Effectiveness of relative low-dose interferon treatment for patients with chronic hepatitis C

To demonstrate effectiveness by relative low-dose of interferon treatment for patients with chronic hepatitis C, we investigated the histological activity index (HAI) score of liver tissue, hepatitis C virus (HCV) genotype by polymerase chain reaction (PCR) with type-specific primers, HCV RNA levels by competitive PCR, serum aminotransferase, sex, age, history of blood transfusion and history of hepatitis in patients with chronic hepatitis C prior to treatment. Twenty-two patients were treated with human lymphoblastoid interferon (3 MU daily, 2 weeks, 3 MU thrice a week, 6 weeks, 1.5 MU thrice a week, 16 weeks) for 24 weeks, of whom 10 (45.5%) were responders within a 6 month follow-up. HAI score before treatment was significantly lower in responders than in a combined group of relapse patients and nonresponders (7.5 +/- 3.4 vs. 12.0 +/- 3.1, p < 0.01). The prevalence of responders in patients with genotypes III and IV was significantly higher than in those with genotype II (85.7% vs. 21.4%, p < 0.05). HCV RNA level (logarithmic transformed copy per 50 microliter of serum) was significantly lower in responders than in a combined group of relapse patients and nonresponders (4.8 +/- 1.2 vs. 5.7 +/- 0.8, p < 0.05). In case of other pretreatment factors, there were no significant differences between responders and a combined group relapse patients and nonresponders. Thus severe histological changes in the liver, HCV genotype II and high HCV RNA levels are markers of unfavorable effects of interferon treatment for patients with chronic hepatitis C.     

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.     

High-dose (9 MU) long-term (60 weeks) alfa-interferon therapy for chronic hepatitis patients infected with HCV genotype 1b

Efficacy of standard regimens (e.g., 3-6 MU for 24 weeks) of alfa-IFN therapy for chronic hepatitis C has been limited, particularly in patients with HCV/1b. To see if higher-dose longer term treatment is more effective, we tried a 9 MU 60-week regimen. HCV/1b-infected chronic hepatitis patients received 9 MU IFN alpha 2a everyday but Sunday for 2 weeks and thrice a week for next 10 weeks, and 76 patients became HCV RNA-negative while 81 remained positive. The RNA-negative patients were then randomized to receive 3 MU (group I, n = 37) or 9 MU (group II, n = 39) for 48 weeks. Of the RNA-positive patients, only those with normal ALT received another 9 MU 48-week treatment (group III, n = 45). Sustained responders (SR) were defined as those with negative RNA and normal ALT 6 months after the therapy. SR rates based on intent-to-treat principle did not differ significantly between groups I and II (30% vs 41%), but those based on the protocol-compatible cases showed a significantly lower than those in group II. Adverse effects of IFN, developed more frequently in groups II and III than in group I, were mostly reversible. In conclusion, our results encourage 9 MU 60-week IFN alpha treatment in HCV/1b-infected patients with careful attention to adverse effects, and suggest that the treatment should be discontinued if HCV RNA does not disappear within 12 weeks.     

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.     

A PET study on cortical and subcortical control of pelvic floor musculature in women

The possibility of hepatitis B virus (HBV) infection in HBsAg-negative patients has been shown. However, an "inapparent" coinfection by HBV in hepatitis C virus (HCV)-positive patients generally is not taken into account in clinical practice. Mechanisms responsible for resistance to interferon (IFN) have not been completely clarified. The aim of this study was to investigate whether an "inapparent" coinfection by HBV in anti-HCV-positive chronic liver disease patients may influence IFN response. Fourteen anti-HCV positive, HBsAg-negative but serum HBV DNA-positive patients by PCR and 111 anti-HCV-positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis were treated with 3 MU of recombinant alpha-2a IFN 3 times weekly for 12 months. Serum HBV DNA and HCV RNA were determined before treatment, after 6-12 months and in coincidence with ALT flare-up by PCR. HBV PCR was performed using primers specific for the S region of the HBV genome and HCV PCR with primers localised in the 5'NC region of HCV genome. IgM anti-HBc was tested using IMx Core-M Abbott assay. By the end of treatment, ALT values had become normal in 4/14 HBV DNA-positive patients (28%), but all "responders" (4/4) relapsed between 2 and 5 months after therapy. All but one patient were HCV RNA-positive before treatment, 6 were also both HBV DNA and HCV RNA-positive during ALT flare-ups. In 5 patients, only HBV DNA and in 3 patients, only HCV RNA was detected when transaminase values increased. All patients remained HBsAg-negative and anti-HCV-positive. IgM anti-HBc was detected both before treatment and during ALT elevation in 3 patients and only during ALT relapse in 3 others. Of the 111 anti-HCV positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis, a biochemical response to IFN treatment was observed in 54% of the cases. Relapse of ALT values was observed in 47% of the cases during a follow-up of 1 year after treatment. "Inapparent" HBV/HCV coinfection may be implicated in cases of resistance to IFN treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by IFN treatment. The pathogenic role of HBV in liver disease was confirmed by detection of IgM anti-HBc in some cases; the appearance of these antibodies only after IFN treatment suggests that IFN may exert a selective role in favour of HBV. Further studies will show the effect of different treatment schedules. HBV DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding interviral relationships and mechanisms involved in multiple hepatitis virus infections.     

HCV RNA levels in serum, liver, and peripheral blood mononuclear cells of chronic hepatitis C patients and their relationship to liver injury

OBJECTIVE: We sought to evaluate the relationship between HCV RNA levels in serum, liver, and peripheral blood mononuclear cells (PBMC) and the degree of liver injury in chronic hepatitis C (CHC) patients. METHODS: Thirty-six consecutive CHC patients were included in the study. The liver damage was evaluated by the histological activity index (HAI) score. The HCV RNA levels in the three compartments studied were assessed by bDNA assay. Nineteen patients were treated with alpha-interferon 2b (IFN). RESULTS: Serum and liver HCV RNA levels in CHC patients were significantly associated with an increasing HAI score irrespective of the HCV genotypes. Cirrhotic patients showed higher HCV RNA levels than the CHC patients with HAI score 1-4 (p < 0.05), but had lower levels than the group with HAI score > 8 (p < 0.03). Patients with HAI score 1-4 showed the lowest levels of HCV RNA in PBMC. There was a strong relation (r = 0.78; p < 0.001) between serum and liver HCV RNA levels, but not between either serum or liver HCV RNA levels and those of PBMC. Seven patients showed a response to IFN and three of these had a sustained response. Pretreatment levels of HCV RNA in PBMC of the IFN responder patients were lower than those of the nonresponder patients (p < 0.02). CONCLUSIONS: The data indicate a relation between serum or liver HCV RNA levels and the degree of liver injury in CHC patients, and show that serum HCV RNA level mirrors the hepatic viral burden.     

An evaluation of the degree of the morphological activity and the stage of the process in patients with chronic liver diseases caused by coinfection with the hepatitis B, C and/or D viruses

In order to determine the differences in histological grade of activity and the stage of fibrosis in patients with chronic liver diseases due to multiple hepatitis virus infection and single infection of HBV and HCV we assessed the 68 liver biopsies samples according to Knodell and Scheuer scoring systems. Retrospectively, 216 liver biopsies reports from consecutive patients with chronic viral hepatitis were analysed. Histological activity index (HAI) in HBV/HCV coinfection was higher than in a single HCV infection; it did not differ in groups of HBV/HBC and HBV. The difference was due to the interface hepatitis; lobular activity and portal inflammation were the same. In HDV superinfection HAI was high due to both portal-periportal and lobular hepatitis. HAI depended mainly upon the presence of HBV replication; in patients with chronic hepatitis C with HBV-DNA HAI was also higher than in single HCV group. No difference in HAI between triple and dual hepatitis virus infection was found. In patients with HBV/HCV coinfection and especially with HDV superinfection the advanced stages occurred more than often than in patients with single infections.     

Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT)

BACKGROUND: Only 15-20% of patients with chronic hepatitis C achieve a sustained virological response with interferon therapy. The aim of this study was to compare the efficacy and safety of interferon alpha2b in combination with oral ribavirin with interferon alone, for treatment of chronic infection with hepatitis C virus (HCV). METHODS: 832 patients aged 18 years or more with chronic HCV who had not been treated with interferon or ribavirin, were enrolled and randomly allocated one of three regimens: 3 mega units (MU) interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 48 weeks; 3 MU interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 24 weeks; or 3 MU interferon alpha2b three times a week and placebo for 48 weeks. All patients were assessed for safety, tolerance, and efficacy at the end of weeks 1, 2, 4, 6, and 8, and every 4 weeks during treatment. After treatment was completed patients were followed up on weeks 4, 8, 12, and 24. The primary endpoint was loss of detectable HCV-RNA (serum HCV-RNA <100 copies/mL) at week 24 after treatment. FINDINGS: Sustained virological response at 24 weeks after treatment, was found in 119 (43%) of the 277 patients treated for 48 weeks with the combination regimen, 97 (35%) of the 277 patients treated for 24 weeks with the combination regimen (p=O.055), and 53 (19%) of the 278 patients treated for 48 weeks with interferon alone (p<0.001 vs both combination regimens, intention-to-treat analysis). Logistic regression identified five independent factors significantly associated with response: genotype 2 or 3, viral load less than 2 million copies/mL, age 40 years or less, minimal fibrosis stage, and female sex. Among patients with fewer than three of these factors the odds ratio of sustained response was 2.6 (95% Cl 1.4-4.8; p=0.002) for the 48 week combination regimen compared with 24 weeks of the combination regimen. Discontinuation of therapy for adverse events was more frequent with combination (19%) and monotherapy (13%) given for 48 weeks than combination therapy given for 24 weeks (8%). INTERPRETATION: An interferon alpha2b plus ribavirin combination is more effective than 48 weeks of interferon alpha2b monotherapy and has an acceptable safety profile. Patients with few favourable factors benefit more from extending the duration of combination therapy to 48 weeks.     

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 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.     

Lymphoblastoid interferon therapy in chronic hepatitis C: biochemical, virological and histological evaluation of two different doses

Sixty patients of both sexes with biopsy-proven chronic hepatitis C were randomized to receive lymphoblastoid interferon 3 MU or 6 MU three times weekly for 6 months. A follow-up period of 3 months at the end of the therapy was scheduled. Thirty-two patients (53.3%) normalized alanine aminotransferase at the end of the therapy. Of these, 17 received 3 MU (56.7%) and 15 (50%) received 6 MU. Eighteen of the 32 patients (56.2%) relapsed in the follow-up period after treatment. No significant difference in relapse rate was observed between the two groups. The overall percentage of the non-responder patients was 36.6%. The treatment was discontinued because of non-compliance and/or side effects in six patients (10%): three in the 3-MU group and three in the 6-MU group. An improvement in liver histology was observed in about a quarter of chronic active hepatitis patients whose overall diagnosis changed to chronic persistent hepatitis. Knodell's score system showed a significant improvement (p < 0.05) with regard to peripheral necrosis, fibrosis and total score. HCV-RNA was positive at the beginning in all patients and it became undetectable in almost all responder patients. In some cases there was no correlation between viraemia and biochemical signs of liver disease. Our study shows that 6 MU does not increase the response rate compared to 3 MU. Moreover, the lower dose is able to improve the liver histology and to abolish the HCV viraemia in responder patients.     

Subjective experience of treatment, side-effects, mental state and quality of life in chronic schizophrenic out-patients treated with depot neuroleptics

Treatment of chronic hepatitis B and C aims to achieve viral eradication. Decreasing the number of carriers subsequently reduces the transmission of the viruses. For an individual patient, therapy is aimed at preventing cirrhosis, liver failure and hepatocarcinoma. Among potential therapies, interferon alfa offers the best results. In one study involving the treatment of children from a region of intermediate endemicity, interferon alfa accelerated the clearance of hepatitis B virus (HBV) replication. In long-term follow-up, the study did not show a significant difference between patients who were treated and those who were not in the rate of disappearance of serum HBV-DNA, normalization of alanine aminotransferase (ALT) levels or seroconversion to antibodies to hepatitis B e antigen. The most important factors in predicting a rapid decrease in HBV replication were AI T levels more than twice normal, low levels of serum HBV-DNA (less than 100 pg/mL) and inflammatory activity on liver biopsy (chronic active hepatitis). A select group of children with HBV infection has thus been shown to benefit from interferon alfa therapy. Treatment should be administered in a dosage of 6 MU/m2 three times each week for 6 months. Chronic active hepatitis, develops in approximately 30% of children with a chronic hepatitis C virus (HCV) infection. Cirrhosis due to HCV appears to be a very rare complication among children. Results of interferon alfa treatment for children with HCV are scarce. A pilot study of 12 children treated with interferon alfa in a dosage of 3 MU/m2 three times each week for 6 months showed that ALT levels normalized in approximately 90% of the patients after 15 months of follow-up. All of the patients had a decrease in the histological activity of the disease. Factors predictive of a favourable response in adults were: low levels of gamma-glutamyl transferase, young age, female sex, short duration of disease, absence of cirrhosis and low histological activity of the disease. Controlled randomized studies are needed to determine the indications for interferon alfa therapy in children infected with HCV. Available data suggest that children may have a better response than adults.     

Long-term interferon-alpha therapy does not affect sex hormones in males with chronic hepatitis C

The effects of interferon-alpha (IFN-alpha), given at a dosage of 6 MU thrice weekly for 12 months, on gonadal function were investigated in 18 males affected by chronic hepatitis C. Periodically, all patients were clinically monitored and questioned about sexual function. Gonadotropin and serum androgen concentrations (follicle-stimulating hormone, luteinizing hormone, total testosterone, free testosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and sex hormone binding globulin) were tested every 3 months. Ten of 18 patients (55%) responded to IFN-alpha therapy. Serum total testosterone and sex hormone binding globulin values decreased slightly at the third month of treatment, then returned to baseline values. Serum free testosterone and other sex hormones remained essentially unchanged during IFN-alpha therapy. Four patients (22.2%) complained of sexual dysfunction (impaired libido, erectile failure, and impaired ejaculation), which was unrelated to any significant hormonal change and resolved after IFN therapy was stopped. Serum sex hormones values did not differ between responders and nonresponders to IFN-alpha. This study indicates that 12 months treatment with 6 MU of IFN-alpha thrice weekly does not significantly affect gonadal function in men with chronic hepatitis C. The sexual dysfunction observed could be ascribed to such other side effects of IFN as asthenia, fatigue, or anxiety, or it could have a psychologic basis.     

Treatment of chronic hepatitis C with interferon-alpha: a preliminary report

Interferon alpha (IFN-alpha) has been indicated to be dramatically effective in some but not all patients with chronic hepatitis C virus (HCV) infection. We investigated prospectively 27 patients of chronic hepatitis C, 12 females and 15 males, treated with IFN-alpha for a better regimen of the therapy and for any effective predictor of response to the treatment. All patients were treated with 3 to 6 million units (MU) of recombinant IFN-alpha 2b (n = 15) or lymphoblastoid IFN-alpha (n = 12) given 3 times weekly for 12 to 36 weeks. Patients with normal alanine aminotransferase (ALT) value during therapy, who sustained this response throughout 6 months follow-up after treatment was completed, were grouped into the complete responders. Patients with normal ALT value during therapy but who relapsed after treatment completed, were grouped as partial responders. Non-responders were defined as patients without normal ALT value during therapy. The rates of complete response, partial response, and non-response were 29.6%, 40.8%, and 29.6%, respectively. The degree of response to IFN-alpha therapy was not related to age, sex, type of IFN-alpha, history of blood transfusion, the state of liver pathology, or pretreatment level of ALT value. The complete responsive rate to IFN-alpha was higher in patients treated with total dose above 215 MU [38.1% (8/21) vs. 0% (0/6), p = 0.06], in patients treated for at least 24 weeks [40% (8/20) vs. 0% (0/7), p < 0.05], and in patients with non-genotype 1b/II HCV infection [40% (8/20) vs. 0% (0/7), p < 0.05]. We concluded that IFN-alpha was effective in the treatment of chronic HCV infection, particularly in those other than HCV genotype 1b/II. A high-dose, and long-duration regimen may be recommended for better response of chronic hepatitis C to IFN-alpha therapy.     

Histological characteristics of chronic hepatitis C in biopsy material

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection is one of the most important diseases with high chronicity rate (50-80%) leading to end-stag cirrhosis and hepatocellular carcinoma. Hepatic histology shows a characteristic but not diagnostic picture. The aim of this study was to evaluate the characteristic histological findings in correlation with epidemiological features in our liver biopsy material. PATIENTS/METHODS: 106 liver biopsies were studid between 1993-1996. All patients (60 males, 46 females, age between 11-81 years, mean age: 43 years) were found to be positive for HCV antibody by a second-generation ELISA method. The biopsy materials were fixed in buffered formalin and having embedded in paraffin, stained with hematoxylin and eosin, periodic acid-Schiff after diastase digestion, G?m?ri's reticulin stain and picrosirius red for collagen. The histological evaluation was based upon the new classification of chronic hepatitis proposed by Desmet et al. The statistical analysis was performed by the Chi square test. RESULTS: Minimal chronic hepatitis (HAI: 1-3) was found in 14 (13.2%), mild chronic hepatitis (HAI: 4-8) in 69 (65.09%) and moderate chronic hepatitis (HAI: 9-12) in 23 (21.69%) cases, while assessment of fibrosis (staging) resulted fibrosis 0/1 in 44 (41.5%), fibrosis 2 in 14 (13.2%), fibrosis 3 in 37 (34.9%) and cirrhosis (fibrosis 4) in 11 (10.37%) cases. Among histological features of chronic hepatitis C, the frequency of steatosis (70.75%), lymphoid F/A (63.2%), and bile duct lesions (12.26%) have paralelly increased with activity (grade) of hepatitis and these changes were more pronounced in moderate chronic hepatitis (p < 0.001). CONCLUSIONS: More than half of chronic hepatitis C patients presented mild histological lesions with stage 1 fibrosis. Lymphoid F/A, bile duct damage and steatosis are important diagnostic features that show a strong correlation with the activity of chronic hepatitis. The assessment of fibrosis (stage: 3 and stage: 4) in mild chronic hepatitis cases does alert the hepatologist to perform the liver biopsy to detect the fibrotic changes in chronic hepatitis C.     

Phase II clinical trial of combined natural interferon-beta plus recombinant interferon-gamma treatment of chronic hepatitis B

BACKGROUND/AIMS: Alpha-interferon (IFN-alpha) is an effective treatment for chronic hepatitis B but only 25-40% of patients will profit from a long-term beneficial response to the currently recommended schedule of 3-6 MU given 3 times a week for 6 months. Clinical trials are therefore needed to investigate alternative modifications of interferon therapy, including combinations of different antivirals or immune modulators in order to improve the therapeutic approach to chronic hepatitis B infection. In a phase II trial we evaluated whether a combination of natural interferon-beta (nIFN-beta) with strong antiviral activity plus recombinant interferon-gamma (rIFN-gamma) with a predominantly immunomodulatory activity is able to increase the response rate compared to historical controls treated with IFN-alpha in a conventional regimen. METHODOLOGY: Forty patients with chronic hepatitis B were included in this trial of combined interferon therapy at a dosage of 6 MU nIFN-beta during week 1 followed by 3 MU for weeks 2-4 plus rIFN-gamma at a daily subcutaneous (s.c.) injection of 150 microg during the entire 4 weeks of the treatment period. Patients entered the trial on the basis of the following criteria: hepatitis B surface antigen (HBsAG), HBeAG and HBV-DNA positive for at least 6 months, HDV, EBV, CMV, anti-HIV negative, and chronic hepatitis proven on biopsy taken within 4 weeks of entry as well as 6 and/or 12 months after interferon therapy. The final diagnosis and classification of chronic hepatitis has been based on guidelines according to a revised classification of chronic hepatitis (Desmet 1994). The post-treatment follow-up was 12 months. RESULTS: The combined interferon therapy achieved complete responses with seroconversion from HBeAG to anti-HBe and a negative HBV-DNA (dot blot) test, as well as normalization of ALT activity in 15 patients, and partial response with negativation of HBV-DNA concomitant to a decrease in aminotransferase activity to near normal levels in 6 patients. Nineteen patients showed no response to viral markers but showed relief of clinical symptoms as well as pronounced decrease of serumtransaminase activity. Grading of liver biopsies demonstrated an improvement of histologic parameters after the interferon regimen in half of the evaluable patients (n=22). Histological response has been quantified by a reduction in the score of histological activity (HAI-index) from 12.6 before to 7.6 after interferon therapy, and in the inflammation and cellular degeneration score (ICD) from 9.9 to 5.2. Histological response, however, failed to show a consistent correlation with serologic response. This medium-dose combination of interferon-beta and interferon-gamma was tolerated very well by the patients, this good tolerability being explained by tachyphylaxis in response to daily interferon doses. No serious side effects or decompensation of liver function were observed during the 4-week period of therapy or the follow-up, despite the special clinical situation where 60% of the patients included in the study presented with histologically proven cirrhosis (35% of them with clinical manifestation of mildly decompensated cirrhosis). CONCLUSIONS: This short-term regimen of combined nIFN-beta + rIFN-gamma therapy in patients with chronic hepatitis B proved to be equieffective to long-term treatment with interferon-alpha and combines high clinical tolerability with good practicability, as it can be administered on an in-patient basis, ensuring close patient monitoring.     

The incidence of hepatocellular carcinoma in patients with chronic hepatitis C after interferon treatment

To determine whether serum hepatitis C virus (HCV) RNA disappearance after interferon (IFN) treatment prevents development of hepatocellular carcinoma (HCC), we evaluated retrospectively the incidence of HCC in patients with chronic hepatitis C. A total of 213 patients were monitored for more than 6 months after completion of IFN treatment. Sixty-three of the 213 patients (29.6%) achieved a complete response (CR) to treatment and 150 (70.4%) had no response (NR). HCC developed in 12 (5.6%), all of whom were NR. Logistic analysis showed age, alpha -fetoprotein, and staging of histological finding before IFN treatment were independent factors to development of HCC. The fact that there was no HCC development from CR provides a basis for IFN treatment in chronic HCV infection.