Treatment of chronic hepatitis C with amantadine

Treatment of chronic hepatitis C infection with interferon has been disappointing, with less than one third of patients achieving a sustained response and most experiencing significant side effects. For these reasons, an open-labeled prospective pilot study was conducted to test the safety and efficacy of the antiviral drug, amantadine, in patients with chronic hepatitis C infection who had previously failed therapy with interferon-alpha 2b. Twenty-two patients with chronic hepatitis C were enrolled into the study and treated with amantadine 100 mg orally twice daily for six months. Control groups included the same cohort followed off therapy for 29-36 months or during therapy with interferon. Serum alanine aminotransferase (ALT) values decreased in 64% (P = 0.01) of patients with amantadine therapy compared to intervals without therapy or to interferon therapy. Twenty-seven percent of patients treated with amantadine had normalization of ALT values and loss of HCV RNA after six months while 18% achieved a sustained response with loss of HCV RNA by PCR six months after discontinuation of amantadine. Therapy with amantadine improved both biochemical and virological markers in patients with hepatitis C who had previously not responded to treatment with interferon.     

Immunoglobulin M antibody response to hepatitis C virus core protein in patients with chronic hepatitis C

We retrospectively assessed the frequency and clinicopathologic and virologic significance of production of immunoglobulin M (IgM) antibody to hepatitis C virus (HCV) core protein in patients with chronic hepatitis C. Sera from 60 patients with chronic hepatitis C were tested for IgM anti-HCVcore (anti-HCc). Twenty of these patients received ribavirin plus interferon-alpha for 24 weeks, and were classified as sustained, transient, or nonresponders on the basis of alanine aminotransferase levels and the presence of HCV RNA at the end of treatment and 24 weeks later. IgM anti-HCc was detected in 21 patients. There was no correlation between the presence of IgM anti-HCc and clinical features such as sex, age, mode of transmission, serum levels of alanine aminotransferase, HCV genotype, serum HCV titer, or histologic findings. Among the patients who received ribavirin plus interferon-alpha, the mean IgM anti-HCc level before therapy was comparable between sustained (n = 10), transient (n = 8), and nonresponders (n = 2). A statistically significant decrease in IgM anti-HCc response during antiviral therapy was observed in the 18 responders who became negative for serum HCV RNA at the end of therapy. These data suggest that IgM anti-HCc is of limited clinical usefulness as a marker of chronic HCV infection. Serial testing for IgM anti-HCc may provide a marker of antiviral response.     

Efficacy of interferon dose and prediction of response in chronic hepatitis C: Benelux study in 336 patients

BACKGROUND/AIMS: In an attempt to improve the limited efficacy of treatment of chronic hepatitis C with interferon-alpha 3 MU tiw, we studied the effects of double-dose therapy followed by downward titration, and analyzed the pre- and pertreatment factors associated with response or non-response. METHODS: Three hundred and fifty-four consecutive patients in 19 centers were randomized to interferon-alpha 3 MU tiw for 6 months or 6 MU tiw for 8 weeks followed by down-titration (3,1 MU tiw) till alanine aminotransferase remained normal and plasma HCV RNA was repeatedly undetectable. The primary outcome measure was sustained alanine aminotransferase and HCV RNA response 6 months after treatment. RESULTS: Three hundred and thirty-six patients received treatment. The sustained response rate for patients receiving 3 MU tiw for 6 months was 14% (9-21%,) and for patients receiving double dose tiw for 8 weeks and thereafter titrated therapy 15% (10-21%) (p=0.8). Pretreatment factors associated with a sustained alanine aminotransferase plus HCV RNA response were the absence of cirrhosis, presence of genotype 2 or 3, a low viral load and, in addition, a low alanine aminotransferase/aspartate aminotransferase ratio; a model was developed to allow estimation of the chance of response for the individual patient. The most powerful predictor of sustained response, however, was plasma HCV RNA at week 4; a positive test virtually precluded a sustained response (1.7%, 0.4-5.0%). If week 4 HCV RNA was not detectable, the chance of a sustained response was 21% (12-34%) for genotype 1 versus 40% (28-54%) for the others (p=0.02). Six MU tiw led to a significantly higher week 4 HCV RNA response (47% not detectable) than 3 MU (37%) (p=0.02). During down-titration this difference in viral on-treatment response was lost. CONCLUSIONS: In the treatment of hepatitis C, an early HCV RNA response is a prerequisite for long-term efficacy. Doubling the initial interferon dose increases this early response, but subsequent downward titration negates this effect, especially in genotype 1.     

Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone.     

Efficacy of interferon monotherapy in the treatment of relapsers and nonresponders with chronic hepatitis C infection

Results of numerous studies have demonstrated similar efficacy profiles for the interferons (IFNs) currently approved for the treatment of chronic hepatitis C virus (HCV) infection. Although it has been suggested that some IFNs are more efficacious in certain patient populations, the current data support an equivalent efficacy and safety profile for these agents. Among patients requiring retreatment, no single study has made a direct comparison of IFN alfa-2b (IFN-alpha 2b) and consensus IFN (CIFN) in patients who have relapsed or have not responded to previous IFN therapy. However, at least 11 studies using IFN-alpha 2b and 1 using CIFN have demonstrated efficacy in the relapsing and nonresponding patient populations. A review of these studies suggests that overall efficacy and tolerability are similar regardless of IFN-alpha subtype. Overall, up to 59% and 83% of relapsed patients retreated with IFN have shown sustained response rates, as measured by negative HCV RNA titer and normalization of alanine aminotransferase (ALT) levels, respectively. Up to 14% and 25% of patients who failed to respond to previous IFN therapy have shown sustained HCV RNA response and normalization of ALT, respectively, after retreatment.     

Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 of interferons in treating children with chronic hepatitis C

Twenty-two children with chronic hepatitis serologically positive for hepatitis C virus (HCV) were treated with interferon-alpha (IFN-alpha). Liver biopsy showed chronic active hepatitis in 13 and chronic persistent hepatitis in 9 patients. A sustained clearance of HCV was observed in 8/22 children 12 months after the administration of IFN-alpha for 26 weeks, associated with normalization of HCV core antibody. Of these eight patients six had HCV genotype III and two HCV genotype II or IV. Hepatitis relapsed in seven other patients after completion of IFN-alpha with an increase in HCV core antibody titre, five with HCV genotype II, and two with HCV genotype III or IV. A second course of IFN-alpha suppressed the reactivation of HCV in all seven patients. Three of seven responders who relapsed after the first course remained negative for HCV RNA 12 months after their second course of IFN-alpha. However, the remaining four patients with HCV genotype II again relapsed after completing their second course of IFN-alpha. Seven children with the HCV genotype II resistant to IFN, including 8 weeks of IFN-beta administration, and showed no significant reduction in HCV core antibody titre. CONCLUSION: The genotype of HCV (III) and a reduction in the core antibody titre appear to be useful parameters for predicting the response to IFN-alpha therapy.     

Activity and tolerance of a continuous subcutaneous infusion of interferon-alpha2b in patients with chronic hepatitis C

We administered interferon-alpha2b (IFN-alpha2b) by continuous subcutaneous infusion (60,000 IU/h, or 10 million IU/week) over 3 months to 7 patients with chronic hepatitis C. All had previously responded, as assessed by normalization of transaminases to the same dose of IFN administered by intermittent injection over 6 months, but had relapsed after cessation of therapy. The continuous infusion was tolerated well at the site of infusion, and the systemic side effects were similar in type but were lesser in intensity than with intermittent dosage. Four of 7 subjects had normalization of transaminase at the end of week 12 of therapy. Serum HCV RNA and HCV by PCR decreased with treatment, and there was a prompt and sustained increase in serum beta2-microglobulin and of 2', 5' OAS activity. The level of the latter appeared to correlate with response of the transaminase. Serum IFN concentrations were low but detectable throughout therapy. After stopping IFN administration, the transaminases in responders increased again to pretreatment levels.     

Ethanol exposure potentiates fosB and junB expression induced by muscarinic receptor stimulation in neuroblastoma SH-SY5Y cells

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) have been shown to play a role in host defense and pathogenesis of chronic HCV infection. Our aim was to test the hypothesis that intrahepatic HCV-specific CTL activity may impact subsequent response to interferon alfa (IFN-alpha) therapy. Of the 37 patients that we have prospectively evaluated for HCV-specific CTL activity in liver, 21 received IFN therapy, and 19 completed a 6-month course and attended 6 to 18 months of follow-up. Intrahepatic CD8+ cells were isolated from liver biopsy tissue and tested against target cells expressing HCV antigens to determine intrahepatic CTL activity. The relationship between treatment response and HCV-specific CTL activity and other factors known to associate with response (genotype, viremia, histology) was analyzed. HCV-specific CTL activity was detected in 9 of 21 patients (and 9 of 19 who completed therapy). After 6 months of IFN therapy, 8 of 19 (42%) patients had normal serum alanine transaminase (ALT) (complete responders). After 18 months of follow-up, only 3 patients (16%) had a sustained biochemical response. Of the 9 patients with detectable HCV-specific CTL activity in their liver before treatment, 7 (78%) developed a complete response. In contrast, only 1 of the 10 patients with no detectable HCV-specific CTL activity developed a complete response to IFN (P < .01). In 6 of 8 patients with a complete response, including the 3 sustained responders, the CTL response appeared to be directed predominately to the HCV core region. These data suggest that the host immune response, particularly that mediated by CD8+ CTL, may be important in determining the outcome of IFN therapy for chronic HCV infection. Further understanding of the mechanism of action of IFN should impact the design of better therapeutic strategies against chronic HCV infection.     

Physical activity status and adverse age-related differences in coagulation and fibrinolytic factors in women

BACKGROUND/AIMS: Current criteria to predict sustained response for a patient with chronic hepatitis C virus during interferon treatment are not consistent. The aim of this study was to determine a reliable point in time to predict non-response to therapy, as a theoretical basis for early cessation of treatment. METHODS: Sera (-70 degrees C) from 66 patients treated with interferon (3 million units three times a week for 6 months) were assayed with a quantitative polymerase chain reaction (sensitivity < or =100 copies per milliliter). Evaluations were made at baseline, during treatment at weeks 1, 2, 4, 12, and 24, and at follow-up week 48. Biochemical response was defined using standard alanine aminotransferase criteria. Virologic response was defined as: sustained if loss of HCV RNA persisted through therapy and follow-up; relapse if HCV RNA became undetectable but reappeared during treatment or follow-up; and non-response if HCV RNA remained detectable during the study period. Alanine aminotransferase and HCV RNA results were analyzed at defined time intervals to determine a predictive value for non-response and sustained response. RESULTS: HCV RNA results are a more accurate predictor than alanine aminotransferase for both non-response and sustained response. Serum HCV RNA predicted non-response better than sustained response. The optimal time to predict non-response with serum HCV RNA was treatment week 12. CONCLUSIONS: Treatment week 12 results indicate that HCV RNA was a more accurate predictor for non-response than serum alanine aminotransferase. This prediction would have theoretically permitted stopping treatment for 75% of the patients in this study at treatment week 12 allowing an overall cost savings of 28%.     

Interferon treatment for hepatitis C virus infection in patients on haemodialysis

BACKGROUND: This study examined the efficacy and tolerability of interferon alpha-2b (IFN) in the treatment of chronic hepatitis C virus (HCV) infection in patients on maintenance haemodialysis. METHODS: A 24-month prospective cohort study was performed in 11 HCV RNA-positive haemodialysis patients, who were treated with IFN at 3 MU thrice weekly for 6 months. Serial biochemical and virological monitors included serum alanine aminotransferase levels, and HCV RNA by both qualitative PCR assay and quantitative bDNA assay. HCV genotypes were determined by PCR and nucleotide sequencing. Ten patients had baseline liver biopsy. RESULTS: HCV genotypes 1b and 2b were identified in 10 and one patients respectively. Six (55%) patients had biochemical and/or histological features of chronic active hepatitis before treatment. All 11 patients became HCV RNA-negative by PCR, with normalization of deranged aminotransferase levels, within 2-8 weeks of IFN therapy. HCV RNA reappeared in eight (73%) patients 2-8 weeks after the cessation of IFN, while biochemical relapse occurred in six (55%) patients. Sustained eradication of HCV was achieved in three (27%) patients. Sustained responders were characterized by pretreatment HCV RNA level < 3.5 x 10(5) Eq/ml as determined by the bDNA assay, and less severe histological abnormalities ('Total score' 1.7 +/- 1.2 compared to 5.4 +/- 2.2 in relapsers, P < 0.05). HCV RNA levels were similar before and after IFN treatment in non-responders and relapsers. Persistent malaise and poor appetite were noted in eight (73%) patients during IFN therapy. Other side-effects of IFN included the exacerbation of anaemia, induction of resistance to erythropoietin, weight loss, and reduced serum albumin level. CONCLUSIONS: Eradication of chronic HCV infection with IFN can be achieved in 27% of haemodialysis patients. Predictors of sustained response include low baseline HCV RNA level and mild liver pathology. Virological relapse can occur despite normal liver biochemistry. Exacerbation of anaemia, erythropoietin resistance, and malnutrition constitute the side-effects of IFN that deserve special attention in uraemic subjects.     

Large dose natural interferon alpha therapy for patients with chronic hepatitis C

To evaluate the efficacy of large dose interferon treatment for patients with chronic hepatitis C virus (HCV) infection, we studied 99 Japanese patients treated with either 6 million units (MU) or 9 MU natural interferon alpha. Serum samples were tested for HCV RNA by polymerase chain reaction (PCR). HCV RNA genotypes were determined by PCR with type-specific preimers, and the HCV RNA level was measured by competitive PCR. HCV RNA was detected in all patients, prior to the initiation of treatment. We examined interleukin-1 receptor antagonist (IL-1 Ra) by enzyme-linked immunosorbent assay. Forty-four patients were treated with 9 MU natural interferon alpha for 24 weeks (group A), and fifty-five patients were treated with 6 MU natural interferon alpha for 24 weeks (group B). There were no significant differences in HCV RNA levels, HCV RNA genotype or histological activity index (HAI) score between the two groups. Of the 94 patients who completed this treatment, nine (23.1%) in group A and 14 (25.5%) in group B sustained elimination of HCV RNA throughout a 6-month follow-up. There were no differences in the rate of complete response when comparing HCV RNA genotype, levels and HAI score and no significant differences in elevation of IL-1 Ra levels between the two groups. Five of group A patients refused further treatment because of severe side effects such as retinal hemorrhage, while no patient in group B had severe side effects. Thus, large dose natural interferon alpha treatment confers no additional benefit to the patient, compared with the current use of a lower dose.     

Effects of interferon-alpha on serum hepatitis C virus in patients with chronic hepatitis C

Interferon is beneficial in some patients with chronic hepatitis C. To assess the efficacy of interferon, we used the polymerase chain reaction (PCR) to measure HCV RNA in serial serum samples from 13 chronic hepatitis C patients who were treated with interferon-alpha. Serum alanine aminotransferase (ALT) values normalized in association with the disappearance of serum HCV RNA in nine cases during the therapy. Serum HCV remained negative after the therapy in the three patients who had no relapse, while serum HCV RNA reappeared in the six patients with elevation of ALT values. The persistence of normal ALT levels appears to be correlated with the clearance of the serum HCV. There were two patients whose ALT became normal immediately after the cessation of interferon. Serum HCV was detectable at the end of treatment when serum ALT was elevated, and thereafter serum HCV disappeared. This result suggests an immunomodulatory effect of interferon in the clearance of HCV in some cases. Furthermore, the semiquantitative PCR assay showed that all five patients in whom ALT values were normal at the end of follow-up without detectable serum HCV genome had lower HCV titers in the pretreatment sera than the other eight patients. The detection of HCV RNA by the PCR assay is useful in determining the efficacy of interferon and its mechanisms.     

Re-treatment with interferon alfa of patients with chronic hepatitis C

Treatment of patients with chronic hepatitis C has had limited success because of relapses and nonresponse to interferon alfa therapy (currently the only established therapeutic agent). A retrospective study was done to determine the efficacy of re-treatment with interferon and the predictors of response in patients who failed to achieve sustained response after one standard course of interferon therapy (3 million units three times a week for 24 weeks). One hundred and eleven patients (47 relapsers and 64 nonresponders), mean age 45 years, were included in the study. Eighteen relapsers and 13 nonresponders received a higher dose (5 MU), and 11 relapsers and 6 nonresponders received a longer duration (48 weeks) of interferon therapy. The remaining patients received the same regimen as the first treatment. Eighty-one percent and 23% of relapsers and nonresponders, respectively, had an end-of-treatment response, and 19% and 3% of the corresponding patient groups had a sustained response to re-treatment. Two patients with breakthrough during their first treatment were the only nonresponders with sustained response after re-treatment. Sustained response was observed only in patients who received an increased dose or duration of interferon therapy. No predictor of sustained response was found. In conclusion, sustained response to re-treatment with interferon was only observed with augmentation of dose or duration of therapy in some relapsers and patients who had breakthrough. Established predictors of response to interferon in naive patients, in particular serum hepatitis C virus RNA and genotype, were not associated with sustained response to re-treatment.