alpha2b plus ribavirin (600 mg/day) for 24 weeks and IFN-alpha2b alone for the next 24 weeks (R2: 48 patients). Patients with high viral load received either IFN-alpha2b plus ribavirin for 24 weeks and then IFN-alpha2b alone for the next 24 weeks (R3: 104 patients) or IFN-alpha2b plus ribavirin for 48 weeks (R4: 103 patients). In low viraemic patients the rate of SR was 37.7% in group R1 and 59.6% in group R2 (P < 0.05). In high viraemic patients, the rate of SR was 44.7% in group R3 and 51.4% in group R4 (P: NS). Thirty-one patients discontinued treatment (10.4%) without difference regarding treatment regimen. In the regimen using ribavirin we found no difference in terms of SR between patients receiving a dose of ribavirin below 10.6 mg/kg/day (55%) or over 10.6 mg/kg/day (58%). Histological improvement occurred in 70.2% of patients regardless of the regimen. Logistic regression showed that genotype 2 and 3, Knodell score <6 and alanine aminotransferase pretreatment level >3 x upper limit of normal were significantly and independently correlated with SR. In low viraemic patients who relapsed to a previous IFN treatment, combination therapy using high-dose IFN and low-dose ribavirin is better than high-dose IFN alone. In high viraemic patients there was no benefit in increasing the duration of combination therapy from 24 to 48 weeks. In this study, it was found that low dose of ribavirin can be used safely and there is no effect of ribavirin dose on SR. Alpha interferon (IFN-alpha) treatment is effective on a long-term basis in only 15 to 25% of patients with chronic hepatitis C. The results of recent trials indicate that response rates can be significantly increased when IFN-alpha is given in combination with ribavirin. However, a large number of patients do not respond even to combination therapy. Nonresponsiveness to IFN is characterized by evolution of the hepatitis C virus (HCV) quasispecies. Little is known about the changes occurring within the HCV genomes when nonresponder patients are retreated with IFN or with IFN plus ribavirin. In the present study we have examined the genetic divergence of HCV quasispecies during unsuccessful retreatment with IFN or IFN plus ribavirin. Fifteen nonresponder patients with HCV-1 (4 patients with HCV-1a and 11 patients with HCV-1b) infection were studied while being retreated for 2 months (phase 1) with IFN-alpha (6 MU given three times a week), followed by IFN plus ribavirin or IFN alone for an additional 6 months (phase 2). HCV quasispecies diversification in the E2 hypervariable region-1 (HVR1) and in the putative NS5A IFN sensitivity determining region (ISDR) were analyzed for phase 1 and phase 2 by using the heteroduplex tracking assay and clonal frequency analysis techniques. A major finding of this study was the relatively rapid evolution of the HCV quasispecies observed in both treatment groups during the early phase 1 compared to the late phase 2 of treatment. The rate of quasispecies diversification in HVR1 was significantly higher during phase 1 versus phase 2 both in patients who received IFN plus ribavirin (P = 0.017) and in patients who received IFN alone (P = 0. 05). A trend toward higher rates of quasispecies evolution in the ISDR was also observed during phase 1 in both groups, although the results did not reach statistical significance. However, the NS5A quasispecies appeared to be rather homogeneous and stable in most nonresponder patients, suggesting the presence of a single well-fit major variant, resistant to antiviral treatment, in agreement with published data which have identified an IFN sensitivity determinant region within the NS5A. During the entire 8 months of retreatment, there was no difference in the rate of fixation of mutation between patients who received combination therapy and patients who were treated with IFN alone, suggesting that ribavirin had no major effects on the evolution of the HCV quasispecies after the initial 2 months of IFN therapy. In chronic hepatitis C the schedule of interferon (IFN), 3 MU thrice weekly (tiw) plus ribavirin (1000-1200 mg/daily) needs further evaluation, as IFN dosages >3 MU achieve better responses.
                To compare the efficacy of 5 MU tiw of IFN with (96 patients) or without ribavirin (96 patients) for 12 months in naïve patients, to evaluate the effect of baseline features on the response to therapy, and to determine a reliable point in time during treatment to predict non-response.
                Sustained virologic response was 20.8% (95% CI 13-29) with IFN monotherapy and 54.2% (95% CI 44-64) with combination (P = 0.0001), the relapse rate 39.4% (95% CI 23-56) and 9% (95% CI 1-16) (P = 0.0007), and the combined rate of sustained biochemical and virologic response 22.7% (95% CI 14-31) and 60.5% (95% CI 50-71) (P = 0.0001), respectively. Patients given combination therapy were more likely to respond regardless of baseline features. Apart from genotype non-1, predictive factors for IFN monotherapy were ineffective in predicting response to combination therapy. Using logistic regression analysis, IFN-ribavirin was the strongest predictor of response (X2 = 21.3; P = 0.0001). Viral persistence at month 3 of therapy was a more accurate predictor than aminotransferase values for non-response to IFN monotherapy but not to combination therapy (positive predictive values of 98 and 82%, respectively).
                In this study, 5 MU of IFN combined with a standard dose of ribavirin has yielded the highest rate of sustained response reported to date. Further dose finding studies are warranted. In chronic hepatitis C, interferon-alpha (alpha-IFN) and ribavirin combination therapy improves sustained response compared to alpha-IFN monotherapy, both in naive patients and in previous alpha-IFN relapsers, but the efficacy of such therapy remains limited in non-responder cases. The aim of this study was to assess whether the pattern of response to alpha-IFN alone may predict sustained response to combination therapy during retreatment.
                Fifty previous alpha-IFN relapsers and 50 previous alpha-IFN non-responders were retreated with a high alpha-IFN dose (6 MU/thrice weekly for 2 months; induction phase) and then randomised to continue with alpha-IFN alone (3 MU/thrice weekly) or to receive combination therapy (3 MU/thrice weekly of alpha-IFN and 1000-1200 mg/daily of ribavirin) for an additional 6 months according to the biochemical response to alpha-IFN shown after the induction phase. All patients were also evaluated for virological and histological response.
                Eleven of 25 (44%) relapsers treated with combination therapy and 4/25 (16%) treated with alpha-IFN alone achieved a sustained response. The corresponding figures among non-responders were 1/25 (4%) and 0/25, respectively. Among 26 patients with a complete ALT and HCV-RNA response after 2 months of alpha-IFN, sustained response was seen in 11/14 (79%) treated with combination therapy and in 4/12 (33%) treated with alpha-IFN alone (p=0.05). On the other hand, of 74 cases still HCV-RNA positive after 2 months of alpha-IFN alone, biochemical and virological end of therapy response was better with combination therapy (11/36; 30.5%) compared to alpha-IFN alone (4/38; 10.5%), but only one patient developed a sustained response (1/36; 3%).
                The retreatment with a 6-month combination therapy was associated with a high rate of sustained response only in patients showing a complete biochemical and virological response to alpha-IFN alone. Longer retreatment with combination therapy may be needed to achieve a sustained response in patients without a prompt virological response to alpha-IFN. Subjects with chronic hepatitis C who fail treatment with interferon-alpha are generally divided into two groups: "relapsers" who normalized serum aminotransferase activity and have undetectable viral RNA during treatment and "non-responders" who do not achieve these results. The aim of this study was to examine retreatment of such subjects.
                We studied 117 subjects with chronic hepatitis C who failed treatment with interferon-alpha, 87 of whom were "non-responders" and 30 "relapsers." Retreatment was with either interferon-alpha-2b plus ribavirin for 48 weeks or with interferon-alpha-2b plus placebo for 24 weeks followed by 24 weeks of combined therapy.
                Sustained response rates, defined as undetectable viral RNA in serum 6 months after retreatment, were 53% in "relapsers" and 10% in "non-responders" (P < 0.005). There was no significant difference if ribavirin was given for 24 or 48 weeks. In "non-responders" infected with genotypes other than type 1, 42% achieved a sustained response compared to 5% infected with genotype 1 (P = 0.027; odds ratio 7.09).
                Treatment with interferon-alpha-2b plus ribavirin is effective in approximately 50% of "relapsers" and "non-responders" infected with non-type 1 genotypes of hepatitis C virus. This therapy is only marginally effective in "non-responders" infected with genotype 1a or 1b. Treatment of chronic hepatitis C patients, infected with genotype 4 with interferon-alpha yielded a limited response. Our aim was to compare the efficacy of interferon-alpha alone and in combination with ribavirin in chronic hepatitis C patients infected with genotype 4.
                Fifty-two chronic hepatitis C patients (all males) infected with genotype 4, who had not received interferon, were randomized into 2 equal comparable groups.
                Group I received interferon alpha-2b "Schering Plough" 3 MU, tiw combined with ribavirin (1000 mg/day). Group II received interferon alpha-2b alone in the same dose. Both groups were evaluated monthly, at the end of 24 weeks of treatment and 24 weeks later. Two patients were dropped from group I and one patient from group II.
                Biochemical response: at the end of treatment, a return to normal of ALT was obtained in 16/24 (66.7%) patients on combination therapy vs 8/25 (32%) patients on interferon alone (p = 0.0152). At the end of follow-up, a sustained response was achieved in 10/24 (41.7%) patients on combination therapy vs 4/25 (16%) patients on interferon (p = 0.0468). Virologic response: at the end of treatment, the rates of virological response were higher in the patients on combination therapy 9/24 (37.5%) than in those on interferon 4/25 (16%) (p = 0.0380). At the end of follow-up, loss of serum HCV RNA was reported in 5/24 (20.8%) patients on combination therapy vs 2/25 (8%) patients on interferon (p = 0.1916). Histologic response: mild histologic improvement was shown by a decrease in the inflammatory score, which was highest in patients in the combination group.
                In chronic hepatitis C patients infected with genotype 4, combination therapy with interferon-alpha and ribavirin was more effective than treatment with interferon monotherapy. At the end of the follow-up, about 50% of patients in both groups were still viraemic though their ALT remained normal. Treatment of chronic hepatitis C with interferon can be ineffective due to relapse. We aimed to reduce the 40% relapse rate of 6 months interferon-ribavirin combination therapy by prolonging treatment to 18 months.
                Three hundred patients with treatment-naive hepatitis C, were randomized to 18 months combination therapy with interferon (3MU tiw) and ribavirin (1000-1200 mg/day), 18 months interferon combined with placebo, or 6 months combination therapy with interferon and ribavirin, in a double blinded manner. All 295 patients who received at least one dose of treatment were included in the intention to treat analysis.
                At the end of treatment, HCV RNA was undetectable in 55 and 49% of those on 6 and 18 months combination therapy, respectively, versus 26% of those on monotherapy (P<0.001). The relapse rate was 38% for 6 months combination therapy, 38% for 18 months monotherapy, and only 13% for 18 months combination treatment (P=0.002). The sustained response rates were 34% for 6 months combination therapy, 16% for 18 months monotherapy and 43% for 18 months combination therapy (P<0.05).
                Reduction of relapse rates to 15% or less is feasible by prolongation of interferon-ribavirin treatment to 18 months. Only 15-20% of patients with chronic hepatitis C achieve a sustained virological response with interferon therapy. The aim of this study was to compare the efficacy and safety of interferon alpha2b in combination with oral ribavirin with interferon alone, for treatment of chronic infection with hepatitis C virus (HCV).
                832 patients aged 18 years or more with chronic HCV who had not been treated with interferon or ribavirin, were enrolled and randomly allocated one of three regimens: 3 mega units (MU) interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 48 weeks; 3 MU interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 24 weeks; or 3 MU interferon alpha2b three times a week and placebo for 48 weeks. All patients were assessed for safety, tolerance, and efficacy at the end of weeks 1, 2, 4, 6, and 8, and every 4 weeks during treatment. After treatment was completed patients were followed up on weeks 4, 8, 12, and 24. The primary endpoint was loss of detectable HCV-RNA (serum HCV-RNA <100 copies/mL) at week 24 after treatment.
                Sustained virological response at 24 weeks after treatment, was found in 119 (43%) of the 277 patients treated for 48 weeks with the combination regimen, 97 (35%) of the 277 patients treated for 24 weeks with the combination regimen (p=O.055), and 53 (19%) of the 278 patients treated for 48 weeks with interferon alone (p<0.001 vs both combination regimens, intention-to-treat analysis). Logistic regression identified five independent factors significantly associated with response: genotype 2 or 3, viral load less than 2 million copies/mL, age 40 years or less, minimal fibrosis stage, and female sex. Among patients with fewer than three of these factors the odds ratio of sustained response was 2.6 (95% Cl 1.4-4.8; p=0.002) for the 48 week combination regimen compared with 24 weeks of the combination regimen. Discontinuation of therapy for adverse events was more frequent with combination (19%) and monotherapy (13%) given for 48 weeks than combination therapy given for 24 weeks (8%).
                An interferon alpha2b plus ribavirin combination is more effective than 48 weeks of interferon alpha2b monotherapy and has an acceptable safety profile. Patients with few favourable factors benefit more from extending the duration of combination therapy to 48 weeks. To study the effects of monotherapy with leucocyte interferon-alpha (IFNalpha) versus IFNalpha + ribavirin in patients with chronic hepatitis C who were nonresponders to previous courses of recombinant or lymphoblastoid IFNalpha.
                This was a nonblind randomised study of outpatients at 3 centres in Palermo, Sicily, Italy.
                We recruited 72 patients (48 males, 24 females), mean age 48.8 +/- 6.6 years (range 31 to 63 years), with biopsy-proven chronic hepatitis C, predominantly genotype 1b.
                24 patients (group A) received IFNalpha 6MU 3 times weekly for 6 months, and 48 patients (group B) received IFNalpha 6MU 3 times weekly + ribavirin 1200 mg/day for 6 months. ALT levels and adverse effects were monitored monthly, and hepatitis C virus (HCV) RNA levels were measured at study entry, at the end of treatment and after a 6-month follow-up.
                At baseline all patients were HCV-RNA positive and had ALT levels greater than twice normal. Mean post-treatment serum HCV-RNA levels were below baseline in group A, but the virus was eradicated in only 1 patient; 6 patients had normalised serum ALT levels. In group B at end of treatment, 12 patients were negative for HCV-RNA and serum ALT levels were normal in 18. At follow-up, all group A patients had elevated ALT levels and positive HCV-RNA. In group B, 3 patients were still negative for HCV-RNA and 4 had normal ALT. In 4 patients in group B, therapy was suspended because of anaemia, depression and decrease in neutrophil count; a flu-like syndrome was recorded with no frequency difference between groups.
                These results suggest that patients with chronic hepatitis C unresponsive to IFNalpha monotherapy could benefit from combination therapy with IFNalpha + ribavirin. Only 15 to 20 percent of patients with chronic hepatitis C have a sustained virologic response to interferon therapy. We compared the efficacy and safety of recombinant interferon alfa-2b alone with those of a combination of interferon alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C.
                We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy.
                The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher among patients who received combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of 228 patients, 38 percent) than among patients who received interferon alone for either 24 weeks (13 of 231 patients, 6 percent) or 48 weeks (29 of 225 patients, 13 percent) (P<0.001 for the comparison of interferon alone with both 24 weeks and 48 weeks of combination treatment). Among patients with HCV genotype 1 infection, the best response occurred in those who were treated for 48 weeks with interferon and ribavirin. Histologic improvement was more common in patients who were treated with combination therapy for either 24 weeks (57 percent) or 48 weeks (61 percent) than in those who were treated with interferon alone for either 24 weeks (44 percent) or 48 weeks (41 percent). The drug doses had to be reduced and treatment discontinued more often in patients who were treated with combination therapy.
                In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone. Conventional interferon monotherapy fails to achieve virological clearance in most hepatitis C-infected patients. The use of high-dose induction regimens may improve the initial clearance of virus, while the addition of ribavirin appears to improve the rates of sustained response once clearance is achieved.
                To compare the efficacy and safety of re-treatment with an induction regimen of high-dose interferon alpha-2b, with or without ribavirin, in chronic hepatitis C patients who have not responded to standard dose interferon monotherapy.
                Previous virological non-responders to standard dose interferon (3-5 MU three times weekly for > or = 12 weeks) were randomized to receive, unblind, either 10 MU interferon alpha-2b daily for 10 days, then 5 MU daily for 74 days, then 5 MU three times weekly for 24 weeks (total 36 weeks) (group A), or the above regimen with the addition of ribavirin, 1000-1200 mg/day, at day 11 (group B). All patients were followed up for 24 weeks after completion of therapy.
                End of treatment virological response was noted in one of 10 (10%) patients in group A and in eight of 15 (54%) patients in group B (P=0.04). The sole end treatment responder in group A and three in group B relapsed on follow-up. The apparent improvement in response in group B compared to group A nearly reached statistical significance (group B 5/15 vs. group A 0/10; P=0.06).
                In this small pilot study, a 36-week high-dose induction interferon monotherapy protocol did not yield sustained responses in previous non-responders to standard dose interferon. However, the same regimen with ribavirin yielded a 33% sustained response rate, nearly reaching statistical significance. The therapy was well tolerated, despite the higher doses of interferon used and the addition of ribavirin. High-dose interferon with ribavirin appears to be a therapeutic option for non-responders to conventional interferon monotherapy. To assess the efficacy of interferon alpha-2b and ribavirin in combination in the treatment of patients with chronic hepatitis C who had either failed to respond to therapy with interferon alpha (nonresponders), or who had relapsed after interferon therapy (relapsers).
                Four hundred patients with chronic hepatitis C (200 nonresponders and 200 relapsers) were randomly assigned in equal numbers to receive either subcutaneous administration of recombinant interferon alpha-2b (3 million units three times per week) and ribavirin (1,000 to 1,200 mg/daily orally) or interferon alpha-2b alone (6 million units three times per week). Both ribavirin and interferon alpha-2b were given for 24 weeks. The patients were then followed for an additional 24 weeks.
                At the end of the treatment period, normalization of serum alanine aminotransferase levels and absence of hepatitis C virus RNA were seen in 21% of nonresponders and in 39% of relapsers who were treated with interferon alpha-2b and ribavirin, compared with 5% of nonresponders (P = 0.001) and 9% of relapsers treated with interferon alpha-2b alone (P <0.001). At the end of follow-up, 14% of nonresponders and 30% of relapsers treated with the combination therapy had a sustained response, compared with 1% of nonresponders (P = 0.001) and 5% of relapsers treated with interferon alpha alone (P <0.001).
                A 24-week course of treatment with interferon alpha-2b and ribavirin offers a chance of sustained response, whereas retreatment with interferon alpha-2b alone does not give satisfactory results. The role of long-term therapy in inducing prolonged remission remains to be explored. Infection with hepatitis C virus genotype 1b (HCV1b) is known to be a predictive factor of poor response to both interferon-alpha (IFN alpha) alone and IFN alpha plus ribavirin combination therapy.STUDY DESIGN, PATIENTS AND METHODS: This randomised study evaluated the efficacy and safety of daily IFN alpha administration versus the combination of IFN alpha plus ribavirin in treatment-naive patients infected with chronic HCV1b. Sixty-two patients were randomised to receive either human leucocyte IFN alpha 6MU three times weekly for 12 months plus ribavirin 15 mg/kg/day for the first 6 months (group A: 29 patients), or human leucocyte IFN alpha 3MU daily for 12 months (group B: 33 patients). Response was evaluated by monitoring serum alanine aminotransferase (ALT) and HCV-RNA levels during treatment and follow-up (12 months).
                Both treatment schedules were relatively well tolerated. Normal ALT levels and negative serum HCV-RNA were observed in 16 of 29 patients (55%) of group A and in 18 of 33 patients (54.5%) of group B at the end of treatment, as well as in 10 of 29 patients (34.5%) of group A and in 12 of 33 patients (36%) of group B at the end of the follow-up. There was no significant difference between the response rates obtained with the two regimens. In naive patients with chronic HCV1b infection, the efficacy of daily administration with IFN alpha is similar to that of IFN alpha plus ribavirin administered three times a week. The aim of the study was to assess the efficacy of interferon (IFN)-alpha-2b and ribavirin in combination in the treatment of chronic hepatitis C (CHC) patients unresponsive to a previous treatment with IFN-alpha-2b alone.
                We conducted a randomized study in 303 CHC patients. One hundred fifty-two patients received subcutaneous administration of recombinant IFN-alpha-2b (3 MU thrice weekly) and ribavirin (1000-1200 mg/daily per os), whereas 151 received IFN-alpha-2b alone (6 MU thrice weekly). Both ribavirin and IFN-alpha-2b were given for 24 wk, regardless of treatment response. Alanine aminotransferase (ALT) levels and HCV RNA titer were checked during the treatment period and for a further 24 wk.
                Normal ALT levels were observed in 64.5% of the patients treated with IFN-alpha and ribavirin and in 22.6% of the patients treated with IFN-alpha alone. In the group of patients receiving IFN-alpha and ribavirin HCV RNA was not detectable in 40% of patients responders and remained undetectable in 44.2% of sustained responders. In the group of patients receiving IFN-alpha alone HCV RNA was not detectable in 24.2% of patients responders and remained not detectable in 33.3% of sustained responders.
                A 24-wk treatment course with IFN-alpha and ribavirin given to patients with a previous lack of response to IFN-alpha alone offers a chance of a sustained biochemical and virological response, at least in a subset of such patients. The role of long-term therapy in inducing prolonged remission still remains to be explored. This trial investigated the efficacy of a combination of high-dose interferon-alpha (IFN-alpha) with ribavirin in IFN nonresponders. Study protocol: 304 patients with chronic hepatitis C were treated with 5 MU IFN-alpha2b (IntronA(R), Schering-Plough) per TIW for 3 months. Nonresponders (defined by HCV-RNA positivity in serum after the 3 months of therapy) were randomized either to continue with IFN (5 MU IFN per TIW followed by 10 MU per TIW for each 3 months) alone (group A) or in combination with ribavirin (1-1.2 g per day) (group B). ALT was measured in monthly intervals, HCV-RNA in 3 monthly intervals. Pretreatment characteristics of the randomized patients were as follows: group A, n = 76; m/f, 54/22; 16% cirrhosis, age, 45. 7 +/- 12 years; ALT (U per litre), 66 +/- 35; group B, n = 81; m/f, 57/24; 17% cirrhosis, age, 48.2 +/- 12; ALT, 71 +/- 40. After 9 months of treatment, nine (11.6%) and 27 (32.5%, P = 0.0066) patients were HCV-RNA negative and 51 and 39 were HCV-RNA positive, in groups A and B, respectively. There were 17 drop-outs in group A and 15 in group B. Six months after treatment only two patients in group A (2.5%) and five (6%, P = 0.06) in group B had normal ALT and no detectable HCV-RNA in serum. In addition to the well-known side-effects of IFN the mean haemoglobin concentration dropped by 2 g per litre in group B. These data indicate that a combination of high-dose IFN with ribavirin is effective in inducing a short-lasting complete response in one-third of IFN nonresponders. Prolonged treatment with IFN/ribavirin may be necessary to obtain a sustained response. There are no established therapeutic regimens for hepatitis C virus (HCV) patients who relapse following treatment with interferon alpha-2b and ribavirin or those who break through while on interferon alpha-2b and ribavirin. We therefore evaluated various combination therapies in HCV patients who relapsed or experienced a viral breakthrough. Patients (n = 124) were randomized to 48 weeks of treatment with once-weekly subcutaneous injections of 180 microg pegylated (peg-) interferon alpha-2a plus oral ribavirin (800-1000 mg/day), mycophenolate mofetil (2 g/day), amantadine (200 mg/day), or ribavirin and amantadine and followed for an additional 24 weeks. The sustained virologic response was higher in patients administered peginterferon alpha-2a plus ribavirin (38%) or ribavirin and amantadine (45%) than in those administered peginterferon alpha-2a plus mycophenolate mofetil (17%) or amantadine (10%). As in previous studies, patients with genotype non-1 and those with lower viral loads had better responses than those with genotype 1 and high viral loads, though the differences did not reach significance. The four treatment regimens had similar safety profiles, except that patients receiving ribavirin had greater maximal hemoglobin decreases. These findings suggest that the combination of peginterferon alpha-2a plus ribavirin or with ribavirin and amantadine is effective in some HCV patients who relapse after treatment with interferon alpha-2b plus ribavirin. Interferon-alpha (IFN-alpha) induces sustained remission of chronic hepatitis C in approximately 25% of patients. In patients who are non-responders to the first course of therapy, retreatment with IFN-alpha is of limited efficacy. Ribavirin has also been used to treat chronic hepatitis C, but it induces only a transient response. In this study, we evaluated the efficacy of ribavirin and IFN-alpha combination therapy for IFN-alpha resistant chronic hepatitis C. Twenty-four IFN-alpha non-responders and 24 relapsers were randomized to receive either ribavirin (1000 mg per day) together with IFN-alpha (3-6 million units (MU) thrice weekly) or the same dose of IFN-alpha alone, for 6 months. Both at the end of treatment and 6 months later, normal transaminase levels were more common in the patients receiving combination therapy than in the group receiving IFN-alpha alone: 17 (70.8%) vs seven (29.2%) patients (P = 0.009) and six (25%) vs one (4.2%) patient (P = 0.034), respectively. At the end of treatment and 6 months later, serum HCV RNA was no longer detectable in eight (33.3%) and five (20.8%) patients in the combination therapy group and in six (25%) and one (4.2%) patient in the IFN-alpha therapy group, respectively. Three patients (12.5%) were withdrawn prematurely from combination therapy because of side-effects; ribavirin therapy was ceased or dosage reduced in six other patients (25%), again because of side-effects. In conclusion, this combination treatment was more effective than retreatment with IFN-alpha, alone, in inducing sustained biochemical remission of chronic hepatitis C that was resistant to a previous course of IFN-alpha. The combination treatment, however, was frequently associated with significant side-effects. A combination of interferon alpha and ribavirin has been suggested to reach a higher rate of sustained virological response in patients with chronic hepatitis C than monotherapy. In this study we assessed the long-term efficacy of this combination therapy in the treatment of selected Italian naive chronic hepatitis C patients compared to interferon alpha monotherapy.
                We enrolled 428 naive patients who were randomly assigned to receive either recombinant interferon alpha-2b and ribavirin for 24 weeks or interferon alpha-2b alone for 48 weeks. The primary end-point of the study was the rate of sustained virological response. Serum HCV RNA levels were determined before treatment; during treatment at weeks 12 and 24 in the patients receiving the combination therapy; at weeks 12, 24, 36 and 48 in the patients receiving monotherapy; and after therapy at weeks 12, 24 and 48 in the patients in both study groups.
                Sustained virological response was observed in 43% of the patients treated with combination therapy and in 14% of the patients treated with monotherapy. Logistic regression analysis showed that sustained response was associated with the combination therapy, with HCV genotype other than 1b, with an HCV viral load of 3x10(6) copies/ml or less, with an inflammation score of 7 or less, and with an estimated duration of disease of 10 years or less.
                A 24-week treatment course with interferon alpha-2b and ribavirin offers a greater chance of sustained virological response compared to treatment with interferon alpha-2b alone for 48 weeks, and may be indicated as initial therapy in such patients. Interferon a with ribavirin combination therapy is effective but still unsatisfactory in the treatment of patients with interferon-relapsed chronic hepatitis C.
                To compare, in a randomized, double blind, placebo-controlled study, high-dose interferon-alpha2b with or without ribavirin in the treatment for interferon-relapsers.
                A total of 52 patients with interferon-relapsed chronic hepatitis C were randomly assigned to receive 24-week treatment with interferon-alpha2b (6 MU three times per week) combined with either ribavirin (1,000 to 1,200 mg per day) or a matched placebo and then followed for an additional 24 weeks.
                Hepatitis C virus RNA was detected by reverse-transcription polymerase chain reaction. For determining viral concentration, the commercial bDNA Quantiplex hepatitis C virus-RNA 2.0 assay was used. Genotyping was performed by reverse hybridization assay
                At the end of treatment, no detectable hepatitis C virus RNA levels were observed in 92% (24/26) of patients on interferon alpha2b/ribavirin and 81% (21/26) of patients on interferon alpha2b/placebo. At the end of the follow-up, a higher sustained virological response rate was seen in patients treated with interferon alpha2b/ribavirin than those treated with interferon alpha2b/placebo (69% vs 23%, p < 0.001). Patients with either initially high levels of viral concentration or with genotype 1 responded poorly. Patients who received interferon-alpha2b/ribavirin treatment and in whom no hepatitis C virus RNA was detected at 4th week after treatment had 90% chance to achieve sustained virological response.
                High-dose interferon-alpha2b plus ribavirin treatment is highly effective in interferon-relapsed patients. Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic 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.
                A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks.
                A significantly higher proportion of 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 of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P<0.001) or peginterferon alfa-2a alone (56 percent vs. 29 percent, P<0.001). The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent, 36 percent, and 21 percent, respectively, for the three regimens. Among patients with HCV genotype 1 and high base-line levels of HCV RNA, the proportions of those with sustained virologic responses were 41 percent, 33 percent, and 13 percent, respectively. The overall safety profiles of the three treatment regimens were similar; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin.
                In 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 virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.
                Copyright 2002 Massachusetts Medical Society 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.
                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.
                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).
                In conclusion, the combination of 3 MU of interferon plus 600 mg of ribavirin is not effective in chronic hepatitis C resistant to interferon. 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.
                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).
                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.
                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. To compare the efficacy of a descalating dose of interferon (48 weeks) versus a combination therapy of interferon and ribavirin (24 weeks) in hepatitis C positive subjects who relapsed within six months of cessation of a standard six month course of interferon three million units thrice weekly.
                All 32 subjects had biopsy proven chronic hepatitis C, were PCR positive and had elevated transaminase enzymes at least one and a half times the upper limit of normal. Subjects were randomly assigned to either a descalating dose of interferon-alpha-2a; six million units thrice weekly for 24 weeks followed by 3 MIU 3x for 24 weeks or interferon three million units thrice weekly for 24 weeks plus ribavirin 1,000 mg/day for 12 weeks. A complete virological response was defined as a negative PCR for HCV RNA at 24 weeks after cessation of therapy.
                Sixteen patients were assigned to each arm and the sustained virological response was 50% for both the interferon and combination therapy arm (pNS). The biochemical response correlated with the virological response; 7/8 virological responders in the interferon alone had normalisation of transaminase 24 weeks post treatment as did 8/8 of those in the combination arm. One patient withdrew from treatment in the descalating interferon group and three required dose reduction. No subjects in the combination arm discontinued therapy but dose reduction was required in three subjects.
                High dose descalating interferon-alpha 2a and a combination of interferon-alpha 2a and ribavirin were effective in achieving a sustained virological response in 50% of subjects who had relapsed after a standard six month course of interferon. With the favorable result of interferon (IFN)-ribavirin combination therapy for 24 weeks among naive Taiwanese chronic hepatitis C (CHC) patients, the optimal regimens of re-treatment for CHC patients who failed initial IFN monotherapy is not well-established. The study evaluated the effectiveness of re-treatment for 24 weeks with 3 different regimens and predictors for sustained virological response (SVR).
                Total 120 Taiwanese CHC patients (81 males, 70 relapsers, mean age: 48.6 years) who failed initial IFN monotherapy were enrolled. They were assigned randomly (with a ratio of 1:1:2) to receive one of the three regimens for re-treatment for 24 weeks; group A: IFN 6 million units (MU) monotherapy (N=30), group B: combination therapy with ribavirin and IFN 3 MU (N=30) or group C: combination therapy with ribavirin and IFN 6 MU (N=60). The intention-to-treat rate of sustained virological response (SVR) was 38.3%. The SVR rate in group C (53.3%) was significantly higher than group A (16.7%, P<0.005) and group B (30%, P<0.05). Drop-out rates were similar between the three groups. Patients achieving SVR had significant improvement histologically. Hepatitis C virus (HCV) genotype non-1b infection, lower pretreatment HCV RNA levels, combined with ribavirin and with higher IFN dose, and relapsers were independent predictors for SVR.
                We concluded that more than one-third Taiwanese CHC patients achieved SVR after 24 weeks re-treatment and combination therapy, especially with higher dose of IFN, yielded higher efficacy. We investigated the long-term efficacy of a 12-month course of interferon (IFN)+ribavirin in chronic hepatitis C relapsers. We randomized 191 relapsers with a 2:1 ratio to receive 3 million units three times a week of interferon alpha (IFN alpha)-2b+ribavirin (1-1.2 g/day) (group A=127 patients) or IFN alpha-2b (group B=60 patients) of same dosage and duration for 1 year. General and hepatitis C data of group A and B patients were similar. The main goal of the study was to determine the rate of sustained virological response evaluated 1 year after treatment.
                Virological sustained response (SR) was 61% and 12% for groups A and B, respectively (P<0.001). A significant histological improvement was observed in both treatment groups. The Metavir activity score became significantly lower in the IFN+ribavirin group than in the IFN group (P<0/0001). The Metavir fibrosis scores remained unchanged. Also, at the end of the treatment, the virological response was 69% (88/127) for group A and 33% (20/60) for group B (P<0.001).
                One-year retreatment of relapsers with the combination of IFN+ribavirin led to 61% of virological SR and to a significant improvement of histological activity. Therefore, the therapeutic schedule presented here can be considered of particular interest for the retreatment of relapsers. The optimal treatment for hepatitis C patients unresponsive to interferon is unclear. High-dose induction interferon may enhance early viral clearance, whilst ribavirin reduces relapse; in combination, they may improve sustained virological response rates.
                To compare the efficacy and safety of re-treatment with interferon induction, with or without ribavirin, in interferon non-responders.
                We randomized 218 biochemical interferon non-responders to 10 MU interferon alpha 2b daily for 4 weeks, followed by 5 MU thrice weekly for 48 weeks plus ribavirin (II + R), or to the same interferon regimen plus placebo (II + P). All patients were viraemic at entry.
                The sustained virological response in the II + R group was 39%[95% confidence interval (CI), 30-48%], compared with 16% (95% CI, 9-23%) in the II + P group (P < 0.002). The study drug was discontinued for intolerable symptoms during induction in 9% of the II + R group and in 5% of the II + P group. By logistic regression, a sustained virological response was more likely following II + R treatment (odds ratio, 4.4; 95% CI, 2.1-9.7) and less likely in patients with genotype 1 or 4 (odds ratio, 0.16; 95% CI, 0.07-0.36).
                High-dose induction interferon plus ribavirin is well tolerated and effective for patients unresponsive to interferon alone. Chronic hepatitis C may lead to cirrhosis and hepatocellular carcinoma in a subset of patients. Because response rates with interferon alfa therapy are unsatisfactory, new therapies are needed.
                We conducted a three-arm, randomized trial in 45 interferon-naive men (mean age 40.6 +/- 12 years) with chronic hepatitis C to compare treatments: group A, ribavirin alone (15 mg/kg daily for 6 months); group B, interferon alone (3 MU thrice weekly for 6 months); and group C, interferon plus ribavirin at the above doses. Histologic outcomes of therapy were assessed by pretreatment and post-treatment liver biopsies.
                In group A, alanine aminotransferase levels normalized during therapy in 66% of those with HCV-1b and 34% of those with HCV-2a, but all patients relapsed after treatment ended. In group B, alanine aminotransferase levels normalized during treatment in 66%, 75%, and 100% of patients infected with HCV-1b, HCV-2a, and HCV-3, respectively; however, a sustained response was noted in only 25% of those with HCV-3. In group C, a sustained normalization of alanine aminotransferase with negative serum HCV RNA was seen in 20% of those with HCV-1b, 40% of those with HCV-2a, and 75% of those with HCV-3 12 months after therapy. One year after therapy ended, group C demonstrated a significant sustained response (47%) as well as a significant reduction in piecemeal necrosis and portal inflammation (p < 0.05).
                Combination therapy was significantly superior to ribavirin or interferon monotherapy in producing a sustained response in interferon-naive patients with chronic hepatitis C (p < 0.05). The results of our study suggest that ribavirin potentiates the effect of interferon therapy in chronic hepatitis C. We aimed to compare the efficacy of interferon-alpha2b (IFN) induction treatment in combination with ribavirin to IFN induction alone in chronic hepatitis C. In total, 125 patients (66 male, 59 female, mean age: 48 +/- 9, range: 21-70) were enrolled and randomized into two arms: In the first, patients received 5 MU/day of IFN for 4 weeks followed by 3 MU/day for the next 4 weeks. Treatment was continued with 3 MU three times a week IFN for an additional 40 weeks. Ribavirin was administered 1000-1200 mg/day according to the body weight for the entire 48-week period. In the second arm, patients received placebo in addition to IFN. Fifty-nine patients were placed in the ribavirin arm and 66 in placebo arm. All patients were genotype 1. At week 48, 24/66 (36%) from the placebo and 31/59 (52%) from the ribavirin group responded (P > 0.05). However, during the 24-week untreated follow-up period, 13/24 (54%) from the placebo, and 8/31 (26%) from the ribavirin group relapsed (P = 0.002.), resulting in a sustained virologic response (SVR) rate of 17% in the placebo and 39% in the ribavirin group (P = 0.005.) In conclusion, IFN induction treatment in combination with ribavirin is superior to IFN induction treatment alone in genotype 1 patients, and the SVR rate of 39% is encouraging. Pilot studies suggested that more patients with chronic hepatitis C virus (HCV) infection had a sustained virological response when treated with the combination of interferon alpha-2b and ribavirin than with interferon alpha-2b alone. We investigated the biochemical and virological responses and safety of treatment with interferon alpha-2b and ribavirin compared with interferon alpha-2b alone.
                In this double-blind trial 100 patients were randomly assigned to treatment with interferon alpha-2b (3 MU three times a week) in combination with ribavirin (1000 or 1200 mg per day) or placebo for 24 weeks and then followed up for a further 24 weeks. A further follow-up was done 1 year after active treatment stopped. The primary endpoint was the sustained virological response, defined as no detectable HCV RNA by PCR at both week 24 and week 48. Retrospectively, the baseline HCV-RNA load was analysed as a predictor of a sustained virological response. Data were analysed by intention to treat.
                18 (36%) of the 50 patients in the interferon alpha-2b and ribavirin group had a sustained virological response compared with nine (18%) of the 50 patients in the interferon alpha-2b and placebo group (p = 0.047). At the 1 year follow-up the proportion of patients with a virological response was greater in the interferon alpha-2b and ribavirin group than the interferon alpha-2b and placebo group (42 vs 20%, p = 0.03), respectively. More patients with baseline HCV-RNA concentrations greater than 3 x 10(6) genome equivalents (Eq) per mL had a sustained response with interferon alpha-2b and ribavirin than with interferon alpha-2b and placebo (12/29 vs 1/26, p = 0.009), whereas the sustained response did not differ between the two treatment groups for HCV-RNA amounts less than 3 x 10(6) Eq per mL (6/21 vs 8/24, p = 0.67), respectively.
                More patients with chronic hepatitis C have a sustained virological response with interferon alpha-2b and ribavirin than with only interferon alpha-2b treatment. We suggest that patients with high HCV-RNA loads should be treated with interferon alpha-2b and ribavirin. Sustained response to interferon treatment for chronic hepatitis C is unsatisfactory. This study examined whether combining interferon alfa with ribavirin induces a better sustained efficacy than interferon alone in the treatment of chronic hepatitis C.
                Sixty noncirrhotic patients with chronic hepatitis C were randomly assigned to three groups. Group 1 received 1200 mg oral ribavirin daily plus 3 million units of recombinant interferon alfa 2a thrice weekly for 24 weeks, group 2 received the same dose of interferon alfa 2a alone for 24 weeks, and group 3 received no treatment. The patients were then followed up for an additional 96 weeks.
                At the end of treatment, a complete response (normal serum alanine aminotransferase level and undetectable serum hepatitis C virus RNA) was achieved in 16 of the 21 patients in group 1 (76%), as compared with 6 of 19 in group 2 (32%) and none in group 3. At 96 weeks after the end of treatment, patients in group 1 sustained a higher complete response rate than patients in group 2 (43% vs. 6%).
                Combined treatment with ribavirin and interferon alfa 2a for 24 weeks is more effective than interferon alfa 2a alone for the treatment of chronic hepatitis C. The biochemical and virological responses were sustained in about one half of the treated patients for at least 2 years after cessation of the therapy. R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a +/- ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa-2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa-2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa-2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa-2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log(10) IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions. Conclusion: A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a +/- ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway. Preliminary results from combination therapy with interferon-alpha and ribavirin (IFN/Rib) in patients with chronic hepatitis C have been promising, with up to 50% sustained hepatitis C virus (HCV) RNA response. The aim of this study was to investigate whether a sustained HCV RNA response could be obtained with combination therapy in patients who were non-responders or relapsers after IFN treatment.
                In a multicenter study we randomized 53 HCV RNA-positive patients into 2 treatment groups. They all had biopsy-confirmed chronic hepatitis C, and all were recruited from a previous IFN study: 26 were previous non-responders and 27 responders with relapse. Group A received interferon-alpha2a, 4.5 MIU thrice weekly for 6 months, and group B received ribavirin, 1000-1200 mg/day, in combination with the same dose of interferon-alpha2a for 6 months. Median Knodell index was 5.0 in both groups. Genotype 1 was found in 24 (45%), type 2 in 3 (6%), and type 3 in 26 (49%).
                Sustained clearance of HCV viremia 6 months after interferon-alpha2a treatment stop was obtained in 12 of 53 patients (23%): 6 of 27 in the IFN group (22%) and 6 of 26 (23%) in the IFN/Rib group (NS). Nine of 27 (33%) former responders with relapse, compared with 3 of 26 (12%) non-responders, obtained a sustained HCV RNA response (P = 0.054). In previous relapse patients sustained loss of viremia was more frequent in genotype 3 (50%) than in genotype 1 (11%) patients (P = 0.022).
                In a group of previous IFN-alpha2a-treated chronic HCV patients we obtained a similar sustained clearance of viremia when retreated either with IFN-alpha2a alone or with a combination of IFN-alpha2a and ribavirin for 6 months. Previous relapse patients with HCV genotype 3 obtained sustained loss of viremia significantly more often (50%) than type-patients (11%). Previous IFN responders with relapse responded better than previous non-responders. To evaluate the efficacy and safety of therapy for patients with histologically mild hepatitis C virus (HCV) liver disease.
                A randomized, double blind, placebo controlled trial of interferon alpha-2b with or without ribavirin.
                Regional and university hospitals.
                One hundred and sixteen treatment naive patients with mild chronic HCV infection. Mild HCV infection was defined according to Knodell as a grade score of > or = 1 and < or = 6 and a stage score of < or = 1.
                Interferon alpha-2b (3 MU three times weekly) for 52 weeks in combination with either ribavirin or a matched placebo.
                The study endpoint was the absence of HCV RNA in plasma and liver tissue 26 weeks post-treatment. In addition, liver histology was compared pre- and post-treatment.
                Combination therapy was superior to interferon monotherapy, with a virological sustained response rate of 54% (31/57) and 20% (12/59), respectively, in both serum and liver tissue (P = 0.001). The sustained response rate was higher with combination therapy than monotherapy both in genotype non-1 (81% vs 36%) and in genotype 1 (28% vs 4%). There was a significant improvement in mean grade score in all sustained responders, irrespective of treatment arm.
                Combination therapy with interferon and ribavirin was safe and as effective in patients with histologically mild HCV infection as previously reported for more advanced disease. Interferon-alpha treatment of chronic hepatitis C is beneficial in only 20-30% of patients. This study evaluates if combination therapy with Interferon-alfa plus ribavirin is effective in inducing a response in patients who did not respond to, or relapsed after, a standard Interferon-alfa treatment.
                A total of 88 patients, 49 non-responders and 39 relapsers to previous Interferon-alfa therapy, were randomized to receive either natural Interferon-alfa (6 MU t.i.w.) plus ribavirin (1000 mg/daily) or natural Interferon-alfa alone (6 MU t.i.w.) for 6 months. All were followed for 12 months after stopping therapy. Serum aminotransferase levels were assessed monthly and HCV RNA was evaluated by RT-PCR (Amplicor, Roche) at end of therapy and the end of follow-up.
                After treatment, a higher response rate defined as return to normal of aminotransferases and absence of serum HCV RNA was observed among patients treated with Interferon-alfa-ribavirin: 4/28 (14%) vs 1/21 (5%) non-responder patients and 9/19 (47%) vs 5/20 (25%) in the relapsers group. At the end of follow-up, a sustained response was found only in the combination treatment group: 4% and 32% in non-responder and relapser patients, respectively.
                Our results suggest that retreatment with natural Interferon-alfa plus ribavirin is more effective than Interferon-alfa alone in increasing the response rate in patients with chronic hepatitis C who relapse after a previous standard IFN treatment whereas it is less effective in non-responder patients. The treatment of chronic hepatitis C patients was enhanced when the combination of interferon alfa-2b and ribavirin was shown to be safe and more effective than interferon monotherapy. To date, no published reports have addressed the use of consensus interferon (CIFN) when combined with ribavirin. We conducted a pilot study to compare the safety and tolerability of daily CIFN plus ribavirin to CIFN monotherapy for the initial treatment of chronic hepatitis C patients. Forty subjects were randomized to two treatment groups; CIFN 9 microg daily, or CIFN 9 microg daily plus ribavirin 1000 or 1200 mg daily. All subjects received 48 weeks of therapy except for nongenotype 1 subjects in the combination treatment group who received only 24 weeks of therapy. The results show that at baseline, age, gender, risk factors, race, RNA titres, and liver histology were not different between the two groups. The proportion of subjects with genotype 1 infection was 50% (10/20) and 55% (11/20) for the monotherapy and combination therapy groups, respectively. Fifty (10/20) and sixty-five (13/20) per cent of subjects in the monotherapy and combination therapy groups exhibited a 2-log or greater decrease in viral titre at week 12 (P = NS). Using intent-to-treat analysis, 20% and 40% of enrolled subjects exhibited a sustained viral response in the monotherapy and combination therapy groups, respectively (P = NS). The proportion of subjects requiring dose reduction was 55% (11/20) and 65% (13/20), respectively. Study discontinuations for any reason were 25% (5/20) and 35% (7/20) for the monotherapy and combination groups, respectively. Discontinuations due to adverse events related to study drug were 20% (4/20) and 25% (5/20), respectively. A total of four serious adverse events occurred, two in each treatment group, only one of which was determined to be study-drug related. It is concluded that the safety and tolerability profiles of the two treatments were similar suggesting that daily dosing of CIFN may be difficult to tolerate resulting in discontinuation of therapy in a significant proportion of patients. The combination regimen resulted in a trend towards a higher viral response rate than monotherapy treatment. These data suggest that CIFN may be safely combined with ribavirin and may enhance the sustained response rate but is not well tolerated in US patients when given in a daily dosing regimen. Studies of viral hepatitis C have suggested that fibrosis can regress, at least in patients with sustained virological response. A recent study suggested that cirrhosis was reversible in sustained and non-virological responders.
                To study fibrosis progression rate and cirrhosis reversion in patients treated for severe fibrosis with interferon or interferon + ribavirin.
                Ninety-nine patients were treated with interferon + ribavirin and 64 with interferon. The Metavir fibrosis score and the semiquantitative fibrosis score (SFS) were used to assess fibrosis.
                In sustained responders, fibrosis progression rate decreased from 0.26 Metavir unit (interquartile range: 0.19-0.34) to -0.67 (-0.67 to 0) (P < 0.0001) and from 0.81 SFS unit (0.48-1.13) to -1.33 (-3.67 to 0) (P < 0.0001). In non-responders, fibrosis progression rate decreased from 0.25 Metavir unit (0.17-0.33) before treatment to 0 (0-0) during treatment (P = 0.002) and from 0.63 SFS unit (0.49-1.12) to 0 (-2.67-1.33) (P = 0.18). Six out of 18 (33%) sustained virological responders and four of 43 (9%) non-responders regressed from cirrhosis (F4) to severe fibrosis (F3) (P = 0.058). No patient with cirrhosis had a decrease of Metavir fibrosis score of 2 points.
                Interferon can slow fibrosis progression in sustained virological responders with severe fibrosis. In patients with a non-virological response and treated for 12 months the fibrosis progression rate was nil, meaning that only fibrosis stabilization could be obtained in these patients. Then, longer treatment duration (3-4 years) could be evaluated in non-virological responders. Recently, in vitro and in vivo studies demonstrated that non-steroidal anti-inflammatory drugs are able to enhance the activity of interferon alpha.
                To evaluate the efficacy and tolerability of ketoprofen (a non-steroidal anti-inflammatory drug) plus interferon alpha (group B) compared to interferon alpha plus ribavirin (group C) and interferon alpha alone (group A) in chronic hepatitis C non-responders after a 5-month course with interferon alpha.
                Without stopping interferon alpha, 49 patients were randomized to receive one of the three treatment regimens for 4 months.
                Three patients discontinued the therapy. One out of 16 patients in group A, 6/16 in group B and 5/14 in group C, alanine aminotransferase returned to normal at the end of the therapies (B vs A: p=0.04); serum hepatitis C virus-RNA became negative in 1 patient in group A and in 4 patients in both group B and group C. Six months after treatment, normal alanine transferase and negative hepatitis C virus-RNA were observed in 3 patients in group B and 2 in group C. In these patients, liver histology significantly improved.
                These results indicate that a certain number of non-responder patients to interferon alpha can benefit from a combination therapy of interferon alpha plus ketoprofen that is at least as effective as the combination interferon alpha plus ribavirin. Interferon-alpha plus ribavirin seem to be more efficacious than interferon monotherapy in chronic hepatitis C. In a multicenter randomized trial, we evaluated the efficacy of this association for interferon-alpha resistant chronic hepatitis C.
                Fifty patients who were non-responders to recombinant or lymphoblastoid interferon-alpha were randomized to receive either ribavirin (800 mg/day) plus leucocytic interferon-alpha (3 mega units thrice weekly) or the same dose of interferon-alpha alone, for 6 months. Effects of therapy were evaluated by serum aminotransferase and hepatitis C virus RNA levels and control liver biopsies.
                At the end of treatment, aminotransferase levels become normal in 9/26 patients receiving combination therapy (35% [confidence interval, 16% to 53%]) and in 2/24 receiving interferon-alpha alone (8% [confidence interval, -3% to 19%]) (p = 0.03). Aminotransferase normalization was never associated with hepatitis C virus RNA clearance. All patients with normal aminotransferase relapsed after discontinuation of therapy. At the end of treatment, mean hepatitis C virus RNA levels significantly decreased only in the group receiving combination therapy, but returned to pretreatment values 6 months thereafter. No histological improvement was observed in either group.
                There is no indication for treatment with interferon-alpha at the dose of 3 mega units thrice weekly plus 800 mg/day of ribavirin for 6 months in chronic hepatitis C resistant to interferon-alpha. The purpose of this study was to compare interferon-alfa alone (12-month course with high initial doses) with a combination of interferon-alfa and ribavirin in patients infected with genotype 1b. Three hundred and seven patients were randomized into 3 groups to receive 6 mega units (MU) of interferon-alfa-2b subcutaneously 3 times weekly for 6 months followed by 3 MU for 6 months (n = 95, group A); 10 MU for 3 months followed by 6 MU for 3 months, followed by 3 MU for 6 months (n = 83, group B); or the group-A schedule in combination with ribavirin (n = 129, group C) for 4 (n = 46), 6 (n = 44), or 12 months (n = 39). Negative polymerase chain reaction (PCR) was more frequent in group C than in groups A or B after 3 months of treatment (P <.006), at the end of treatment (P =.017), and at the end of follow-up (32.8%, 16.9%, and 14.1%, respectively, P <.003). A complete response (negative PCR and normal alanine transaminase) was higher in group C than in the other groups and when comparing 12- to 4- and 6-month combination therapy at the end of treatment (P =.05) and of follow-up (45.2% vs. 25.4%, respectively, P =.05). The greater efficacy of the combination was related to the higher rate of primary virological response and also to a decrease in the percentage of breakthrough and of relapse. In 1b-infected patients, the combination of high doses of interferon-alfa (6 MU) and ribavirin for 12 months appears to be the best therapy, with a high rate of sustained response. Recently, the combination treatment of recombinant alpha-interferon plus ribavirin has been proposed for chronic hepatitis C patients unresponsive to previous therapy with recombinant alpha-interferon alone.
                To determine the effectiveness of the combination therapy for the re-treatment of chronic hepatitis C patients unresponsive to previous interferon therapy. Immediate and long-term follow-up data are reported.
                A series of 100 patients with chronic hepatitis C not responding to recombinant alpha-interferon 3 MU tiw, were randomly assigned to two groups of 50 patients each: Group A, treated with recombinant alpha-interferon therapy for an additional six months but at a double dosage (6 MU tiw) in association with ribavirin. Group B, same treatment as group A but without ribavirin. All patients responsive to therapy were then followed-up for at least 12 months. At the end of the treatment and at the end of the follow-up period, we distinguished between complete responses (return to normal of alanine aminotransferase with undetectable serum HCV-RNA] and biochemical responses (return to normal of alanine aminotransferase still with detectable viraemia).
                Side-effects were observed only in patients treated with recombinant alpha-interferon plus ribavirin: 12% discontinued the therapy due to haemolytic anaemia. In group A, the percentages of end-of-treatment complete response, end-of-treatment biochemical response, sustained complete response, and sustained biochemical response, were 38%, 20%, 8%, and 14%, respectively, whilst in group B, these percentages were 12%, 16%, 6%, and 16%, respectively.
                The results indicate that in patients with chronic hepatitis C unresponsive to previous recombinant alpha-interferon therapy, re-treatment with higher recombinant alpha-interferon doses, either alone or in combination with ribavirin, lead to mild long-term benefit. However, the satisfactory end of treatment complete response in group A suggests that a significant percentage of patients are sensitive to the combination therapy; and that a more aggressive therapeutic protocol in this selected subset of patients could result in a larger number of long-lasting responses leading, in turn, to a more favourable cost-effect ratio. We conducted a three-arm, randomized trial in 96 patients with chronic hepatitis C who did not respond to interferon alfa to compare treatments. Group 1 (33 patients) received ribavirin alone (1,000 mg/daily for 6 months) followed by interferon alfa n-3 alone (3 MU thrice weekly for 6 months); group 2 (33 patients) received ribavirin plus interferon alfa n-3 for 6 months at the above doses; and group 3 (30 patients) received interferon alfa n-3 alone (3 MU thrice weekly for 6 months). At the end of treatment, 3 patients (10%) in group 1, 13 (41%) in group 2, and 5 (17%) in group 3 had normal alanine transaminase (ALT) levels (group 2 vs. groups 1 and 3, P = .008). After 6 months of follow-up, only 4 patients (12.5%) in group 2 still had normal ALT values (P = .03). At the end of therapy, hepatitis C virus (HCV) RNA was no longer detectable by polymerase chain reaction in 4 (13%), 9 (27%), and 2 (7%) patients, respectively, in groups 1, 2, and 3 (P = NS). Six months posttherapy, only 5 (15%) patients in group 2 were still HCV RNA negative (P = .02). At the time of follow-up liver biopsy, performed 6 months after the end of treatment, a significant improvement of the necroinflammatory scores was observed among group 2 patients (P = .01) but not in the other two groups. Side effects reflected the profile of each drug as monotherapy; mild hemolytic anemia was the most frequent side effect caused by ribavirin. In conclusion, concomitant administration of ribavirin and interferon alfa n-3 was significantly superior to the sequential schedule or interferon alfa n-3 monotherapy in inducing a sustained response in patients with chronic hepatitis C who had not responded to interferon alone. However, combination therapy at the dose and duration adopted in this study is capable of modifying the natural course of the disease in only a minority of these patients. The objectives of this study were to assess the safety, pharmacokinetics, and efficacy of pegylated interferon alfa-2b (PEG-Intron) plus ribavirin in patients with chronic hepatitis C. A total of 72 patients (35 men/37 women, age range 20-68 years) with clinically compensated chronic hepatitis C virus (HCV) were enrolled into this open-label, randomized, active controlled study. Patients received either PEG-Intron 0.35, 0.7, or 1.4 microg/kg subcutaneously weekly for 24 weeks alone, or in combination with ribavirin 600, 800, or 1,000 to 1,200 mg orally daily. Patients were evaluated during treatment and after a 24-week follow-up period for safety and efficacy. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. PEG-Intron alone produced expected dose-related reductions in white cells, neutrophils and platelets. Addition of ribavirin reduced hemoglobin levels in a dose-related manner, did not further reduce PEG-Intron-induced decreases in neutrophil or white cell count, and increased platelet counts. Neutrophil function tests (C5a and FMLP migration, killing curves) were unaltered. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in all dose groups. Anti-HCV activity, as measured by loss of detectable serum HCV RNA (i.e. <100 copies/mL) at the end of treatment (week 24) and after 24 weeks of follow-up (week 48) showed dose-response trends for PEG-Intron. At each PEG-Intron dose level, anti-HCV activity was higher in patients coadministered ribavirin than in patients treated with PEG-Intron monotherapy. There was no evidence of pharmacokinetic interactions with either drug. We conclude that the safety and tolerability of combined PEG-Intron/ribavirin and PEG-Intron alone were comparable. Combined PEG-Intron/ribavirin showed dose-related synergistic anti-HCV effects, which were numerically superior to those obtained with PEG-Intron monotherapy. In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment.
                A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups.
                The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.
                In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)
                2009 Massachusetts Medical Society Interferon alfa is the only effective treatment for patients with chronic hepatitis C. Forty percent of patients have an initial response to this therapy, but most subsequently relapse. We compared the effect of interferon alone with that of interferon plus oral ribavirin for relapses of chronic hepatitis C.
                We studied 345 patients with chronic hepatitis C who relapsed after interferon treatment. A total of 173 patients were randomly assigned to receive standard-dose recombinant interferon alfa-2b concurrently with ribavirin (1000 to 1200 mg orally per day, depending on body weight) for six months, and 172 patients were assigned to receive interferon and placebo.
                At the completion of treatment, serum levels of hepatitis C virus (HCV) RNA were undetectable in 141 of the 173 patients who were treated with interferon and ribavirin and in 80 of the 172 patients who were treated with interferon alone (82 percent vs. 47 percent, P<0.001). Serum HCV RNA levels remained undetectable 24 weeks after the end of treatment in 84 patients (49 percent) in the combination-therapy group, but in only 8 patients (5 percent) in the interferon group (P<0.001). Sustained normalization of serum alanine aminotransferase concentrations and histologic improvement were highly correlated with virologic response. Base-line serum HCV RNA levels of 2 x 10(6) copies per milliliter or less were associated with higher rates of response in both treatment groups. Viral genotypes other than type 1 were associated with sustained responses only in the combination-therapy group. Combined therapy caused a predictable fall in hemoglobin concentrations but otherwise had a safety profile similar to that of interferon alone.
                In patients with chronic hepatitis C who relapse after treatment with interferon, therapy with interferon and oral ribavirin results in higher rates of sustained virologic, biochemical, and histologic response than treatment with interferon alone. Efficacy and safety of interferon induction therapy alone or in combination with ribavirin or ribavirin plus amantadine were evaluated in chronic hepatitis C patients who were nonresponders to primary antiviral treatment.
                The study was designed to have 225 HCV nonresponder patients, but at an interim analysis the response rate difference between groups was lower than expected and the enrollment was stopped when 75 patients had been randomized to receive interferon-alpha2a (group A, n = 26), interferon-alpha2a plus 15 mg/kg per day of ribavirin (group B, n = 24), or interferon-alpha2a plus ribavirin plus 200 mg/day of amantadine hydrochloride (group C, n = 25). Treatment duration was 48 weeks. The dose of interferon was 6 MU/day for 4 weeks followed by 3 MU/day for the remaining 44 weeks.
                On intention-to-treat, the sustained virological response at 24 weeks of follow-up was 11.5% in group A, 12.5% in group B, and 12% in group C. Therapy was discontinued because of adverse effects in three patients in group A (11.5%), three in group B (12.5%), and two in group C (8%).
                Nonresponders with chronic hepatitis C may achieve a sustained virological response rate of approximately 12% if retreated with interferon induction treatment followed by administration of a daily dose. The addition of ribavirin or amantadine did not seem to improve the response rates. 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. Response to treatment with alpha interferon with or without concomitant ribavirin varies according to the viral genotype in patients with chronic hepatitis C.
                This study was undertaken in order to determine the response of genotype 4 chronic hepatitis C to interferon and ribavirin combination compared to interferon alone in patients without cirrhosis.
                Fifty-two patients were given interferon alone at a dose of 5 million units, 3 times a week and another 60 patients were administered with interferon combined with ribavarin (1,000-1,200 mg/ day) for 24 weeks. Sustained biochemical response was defined as normal ALT, 6 months after end of therapy. Sustained virologic response was defined as negative HCV RNA, 6 months after the end of therapy.
                Only 10/52 (19%) patients showed sustained biochemical response after interferon alone, while 31/60 (52%) showed sustained biochemical response after interferon combined with ribavirin (p<0.01). Only 4/52 (8%) patients showed sustained virologic response after interferon alone, while 25/60 (42%) showed sustained virologic response after interferon combined with ribavirin (p<0.001).
                These results show that patients with chronic hepatitis due to hepatitis C virus type 4 show a poor response to interferon alone but a better response to interferon combined with ribavirin. The efficacy and safety of peginterferon alpha-2a (40 KD) (peg-IFNalpha-2a) plus ribavirin has not been reported for Japanese patients with chronic hepatitis C. The aim of this study was to evaluate this combination in treatment-naïve patients and in non-responders or relapsers to interferon monotherapy.
                Overall, 201 treatment-naïve patients with hepatitis C virus (HCV) genotype-1b were randomly assigned to 180 microg peg-IFNalpha-2a once-weekly plus ribavirin 600-1000 mg/day or peg-IFNalpha-2a plus placebo for 48 weeks. Additionally, peg-IFNalpha-2a plus ribavirin was administered for 48 weeks to 100 non-responders or relapsers (85% genotype-1) to previous interferon monotherapy.
                A sustained virological response (SVR) was attained among significantly more treatment-naïve patients receiving combination therapy than monotherapy (61% vs 26%, P < 0.001). For patients with high baseline HCV RNA, the SVR rate was 59% with peg-IFNalpha-2a plus ribavirin versus 24% with peg-IFNalpha-2a monotherapy. Among non-responders or relapsers to previous interferon monotherapy, 54% attained an SVR. Adverse events were generally mild, and discontinuations rates due to adverse events or laboratory abnormalities were low.
                In Japanese patients, peg-IFNalpha-2a plus ribavirin provided significant improvement in SVR rates compared with peg-IFNalpha-2a alone in treatment-naïve patients, and was effective as re-treatment for non-responders or relapsers to previous treatment with interferon monotherapy. The present study was designed to evaluate the effectiveness of interferon-ribavirin combination therapy for treatment of chronic hepatitis C virus (HCV) in patients who failed previous treatment with interferon monotherapy.
                A total of 140 patients with well-documented chronic HCV who failed to achieve a virological (if HCV-RNA was assessed) or biochemical response (if HCV-RNA was not assessed) to interferon monotherapy, 3 mU three times weekly (TIW) for 3-18 months, were randomly assigned to one of three treatment groups. Group A patients were treated with 5 mU interferon TIW for 6 months. Ribavirin (1000-1200 mg daily) was added in those patients HCV-RNA positive at month 3. Group B patients were treated with 3 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. The dose of interferon was increased to 5 mU TIW in those patients HCV-RNA positive at month 3. Group C patients were treated with 5 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. Serum ALT and HCV-RNA were monitored during and after treatment for a total of 15 months.
                Seventeen percent of patients in group A became HCV-RNA negative by treatment month 3. Adding ribavirin resulted in one additional patient becoming HCV-RNA negative. However, none of the patients in this group achieved sustained virological response. Twenty-six percent of patients in group B became HCV-RNA negative by treatment month 3. Increasing the dose of interferon from 3 to 5 mU TIW increased virological response to 30%. However, sustained virological response was observed in only 14%. Thirty percent of patients in group C became HCV-RNA negative, but sustained virological response was observed in only 12%. Sustained virological response was found to be significantly greater in patients with a nontype I HCV genotype (p < 0.002) and in patients who had a decline in HCV-RNA titer to a value < 100,000 copies/ml during their previous course of interferon monotherapy (p < 0.0001). None of the 12 sustained responders were African Americans (p < 0.013).
                Retreatment of nonresponders with interferon-ribavirin combination therapy results in limited benefit; only 13% of patients achieved sustained virological response. Response was extremely poor in African Americans and those with HCV genotype 1. Chronic active hepatitis due to HCV represents a severe progressive disorder of the liver, At present, Interferon seems to be the most efficacious treatment available, however, only 20-25% of the patients treated achieve complete remission. The efficacy has, therefore, been evaluated of Ribavirin, a nucleoside analogue active both on DNA and RNA viruses, in the treatment of non responders to a previous course of interferon. Twenty patients were randomly assigned to two groups: A) received the association R (800 mg/day for 2 months)+interferon (9 Mu/week for 6 months); B) received IFN (9 Mu/week for 6 months). All patients completed the study without important side effects. Four patients in group A presented reduced ALT and loss of viraemia during treatment with Ribavirin. Only one patient in group B had reduced indices of cell lysis and was negative for HCV-RNA during the course of the study. However, viremia and an increase of ALT values were observed in all of these subjects once treatment was interrupted. The results emerging from this study indicate that Ribavirin therapy, at the dose and duration of treatment employed, is not sufficient to change the natural course of events of chronic active hepatitis from HCV. Adolescents and adults with inherited disorders of coagulation have one of the highest prevalence rates of hepatitis C among known risk groups. Few data are available on the use of combination therapy with interferon and ribavirin in this population. Patients 13 years of age and older who were positive for hepatitis C virus (HCV) RNA by polymerase chain reaction and negative for human immunodeficiency virus were randomized to receive interferon alfa-2b (3 million units 3 times a week) plus ribavirin (1,000 mg/day) or interferon alfa-2b alone for 48 weeks with 24 weeks of posttreatment follow-up. Patients started on interferon alone who remained positive for HCV RNA at week 12 crossed over to treatment with interferon plus ribavirin. A total of 113 patients were treated. Thirty-seven patients were younger than 18 years. At the end of treatment, 18 of 56 (32%) treated with interferon plus ribavirin and 6 of 57 (11%) treated with interferon alone were negative for HCV RNA (P =.005). Sustained virologic response in the combination arm was 29% (16 of 56) compared with 7% (4 of 57) for those started on interferon alone (P =.027). Among adolescents younger than 18 years who were treated with combination therapy, 10 of 17 (59%) had sustained response compared with 6 of 39 (15%) of adult patients on the same regimen (P =.001). In conclusion, in this U.S. multicenter, randomized trial of therapy for HCV in patients with inherited bleeding disorders, sustained virologic response rate was significantly improved for patients treated with interferon and ribavirin compared with those started on interferon alone. Adolescents treated with combination therapy had a significantly higher sustained response than adults did on the same regimen. The primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon alpha-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone.
                In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study.
                The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout half-lives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase half-lives was 5-7 h. IFN demonstrated an increase in bioavailability (approximately 2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2',5'-oligoadenylate synthetase (2'5'-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2'5'-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN--reductions in white cells, neutrophils and platelets; ribavirin--reduced haemoglobin) and characteristic adverse event profiles (IFN--headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin--headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation.
                There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.
Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus from the blood. Combination therapy may reduce liver-related morbidity and all-cause mortality, but we need more evidence. The number needed to treat to obtain a beneficial effect is considerable considering the increased risk of several severe adverse reactions and costs.