Histologic Improvement of Fibrosis in Patients with Hepatitis C Who Have Sustained Response to Interferon Therapy

By Y. Shiratori, F. Imazeki, M. Moriyama, M. Yano, Y. Arakawa, O. Yokosuka, T. Kuroki, S. Nishiguchi, M. Sata, G. Yamada and 3 more. Annals of Internal Medicine, 2000

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Chronic hepatitis C is a common disease that may progress to cirrhosis (1-4) and hepatocellular carcinoma (5-8). In some patients, treatment with interferon, alone or in combination with ribavirin, leads to sustained eradication of virus (9). Recent follow-up studies revealed that patients who were negative for hepatitis C virus (HCV) RNA 6 months after treatment remained in remission and had normal liver function and improved histologic features, suggesting possible cure (10-12). Although hepatic inflammation improves histologically in such patients (13-17), it remains uncertain whether hepatic fibrosis can also regress. Evaluation of effectiveness of therapy for hepatitis C, a slowly progressive disease, requires long-term follow-up of patients. Although questions may arise about the appropriateness of liver biopsy after treatment to evaluate the effects of therapy, such biopsies may provide information about long-term response. Recently, a simple histologic fibrosis and activity score was shown to be a better scoring system than the Knodell activity index (18) in terms of intraobserver and interobserver variation (19-21). We examined whether interferon therapy was associated with regression of histologic fibrosis in 593 patients, a subset of whom received interferon, by using paired biopsy samples obtained 1 to 10 years apart. Methods Patients This study was conducted as one of the projects in the Inhibition of Hepatocarcinogenesis by Interferon Therapy [IHIT] study. The IHIT study, a multicenter, large-scale, retrospective cohort study, was begun in 1994 as one of the National Projects for Survey of High-Risk Patients for Cancer organized by the Ministry of Health and Welfare in Japan. The IHIT Study Group approved the design of various cohort studies on 21 September 1994, one of which was to evaluate the long-term effect of interferon on histologic improvement by using repeated liver biopsies. To address the appropriateness of liver biopsy after interferon treatment in terms of benefit to patients, repeated biopsy should be performed under the following conditions: 1) Repeated liver biopsy may be performed before re-treatment with interferon in patients with a nonsustained response and before first-time treatment in untreated patients, because liver biopsy was recommended before interferon therapy by Japanese national health insurance. 2) Repeated liver biopsy may be performed if patients wish to know the disease progression or regression state. 3) When lesions indicating hepatocellular carcinoma are detected during follow-up, biopsy specimens should be obtained from both the suspicious lesion and background liver to allow definitive diagnosis of the lesions. Histologic assessment of repeated biopsy specimens was done and results were compared with those from the previous samples before a repeated liver biopsy sample was obtained. This study and the parent study were approved by the ethics committee of each participating institution. Informed consent was obtained from each patient in accordance with the Helsinki Declaration. Of the 3233 patients in the IHIT study, we analyzed 593 patients with chronic hepatitis C who underwent examination of pretreatment HCV RNA status and paired liver biopsies at an interval of more than 1 year between biopsies. Patients were seen at eight institutes from January 1987 to October 1997. We excluded 2640 patients for various reasons, such as lack of a follow-up biopsy; other exclusion criteria are stated below. The design of systematic histologic assessment in this study was discussed by committee on 30 May 1997 and was finalized on 30 January 1998. The patients in this study were included in several previous cohort studies that analyzed the efficacy of interferon therapy (22-27) and in the IHIT study (28). Inclusion and Exclusion Criteria Diagnosis of chronic hepatitis C was based on serum alanine aminotransferase (ALT) levels that had been elevated for 6 or more months, positivity for anti-HCV antibody according to second-generation assays, and histologic examination of liver biopsy specimens. The test for anti-HCV antibody was checked by using stored sera of the patients who received interferon before 1992. To determine the presence of HCV RNA in serum before interferon therapy, stored sera were tested by using in-house reverse transcription polymerase chain reaction or a polymerase chain reaction-based Amplicor qualitative assay (Roche Molecular, Kanagawa, Japan); patients who tested positive for HCV RNA were eligible for the study. However, patients were excluded if they had chronic hepatitis combined with other conditions, such as hepatitis B virus (positivity for hepatitis B surface antigen), autoimmune hepatitis, primary biliary cirrhosis, drug addiction, or heavy alcohol consumption (>80 g/d). Previous Interferon Therapy and Follow-up Interferon therapy was begun within 6 months after the initial biopsy in 487 patients. Patients received 3 to 10 million U of interferon- (interferon-2a [Nippon Roche K.K., Tokyo, Japan]), interferon-2b (Schering-Plough Co., Osaka, Japan), or natural interferon- (Sumitomo Pharm. Co., Osaka, Japan) by subcutaneous or intramuscular injection three times per week for 3 to 6 months or an intravenous injection of 6 million U of interferon- (Toray Co., Tokyo, Japan) six to seven times per week for 8 weeks. Treatment procedures were not changed according to HCV RNA levels or histologic findings. We enrolled 106 patients with chronic hepatitis C who had not received interferon for diverse reasons: anxiety over adverse effects of interferon (7 patients); being busy during the scheduled treatment (15 patients); disease that developed before the national health insurance covered this therapy (70 patients); or physician judgment that the patient had tendencies toward depression (9 patients), combined cardiovascular diseases (1 patient), pulmonary diseases (2 patients), or severe diabetes (2 patients). Patients underwent biochemical blood tests (measurement of ALT, aspartate aminotransferase, albumin, bilirubin, and -fetoprotein levels) every 1 to 2 months and had abdominal ultrasonography every 3 to 6 months. If hepatocellular carcinoma was suspected, they underwent additional examinations by dynamic computed tomography, magnetic resonance imaging, arteriography, and ultrasonography-guided tumor biopsy, if necessary. Criteria for Response to Interferon Therapy Virologic response to interferon therapy was defined as loss of serum HCV RNA determined by reverse transcription polymerase chain reaction assay (detection limit, 102 copies/mL). Patients who tested negative for HCV RNA more than 6 months after treatment were classified as showing sustained virologic response; those who tested positive for HCV RNA more than 6 months after treatment were classified as showing nonsustained virologic response. Histologic Evaluation All patients underwent repeated liver biopsy 1 to 10 years apart (median, 3.7 years) for various reasons: to confirm histologic improvement in all patients with sustained response (12 patients underwent three biopsies), to assess the effects of retreatment with interferon in 247 patients with nonsustained response and the effects of treatment in 79 untreated patients, to re-evaluate disease status in patients with fluctuating serum ALT levels (32 patients with nonsustained response and 15 untreated patients), and to evaluate suspicion of hepatocellular carcinoma in 25 patients with nonsustained response and 12 untreated patients (hepatocellular carcinoma was confirmed in 19 patients). Fibrosis staging scores and activity grades were assigned according to the criteria of Desmet and colleagues (20) and the French METAVIR Cooperative Study Group (3, 19, 21). Staging was defined as F0 (no fibrosis), F1 (mild fibrosis), F2 (moderate fibrosis), F3 (severe fibrosis), or F4 (cirrhosis), and grading was defined as A0 (no activity), A1 (mild activity), A2 (moderate activity), or A3 (severe activity). Three pathologists independently evaluated disease stage and grade. Ninety-eight percent of biopsy specimens were more than 1 cm long (most were 10 to 18 mm long); the amount of material obtained was therefore adequate for histologic evaluation of fibrosis. If the pathologists disagreed, the scores assigned by the majority of the pathologists were used for the following analyses. Comparison of Grade and Staging between Paired Biopsy Samples The activity grade and fibrosis staging scores of the paired biopsy samples were compared. In addition, because the time between biopsies was long (range, 1 to 10 years), changes in activity grade and fibrosis staging were calculated in two categories defined by the median value of the interbiopsy interval (<3 years and 3 years). The following equations were used: Changes in activity grade=grade at second biopsy grade at initial biopsy Changes in fibrosis stage=stage at second biopsy stage at initial biopsy Rates of Fibrosis Progression and Regression We used the method of Poynard and colleagues (3) to calculate yearly progression or regression of fibrosis as the change in fibrosis staging score divided by time between biopsies. For example, if stage F3 fibrosis before therapy was reduced to F2 after 4 years, the fibrosis progression rate would be 0.25 unit/y (that is, regression). If it increased to F4 after 5 years, the rate of progression would be 0.2 unit/y. Histologic comparisons and changes were analyzed among patients with sustained virologic response and those with nonsustained virologic response. Statistical Analysis Statistical analyses were performed by using the Kruskal-Wallis test, the chi-square test, the Fisher two-tailed exact test, or analysis of variance to compare the distribution of variables between the groups. Spearman correlation coefficient analysis was used to compare the pathologists' histologic findings. To test potential predictive factors (duration of interferon treatment or resp

Subfields: Epidemiology, Hepatology

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Citations in the corpus

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma (2010, background): “The fact that IFN therapy improves liver histology in sustained virologic responders may also contribute to prevention of HCC [96].”
WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: liver. (2015, background): “…documented in studies of paired liver biopsies from patients with chronic hepatitis C who achieved sustained viral eradication (Poynard et al. 2002; Shiratori et al. 2000) and patients with chronic hepatitis B who received long-term antiviral therapy (Chang et al. 2010; Hadziyannis et al. 2006).”
EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. (2015, result): “Recommendations • Routine use of non-invasive tests during treatment or after SVR in non-cirrhotic patients does not add to clinical disease management (A1) • Routine use of non-invasive tests after SVR in patients with HCV cirrhosis has a high false negative rate and cannot be used to determine whi”
Liver fibrosis -- from bench to bedside. (2003, background): “Moreover, since fibrosis in HCV typically progresses over three decades, one might anticipate that an equally slow but steady regression might follow its clearance .”