Efficacy and safety of prophylaxis with entecavir and hepatitis B immunoglobulin in preventing hepatitis B recurrence after living‐donor liver transplantation

Aim: Hepatitis B recurrence after liver transplantation can be reduced to less than 10% by combination therapy with lamivudine (LAM) and hepatitis B immunoglobulin (HBIG). The aim of this study was to evaluate the efficacy and safety of prophylaxis with entecavir (ETV), which has higher efficacy and lower resistance rates than LAM, combined with HBIG in preventing hepatitis B recurrence after living‐donor liver transplantation (LDLT). Methods: Twenty‐six patients who received ETV plus HBIG (ETV group) after LDLT for hepatitis B virus (HBV)‐related end‐stage liver disease were analyzed by comparing with 63 control patients who had received LAM plus HBIG (LAM group). Results: The survival rates of the patients treated with ETV plus HBIG was 73% after both 1 and 3 years, and there was no statistical difference between the patients in the ETV group and LAM group. No HBV recurrence was detected during the median follow‐up period of 25.1 months in the ETV group, whereas the HBV recurrence rate was 4% at 3 years and 6% at 5 years in the LAM group. No patients had adverse effects related to ETV administration. Conclusion: ETV combined with HBIG provides effective and safe prophylaxis in preventing hepatitis B recurrence after LDLT.     

Treatment strategy for hepatitis C after liver transplantation

A significant proportion of patients with chronic hepatitis C virus (HCV) infection develop liver cirrhosis and complications of end-stage liver disease over periods of two to three decades and require liver transplantation, although re-infection is common and leads to further adverse events, given that such patients receive life-long immunosuppression. Because of the critical organ shortage worldwide, living-donor liver transplantation has an important role in many countries, especially in the Far East. Despite previous arguments, the results of recent well-designed studies suggest equivalent outcomes for deceased-donor and living-donor liver transplantation. No specific immunosuppression regimen has proven advantageous, but the general rule is “low and slow”. Combined pegylated interferon and ribavirin therapy is the current standard treatment, but compared to this therapy in the immunocompetent population, its efficacy in clearing the virus remains low. Moreover, its general application is hindered by the high prevalence of intolerability, lowering its efficacy from the aspect of intention to treat. Retransplantation becomes an option when treatment for disease progression fails, but it should be considered at an earlier stage in patients with a lower MELD (model for end-stage liver disease) score compared to that used for primary transplantation, which is a great challenge with the current critical organ shortage. The need for new anti-HCV drugs to further delay disease progression or even to enhance viral clearance, presumably specific HCV life-cycle inhibitors, is urgent. The liver transplant community must maintain an open mind regarding the development of these drugs and focus on their availability for early clinical trials in liver transplant recipients.     

Living donor liver transplantation for hepatitis C related hepatocellular carcinoma in a haemophilia A patient

We report the first case of unrelated living liver transplantation for hepatitis C related hepatocellular carcinoma (HCC) in a Chinese patient with haemophilia A. The development of cirrhosis and HCC was insidious in this patient, who has previously failed interferon treatment despite low viral load and genotype 6a. With factor VIII and novoseven support, there were no operative complications and there was no need for blood transfusion. Postoperative pegulated interferon treatment resulted in viral clearance with no increased cellular rejection. The use of living donors represent a potential life saving therapeutic options for hepatitis C virus related complications in haemophiliac, especially in countries of organ shortage. Careful patient and donor choice, meticulous surgical expertise and proper counselling, however, are prudent requirements.     

Clinical characterization of patients developing histologically‐proven fibrosing cholestatic hepatitis C post‐liver transplantation

Aim: Fibrosing cholestatic hepatitis C (FCH) post‐liver transplantation (LT) is an uncommon disorder with extremely poor outcome. Using stringent histological criteria, we sought to identify cases of FCH to better characterize its incidence, clinical features and outcomes. Methods: From January 1991 to December 2007, 973 LT for hepatitis C virus (HCV) were performed at our center. Using the pathology database, 51 cases with a provisional diagnosis of FCH were identified. FCH was diagnosed histologically by cholestasis accompanied by thin periportal fibrous septa, ductular reaction and mild inflammation. Results: FCH was reconfirmed in 24 recipients; seven had concurrent biliary problems. Twenty‐seven cases were excluded; biopsy was unavailable in nine cases, 15 did not meet the histological criteria of FCH and three had missing clinical information. All received deceased donors at a mean age of 64.4 years (15/17 aged >50 years). Mean time from LT to FCH was 7.6 months with 16 of 17 diagnosed within 1 year of LT. At diagnosis, mean viral load was 14.4 million IU/mL, bilirubin 16.2 mg/dL, aspartate aminotransferase 262 IU/mL, alanine aminotransferase 192 IU/mL and alkaline phosphatase 299 IU/mL. All 17 patients died or required re‐LT a mean of 7.8 months after the FCH diagnosis. Conclusion: FCH occurs infrequently and is typified by hyperbilirubinemia, donor age of more than 50 years, extremely high HCV RNA and specific histological changes occurring within the first several months post‐LT with extremely poor patient and graft survival. Histology alone is not reliable for the diagnosis of FCH, especially in the setting of recurrent HCV with concurrent biliary problems.     

Hepatitis B vaccination after living donor liver transplantation.

BACKGROUND: The efficacy of hepatitis B vaccination after living donor liver transplantation (LDLT) in patients transplanted anti-HBc-positive grafts or in patients who underwent LDLT for fulminant hepatitis B remains unknown. METHOD: A total of 11 recipients who underwent LDLT between October 1996 and October 2002 prospectively received hepatitis B vaccination three times within 6 months, starting a few weeks after the cessation of hepatitis B immunoglobulin (HBIG) prophylaxis. Serial quantification of the hepatitis B surface antibody (HBsAb) was performed. RESULTS: At the last follow-up, six out of 11 patients (54.5%) had seroconversion and were free from HBIG thereafter. Four out of those six responders had a peak HBsAb level of more than 1000 IU/L, while the other two patients had peak HbsAb levels below 1000 IU/L. Five patients never responded to the treatment and were back to HBIG prophylaxis. The average age of the six responders was 25.5 years, which was significantly younger than that of non-responders (44.4 years, P<0.05). None had side effects or hepatitis B infection during the study period. CONCLUSIONS: In conclusion, the use of this treatment modality could be used to reduce the cost of HBIG.     

Two patients treated with pegylated interferon/ribavirin/telaprevir triple therapy for recurrent hepatitis C after living donor liver transplantation

It is difficult to use protease inhibitors in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) due to interaction with immunosuppressive drugs. We report our experience with two patients treated with telaprevir (TVR) combined with pegylated interferon/ribavirin (PEG IFN/RBV) for recurrent HCV genotype 1 infection after LT. The first was a 63‐year‐old man with HCV‐related liver cirrhosis, who failed to respond to IFN‐β plus RBV after LT. Treatment was switched to PEG IFN‐α‐2b plus RBV and TVR was started. The donor had TT genotype of interleukin (IL)‐28 single nucleotide polymorphisms (SNP) (rs8099917). The recipient had TT genotype of IL‐28 SNP (rs8099917). Completion of 12‐week triple therapy was followed by PEG IFN‐α‐2b plus RBV for 36 weeks. Finally, he had sustained viral response. The second was a 70‐year‐old woman with HCV‐related liver cirrhosis and hepatocellular carcinoma. She failed to respond to PEG IFN‐α‐2b plus RBV after LT, and was subsequently switched to PEG IFN‐α‐2b/RBV/TVR. Genotype analysis showed TG genotype of IL‐28 SNP for the donor, and TT genotype of IL‐28 SNP for the recipient. Serum HCV RNA titer decreased below the detection limit at 5 weeks. However, triple therapy was withdrawn at 11 weeks due to general fatigue, which resulted in HCV RNA rebound 4 weeks later. Both patients were treated with cyclosporin, starting with a small dose to avoid interactions with TVR. TVR is a potentially suitable agent for LT recipients who do not respond to PEG IFN‐α‐2b plus RBV after LT.     

Living donor liver transplantation to patients with hepatitis C virus cirrhosis

Living donor liver transplantation (LDLT) is an alternative therapeutic option for patients with end-stage hepatitis C virus (HCV) cirrhosis because of the cadaveric organ shortage. HCV infection is now a leading indication for LDLT among adults worldwide, and there is a worse prognosis with HCV recurrence. The antivirus strategy after transplantation, however, is currently under debate. Recent updates on the clinical and therapeutic aspects of living donor liver transplantation for HCV are discussed in the present review.     

Hepatitis C virus kinetics during the first phase of pegylated interferon-α-2b with ribavirin therapy in patients with living donor liver transplantation

Aim:  To identify the problems of pegylated interferon (PEG IFN) with ribavirin therapy against hepatitis C virus (HCV) reinfection in living donor liver transplantation (LDLT) patients. HCV kinetics during the PEG IFN with ribavirin therapy were analyzed in LDLT patients, as well as in chronic hepatitis C (CHC) patients.
Methods:  The study included 80 consecutive HCV infected patients undergoing PEG IFN with ribavirin therapy (64 CHC and 16 LDLT patients) who attended the Nagasaki University Hospital for an initial visit between January 2005 and December 2007.
Results:  The sustained viral response (VR) rate of the CHC group (80%) was superior to the LDLT group (22%). The viral disappearance rate of the CHC group was also superior to the LDLT group, regardless of the HCV serotype. The HCV core antigen (cAg) titer under treatment in the LDLT group was more than that of the CHC group from day 0 to week 12. The HCV cAg decrease rate of the LDLT group on the first day of treatment was less than that of the CHC group.
Conclusion:  The HCV infection of a transplanted liver is more refractory to treatment than a non-transplanted liver. The low reduction HCV cAg rate on day 1 is one of the problems of the combination therapy.     

Plasma cell hepatitis induced by the termination of antiviral therapy for recurrent hepatitis C after living donor liver transplantation

Plasma cell hepatitis (PCH) is an idiopathic disorder characterized by plasma cell infiltration in the allografts of patients who have undergone liver transplantation. Although an increasing number of cases of PCH have been reported in liver transplant recipients with hepatitis C recurrence treated with interferon, it is unclear whether PCH is induced by interferon itself. Here, we describe the cases of two patients who developed PCH just after the termination of antiviral therapy for recurrent hepatitis C after living donor liver transplantation. Liver dysfunction appeared at 1 month in one patient and 2 months in the other patient after pegylated interferon plus ribavirin therapy, and liver histology showed interface hepatitis with plasma cell‐rich lymphoid aggregates. Both patients recovered after steroid therapy and achieved sustained virological response. These cases suggest that PCH could be induced by the alteration of the immune condition resulting from the termination of antiviral therapy. PCH should be considered when the transaminase levels increase after antiviral therapy, and it should be carefully distinguished from hepatitis C relapse.