A pilot study of recombinant interferon beta‐1a for the treatment of chronic hepatitis C

Abstract: Aims: Interferon alpha monotherapy induces a sustained response in less than 20% of patients treated for chronic hepatitis C. Interferon beta represents a potential therapeutic alternative for the treatment of chronic hepatitis C. The aim of this pilot study was to evaluate the efficacy and tolerance of recombinant interferon beta‐1a administered subcutaneously. Methods: Twenty‐one drug‐naive patients with chronic hepatitis C were treated with recombinant interferon beta‐1a administered, subcutaneously, for 24 weeks using two different regimens: 9 MU, three times per week (n=11) and 12 MU, three times per week (n=10). Results: At the end of the treatment period, nine (43%) patients had a biochemical and virological response (i.e. normal ALT and absence of hepatitis C virus RNA by PCR). Four of these patients were in the 9 MU group and five in the 12 MU group. A biochemical and virological sustained response occurred in four (19%) patients, all in the 9 MU dose group. The 4 patients with a sustained response maintained their response during a follow‐up period of 33 to 58 months. Side effects were mild and 19 (90%) patients completed the treatment period. Conclusions: The results of this pilot study indicate that interferon beta‐1a administered subcutaneously is an effective therapy for some patients with chronic hepatitis C, and suggest that interferon beta‐1a deserves further evaluations in larger trials especially in combination with ribavirin.     

Treatment of hepatitis C related thrombocytopenia with interferon alpha.

Thrombocytopenia is a common extrahepatic manifestation of hepatitis C (HCV) infection. Treatment with steroids may be effective, but can exacerbate the viral infection. Interferon alpha (INF) has documented efficacy in the treatment of HCV, but its use in the treatment of HCV thrombocytopenia is controversial. We treated eight patients with HCV-related thrombocytopenia, who had platelet counts of fewer than 50 x 10(9)/l (range: 16 to 46 x 10(9)/L) with INF 3 MU SQ three times a week. Planned duration of treatment was 24 weeks. Five patients had no evidence of hepatic cirrhosis, three had cirrhosis, and two had palpable splenomegaly. Only three patients tolerated the full course of treatment, and all three had improvement in their platelet counts to greater than 50 x 10(9)/l. Two other patients had improvement in platelet counts to more than 50 x 10(9)/l with shorter duration of treatment (six and 16 weeks, respectively). The mean increase in platelet count in the five responders was 44 x 10(9)/lL (range: 28 to 90 x 10(9)/l). The average peak platelet count in the responders was 81 x 10(9)/l (range: 62 to 136 x 10(9)/l). Duration of response ranged from four to 18+ months, with the shortest responses observed in the two patients treated with a shorter course of INF. Response was independent of the presence of cirrhosis. Responding patients had improvement in hepatic transaminases, reduction in cryoglobulin and anticardiolipin antibodies, and HCV plasma RNA when tested. Relapse was associated with an increase in these laboratory markers of HCV infection. We conclude that INF can be an effective treatment in patients with HCV-related thrombocytopenia.     

Consensus interferon: a novel interferon for the treatment of hepatitis C

Although alpha interferons are currently the only therapies approved for treatment of HCV infection approximately half of the treated patients do not respond to the standard regimen of IFN-α-2b 3 MU administered 3 times per week (tiw) for 6 to 12 months. Of those who do demonstrate a response, 50–80% will relapse within 6 months after treatment cessation. Thus, the overall response to treatment is low. This paper focuses on studies that have been conducted with a newly developed interferon, Consensus Interferon (CIFN), in the treatment of chronic Hepatitis C. This type-1 interferon links the most common occurring amino acid sequences at each position of available natural alpha interferons into one 'consensus' protein. The thus synthesized molecule shows a 10-fold higher in vitro biological activity as compared to single recombinant IFN-α-2b or IFN-α-2a, possibly due to its greater binding affinity to interferon receptors. In patients with chronic hepatitis C, CIFN 9 μg, three times weekly for 24 weeks, proved to be equally efficacious and as safe as IFN-α-2b, but compared to 3 MU IFN-α-2b, CIFN 9 μg demonstrated improved responses in patients with high baseline viral titres.     

Treatment of hepatitis C with interferon and ribavirin

Hepatitis C is a worldwide problem that frequently results in end-stage liver disease and its complications. Treatment for hepatitis C virus (HCV) has been rather ineffective but several recent studies have clarified the role of interferon and ribavirin therapy. In line with therapeutic progress in HIV infection, hepatitis C is now entering the era of multidrug antiviral therapy. Ribavirin is an orally active synthetic guanosine analogue with theoretical antiviral and immunomodulatory actions. In this review we have evaluated the role of interferon and ribavirin in treatment-naive patients, relapsers and non-responders. In naive patients the combination results in improved end-of-treatment and sustained response rates, with an overall 41% sustained virological response rate in patients treated for 48 weeks. Therapeutic benefit also extends to the traditionally difficult to treat patients (genotype 1, high vital load and advanced fibrosis). The addition of ribavirin to interferon has also resulted in an increased toxicity profile, which has made therapy more difficult for both the patient and managing physician. However, the significant improvement in response rates for all patients makes combination therapy the most appropriate choice as the first-line therapy for suitable patients with chronic viral hepatitis C. Appropriate management with interferon and ribavirin includes assessing the patient's HCV genotype to determine the optimal duration of therapy, assessing therapeutic efficacy by measuring HCV-RNA at 24 weeks and monitoring for the additional ribavirin side-effects.     

Long-term cohort study of chronic hepatitis C according to interferon efficacy

Background and Aim: We investigated the prognosis of patients with C‐viral chronic liver disease (C‐CLD) according to the efficacy of interferon (IFN) therapy in a long‐term retrospective cohort study. Methods: Of 721 patients with C‐CLD who underwent liver biopsy between January 1986 and December 2005, 577 were treated with IFN, and 221 of these patients achieved sustained virological response (SVR) with a follow‐up period of 9.9 ± 5.3 years. Results: The annual rate of HCC development was 2.71%/year, 2.31%/year, and 0.24%/year in untreated, non‐SVR, and SVR patients, respectively. Multivariate Cox proportional regression analysis showed that the risk of HCC development was significantly lower in SVR patients than in untreated or non‐SVR patients; moreover, this risk was similar in non‐SVR patients and untreated patients. The annual mortality rate in overall death was 3.19%/year, 1.98%/year, and 0.44%/year in untreated, non‐SVR, and SVR patients, respectively. Multivariate Cox proportional hazards regression analysis showed that the SVR status reduced the risk ratio for overall death to 0.173, whereas the non‐SVR status did not significantly reduce the risk ratio. Conclusions: The risk ratio of overall death and HCC development was significantly reduced in SVR patients, whereas no significant reduction was found in non‐SVR patients in a long‐term cohort study.     

Cyclooxygenase-2 expression in chronic hepatitis C and the effect of interferon alpha treatment

BACKGROUND AND AIM: Cyclooxygenase-2 (COX-2), a target of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), is upregulated in chronic hepatitis B and may have a role in hepatocellular carcinoma. Little is known about the expression of COX-2 in chronic hepatitis C (HCV) infection. The aim the present study was to evaluate the extent of COX-2 expression in liver biopsies in patients with HCV infection and to determine the effect of treatment with interferon alpha (IFN). METHODS: Percutaneous liver biopsy specimens were retrieved. Following formalin fixation and paraffin embedding, the biopsies were histologically evaluated for inflammation and fibrosis. The extent of COX-2 expression was measured by the avidin biotin immunohistochemical technique using a monoclonal COX-2 antibody. The extent of COX-2 expression was graded according to the number of hepatocytes expressing COX-2. Data were analyzed using Student's t-test. RESULTS: Liver biopsies from 10 patients before and after treatment with IFN were obtained and compared with nine normal liver biopsies. All of the liver biopsies showed some COX-2 expression. COX-2 expression was confined to hepatocytes and bile duct epithelium and was not detected in vascular endothelium or inflammatory cells. The extent of COX-2 expression was greater in hepatitis C infected liver biopsies than in normal biopsies. Following treatment with IFN, there was a greater than threefold reduction in COX-2 expression (P < 0.01). This result was independent of the sustained virological response. CONCLUSION: In this small pilot study we have shown that COX-2 is overexpressed in liver biopsies infected with HCV and COX-2 expression is reduced following treatment with IFN.     

Two week induction of interferon‐beta followed by pegylated interferon alpha‐2b and ribavirin for chronic infection with hepatitis C

Objectives: To elucidate the efficacy of interferon (IFN)‐beta induction therapy followed by pegylated IFN alpha and ribavirin for chronic infection with hepatitis C virus (HCV). Methods: Patients chronically infected with HCV genotype 1, high titer were enrolled. Twice daily bolus injections of 3 million units IFN‐beta were administered for 14 days. Thereafter, weekly injection of pegylated IFN alpha 2b and daily intake of ribavirin were followed. Therapy duration was adjusted according to the response to the therapy. When time to an undetectable HCV‐RNA was 1, 2, 4, 8, and 12 weeks, total duration of therapy was 12, 24, 36, 48 and 60 weeks, respectively. Patients who failed to achieve an undetectable HCV‐RNA within 12 weeks discontinued therapy on 12 week. Results: Among the 101 patients treated, 56 (55.4%) achieved sustained virological response (SVR). SVR rate for each treatment duration was 10/10 for 12 weeks, 12/14 for 24 weeks, 18/19 for 36 weeks, 15/26 for 48 weeks, 1/4 for 60 weeks and 0/28 for patients who discontinued therapy at 12 weeks. Mean time to an undetectable HCV‐RNA was 35.5 ± 2.7 days. Mean therapy duration was 27.3 ± 1.4 weeks. Using a cut off value of 21.5 fmol/L of HCV core‐antigen in the first week, SVR could be predicted by sensitivity of 0.91 and specificity of 0.78. Conclusion: IFN‐beta induction therapy resulted in acceptable SVR rates despite short therapy duration. Steep reduction of HCV by IFN‐beta enables us to predict SVR in the first week of therapy.     

Predicting interferon therapy efficacy from hepatitis C virus genotype and RNA titer

We classified 53 Japanese patients with chronic hepatitis C who were treated with natural interferon- into genotypes and also tested the amounts of hepatitis C virus (HCV) RNA. The rate of the long-term complete response group, whose alanine aminotransferase levels remained within the normal range during the six months after therapy, was significantly higher (P<0.01) in the type-III patients (4/5, 80.0%) than in type-II patients (4/43, 9.3%). For these long-term complete responders, the amounts of HCV RNA was less than 10⁷ copies/ml serum in type-II patients, whereas two type-III patients with relatively high amounts of HCV RNA responded completely. These results confirm that the genotype of HCV is an important factor for predicting the response to interferon therapy. The amounts of HCV RNA can also predict its efficacy in type-II patients.This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan, and the Research Group of Intractable Hepatitis sponsored by the Ministry of Health and Welfare of Japan.     

Clearance of serum hepatitis C virus RNA after interferon therapy in relation to virus genotype

Abstract: The effect of recombinant interferon-alfa on serum HCV RNA levels in Japanese patients with chronic hepatitis C was investigated. At 24 weeks of treatment, 41 (32.5%) of 126 patients lost HCV RNA from serum, and aminotransferases were normalized in 31 (75.6%) of these 41 cases. HCV genotypes were categorized into four types (Type I, II, III, IV); the frequencies among the patients were: Type I: 0%, Type II: 70.6%, Type III: 20.6%, and Type IV: 6.3%. At the end of the 24-week treatment, HCV RNA levels were remarkably decreased in Type III patients and became undetectable in 18 (69.2%) of 26. In contrast, only 18 (20.2%) of 89 patients with Type II and two of eight with Type IV lost HCV RNA from sera. The relation between HCV genotype (Type III) and response to IFN therapy was also confirmed using a logistic regression model. HCV genotype seems to be an important factor in determining the response to IFN in patients with chronic hepatitis C.     

Hepatitis C virus genotypes and hepatic fibrosis regulate 24-h decline of serum hepatitis C virus RNA during interferon therapy in patients with chronic hepatitis C

BACKGROUND AND AIMS: Recently, hepatitis C virus (HCV) dynamics during interferon (IFN) therapy have been studied in detail. We examined factors that regulate the viral kinetics and the relationship between the viral kinetics and clinical effect of IFN therapy. METHODS: Eighty-eight patients with chronic hepatitis C entered this study. All patients had been treated with 3 MU of IFN-beta twice a day for the first 2-4 weeks, then IFN-alpha for the next 20-22 weeks (three injections per week). The levels of serum HCV RNA were determined by Amplicor HCV Monitor version 1.0, before and 24 h after the first injection of IFN; then the decline of HCV was calculated. Liver inflammation and fibrosis were scored as 0 (none), 1 (mild), 2 (moderate) or 3 (severe) using biopsy specimens. RESULTS: The decline of serum HCV RNA was 1.42 +/- 0.65 log copies/mL in genotype 1b and 1.83 +/- 0.72 in genotype 2a or 2b (P < 0.01). By a logistic regression model, genotype (1b, 2a or 2b) and hepatic fibrosis (0 or 1, 2 or 3) associated with 24-h decline of serum HCV RNA, independently. As the predictor of IFN therapy, the decline of serum HCV RNA and serum HCV RNA levels before IFN therapy were the independent significant factors (P < 0.001). CONCLUSIONS: The decline of serum HCV RNA during the first 24 h of IFN therapy was regulated by genotypes and hepatic fibrosis. The decline of serum HCV RNA and initial HCV load were independent factors that can be the predictor of the subsequent sustained viral response to IFN therapy.     

Short and long-term effects of interferon on serum markers of hepatitis C virus replication

Abstract Hepatitis C virus RNA (HCV-RNA) and serological markers of HCV infection were measured in 30 patients with chronic hepatitis C who had been treated with interferon (IFN). Patients were classified into four groups according to serum alanine aminotransferase (ALT) levels after treatment. These were: as complete responders (CR); partial responders (PR); transient responders (TR); and non-responders (NR). In all 11 patients in the CR group, HCV-RNA disappeared from serum for at least 24 months and anti-c100-3 decreased progressively during this time. In the PR group, four of five patients were positive for HCV-RNA in spite of the improvement of ALT levels and decline of anti-c100-3. In the TR and NR groups, HCV-RNA disappeared transiently or remained persistently positive. The results indicate that IFN-mediated improvement of ALT and decrease of anti-HCV (anti-c100-3) were not always related to the disappearance of HCV-RNA from serum. On the other hand, sustained disappearance of HCV-RNA from serum was demonstrated in the patients who did not have post-treatment ALT relapse. This indicates that IFN can eradicate HCV from serum in some patients and provide a clinical remission of chronic hepatitis C.     

Integrity of the NS5A (amino acid 2209 to 2248) region in hepatitis C virus 1b patients non‐responsive to interferon therapy

Abstract: Background/Aims: In hepatitis C virus‐1b, it has been suggested that an amino acid stretch (aa 2209–2248) of the carboxy terminal half of the non‐structural 5A (NS5A) region participates in the response to interferon treatment. We tested the hypothesis that absence of mutations in the NS5A (aa 2209–2248) sequence is required for interferon resistance. We also investigated the importance of different HCV‐1b isolates in interferon response in France. Methods: We determined the NS5A sequences of 70 patients with chronic hepatitis C before IFN therapy and then compared them with HCV‐J prototype sequence. The isolates were determined by NS5B sequencing, the “gold standard” method for genotyping and subtyping. Pre‐therapeutic viral load was also measured. Results: No sustained virological response was observed in the patients without amino acid substitutions in the NS5A (aa 2209–2248) sequence, and in the patients with HCV‐J isolates. Viral load was significantly higher in the patients with no amino acid substitutions in the NS5A (aa 2209–2248) sequence. Conclusions: In HCV‐1b infected patients, an HCV‐J strain with no amino acid substitution in the NS5A (aa 2209–2248) region indicates a poor prognosis for response to IFN therapy. The low interferon response rate in HCV‐1b infection in Europe is probably not due to a difference between isolates.     

Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan

AIM：To evaluate the efficacy of pegylated interferon α-2b（peg-IFNα-2b） plus ribavirin（RBV） therapy in Japanese patients with chronic hepatitis C（CHC） genotype Ib and a high viral load.METHODS：One hundred and twenty CHC patients（58.3% male） who received peg-IFNα-2b plus RBV therapy for 48 wk were enrolled.Sustained virological response（SVR） and clinical parameters were evaluated.RESULTS：One hundred（83.3%） of 120 patients completed 48 wk of treatment.53 patients（44.3%） achieved SVR.Early virological response（EVR） and end of treatment response（ETR） rates were 50% and 73.3%,respectively.The clinical parameters（SVR vs non-SVR） associated with SVR,ALT（108.4 IU/L vs 74.5 IU/L,P = 0.063）,EVR（76.4% vs 16.4%,P 〈 0.0001）,adherence to peg-IFN（≥ 80% of planned dose） at week 12（48.1% vs 13.6%,P = 0.00036）,adherence to peg-IFN at week 48（54.7% vs 16.2%,P 〈 0.0001） and adherence to RBV at week 48（56.1% vs 32.1%,P = 0.0102） were determined using univariate analysis,and EVR and adherence to peg-IFN at week 48 were determined using multivariate analysis.In the older patient group（〉 56 years）,SVR in females was significantly lower than that in males（17% vs 50%,P = 0.0262）.EVR and adherence to Peg-IFN were demonstrated to be the main factors associated with SVR.CONCLUSION：Peg-IFNα-2b plus RBV combination therapy demonstrated good tolerability in Japanese patients with CHC and resulted in a SVR rate of 44.3%.Treatment of elderly female patients is still challenging and maintenance of adherence to peg-IFNα-2b is important in improving the SVR rate.     

Low dose erythropoietin‐beta improves anemia and maintains ribavirin dose in chronic hepatitis C patients receiving combination therapy with ribavirin plus pegylated interferon Alfa‐2b

Aim: Anemia during combination therapy with pegylated interferon alfa‐2b plus ribavirin (RBV) for chronic hepatitis C virus (HCV) patients usually leads to RBV dose reduction or discontinuation. This study evaluated the effect of erythropoietin‐beta (EPO‐β) to maintain RBV dose and hemoglobin (Hb) level in chronic HCV patients treated with antiviral combination therapy. Methods: Eighty‐eight chronic HCV patients who developed anemia during therapy were enrolled into this retrospective study: 55 in the EPO‐β group and 33 in the untreated group. The study endpoints were to assess the RBV maintenance and the changes in Hb. Results: A higher percentage of patients with RBV maintenance was observed in the EPO‐β group compared with the untreated group (nadir Hb level <10.5 g/dL; 70% vs. 38%, P = 0.020; nadir Hb < 10 g/dL; 62% vs. 27%, P = 0.046). The mean Hb change from week 12 to week 20 was higher in the EPO‐β group when compared with the untreated group, especially for patients receiving a total EPO‐β dose of more than 16 000 U (+0.70 g/dL vs. ?0.32 g/dL, P = 0.023) and of 10 000 U‐14 000 U (+0.60 g/dL vs. ?0.32 g/dL, P = 0.023). Conclusions: Low‐dose EPO‐β can maintain RBV dose and increase Hb levels in anemic chronic HCV patients receiving combination therapy.