The impact of antiviral therapy on the course of chronic HCV infection: A systematic review

Category 6: Viral hepatitis: clinical aspects MUTATIONS

IN THE PROTEIN

THE NONSTRUCTURAL VIROLOGICAL

KINASE-BINDING

DOMAIN

OF

5A PROTEIN AND SUSTAINED

RESPONSE

PATIENTS CHRONICALLY

TO COMBINATION INFECTED

THERAPY

IN

WITH HEPATITIS C

VIRUS TYPE-l B

H. Akkiz, Y. Ergun, S. Colakoglu, M. Sandikci, M. Serin, A. Bekar, M. Oksuz, F. Y. Isiksal, B. Abayli, F. Kocak. ‘Department Of Gastroenterology, Cukwova University, Adana, Turkey Aim: An interaction of hepatitis-C-virus (HCV) NSSA protein with the interferon @‘N-alpha-inducible double-stranded RNA-activated protein kinase (PKR)was demonstrated in-vitro. The clinical correlation between amino acid mutations within the HCV-NSSAregion and response controversial. We investigated the correlation between NS5A2209-2274 sequences of HCV-lb-isolates and sustained virological response in Turkish patients with II+-alpha and ribavirin. Methods: Sixty-eight patients chronically infected with HCV-lb isolates who were treated with-3-mu II+-alpha-3-times-a-week and ribavirin( lOOO-1200mg/day)were studied. Serum HCV RNA was amplified by RT-PCR and the NS5A2209-2274 region was analysed-by-DNAsequencing. Results: Of 68 patients 40 were females and 28 were males. Ages of the patients reported ranged from 22-58 years (median-age was 43 years). Compared with HCV-lb prototype sequences, 26 patients (38%)had no amino acid changes (wild-type), 22 patients (32%)had 1-3 mutations (intermediate type) and 20patients(29%) had at least 4 mutations (mutant type) in the NS5A2209-2274 region. Eleven patients achieved a sustained response. 4of22 patients (18%)infected with intermediate type HCV-lb had sustained virological response. A sustained virological response was achieved in 12.of-20 patients (70%)infected with mutant type HCV-lb. Sustained virological response rate was (5%) in patients infected with wild-type-HCV-lb isolates. The median number of mutations within the PKR-BD was significanty higher for patients with sustained virological response than for nonresponders (6 mutations vs 2 mutations). Conclusions: The prevalence of mutant type HCV-lb isolates in T rkish patients is low. In patients treated with combination threrapy II+-alpha and ribavirin, a correlation between the number of mutations in NS5A22092274 region of HCV-lb isolates and sustained virological response was observed.

I

420

EVALUATION MUTATIONS

OF HEPATITIS B VIRUS POLYMERASE

GENE

IN HEPATITIS-B-E-ANTIGEN-NEGATIVE

PATIENTS RECEIVING

LAMIVUDINE

THERAPY

H. Akkiz, Y. Ergun, M. Sandikci, S. Colakoglu, M. Serin, M. Oksuz, F. Y. Is&al, F. Kocak, B. Abayli. Department Of Gastroenterology, Cukwova University, Adana, Turkey Aim: Lamivudine has been shown to-be effective in-patients with hepatitisB-e-antigen (HBeAg)-positive chronic hepatitis-B, but it’s long-termefficacy and the rate of polymerase-gene mutations in patients with HBeAg-negative chronic hepatitis-B isn’t well known. The aim of this study was to determine the antiviral response, rate and pattern of lamivudine-resistant mutations and the effect of lamivudine resistant mutations on precore/core promoter sequences in patients with HBeAg-negative chronic hepatitis-B-treated with lamivudine. Methods: Eighty-six-patients with HBeAg-negative chronic-hepatitis-B who have received lamivudine were studied. The mean duration of treatment was-34.6.months. Serum samples were PCR-amplified, and nucleotide sequences of hepatitis-B-virus(HBV)were analysed. Results: Before treatment, precore-stop-codon and core-promoter mutants were detected in 54(62. 7%) and 20(23. 2%) of 86 patients, respectively. Both precore stop codon and core promoter mutants were found in 8 patients. The cumulative rates of detection lamivudine-resistant mutations after 1,2 and, 3 years of treatment were 12%, 24% and 52% respectively. A new mutation has been showed at position555, resulting in a valin to

123

methionine (VSSSM). A precore stop codon mutant was replaced by awild-type virus in 6 patients infected with precore mutant at a median treatment of 14 months. Reversion in the core promoter mutation appeared in only 1-of-20.patients. Three patients with lamivudine-resistant mutants had reversion of precore stop codon mutations and in these patients this was accompanied by reappearence of HBeAg. HBV genotypes were investigated in-42.patients and all patients were infected with genotype-D-HBV. Conclusion: We found that lamivudine-resistant mutants were detected at similar rates as in patients with HBeAg-positive chronic hepatitis B. Additional changes in other parts of the HBV genome may restore the replication fitness of lamivudine-resistant mutants.

I 421

THE IMPACT OF ANTIVIRAL

THERAPY

CHRONIC

A SYSTEMATIC

HCV INFECTION:

ON THE COURSE

OF

REVIEW

P.L. Almasio, G. Venezia, A. Craxi. Division Of Gastroenterology, University Of Palermo, Palermo, Italy Background: Chronic hepatitis C is a progressive disease that leads to liver cirrhosis and hepatocellular carcinoma (HCC) in a period ranging from 10 to 30 years. Many factors have been related to disease progression and, among them, persistent HCV replication has been advocated as one of the major determinant of hepatic deterioration. With this respect any treatment of chronic hepatitis C is mainly aimed to reduce necro-inflammation by suppressing viral activity in the long-term. Aims: We evaluated the persistence of HCV clearance after interferon therapy during follow-up in patients considered as long-term responders. Secondly, we analyzed the rate of progression from hepatitis to cirrhosis and HCC in patients with persistent viral elimination as compared to those who did not respond to treatment. Methods: We performed a systematic review of published data on longterm follow-up of patients with persistent HCV suppression and the rate of cirrhosis and HCC in long-term responders as compared to non-responders. Data were pooled to obtain a combined estimate of the reduced relative risk using the random effect model. Results: In patients achieving a sustained virological response a relapse was observed in about 13% (range 0.86%). In subjects with a sustained viral response progression to cirrhosis is uncommon. When compared to relapsers or non-responders the calculated risk reduction in this group was -0.22 (95% C.I. -0.36 - -0.08). Th e calculated estimates of risk reduction of developing HCC in patients achieved sustained response were -0.097 (95% C.I. -0.13 - -0.07). Conclusions: Vast majority of patients in remission during the first six months after antiviral treatment will remain so for the rest of their life. Cumulative data from literature showed a significant reduction in the rate of progression to cirrhosis and development of HCC in sustained viral responders as compared to non-responders or relapsers. However, since factors predictive of sustained response to interferon are independently associated with less frequent and/or later development of decompensation or HCC, the beneficial effects of antiviral therapy may be probably overestimated.

I 422

THE ADJUVANT

ACTIVITY

OF AM3 (INMUNOFER

HEPATITIS B (HBV) VACCINATION

PATIENTS IS DUE TO ITS ABILITY TO RESTORE AS WELL AS THE ADAPTATIVE

N@) TO

IN HAEMODIALYSIS THE INNATE

IMMUNITY

E. Reyes’, A. Prieto’, .I. Monserrat’, S. Gonzalez2, V.G. Villarrubia3, ‘Department Of Medicine, University OfAlcala, M. Alvarez-Mon’,4. Madrid, Spain; 2Harvard Medical School, Boston, USA; ‘Department Of Immunology, I.E Cantabtia, Madrid, Spain; 41mmune System Disease And Oncology, University Hospital ‘Principe De Asturias’, Madrid, Spain Patients with end-stage renal disease (ESRD) undergoing haemodialysis have defective cell-mediated immunity that decreases their protective responses to HBV vaccine. The ability of an immunomodulator, AM3, to improve seroconversion was investigated. Since effective HBV vaccina-