Randomized placebo-controlled trial of interferon alpha-2b plus ribavirin with and without lactoferrin for chronic hepatitis C.

Lactoferrin (LF), an iron-binding glycoprotein, exhibits several biological activities, including anti-viral activity and immunomodulatory functions. LF has been reported to inhibit hepatitis C virus (HCV) infection in cultured human hepatocytes and HCV viremia in low pretreatment HCV RNA titers of patients with chronic hepatitis C (CHC). However, the combination of interferon (IFN) alpha-2b plus ribavirin with LF for CHC has not been previously investigated. Thirty-six CHC patients, who were positive for HCV RNA with high serum levels of HCV RNA or who did not respond to or relapsed after interferon monotherapy, were randomly assigned to two groups: IFN alpha-2b and ribavirin plus LF for 24 weeks (18 patients), and IFN alpha-2b and ribavirin plus placebo (18 patients). Treatment was discontinued in three patients (17%) in the LF group and eight patients (44%) in the placebo group. For the 25 patients who finished the 24 weeks of treatment, virological sustained response was seen in 6 (40%) patients in the LF group and in 5 (50%) patients in the placebo group and there was no statistically significant difference between the two groups (p=0.7). Serum alanine aminotransferase concentrations remained normal throughout the follow-up period in nine patients (60%) in the LF group as compared with five patients (50%) in the placebo group (p=0.7). The proportion of patients with a virological or biochemical response at the end of the treatment period did not differ between the two groups. Furthermore, there were no statistically significant differences between the two groups in hemoglobin concentration, serum iron, ferritin, Th1/Th2 ratio or ribavirin concentration throughout the treatment and follow-up periods. In conclusion, we could not demonstrate that LF in combination with IFN alpha-2b and ribavirin increases the virological and biochemical response rate for CHC patients with high serum levels of HCV RNA or for CHC patients who do not response to or relapse after IFN monotherapy.     

Twenty-four weeks of interferon alpha-2b in combination with ribavirin for Japanese hepatitis C patients: sufficient treatment period for patients with genotype 2 but not for patients with genotype 1.

BACKGROUND: Hepatitis C virus (HCV) RNA titer and HCV genotype are two major determinants of the outcome of interferon (IFN) monotherapy. To clarify the usefulness of combination therapy with IFN and ribavirin in Japanese hepatitis C patients, we treated patients with a relatively high dose of IFN in combination with ribavirin for 24 weeks and examined the effects in relation to the viral parameters. METHODS: Two hundred and ninety-five patients were enrolled in the study. The patients received either 6 or 10 million units (MU) of interferon alpha-2b every day for 2 weeks and then three times a week for 22 weeks with a daily dose of either 600 or 800 mg of ribavirin. The treatment response and safety of this treatment were examined. RESULTS: The sustained virologic response (SVR) rates were 26.8% in genotype 1 and 76.5% in genotype 2 (P < 0.001), and 36.1% with the 6 MU group and 45.8% with the 10 MU group (P = 0.09). Multivariate analysis indicated that SVR was associated with genotype 2, HCV RNA <500 kilointernational unit/ml (kIU/ml), and HCV RNA undetectability at week 8 of treatment. CONCLUSION: Our current study showed that a 24-week course of IFN plus ribavirin combination therapy was effective with respect to virologic response in Japanese hepatitis C patients, particularly in patients with HCV genotype 2.     

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.

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). METHODS: 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. CONCLUSION: 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.     

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

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

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

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

Hepatitis C virus kinetics during the first phase of pegylated interferon-α-2b with ribavirin therapy in patients with living donor liver transplantation

Aim:  To identify the problems of pegylated interferon (PEG IFN) with ribavirin therapy against hepatitis C virus (HCV) reinfection in living donor liver transplantation (LDLT) patients. HCV kinetics during the PEG IFN with ribavirin therapy were analyzed in LDLT patients, as well as in chronic hepatitis C (CHC) patients.
Methods:  The study included 80 consecutive HCV infected patients undergoing PEG IFN with ribavirin therapy (64 CHC and 16 LDLT patients) who attended the Nagasaki University Hospital for an initial visit between January 2005 and December 2007.
Results:  The sustained viral response (VR) rate of the CHC group (80%) was superior to the LDLT group (22%). The viral disappearance rate of the CHC group was also superior to the LDLT group, regardless of the HCV serotype. The HCV core antigen (cAg) titer under treatment in the LDLT group was more than that of the CHC group from day 0 to week 12. The HCV cAg decrease rate of the LDLT group on the first day of treatment was less than that of the CHC group.
Conclusion:  The HCV infection of a transplanted liver is more refractory to treatment than a non-transplanted liver. The low reduction HCV cAg rate on day 1 is one of the problems of the combination therapy.     

Changes in serum hepatitis C virus RNA in interferon nonresponders retreated with interferon plus ribavirin: a preliminary report.

Ribavirin, a nucleoside analogue, inhibits replication of RNA and DNA viruses and may control hepatitis C virus (HCV) infection through modulation of anti-inflammatory and antiviral actions. Ribavirin monotherapy has no effect on serum HCV RNA levels. In combination with interferon, this agent appears to enhance the efficacy of interferon. The aim of this study was to monitor serum HCV RNA levels early during therapy with interferon and ribavirin compared with that previously seen in the same patients during interferon monotherapy. Five patients who previously showed no response to therapy with interferon alfa 3 MU three times weekly for 6 months were retreated with the identical dose of interferon alfa 2b in combination with oral ribavirin 1,000 mg/day. Serum HCV RNA levels were monitored at baseline, week 4, week 8, and week 12 of therapy by a quantitative multicycle polymerase chain reaction assay. In the first 8 to 12 weeks, serum HCV RNA levels showed a greater decrease in all patients when retreated with combination therapy compared with interferon alone. Mean (+/- SEM) serum HCV RNA levels for interferon therapy alone were 3.3 +/- 0.95, 1.2 +/- 0.95, 1.6 +/- 1.2, and 2.3 +/- 1.2 x 10(6) copies/ml at week 0, 4, 8, and 12, respectively. This was compared with 3.3 +/- 0.83, 0.3 +/- 0.2, 0.03 +/- 0.02, and 0.15 +/- 0.14 x 10(6), respectively, for the interferon and ribavirin group (p < 0.07 at week 8). Two of five patients had undetectable serum HCV RNA during combination therapy. Combination therapy with interferon and ribavirin in prior interferon nonresponders reduces serum HCV RNA levels compared with interferon alone. This may suggest some additional antiviral effect of ribavirin when given with interferon.     

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

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

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

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

Predictive factors for interferon and ribavirin combination therapy in patients with chronic hepatitis C

AIM： To confirm the predictive factors for interferon （IFN）-α and ribavirin combination therapy for chronic hepatitis patients with hepatitis C virus （HCV） genotype lb. METHODS： HCV RNA from 50 patients infected with HCV genotype lb was studied by cloning and sequencing of interferon sensitivity determining region （ISDR）, PKR- eIF2α phosphorylation homology domain （PePHD）. Patients were treated with IFN-α and ribavirin for 6 mo and grouped by effectiveness of the therapy. A variety of factors were analyzed. RESULTS： Our data showed that age, HCV RNA titer, and ISDR type could be used as the predictive factors for combined IFN-α and ribavirin efficacy. Characteristically, mutations in PePHD appeared only when the combination therapy was effective. Other factors, such as sex and alanine aminotransferase （ALT） level, were not related to its efficacy. Adjusting for age and HCV RNA titer indicated that the ISDR type was the most potent predictive factor. CONCLUSION： HCV RNA ISDR type is an important factor for predicting efficacy of IFN-α and ribavirin combination therapy in Korean patients.     

Up-regulation of IL-18 by interferon alpha-2b/ribavirin combination therapy induces an anti-viral effect in patients with chronic hepatitis C

BACKGROUND/AIMS: Recent large prospective trials demonstrated that the combination therapy of interferon (IFN)-alpha/ribavirin significantly increased a sustained virological response rate in patients with chronic hepatitis C. However, the potential mechanism of ribavirin is not clear. METHODOLOGY: Serum interleukin (IL)-18 and HCV-RNA titer were determined before and 2 weeks after administration in patients with chronic hepatitis C, who were treated with ribavirin in combination with IFN-alpha2b (combination group), and with IFN-alpha2b alone (monotherapy group). RESULTS: All HCV patients were genotype 1b. In the combination group, the decline of HCV-RNA level by treatment highly correlated with the IL-18 ratio (serum IL-18 level 2 weeks after administration/serum IL-18 level before administration). Similarly, the HCV-RNA level 2 weeks after administration inversely correlated with the IL-18 ratio. In contrast, the IL-18 ratio in the monotherapy group was lower. Furthermore, the decline of HCV-RNA level did not correlate with the IL-18 ratio in the monotherapy group. CONCLUSIONS: This study suggests that ribavirin may contribute to the antiviral effect through up-regulation of IL-18 in combination with IFN in patients with chronic hepatitis C.     

Interferon alfa-2b [correction of alpha-2b]and ribavirin for patients with chronic hepatitis C and normal ALT

OBJECTIVES: Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alfa-2b (IFN) with ribavirin (RBV) in patients with normal ALT [correction]. METHODS: Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000-1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy. RESULTS: Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36%vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted. CONCLUSIONS: Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients.     

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

BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

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

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

Lactoferrin inhibits lipid peroxidation in patients with chronic hepatitis C.

Lactoferrin is a milk protein with inhibitory effect on lipid peroxidation induced by oxidative stress. Oxidative stress plays an important role in the pathogenesis of chronic hepatitis C (CHC). The aim of this study was to evaluate the effect of bovine lactoferrin (bLF) monotherapy on lipid peroxidation, hepatic inflammation and iron metabolism in patients with CHC. Ninety Japanese patients with CHC were randomly assigned to two groups: bLF group (n=47) treated with bLF at a dose of 3.6g/day and a control group (n=43) that remained untreated. Plasma 8-isoprostane levels and clinical laboratory data including iron metabolism parameters were measured. Plasma 8-isoprostatne level was significantly decreased from 8.6+/-3.7 to 6.9+/-2.1pg/ml in the bLF group (P<0.05). Plasma levels of 8-isoprostane did not significantly change in the control group. The decline in plasma 8-isoprostane levels was positively correlated with improvement in the level of ALT in the bLF group. No significant change in serum HCV RNA levels or iron metabolism markers was found after bLF treatment. Therapy with bLF was associated with improvement in lipid peroxidation and ALT levels in CHC. Administration of bLF is a promising therapeutic approach for suppressing oxidative stress in non-responders to antiviral therapy.     

扶正解毒方联合标准方案治疗基因1型慢性丙型肝炎的前瞻性研究

目的探索我国基因1型慢性丙型肝炎(chronic hepatitis C,CHC)中西医结合治疗方案的临床疗效。方法给予我国汉族初治基因1型CHC患者中西医结合治疗,进行多中心、大样本、随机、双盲、安慰剂对照的前瞻性研究。研究分为治疗组[聚乙二醇干扰素(pegylated interferon,Peg-IFN)α-2a┼利巴韦林(ribavirin,RBV)┼扶正解毒方]和对照组(Peg-IFNα-2a┼RBV┼中药安慰剂),治疗48周,本文分析治疗至第24周时的数据。结果研究共纳入我国汉族基因1型初治CHC患者352例(治疗组178例,对照组174例)。治疗组和对照组分别有88.0%和81.1%的患者获得完全早期病毒学应答。治疗第24周时,治疗组和对照组HCV RNA阴转率分别为88.2%和83.0%。2组比较,差异均无统计学意义。最多见的不良反应为流感样症状、白细胞或血小板减少。无患者因不良反应而脱失,无严重不良反应发生。结论中西医结合治疗方案一定程度上可提高基因1型CHC患者的HCV RNA阴转率。     

Triple therapy of initial high-dose interferon with ribavirin and amantadine for patients with chronic hepatitis C

Aims: We previously reported the potential effect of combination therapy of an initial high‐dose interferon (IFN) and amantadine on the eradication of HCV‐RNA in patients with chronic hepatitis C. The additive effects of amantadine on interferon and ribavirin combination therapy remain controversial. In this study we investigated the efficacy of initial high‐dose IFN with ribavirin and amantadine on the virological response in patients with chronic hepatitis C with a high viral load of genotype 1b. Methods: Twenty‐two patients with high viral loads of genotype 1b hepatitis C virus were enrolled in this pilot study. Patients were administered IFN‐beta for four weeks and then IFN‐alpha2b for 22 weeks with daily oral administration of ribavirin and amantadine. Results: A sustained virological response (SVR) was shown in 31.8% (seven of 22 patients). With the naïve patients, the SVR rate was 21.4% (three of 14 patients). In patients who could not eradicate HCV‐RNA by previous IFN monotherapy, the SVR rate was 50% (four of eight patients). Conclusion: Triple therapy with an initial high dose of IFN with ribavirin and amantadine may be effective, especially for chronic hepatitis C IFN‐retreatment patients with a high viral load of genotype 1b.     

Early Virological Response in Children with Chronic Hepatitis C Treated with Pegylated Interferon and Ribavirin

Abstract Objective: Infection with hepatitis C virus (HCV) is widespread worldwide. It is estimated that this problem affects approximately 3% of global population. By introducing weekly doses of pegylated interferon (IFN) alfa in combination with ribavirin, given daily, to chronic hepatitis C (CHC) treatment one can achieve a full inhibition of HCV replication in 54–56% of adult patients. The aim of this study was to examine the relationship between prognostic factors and early virological response (EVR) after combination treatment with peginterferon alfa- 2a or alfa-2b and ribavirin in children with CHC. Methods: Twenty-three children with chronic HCV were treated with a combination of peginterferon alfa-2a or alfa-2b once a week and ribavirin twice a day. Assessment included age at the time of infection, the length of infection, HCV genotype, viral load in serum and HCV RNA level in peripheral blood mononuclear cells (PBMCs), alanine aminotransferase (ALT) activity and adherence to therapy. The efficacy endpoint was EVR defined as undetectable HCV RNA in serum or >2 log10 decrease in HCV RNA compared with baseline values. Results: An EVR was achieved in 15 out of 23 patients (65.3%) after 12 weeks of therapy. Conclusions: Lower HCV RNA viral load have positive influence on EVR. HCV RNA presence in PBMCs and lower ALT activity do not influence the achievement of EVR. Oncologic history does not bear any influence on EVR. Adherence to the therapy has an unclear influence on the achievement of EVR in children with CHC.     

Retreatment for 24 vs 48 weeks with interferon-alpha2b plus ribavirin of chronic hepatitis C patients who relapsed or did not respond to interferon alone

We assessed the efficacy of interferon (IFN) plus ribavirin over 24 or 48 weeks for the retreatment of patients with chronic hepatitis C who had relapsed or did not respond to a previous course of IFN. One-hundred and twenty patients (69 non-responders and 51 relapsers) were randomly assigned to receive IFN-alpha2b (3 million units thrice weekly) plus ribavirin (1,000-1,200 mg per day) for 24 weeks (group A: 58 patients) or 48 weeks (group B: 62 patients). Treatment was discontinued at week 12 if the alanine aminotransferase (ALT) level remained elevated. The rate of sustained response was 15.5% in group A and 37.1% in group B (P = 0.013). Relapsers treated for 48 weeks had a sustained response rate of 66.6% compared with a sustained response rate of only 25% in those treated for 24 weeks (P = 0.004). Moreover, a sustained response was seen in 14.3% of non-responders treated for 48 weeks and in 8.8% of those treated for 24 weeks (P = 0.71). Fifty-three per cent of patients with a normal ALT level and undetectable hepatitis C virus (HCV) RNA at week 12 had a sustained response compared with 14% of those who were HCV RNA positive at week 12 (P < 0.001). Independent predictive factors of sustained response were: therapy for 48 weeks (P = 0.0026), relapse after IFN treatment (P = 0.0006), loss of HCV RNA at week 12 (P = 0.0008) and HCV genotype non-1 (P = 0.024). Hence, in patients with chronic hepatitis C who failed to respond to a previous course of IFN monotherapy, combination therapy with IFN plus ribavirin for 48 weeks seems to be more effective than IFN plus ribavirin for 24 weeks.     

Efficacy of high-dose interferon in combination with ribavirin in patients with chronic hepatitis C resistant to interferon alone

OBJECTIVE: Interferon combined with ribavirin has efficacy in the treatment of patients with chronic hepatitis C virus (HCV) infection. However, its utility in patients who have not responded to prior interferon therapy is not clear. Furthermore, the effect of using an increased dose of interferon in combination with ribavirin in patients with chronic hepatitis C resistant to conventional doses of interferon is not known. The aim of our study was to evaluate the effect of high-dose interferon in combination with ribavirin on the efficacy of treating patients with chronic hepatitis C resistant to interferon monotherapy in a large multicenter trial. METHODS: We randomized 154 patients with chronic hepatitis C who failed to achieve a sustained response with prior interferon therapy to receive either 3 or 5 MU of interferon alpha-2b and ribavirin (1000-1200 mg/day) for 12 months. There were 119 patients who had not responded and 35 who initially responded but relapsed after prior interferon monotherapy. Serum HCV RNA levels were measured at entry, 6, and 12 months of treatment and at the end of a 6-month follow-up period. RESULTS: The mean age of the subjects was 47 yr (range 28-68 yr), and 110 (71.4%) were men. One hundred thirty-two patients (86%) had HCV genotype 1, whereas 21 (14%) had cirrhosis. Eighty-one subjects (53%) were randomized to receive 3 MU of interferon alpha-2b. Fifteen of 35 relapse subjects (43%) and 12 of 119 prior nonresponder entrants (10%) achieved a sustained virological response to the 12-month course of treatment. Overall, 11 of 81 patients (14%) receiving 3 MU, and 16 of 73 patients (22%) receiving 5 MU of interferon maintained an undetectable HCV RNA level after cessation of therapy. The difference in sustained response rates between the two interferon dosage groups did not reach statistical significance (p = 0.09). However, among the nonresponder patients alone, there was an increased sustained response in the high-dose interferon group compared with the standard interferon dose group (15.5% vs 4.9%, p = 0.055). Twenty-six patients discontinued therapy before 6 months, including 10 patients (12.3%) in the 3-MU and 16 patients (21.9%) in the 5-MU groups (p = 0.17). CONCLUSIONS: Sustained virological response to combined interferon alpha-2b and ribavirin was significantly higher in relapse patients than those who did not respond to prior interferon monotherapy. Although, when all treated patients were analyzed, there was no significant difference in sustained response between subjects receiving 3 and 5 MU of interferon, among the prior nonresponder patients, treatment with 5 MU of interferon with ribavirin resulted in a slightly increased response compared with treatment with the standard interferon dosage. The tolerability of the treatment regimens was comparable.