Treatment of hepatitis B and C following liver transplantation

Advanced liver disease related to hepatitis B virus (HBV) and hepatitis C virus (HCV) is the leading indication for orthotopic liver transplantation worldwide. This article discusses the strategies for the management of liver disease related to recurrent HBV and HCV.     

Treatment of recurrent hepatitis C following liver transplantation

Patients with chronic hepatitis C infection who are viremic at the time of liver transplantation will have universal recurrence of the virus in the allograft. Long-term survival after transplantation in patients with chronic hepatitis C is diminished as compared with patients who undergo liver transplantation for other indications. The progression of HCV-related fibrosis and the development of cirrhosis appear to be accelerated in the presence of immunosuppression, compared with an immune-competent population. The primary aim of hepatitis C treatment in patients with recurrent hepatitis C infection in the allograft remains eradication of the virus to prevent the progression of liver disease. However, decisions regarding the timing, duration, and optimization of the treatment regimen must be tailored to the individual.     

Treatment of recurrent hepatitis C following liver transplantation

Cirrhosis due to hepatitis C virus infection is now the most common indication for liver transplantation in Western Europe and the United States. In the absence of effective prophylaxis, recurrent hepatitis C virus infection is almost inevitable. Although the natural history and intermediateterm outcome of recurrent infection with hepatitis C virus are now better documented, factors that may influence the recurrence of hepatitis and consequent progression of graft disease remain unclear. Interferon used as a single agent for the treatment of recurrent infection has proven unsatisfactory. Early intervention for recurrent infection with the combination of interferon and ribavirin appears promising, and this approach may prevent or delay progression of hepatitis C virus-related graft disease after liver transplantation     

Treatment strategies for chronic hepatitis C prior to and following liver transplantation

Hepatitis C virus(HCV)-related liver disease is the leading indication for liver transplantation(LT) worldwide. However, HCV is an independent predictor of lower survival following LT, and recurrence of HCV postLT is virtually universal. The historic standard of care during the interferon era of HCV therapy was expectant management-initiation of antiviral therapy in the setting of documented disease progression following LT. With the advent of new direct acting antiviral(DAA) therapies for HCV, the paradigm of expectant treatment for recurrent HCV infection post-LT is shifting. The safety, tolerability, and efficacy of DAAs, even among the sickest patients with advanced liver disease, enables treatment of HCV in the pre-transplant setting among LT waitlist registrants. Finally, emerging data are supportive of preemptive therapy with DAAs in liver transplant recipients as the preferred approach. Expectant management of HCV following LT can rarely be justified in the modern era of HCV therapy.     

Treatment of hepatitis C after liver transplantation

This article summarizes the current therapies, with particular emphasis on antiviral therapy. Because these alternatives have substantial limitations, pretransplant or early post-transplant recognition of patients with high risk of severe post-transplantation outcome is desirable to target these patients for intervention. Alternatively, the implementation of measures aimed at reducing or avoiding factors known to be associated with an aggressive recurrence is an additional strategy that needs to be explored.     

Natural history of hepatitis C following liver transplantation

PURPOSE OF REVIEW: Currently, chronic hepatitis C virus-infection-related cirrhosis is the most common indication for liver transplantation in the USA and most parts of the world. While the incidence of new hepatitis C virus cases has decreased, the prevalence of infection will not peak until the year 2040. In addition, as the duration of infection increases, the proportion of new patients with cirrhosis will double by 2020 in an untreated patient population. If this model is correct, the projected increase in the need for liver transplantation secondary to chronic hepatitis C virus infection will place an impossible burden on an already limited supply of organs. In this article we present a comprehensive review of post-transplant hepatitis C virus infection and address the major challenges that face the transplant community. RECENT FINDINGS: Hepatitis C virus infection recurs virtually in every post-transplant patient. Typically, serum levels of hepatitis C virus RNA increase rapidly from week 2 post-liver transplant, achieving 1-year post-liver transplant levels that are 10-20-fold greater than the mean pre-liver transplant levels. Progression of chronic hepatitis C virus is more aggressive after liver transplantation with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. Approximately 10% of the patients with recurrent disease will die or require re-transplantation within 5 years post-transplantation. Interventions to prevent, improve, or halt the recurrence of hepatitis C virus infection have been evaluated by multiple small studies worldwide with similar overall rates of virological clearance of approximately 9-30%. Current consensus recommends combination therapy with pegylated interferon and ribavirin for those patients with histological recurrence of hepatitis C virus infection and fibrosis of >/= 2/4. Therapy is adjusted to tolerance and rescued with granulocyte colony-stimulating factor and erythropoietin for bone marrow suppression. SUMMARY: The major challenges that face the transplant community in the coming years include new strategies to meet the growing demand for limited organ donor supplies and improvement of treatment for those patients in whom recurrence of viral disease has occurred. Only with improved antiviral treatments and strategies will we make a significant impact on this problem.     

Approach to recurrent hepatitis C following liver transplantation

Hepatitis C-associated liver failure is the most common indication for liver transplantation. Histologic evidence of recurrence is apparent in approximately 50% of hepatitis C virus (HCV)-infected recipients in the first postoperative year. Approximately 10% of HCV-infected recipients will die or lose their allograft due to hepatitis C-associated allograft failure. HCV-infected recipients who undergo retransplantation have 5-year patient and graft survival rates that are broadly similar to those for transplant recipients who are not HCV infected. Although the choice of calcineurin inhibitor, mycophenolate mofetil, or both has not been clearly shown to affect histologic recurrence of hepatitis C, higher cumulative exposure to corticosteroids is associated with increased mortality and more severe histologic recurrence. In contrast to treatment of non-HCV-infected recipients, treatment of HCV-infected transplant recipients for acute cellular rejection is associated with attenuated patient survival. Steroid-resistant rejection with or without the use of T-cell-depleting therapies is associated with a greater than fivefold increased risk of mortality in HCV-infected liver transplant recipients. Pegylated interferon with or without ribavirin should be considered for treatment of recipients with histologically apparent recurrence of hepatitis C before total bilirubin exceeds 3 mg/dL. The role of hepatitis C immunoglobulin and new immuno-suppressive agents in the management of hepatitis C after transplant continues to evolve.     

丙型肝炎相关肝病肝移植后丙型肝炎复发的防治

肝移植是慢性丙型肝炎相关终末期肝病惟一的有效治疗方法，但所有患者均可能出现移植后丙型肝炎复发，移植后5年内约25％～33％的患者可因丙型肝炎复发出现肝硬化，因此对其预防和治疗尤为重要，本文就丙型肝炎相关肝病肝移植后丙型肝炎复发的防治作一介绍。     

Treatment of recurrent hepatitis C after liver transplantation

Chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the United States and Europe, and more than 20,000 patients worldwide have undergone transplantation for complications of chronic hepatitis C. In North America, HCV accounts for 15% to 50% of the liver transplants performed in United States transplant programs. To maximize the long-term survival of liver transplant recipients who have HCV infection, eradication of infection is the ultimate goal. Pretransplant antiviral therapy with the goal of achieving viral eradication before transplantation is a consideration in some patients, especially those who have mildly decompensated liver disease. This article focuses on the management of liver transplant recipients who have HCV infection at the time of transplantation. Prophylactic and preemptive therapies, as well as treatment of established recurrent disease, are the strategies reviewed.     

Natural history of hepatitis C and outcomes following liver transplantation

Chronic hepatitis C virus (HCV) infection is common and affects a significant proportion of the population. Chronic HCV-related cirrhosis is the most common indication for liver transplantation (LT) in Australia, the United States (US), and most European countries. Unfortunately, the post-transplant recurrence of HCV is almost a universal phenomenon with approximately 6% to 23% of transplant recipients progressing to cirrhosis at a median of 3 to 4 years post-LT with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. The 1-year and 3-year actuarial risk of decompensation has been estimated at 42% and 62%, respectively. Similarly, the rate of progression from hepatic decompensation to death is accelerated after LT with a 3-year survival rate of less than 10% in decompensated HCV liver recipients. Ten percent to 25% of the patients with recurrent disease will require re-transplantation within 5 years. Because of the increasing number of patients transplanted for chronic HCV infection and the complexity of factors affecting this population we will present an up-to-date review concerning LT in the setting of HCV infection and cirrhosis with the goal of outlining the natural history, recurrence of infection, risk factors associated with severity of recurrence, treatment strategies for recurrent HCV infection, role of re-transplantation, and de-novo hepatocellular carcinoma.     

Recurrence and accelerated progression of hepatitis C following liver transplantation

The patient described had recurrent hepatitis C following OLT. This hepatitis appeared early postOLT and progressed to fibrosing cholestatic hepatitis, a severe form of HCV recurrence. Factors such as genotype 1, high viral load and severe damage on the first postOLT biopsy may indicate a more severe outcome. We have hypothesized that, in parallel to what is known for hepatitis B, this rare form of recurrence was linked to a high expression of virus C proteins in the liver graft. Severe form of hepatitis C recurrence should be treated early with the best currently available treatment which is a combination of IFN and ribavirin. Large series of patients with comparable virological, histological and immunological inclusions criteria are necessary to evaluate the efficacy of this treatment.     

Natural history of hepatitis C and outcomes following liver transplantation

Hepatitis C-associated liver failure is the most common indication for liver transplantation and the infection recurs nearly universally following transplantation. Histologic evidence of recurrence is apparent in approximately 50% of HCV-infected recipients in the first postoperative year. Approximately 10% of HCV-infected recipients will die or lose their allograft secondary to hepatitis C-associated allograft failure in the medium term. HCV-infected recipients who undergo retransplantation experience 5-year patient and graft survival rates that are similar to recipients undergoing retransplantation who are not HCV-infected. While the choice of calcineurin inhibitor or the use of azathioprine have not been clearly shown to affect histologic recurrence of hepatitis C or the frequency of rejection in HCV-infected recipients, cumulative exposure to corticosteroids is associated with increased mortality, higher levels of HCV viremia, and more severe histologic recurrence. In contrast to non-HCV-infected recipients, treatment for acute cellular rejection is associated with attenuated patient survival among recipients with hepatitis C. The development of steroid-resistant rejection is associated with a greater than 5-fold increased risk of mortality in HCV-infected liver transplant recipients. In lieu of large studies in a posttransplant population, therapy with pegylated IFN (+/- ribavirin) should be considered in recipients with histologically apparent recurrence of hepatitis C before total bilirubin exceeds 3 mg/dl. The role of hepatitis C immunoglobulin and new immunosuppression agents in the management of posttransplant hepatitis C infection is still evolving.     

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.     

Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation

Recurrent infection with hepatitis C virus (HCV) is almost universal following orthotopic liver transplantation although clinical severity varies. Data on 135 patients who underwent transplantation for hepatitis C cirrhosis were reviewed. We describe a progressive, severe cholestatic form of hepatitis occurring in a subgroup of patients with recurrent hepatitis C. Ten patients with severe recurrent hepatitis C were identified; 1 has died, 1 awaits retransplantation, and 8 have undergone retransplantation. All 10 developed severe progressive cholestatic hepatitis, with a mean rise in bilirubin to 24.7 mg/dL at the time of retransplantation. Histology at initial recurrence was of mild hepatitis without evidence of rejection. The failed grafts showed either cirrhosis or confluent hepatic necrosis. The onset of cholestasis preceded retransplantation by less than 5 months. Our study suggests that a minority of patients with recurrent hepatitis C after undergoing liver transplantation develop a severe progressive cholestatic hepatitis and liver failure. (Hepatology 1996 May;23(5):971-6)     

Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation

BACKGROUND AND AIMS: High-dose intravenous hepatitis B immunoglobulin (HBIG) may prevent recurrent hepatitis B virus (HBV) infection, but the cost has limited its widespread use in countries with endemic HBV infection. We report on long-term safety and efficacy of an alternative strategy of very low doses (400-800 IU/month) of intramuscular (IM) HBIG plus lamivudine. METHODS: Australian and New Zealand patients who received low-dose HBIG plus lamivudine following liver transplantation for HBV-related end-stage liver disease were studied. Prior to transplantation, patients with detectable serum HBV DNA received lamivudine 100 mg daily. Posttransplantation, all patients received lamivudine 100 mg daily plus IM HBIG 400 or 800 IU daily for 1 week then monthly thereafter. Serum HBV DNA levels were measured prior to lamivudine, at transplantation, and at 12 months posttransplantation. Serum titers of antibody to HBV surface antigen were measured at 1, 3, and 12 months posttransplantation. RESULTS: Between February 1996 and October 2004, 147 patients received low-dose HBIG plus lamivudine. Thirty-one percent were hepatitis B e antigen positive, and 85% were HBV DNA+ prior to transplantation. The median duration of pretransplantation lamivudine was 92 days (range, 1-1775). Median follow-up posttransplantation was 1860 days. Kaplan-Meier patient survival was 92% at 1 year and 88% at 5 years. The actuarial risk of HBV recurrence was 1% at 1 year and 4% at 5 years. Baseline HBV DNA titer was associated with HBV recurrence. CONCLUSION: Low-dose IM HBIG plus lamivudine provides safe and effective long-term prophylaxis against recurrent HBV at <10% the cost of the high-dose regimen.     

肝移植后乙型肝炎复发的临床与病理特点分析

目的探讨我国乙型肝炎（乙肝）相关性肝移植有效预防后,乙肝复发的临床规律、特点及与病理改变的相关性。方法回顾性分析2007年6月-20HD9年8月我院移植内科收治的16例确诊为术后乙肝复发患者的临床和病理资料。结果复发时间为术后4～48（21．2±13．2）个月。16例中有12例在服用拉米夫定8～46个月出现YMDD变异,2例肿瘤复发行化疗后乙肝复发,2例在服用拉米夫定2年停用后复发。临床类型包括：①纤维化胆汁淤积型肝炎1例,病情凶险,病死率高。②慢性肝炎15例,其中轻度慢性肝炎8例,中度慢性肝炎6例,重度慢性肝炎1例;病理诊断为轻、中度的分别有13、2例。11例临床与病理诊断相符,其中8例临床与病理均诊断为慢性肝炎轻度。4例伴BanffI-I级急性排异反应。3例伴轻度药物性肝损伤。早期抗病毒治疗后预后良好。结论肝移植后乙肝复发多发生在移植术后2年内。YMDD变异是肝移植后乙肝复发的主要原因,化疗亦易致乙肝复发。肝移植术后应长期抗病毒治疗。乙肝相关性肝移植后乙肝复发病毒载量高,临床表现及病理损害重。