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.     

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 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 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 hepatitis B and C following liver transplantation

Advanced liver disease from hepatitis B virus (HBV) and hepatitis C virus (HCV) is the leading indication for orthotopic liver transplantation (OLT) worldwide. Our understanding of recurrent liver disease related to HBV and HCV in the setting of OLT has evolved rapidly in the past decade. Recurrent viral hepatitis may lead to graft failure, death, or the need for retransplantation. Until about a decade ago, HBV was considered a contraindication to OLT due to its frequent recurrence and development of associated liver disease. Medical therapy with hepatitis B immune globulin and nucleoside analogues has diminished the risk of HBV recurrence and led to improvement in patient and graft survival. Consequently, OLT is now considered to be the standard of care in patients with end-stage liver disease related to HBV. HCV recurrence after OLT is almost universal. Although short-term survival in patients undergoing OLT for HCV is similar to survival for those transplanted for other indications, recurrent HCV may have an impact on long-term patient and graft survival. A specific and effective therapy has not been defined for recurrent HCV following transplantation, but the combination of interferon and ribavirin appears promising. Optimal strategies to eradicate these viruses or to slow disease progression are continually being investigated in light of the disparity between supply and demand in a diminishing organ pool for OLT candidates.     

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.     

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.     

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)     

Chronic hepatitis C and liver transplantation

Chronic hepatitis C virus (HCV) is a worldwide health problem. Approximately 4 million people in the United States are chronically infected with HCV. The incidence of infection peaked between 2 and 3 decades ago, and we are now beginning to see an increase in the complications of cirrhosis from HCV. This trend is expected to continue for another 2 to 3 decades. Survival is poor once complications of cirrhosis, such as liver failure or hepatocellular carcinoma, ensue, and liver transplantation is often the only option. Complications of chronic HCV are the most common indication for liver transplantation, accounting for more than 40% of transplants performed in the United States and Europe. HCV recurs in all patients and rapid development of hepatic fibrosis is very common. Several strategies have been proposed to reduce the risk of graft loss from recurrent HCV infection after transplantation, as the progression of the resulting liver disease is rapid. Although antiviral treatment is successful in some patients, it is extremely difficult to administer and requires dose reductions in the majority of cases. Retransplantation in the current era of the Model for End-Stage Liver Disease (MELD) system for prioritizing listing for transplant is associated with very low survival rates at a high cost. Furthermore, the system raises difficult ethical issues of utilization of limited resources and fairness to other transplant candidates.     

Recurrent hepatitis C after liver transplantation: clinical and therapeutical issues

Hepatitis C virus (HCV) reinfection after liver transplantation is almost constant, assessed by the persistence of HCV RNA in 90% of cases. Acute hepatitis appeared in 75% of patients at a median of 4 months' post-transplantation. The 5-year actuarial rate of acute and chronic hepatitis on the graft is 75% and 60%, respectively. The rate of HCV cirrhosis on the graft is variable from 8 to 25% at 5 years. After transplantation, HCV viraemia is dramatically increased and correlates with the occurrence of acute hepatitis on the graft. Intrahepatic levels of HCV are high at the time of acute hepatitis, and decrease with constitution of chronic graft hepatitis lesions, implying an immunological response to the viral infection. A relationship between genotype 1b and the prevalence of HCV hepatitis on the graft has been suggested in European but not American series. The influence of the age of the recipient, quasispecies, viral compartmentalization, immunosuppressive treatment, and of HLA matching is being evaluated. The 5-year patient survival is around 65-80%. However, the occurrence of cirrhosis with a risk of graft failure may decrease the 10 and 15-year patient survival. Attempts to give prophylactic post-transplant antiviral treatment are under evaluation. Antiviral treatment of post-transplant graft lesions with combination therapy interferon–ribavirin gave promising results but indications and duration of treatment should be evaluated.
In conclusion, HCV reinfection is frequent, but medium-term survival is good. However, the long-term graft and patient survival remains unknown, and efficient prevention and treatment of HCV graft is mandatory.     

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.     

Mild donor liver steatosis has no impact on hepatitis C virus fibrosis progression following liver transplantation.

BACKGROUND: This study examines the impact of donor liver macrovesicular steatosis on recurrence of hepatitis C virus (HCV) disease after liver transplantation. METHODS: Between 1998 and 2004, 113 patients underwent liver transplantation for HCV-related cirrhosis. Time to histologic recurrence (fibrosis score >or=2) was the primary endpoint of the study. Recurrence was graded according to the system of Ludwig and Batts. A Cox's proportional hazard regression model was used to analyse the association between donor liver steatosis and HCV recurrence. RESULTS: Recurrence-free survival for patients who received steatotic grafts was 82% and 47% at 1 and 4 years, respectively, and 81% and 52% for patients who received a non-steatotic liver. Donor macrovesicular steatosis (5-45%) was found to have no impact on HCV recurrence (P=0.47). Donor age (P=0.02) and cold ischaemia time (P=0.01) were found to increase the relative risk of HCV recurrence. The estimated risk of HCV recurrence increased by 23% for every 10-year increase in donor age. Similarly the risk of recurrence increased by 13% for every 1-h increase in cold ischaemia time. CONCLUSION: Mild-moderate donor liver macrovesicular steatosis has no impact on HCV recurrence after liver transplantation for HCV-related cirrhosis. Cold ischaemia time and donor age increased the likelihood of HCV recurrence.     

Living donor liver transplantation and hepatitis C

Preliminary results indicate that living donor liver transplantation (LDLT) recipients infected with HCV develop earlier and more severe recurrence than their cadaveric counterparts. The mechanisms underlying this observation are unknown, but could include hepatic regeneration, differences in LDLT recipient demographics, immune homology between donor and recipient, or other factors not previously considered. The optimum clinical approach is to consider LDLT in HCV-infected recipients only as a life-saving procedure and to attempt to eradicate HCV before LT to prevent recurrent infection.     

Living donor liver transplantation and hepatitis C

Preliminary results indicate that living donor liver transplantation patients infected with hepatitis C virus (HCV) develop earlier and more severe recurrence than their cadaveric counterparts. The mechanisms underlying this observation are unknown, but could include hepatic regeneration, differences in living donor liver transplantation recipient demographics, immune homology between donor and recipients, or other factors not previously considered. The optimum clinical approach is to only consider living donor liver transplantation in HCV-infected recipients as a life-saving procedure and to attempt to eradicate HCV before transplantation to prevent recurrent infection.     

Advancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C

BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequently associated with elevated markers of iron stores. Recessively inherited mutations in the HFE gene are responsible for iron accumulation in most cases of hereditary haemochromatosis and may have a role in HCV infection. They may also be associated with progressive liver fibrosis although this remains controversial. AIMS: To assess the prevalence of HFE mutations in Scottish HCV infected patients and to explore the effect of the carrier state on serum and liver iron stores, and the severity of liver disease. PATIENTS: A total of 164 patients with antibodies to HCV who underwent liver biopsy were assessed prospectively. METHODS: Each patient was screened for HFE mutations (Cys282Tyr and His63Asp). Iron markers were assessed in serum (ferritin, transferrin saturation) and on liver biopsy (stainable iron, liver iron concentration (LIC) and hepatic iron index). RESULTS: There were 67 (41%, 26 Cys282Tyr, 33 His63Asp, eight compound) heterozygotes. Forty four (28%) patients had elevated serum iron markers, 24 (15%) had stainable liver iron, and five (3%) had elevated LICs. Carriage of HFE mutations was not associated with any clinical, biochemical, virological, or pathological features, including accumulation of liver iron. Elevated serum iron markers were associated with male sex, increased alcohol consumption, and increased liver inflammation and fibrosis. Patients with elevated LICs were older, acquired HCV infection earlier, and had more liver inflammation. CONCLUSIONS: Patients with chronic HCV infection frequently have elevated serum iron markers although elevated LICs are uncommon. Elevated serum iron studies and LICs occur in patients with more severe liver disease. Carriage of HFE mutations, although frequently observed in these HCV infected patients, does not have a role in the accumulation of iron or the progression of liver disease in HCV infection.