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     

Prevention of hepatitis C recurrence after liver transplantation: An update

Hepatitis C related liver failure and hepatocarcinoma are the most common indications for liver transplantation in Western countries.Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation,being associated with accelerated progression to cirrhosis,graft loss and death.Graft and patient survival is reduced in liver transplant recipients with recurrent Hepatitis C virus(HCV) infection compared to HCV-negative recipients.Many variables may impact on recurrent HCV liver disease.Overall,excess immunosuppression is believed to be a key factor;however,no immunosuppressive regimen has been identified to be more beneficial or less harmful.Donor age limitations,exclusion of moderately to severely steatotic livers and minimization of ischemic times could be a potential strategy to minimize the severity of HCV disease in transplanted subjects.After transplantation,antiviral therapy based on pegylated IFN alpha with or without ribavirin is associated with far less results than that reported for immunocompetent HCV-infected patients.New findings in the field of immunotherapy and genomic medicine applied to this context are promising.     

Hepatitis C virus recurrence after liver transplantation

Cirrhosis due to hepatitis C virus (HCV) is now the most common indication of liver transplantation in Western Europe and the United States. In the absence of effective prophylaxis, recurrent HCV infection is almost inevitable. Though the natural history and intermediate term outcome of recurrent HCV are now better documented, those factors which may influence the recurrence of hepatitis and consequent progression of graft disease remain unclear. Interferon (IFN) as a sole agent for the treatment of recurrent infection has proved unsatisfactory. Early intervention with a combination of IFN and ribavirin seems promising, and this approach may prevent or delay progression of HCV related graft disease after liver transplantation.     

Treatment strategies for recurrent hepatitis C after liver transplantation

Chronic hepatitis C is a common indication for liver transplantation, accounting for 25% to 50% of all transplantation candidates in most transplant centers. Despite uncertainties regarding rates of disease progression after transplantation, a consensus is emerging that recurrent HCV infection results in liver failure in a significant although currently unmeasured proportion of patients, and that the period over which this progression occurs is shorter than in the immunocompetent population. As the disease process moves into its second decade after transplantation it can be anticipated that future morbidity and liver-related mortality will increase. Whether disease progression is accelerated by definable factors is not yet fully established, but HCV RNA levels before or soon after transplantation and aggressive immunosuppressive measures appear to influence the post-transplantation outcome. Strategies to prevent or to reduce the effect of HCV infection after liver transplantation are therefore essential. The ability to intervene in this disease is currently limited. The main obstacles are the difficulty in predicting the outcome in the individual patient and the lack of effective therapy. In contrast with hepatitis B, in which hepatitis B immune globulin has improved survival, there are no therapeutic strategies to prevent recurrent HCV infection. Neither IFN nor ribavirin, when administered as a single agent, results in sustained viral clearance. However, administration of both drugs in combination, either to prevent disease or to treat recurrence, appears promising. The inability of currently available antiviral therapy to eliminate HCV in the setting of liver transplantation suggests that indefinite treatment designed to suppress viral replication will be necessary. The feasibility of such an approach will depend on the development of drugs that reduce the histologic activity of hepatitis, improve graft and patient survival, and have side effect profiles that are acceptable to patients.     

Viral hepatitis in liver transplantation

Liver transplantation is the only alternative for patients with end-stage liver disease. Viral hepatitis B and C are among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent indication for liver transplantation. Hepatitis B virus immunoglobulin and nucleot(s)ide analogues have facilitated the management of patients with hepatitis B who have received liver transplants and resulted in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Current therapeutic approaches are far from optimal, because sustained virologic responses are only achieved in one-third of treated patients, and adverse effects are common and severe. However, the rapid development of direct-acting antivirals against hepatitis C virus will change the management of this disease and in a few years prevent graft infection with this virus.     

Hepatitis C and liver transplantation: fibrosis progression and treatment. Or how to improve management

Hepatitis C virus-related end-stage liver disease, alone or in combination with alcohol, has become the leading indication for liver transplantation in most transplant programs accounting for approximately half of transplants performed in European centers. Hepatitis C virus infection recurs virtually in every post-transplant patient. The natural history of hepatitis C after liver transplantation is variable. 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. Several factors, including those related to the virus, the host, the environment and the donor, are probably implicated in the outcome. The immune status represents the main significant variable in influencing disease severity in hepatitis C virus-infected patients; with higher HCV viral load and the significant association described between the degree of immunosuppression and disease severity. 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. Therapy is adjusted to tolerance and rescued with granulocyte colony-stimulating factor and erythropoietin for bone marrow suppression. In this article we present a comprehensive review of post-transplant hepatitis C virus infection; in particular fibrosis progression and the major challenges according to treatment.     

Hepatitis C infection in transplantation

This review emphasizes the role of HCV in the transplant setting. Prolonged HCV infection results in end-stage liver disease and as such represents a common indication for liver transplantation. Recurrence of infection is almost universal after transplantation in those with viremia before transplantation. Acquired disease is uncommon but nevertheless important, particularly in organ populations in whom screening for infection is not routine. The natural history of post-transplantation disease suggests that the effect on graft or patient survival is minor, at least during short-term follow-up. Long-term follow-up is needed, as well as more detailed study of the factors contributing to severity of post-transplantation disease. Kidney transplant recipients are commonly infected with HCV prior to transplantation. HCV infection after transplantation is associated with an increased risk of liver disease and infectious complications, but its effect on survival is still controversial. Similarly, observations in recipients of other solid organ transplants, such as heart and lung, and bone marrow patients suggest that HCV infection usually is not a major cause of mortality in the first 5 to 10 years of follow-up. Many issues still need to be addressed. The most important is the identification of factors that contribute to disease progression. Finally, effective therapies to eradicate infection and prevent disease progression are awaited.     

Liver transplantation for hepatitis C

Hepatitis C virus (HCV) infection is the leading cause of endstage liver disease in Western and Asian countries. However, after liver transplantation, HCV recurs in virtually all patients, and estimated HCV-related graft cirrhosis at 5-year follow-up is 30%. Although immunosuppression accounts for a major part of the accelerated progression of HCV in the transplant population, the best immunosuppression for recipients with HCV that could avoid such complication remains unknown at present. Combination therapy of interferon and ribavirin is thought to be the most effective for the treatment or prophylaxis of HCV infection. However, who should be treated, when treatment should be initiated, and with what agent should patients with HCV infection be treated are still unknown. The current data on HCV recurrence in patients who have received either living- or deceased-donor liver transplantation are controversial, but they are, presumably, similar. Thus, to avoid HCV recurrence in living-donor liver transplantation, we have to take approaches similar to those used for patients receiving deceased-donor liver transplantation. Based on reports from major transplant centers around the world, we consider the best strategy for liver transplantation-related HCV infection is steroid-free immunosuppression and preemptive low-dose interferon and ribavirin combination therapy. Here we describe our experience with living-donor liver transplantion for patients with hepatitis C at Osaka University. There is a need for standardizing the treatment for HCV infection. This can only be achieved through collaborative work between various liver transplant centers worldwide.     

Management of hepatitis C virus infection in liver transplantation

Because of graft reinfection and recurrence of the primary disease in the graft, patients who undergo transplantation due to cirrhosis caused by chronic hepatitis C virus (HCV) infection have a poorer long-term prognosis than non-HCV-infected transplant recipients. Apart from antiviral therapy, which can occasionally eradicate HCV infection before transplantation, there are no effective measures to prevent graft reinfection. Pre-transplantation antiviral therapy, however, is of limited applicability with currently available drugs. After liver transplantation, 2 options can be used to prevent graft loss due to HCV progression: early treatment in the first 4-6 weeks when there is still no evidence of histological injury and treatment of established HCV infection. Early antiviral therapy is limited not only by its scarce applicability but also by poor tolerability and limited effectiveness (sustained virological response in approximately 20-30% of patients). Treatment of established HCV infection, especially in patients with evidence of disease progression in biopsy, is the most cost-effective alternative with an efficacy of around 35-45% when pegylated interferon combined with ribavirin is used. Adverse effects, such as cytopenia and even induction of rejection, are the main limitation and lead to premature withdrawal in 30% of patients.     

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.     

Risk factors for hepatitis C recurrence after liver transplantation

Summary.  Hepatitis C virus (HCV)-related end-stage liver disease is the main indication for liver transplantation performed in Europe and the United States. Recurrence of hepatitis C in the graft is universal and may lead to chronic hepatitis in most patients and to cirrhosis in 20–30% of patients within 5–10 years of transplantation. The natural history of HCV recurrence is highly variable but leads to a lower survival rate than other recurrent liver diseases. The immunosuppressed status and several other factors have been linked with the pattern and severity of recurrence. What remains controversial are those factors associated with fibrosis progression and how these could be modified to improve outcome of recurrent hepatitis C. No single factor but a combination of several factors is associated with fibrosis progression on the graft. The major factors associated with accelerated disease recurrence include: high viral load pre- (>10⁶ IU / mL) and / or early post-transplantation (>10⁷ IU / mL at 4 months), donor older than 40–50 years, prolonged ischaemic time, cytomegalovirus coinfection, over immunosuppression and / or abrupt changes in immunosuppression, HIV coinfection, infection by genotype 1b. Cautious follow-up of the pathology of the graft is mandatory including routine biopsies and / or noninvasive monitoring of fibrosis.     

Treatment of hepatitis C in potential kidney and heart transplant patients

Hepatitis C virus (HCV) is common in certain solid organ transplant recipients, most notably in those undergoing liver or kidney transplantation. Infection typically antedates transplantation but may have been acquired at the time of transplantation via infected blood products or organs. A more rapid and aggressive course of HCV-related infection and liver disease is the major concern in organ transplant recipients compared with immunocompetent patients. HCV-related liver disease is an important cause of morbidity and mortality in patients with end-stage renal disease treated by dialysis or transplantation. The outcome of HCV infection in renal and liver transplant recipients has been extensively investigated, whereas literature on HCV-related liver disease among patients with orthotopic heart transplantation is scanty. This article reviews the literature concerning the treatment of HCV-related liver disease in renal and orthotopic heart transplantation.     

Natural History and Treatment of Hepatitis C in Liver Transplant Recipients

Hepatitis C is not cured with liver transplantation. Patients with hepatitis C virus (HCV) infection have reduced graft and patient survivals compared with non-HCV patients following liver transplantation. Both HCV recurrence and fibrosis are accelerated under the influence of transplantation and immunosuppression. Antiviral therapy has been shown to reduce fibrosis progression and graft loss. The goal of therapy is sustained virologic response and reduction of damage. However, the optimal timing and treatment regimen for patients with HCV following transplant is unclear. Following transplant, sustained virologic response rates are reduced and patient tolerance is limited. Improved treatment strategies are needed to reduce patient side effects and increase efficacy in this population of patients.     

Aspects of hepatitis C virus infection relating to liver transplantation

End-stage liver disease caused by the hepatitis C virus (HCV) is a major indication for liver transplantation. HCV re-infection after transplantation is almost constant, and recent data confirm that it significantly impairs patient and graft survival. Factors that may influence disease severity and consequent progression of HCV graft injury remain unclear. Chronic HCV infection develops in 75-90% of patients, and 5-30% ultimately progress to cirrhosis within 5 years. Pre-transplantation antiviral treatment is not easily related to poor tolerance. Attempts to administer prophylactic post-transplantation antiviral treatment are under evaluation but are limited by the side-effects of antiviral drugs. Treatment of established graft lesions with interferon or ribavirin as single agents has been disappointing. Combination therapy gave promising results, with sustained virological response in 25-35% of patients, but indications, modality and duration of treatment should be assessed.     

Liver disease after bone marrow transplantation.

Liver dysfunction occurs after bone marrow transplantation but the relative importance of graft versus host disease and other factors, such as infection, radiation, and drugs, has not been clearly established. We have studied liver status before and after bone marrow transplantation in 43 consecutive patients and have related this to survival and factors that are recognised to cause liver injury. Minor abnormalities of liver tests occurred in 21% of patients before grafting but this did not influence survival or the development of liver disease after transplantation. During the first 50 days after grafting, 83% of patients had abnormal liver tests which were more severe in patients who subsequently died. Alanine transaminase was significantly higher in non-survivors and appeared to predict survival early after transplantation. Only non-survivors developed clinical signs of liver disease. Severe liver disease was always associated with graft versus host disease and atypia of the small bile ducts was the most useful histological marker of hepatic involvement with this disease. Two of the patients with hepatic graft versus host disease also has hepatic veno-occlusive disease and three fatalities had opportunistic infection of the liver, although, in the latter, death was not due primarily to liver dysfunction. Previous hepatitis and androgen therapy could not be implicated as important causes of hepatic damage but chemotherapy for acute leukaemia and conditioning regimens for bone marrow transplantation appear to be the most important factors in the development of hepatic veno-occlusive disease.     

Viral hepatitis and liver transplantation

Hepatitis C is the one of the most common indications for liver transplantation. Infection of the allograft after transplantation is universal, and recurrent hepatitis C progresses at an accelerated rate. Antiviral therapy in selected patients on the transplant waiting list may reduce the rate of hepatitis C virus reinfection. Preemptive antiviral therapy after transplantation has been disappointing. However, treatment of established histological disease with a combination of pegylated interferon and ribavirin is associated with sustained virologic response rates of 25 to 40%. Significant advances have been made in the prevention of hepatitis B reinfection after transplantation. Results are now excellent, with graft infection rates less than 10%. The challenges for the future include designing strategies to optimize the use of antiviral agents to prevent the need for transplantation and to avoid antiviral resistance and to determine the dose and duration of hepatitis B immunoglobulin needed in the era of multiple nucleoside analogs.     

Intestinal transplantation in The Netherlands: first experience and future perspectives

Intestinal transplantation for intestinal failure is no longer an experimental procedure, but an accepted treatment for patients who fail total parenteral nutrition (TPN) therapy. Early referral for evaluation for small bowel transplantation has to be considered in patients with permanent intestinal failure who have occlusion of more than two major veins, frequent line-related septic episodes, impairment of liver function or an unacceptable quality of life. With the increased experience in post-transplant patient care and newer forms of induction (thymoglobulin, IL-2 receptor antagonists) and maintenance (tacrolimus) therapies the 1-year graft survival has increased to 65% for isolated and to 59% for liver/small bowel transplantation, and is further improving. Rejection, bacterial, fungal and viral (CMV, EBV) infection, post-transplant lymphoproliferative disease (PTLD) and graft versus host disease (GvHD) are the most common complications after intestinal transplantation. Although most of the long-term survivors are TPN-independent and have a good quality of life, the risk of the procedure and long-term adverse effects of immunosuppressive medication limits small bowel, or liver/small bowel transplantation only to patients with severe complications of TPN therapy.     

Hepatitis B and C and renal failure

Hepatitis C is the most common cause of liver disease in the dialysis patient. The prevalence of chronic hepatitis C determined by anti-HCV testing in this population ranges from 6% to 38%. Using second generation EIA assays, the prevalence of anti-HCV among patients participating in the 1997 National Surveillance of Dialysis Associated Diseases in the United States was 9.3%. Polymerase chain reaction testing for HCV RNA has shown that the prevalence of HCV infection can be as high as 20% to 30% of dialysis patients. The causes and source of infection in patients with chronic renal failure on hemodialysis are multiple. Before the introduction of routine screening of blood donors for anti-HCV, blood transfusions were an important risk factor for acquisition of hepatitis C. Other potential sources of infection include exposure to contaminated equipment and nosocomial routes such as patient-to-patient exposure. The risk of infection appears to correlate with the duration of hemodialysis and the number of transfusions. Interestingly, dialysate and buffers have been shown to be virus free even when used in hepatitis C infected patients. The natural history of chronic hepatitis C infection in patients with renal failure is not well characterized. Although persistent elevations in ALT levels occur in 12% to 50% of dialysis patients, the frequency of persistently normal ALT levels in HCV-infected dialysis patients appears to be higher than in HCV-infected patients without renal failure. Overt liver disease and liver failure rarely occur. The degree of inflammation in liver biopsies of renal failure patients is usually mild. Thus, progressive liver disease may be less common in patients with advanced renal disease but further studies are required to assess the true impact of hepatitis C infection in this high risk population. The impact of hepatitis C infection on morbidity and mortality of patients with end-stage renal disease remains poorly defined. Initial studies have failed to show a significant increase in mortality among HCV-infected hemodialysis or renal transplant patients within the first 5 years following transplantation. In contrast, recent studies with extended follow-up of renal transplant recipients suggest that hepatitis C infection may affect patient and graft survival during the second decade. Further studies are required to identify the mechanisms of infection of patients with end-stage renal disease and to define better treatment strategies for these patients before and after kidney transplantation.     

Recurrence of diseases following orthotopic liver transplantation

Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disese recurrence.