Benefit of sustained virological response to combination therapy on graft survival of liver transplanted patients with recurrent chronic hepatitis C.

Recurrent hepatitis C infection is an important cause of progressive fibrosis, cirrhosis and graft loss after liver transplantation. Treatment for post-transplant recurrence results in sustained virological response (SVR) in up to 30% of cases. The aim of this study was to evaluate the impact of SVR on patients and graft survival. Thirty-four patients with an SVR to IFN-ribavirin were included. Forty-six nonresponders to the combination formed the control group. Follow-up data were recorded every 6 months and included HCV RNA, and the occurrence of clinical problems (cirrhosis, decompensation, hepatocellular carcinoma, death). A graft biopsy was performed every year. The mean follow-up duration was 52 months in responders and 57 months in nonresponders. Two patients died in each group of patients. Two patients with SVR developed late virological relapse. Fibrosis decreased in 38% of patients with SVR, remained stable in 44% and worsened in 18%. In contrast, fibrosis increased in the majority of nonresponder patients (74%, p<0.001). At the end of follow-up, no patient without cirrhosis at inclusion developed cirrhosis of the graft versus 9 among nonresponder patients (p=0.009). No difference in patient survival was observed in the two groups. In conclusion, this study shows that HCV eradication has a positive impact on graft survival.

Triple antiviral therapy with amantadine for IFN-ribavirin nonresponders with recurrent posttransplantation hepatitis C.

BACKGROUND: HCV reinfection after liver transplantation is universal and has an accelerated course with a high risk of progression to cirrhosis. It is now established that combination therapy with interferon (IFN) alpha and ribavirin may achieve a sustained virological response in 20% of transplanted patients. However, the optimal therapy for nonresponders remains an unresolved issue. We conducted a pilot study to determine the efficacy and safety of triple antiviral therapy in IFN-ribavirin nonresponders with recurrent chronic hepatitis C. METHODS: Twenty-four nonresponders to the IFN-ribavirin combination were enrolled in this pilot study. Patients were treated with IFN-alpha (3 million units three times a week subcutaneously with ribavirin [800-1,000 mg daily]) and amantadine 200 mg daily for 48 weeks. The primary end point was the loss of HCV RNA 6 months after the end of treatment. RESULTS: Median age was 50 years; 72% were men and 82% had genotype 1. The median interval between the end of combination therapy and enrollment was 11 months. Twenty-four patients started therapy, but five (21%) withdrew due to side effects, including two with anemia. On an intent-to-treat basis, 18 patients (75%) had a biochemical response and 9 (37%) had a virologic response at the end of triple antiviral therapy. Eight of these nine patients (33%) had a sustained virological response. The mean METAVIR score improved from A 2.2 F2.1 before treatment to A 1.2 F1.9 in sustained virological responders. In virological nonresponders, inflammatory activity did not change, but fibrosis worsened. Several patients required treatment with erythropoietin for anemia. Triple therapy was well tolerated and neither increased the frequency nor severity of side effects. CONCLUSION: Our results show that triple antiviral therapy for 48 weeks induced a sustained virological response in 33% of IFN-ribavirin nonresponders with recurrent hepatitis C.

Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) reinfection after liver transplantation is frequent and leads to chronic hepatitis and cirrhosis. The use of antiviral therapy in this situation remains controversial. This study aimed to assess the safety and efficacy of interferon alfa-2b plus ribavirin for recurrent hepatitis C following liver transplantation. METHODS: Transplant recipients with recurrent chronic hepatitis C were randomized to receive either no treatment or therapy with interferon alfa-2b (3 MU 3 times a week) plus 1000-1200 mg/day ribavirin for 1 year. Patients were followed up for 6 months after the end of treatment. The primary end point was loss of HCV RNA 6 months after the end of treatment. RESULTS: Fifty-two patients were randomized (treatment, 28; placebo, 24). Sixteen patients were withdrawn from the study; 12 (43%) were from the treated group (mainly for anemia [7 patients]) and 4 (17%) from the control group. In the treated group, serum HCV RNA was undetectable in 9 patients (32%) at the end of treatment and 6 (21.4%) at the end of the follow-up period, whereas no patient in the control group lost HCV RNA at any point (P = 0.036 at the end of follow-up). However, there was no significant histologic improvement. CONCLUSIONS: The combination of interferon alfa-2b plus ribavirin induced a sustained virologic response in 21% of transplant recipients with recurrent hepatitis C. However, 43% discontinued therapy due to adverse events (primarily severe anemia). Strategies to enable treatment with lower doses of ribavirin need to be explored.

Dynamic analysis of hepatitis C virus replication and quasispecies selection in long-term cultures of adult human hepatocytes infected in vitro.

Primary human hepatocytes were used to develop a culture model for in vitro propagation of hepatitis C virus (HCV). Production of positive- strand full-length viral RNA in cells and culture supernatants was monitored by PCR methods targeting three regions of the viral genome: the 5' NCR, the 3' X-tail and the envelope glycoprotein E2. De novo synthesis of negative-strand RNA was also demonstrated. Evidence for a gradual increase in viral components over a 3 month period was obtained by two quantitative assays: one for evaluation of genomic titre (quantitative PCR) and one for detection of the core antigen. Production of infectious viral particles was indicated by passage of infection to naive hepatocyte cultures. Reproducibility of the experiments was assessed using cultures from three liver donors and eleven sera. Neither the genotype, nor the genomic titre, nor the anti-HCV antibody content, were reliable predictive factors of serum infectivity, while the liver donor appeared to play a role in the establishment of HCV replication. Quasispecies present in hepatocyte cultures established from three different liver donors were analysed by sequencing hypervariable region 1 of the E2 protein. In all three cases, the complexity of viral quasispecies decreased after in vitro infection, but the major sequences recovered were different. These data strongly suggest that human primary hepatocytes are a valuable model for study of persistent and complete HCV replication in vitro and for identification of the factors (viral and/or cellular) associated with successful infection.