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.     

The long-term efficacy of interferon alfa in chronic hepatitis C patients: A critical review

With current therapeutic regimens, sustained responses occur in no more than 25% of patients with chronic hepatitis C who are treated with interferon. Relapses occur usually within 6 months from therapy suspension, but clinical and virologic recurrencies can be observed as late as after 3 years of follow up. The rate of long-term responses seems to depend on the dosage and the period of administration of interferon, but the best therapeutic protocol remains unknown. As a direct marker of permanent recovery is not available, indirect signs of disease resolution are: (i) continuously normal alanine aminotransferase levels; (ii) clearance of HCV-RNA; (iii) disappearance of anti-C100/NS4; and (iv) significant histological improvements assessed at least 2 years after therapy withdrawal. Known baseline predictive features of long-term response are the absence of cirrhosis, low viraemic levels and infection with HCV of type III or IV genotype (Okamoto's classification). According to recent reports, the lower the heterogeneity of the hypervariable region of the envelope 2 gene of HCV, the higher the chance of a sustained remission. There is not yet any consensus on the efficacy of a second therapeutic course of interferon in inducing a permanent response, and controlled trials are needed to clarify this issue.     

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.     

Hepatic fas antigen expression before and after interferon therapy in patients with chronic hepatitis C

To assess the relationship between hepatitis C virus infection and Fas antigen expression on hepatocytes, we examined changes in hepatic Fas antigen expression in the presence or absence of active hepatitis C virus infection. Twenty patients with chronic hepatitis C infection were treated with interferon and underwent pre- and posttreatment liver biopsies. Patients were classified according to the absence (group A; n=9) or the presence (group B; n=11) of hepatitis C virus RNA (HCV-RNA) in the liver after interferon therapy. An immunohistochemical assay showed Fas antigen staining in hepatocytes membranes and cytoplasm with expression concentrated mainly in periportal areas. The percentage of Fas-positive cells in the liver before treatment was not different between group A (39.5 ± 19.1%) and group B (32.5 ± 15.6%). Hepatic Fas expression was reduced significantly after treatment (24.3 ± 10.6%) compared with the pretreatment values in group A (p < 0.05) but not in group B (25.9 ± 16.9%). There was no significant difference between the two groups in the degree of histologic improvement. These results suggest that hepatic Fas expression is associated with persistent infection of hepatitis C virus.     

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.     

High-dose interferon plus ribavirin in chronic hepatitis C not responding to recombinant alpha-interferon

BACKGROUND: 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. AIM: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.     

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.     

Sarcoidosis after use of interferon for chronic hepatitis C: report of a case and review of the literature

Although interferon has not been classified in the pathogenesis of sarcoidosis, it may rarely lead to this disease during treatment of chronic hepatitis C. The case of a 36-year-old woman with chronic hepatitis C who developed sarcoidosis within 10 weeks of treatment with recombinant interferon-alpha2a and ribavirin is described and all seven similar cases published in English from 1989 to 2001 are discussed.     

Thrombotic thrombocytopenic purpura developed suddenly during interferon treatment for chronic hepatitis C

A 57-year-old man had abnormal hepatic function identified in April 1994. In October 1994, chronic hepatitis C was diagnosed. Based on the findings of a liver biopsy, administration of recombinant interferon (rIFN)-α2b was begun. In the 16th week of treatment, the patient experienced headache and fever and developed a markedly decreased, platelet count and hemolytic anemia. He was admitted on May 19, 1995 and thrombotic thrombocytopenic purpura (TTP) was diagnosed. He died on the 3rd hospital day. The causes of TTP have yet to be elucidated, but in this patient the occurrence of TTP appeared to be related to the IFN treatment for chronic hepatitis C. (Received June 6, 1997; accepted Dec. 19, 1997)     

Vogt-Koyanagi-Harada disease occurring during interferon alpha therapy for chronic hepatitis C

Retinal abnormalities, including retinal hemorrhage and cotton-wool spots, often occur within the first 8 weeks in the course of interferon therapy in patients with chronic hepatitis C. Here, we describe a case of Vogt-Koyanagi-Harada disease occurring 4 months after the start of interferon alpha treatment, probably induced by the immunomodulatory effects of interferon. Therefore, we conclude that chronic hepatitis C patients, especially people with darkly pigmented skin, need to be closely monitored for ophthalmologic complications, by periodic check-up of the optic fundi, for a prolonged period, during interferon treatment.     

Immune response in addicts with chronic hepatitis C treated with interferon and ribavirin

BACKGROUND: The role played by the immune system in the progression of chronic hepatitis C (CHC) is not completely clear. Opioids may facilitate the outbreak of infections through marked immunomodulating effects on the immune response against a virus. To asses if addicts can be treated successfully with interferon (IFN) during detoxification treatment, we evaluated some immune response mediators in addicts affected by CHC. METHOD: A cohort of heroin users with CHC were enrolled during the detoxification period, divided into two groups and treated with IFN pegilate plus ribavirin (group A treated during methadone administration and group B treated at week 8 after methadone treatment completed). A group of patients with CHC and no history of drug addiction were enrolled as controls. Leukocyte subpopulation NK, CD4+, CD8+ and some cytokines Th1 (IFNgamma, interleukin [IL]2) and Th2 (IL-6, IL-10) were evaluated prior to, during and after methadone treatment. Sustained virological response was evaluated 24 weeks after antiviral treatment was completed. RESULTS: During methadone treatment, significantly (P < 0.05) higher cytokine Th1 and NK and lower cytokine Th2 levels were observed in groups A and B compared with levels obtained before treatment in the same groups. Relapse occurred at 56 +/- 8 weeks in 34/55 group A patients, at 24 +/- 8 weeks in 33/52 group B patients and at 24 +/- 4 weeks in group C, there being a significant difference (P < 0.05) between group A and B and between group A and C. No significant differences between all groups were detected in CD4+ and CD8+ cell counts. CONCLUSIONS: Our results revealed that drug addicts with CHC can be treated successfully with IFN pegilate and ribavirin. This therapy can be recommended during the early phase of detoxification treatment to achieve a sustained response.     

Long-term liver histology improvement in patients with chronic hepatitis C and sustained response to interferon

A retrospective multicentre survey was conducted to evaluate, in patients with chronic hepatitis C, the long-term liver histological changes induced by interferon (IFN). A total of 112 patients (mean age 46.4 years) were studied. All patients had received a 6-12-month IFN-alpha course (6-18 MU/week) and had successively undergone clinical, biochemical and virological follow-up for at least 36 months (range: 36-76). In each patient, two liver biopsies had been performed: 1-6 months before treatment and, 12-76 months after its completion. In 87 patients with biochemical and virological sustained response persisting for 12 months after therapy, post-treatment liver necroinflammation and fibrosis mean(+/-SD) scores (Knodell index) were significantly lower than pretreatment scores (2.9 +/- 2.2 vs 6.8 +/- 2.9 and 0.8 +/- 1.0 vs 1.2 +/- 1.1, respectively; P < 0.01). In 25 patients who relapsed within 1 year, necroinflammation and fibrosis post-treatment mean scores were similar to pretreatment scores (7.4 +/- 3.2 vs 6.9 +/- 3.1 and 1.8 +/- 1.3 vs 1.6 +/- 1.2, respectively; P > 0.05). On an individual basis, necroinflammation decreased in 87% of sustained responders but only in 36% of relapsers (P < 0.001), whereas fibrosis decreased in 44% of sustained responders but only in 14% of relapsers (P < 0.001). In sustained responders with biopsies performed 12-23 months (n=34), 24-35 months (n=26) or more than 36 months (n=27) after treatment, a progressive decrease of mean necroinflammatory score was observed (-2.6 +/- 2.1, -4.1 +/- 3.4 and -5.2 +/- 3.7 points, respectively; P < 0.01). A similar pattern was observed in fibrosis score (-0.3 +/- 0.6, -0.3 +/- 0.7 and -0.7 +/- 0.9 points, respectively; P < 0.05). Hence, among chronic hepatitis C patients treated with IFN, those with a 12-month sustained response, unlike those who relapse, have a long-term progressive reduction and, in some cases, a complete regression of liver histological damage.     

Serum markers of hepatic fibrogenesis in chronic hepatitis type C treated with alfa-2A interferon

Hepatic fibrogenesis is a dynamic process which characterizes the course of chronic hepatitis. It has stimulated interest in the possible effect of interferon therapy on liver fibrosis. We have evaluated a panel of serum markers of fibrogenesis, namely N-terminal procollagen III peptide (PII-INP), C-terminal procollagen I peptide (PICP), laminin and hyaluronate in 35 patients with chronic hepatitis type C, before, during and after interferon treatment. Before treatment, PIIINP was elevated in 8.5%, 44% and 71% of patients with chronic persistent hepatitis, chronic active hepatitis and cirrhosis, respectively, while the corresponding figures for PICP were 0%, 50% and 46%, and for laminin 16.5%, 70% and 71%; hyaluronate was elevated in only five out of seven patients with cirrhosis. Patients with high PIIINP levels at presentation and a persistent response to treatment showed persistent normalization of this parameter, which was not observed in non-responders. In contrast, the other markers showed no significant correlation with interferon response. These results indicate that PIIINP correlates with interferon response in chronic hepatitis type C.     

Alanine aminotransferase and HCV-RNA responses following interferon therapy of HCV-RNA positive chronic hepatitis

Interferon (IFN) has been shown to be effective for chronic hepatitis C. This study investigated changes of alanine aminotransferase (ALT) and HCV-RNA in chronic hepatitis C patients treated withα-IFN. IFN was given to 73 patients with HCV-RNA positive chronic hepatitis C. The pattern of changes in ALT activity after IFN aministration was classified into five types. Type 1 was characterized by normalization of ALT (≤25 K.U) during IFN administration and sustained normalization after the IFN therapy. Type 2 involved a rebound of ALT after termination of IFN therapy and subsequent normalization. Type 3 had no ALT normalization during IFN administration, with normalization after the completion of the therapy. Type 4 involved transient normalization of ALT level during IFN therapy, with a subsequent reversion to abnormal levels after the termination of IFN therapy. Type 5 showed sustained abnormally high levels of ALT activity both during and after treatment. Twenty four patients (32.9%) had sustained normalization ALT (≤25 K.U) after the termination of IFN treatment. The HCV-RNA negative rate at 6 months after IFN therapy in patients with sustained normalization of ALT was 87.5% (21/24).     

Treatment of chronic hepatitis C in Europe

The lifetime cumulative risk of developing cirrhosis and hepatocellular carcinoma is the rationale for treating patients with chronic hepatitis C with antivirals. The standard treatment is combination therapy with interferon-alfa and ribavirin. In patients with high transaminases and histologic signs of chronic hepatitis, 6- to 12-month therapy with 3 mega units (MU) interferon-alfa thrice weekly, combined with ribavirin, yielded up to 30% sustained responders, and this was increased to 50% with pegylated interferon combined with ribavirin. Favorable predictors of response to the former treatment were genotype 2 or 3, less than 2 million copies of hepatitis C virus (HCV), no portal fibrosis at biopsy, age less than 40 years, and female sex. The same was true for the latter treatment; however, with body weight less than 82?kg replacing female sex. A 98% cure of community-acquired acute hepatitis C was achieved with early treatment with daily doses of 5?MU interferon, compared with a calculated 30% HCV-RNA clearance in untreated patients. More cost-effective strategies for ceasing treatment, based upon early clearance of HCV, are under investigation, with cutoff equal to or more than a 2?log decrease in serum HCV-RNA at week 12. This approach has 100% negative predictive value and 80% positive predictive value. Treatment can also be optimized by combination retreatment of relapsers and nonresponders to monotherapy, which yielded sustained responses of 50% and 25%, respectively. There are difficult-to-treat patients who have high viremia, genotype 1 and 4, or coinfection with HIV or HBV, or carry an organ graft, and those who did not respond to combination therapy. Extended treatment of the latter patients with pegylated interferon might slow down the progression of fibrosis.     

Factors useful in predicting the response to interferon therapy in chronic hepatitis C

To determine how various factors influence the response to interferon (IFN) therapy, we retrospectively studied 157 consecutive Japanese patients with chronic hepatitis C who received various treatment schedules of IFN. They were divided into two groups on the bases of outcome. One group was comprised of 65 patients who achieved a sustained normalization of serum alanine aminotransferase (ALT) levels for at least 6 months after treatment, while the other group was comprised of 84 patients with persistent elevation of serum ALT levels, despite treatment. Genotyping of hepatitis C virus (HCV) was done by polymerase chain reaction (PCR) with genotype specific primers, analysing the variations in nucleotide sequence within the NS 5 region of the HCV genome, namely genotypes PT, K1, K2a and K2b. We then used a multivariate analysis to determine the factors related to mode of treatment, patient characteristics and HCV genotype in relation to the response to IFN therapy. Of the 16 factors analysed, the HCV genotype (genotype K2a or K2b, P < 0.0008), treatment schedule (intermittent administration following a daily schedule, designated as combined schedule, P > 0.0014) and liver histology just before treatment (chronic persistent hepatitis or mild chronic aggressive hepatitis, P < 0.0324) were the most strongly correlated with a normalizing response to IFN therapy. These results suggest that not only are the IFN treatment schedule and patient profile significant, but the properties of the virus also influences the response. However, as the IFN treatment schedule is the only changeable factor, it should be designed to maximize the benefit of IFN therapy.     

Detection of hepatocellular carcinoma after interferon therapy for chronic hepatitis C: Clinical study of 26 cases

The clinical findings in 26 patients in whom hepatocellular carcinoma (HCC) was detected after the start of interferon (IFN) therapy for chronic hepatitis C were analysed. Histological study before IFN therapy showed that 34.6% of patients were categorized as stage 3 (septal fibrosis with architectural distortion; the 0–4 scale) and 80.8% demonstrated at least some evidence of septal fibrosis or more advanced features. The AFP levels examined before IFN therapy were more than 20 ng/mL in 13 patients (84.6% of those studied). One of 26 patients had a complete response to IFN therapy, while six of 26 patients had only a partial response. HCC was detected within 1 year after the start of IFN therapy in 76.9% of patients. Thus, the possibility of the early occurrence of HCC or its existence at the time of therapy should be seriously considered when IFN therapy is contemplated. Patients with stage 3 or 3–4 histology may already have a small undetectable HCC before IFN therapy. Thus, for this reason, every patient treated with IFN should be examined at short regular intervals for the development of HCC during and after IFN therapy.