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 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.     

Hepatitis C virus and liver transplantation

Hepatitis C virus (HCV) infection is the most common indication for liver transplantation in North America and Europe. While hepatitis C recurrence is common after transplantation, 5-year graft and patient survival in HCV-infected patients are similar to those of patients transplanted for other chronic liver diseases. With longer periods of follow-up, the proportion of patients with fibrosis or cirrhosis increases and graft loss does occur because of recurrent disease. Both viral and host factors have been linked to risk of disease progression. Specific therapies to eradicate infection or slow down disease progression are under study, and the most promising results to date have been obtained with combined interferon and ribavirin.     

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.     

Current therapeutic strategies for recurrent hepatitis B virus infection after liver transplantation

Hepatitis B virus (HBV)-related liver disease is the leading indication for liver transplantation (LT) in Asia,especially in China.With the introduction of hepatitis B immunoglobulin (HBIG) and oral antiviral drugs,the recurrent HBV infection rate after LT has been evidently reduced.However,complete eradication of recurrent HBV infection after LT is almost impossible.Recurrent graft infection may lead to rapid disease progression and is a frequent cause of death within the fi rst year after LT.At present,th...     

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.     

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.     

Management of recurrent hepatitis C after liver transplantation: a concise review

Recurrent hepatitis C infection and subsequent graft failure are increasingly recognized problems after orthotopic liver transplantation. Although many prospective therapeutic, controlled trials in primary hepatitis C disease have been reported, large-scale studies are yet to be performed in patients with posttransplant recurrent hepatitis C after liver transplantation. In this review, we summarize the current literature on the therapeutic approaches for recurrent hepatitis C and discuss the results of published studies on therapy with ribavirin or interferon (IFN) alone and on combination therapy with IFN plus ribavirin. Further, we discuss results of prophylactic approaches to the problem of recurrent hepatitis C after transplant. Finally, we discuss additional aspects of anti-hepatitis C virus therapy 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.     

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.     

Outcome after orthotopic liver transplantation in five HIV-infected patients with virus hepatitis-induced cirrhosis.

BACKGROUND: We report on our experiences with orthotopic liver transplantation (OLT) in HIV-infected patients. Between July 1998 and October 2001, five HIV-infected patients underwent OLT because of virus-induced liver cirrhosis. One patient suffered from hepatitis B virus (HBV)-, three patients from hepatitis C virus (HCV)- and one patient from HCV/HBV/HDV-related cirrhosis (HDV, hepatitis D virus). The mean duration of HIV infection was 15 years. Patients were prospectively followed up with a mean duration of 25.6 months. RESULTS: Three patients died 3, 10 and 31 months after OLT, respectively, due to graft failure. The causes of graft failure were: recurrent thrombosis of the hepatic artery, HCV-associated cholestatic hepatitis and chemotherapy-induced liver damage due to Hodgkin's disease, which was diagnosed 17 months after OLT, in addition to chronic HCV disease. The two survivors show a stable liver function and non-progredient HIV infection under antiretroviral therapy 61 and 23 months after OLT, respectively. CONCLUSIONS: A medium- or even long-term survival after OLT can be achieved in HIV-infected patients without progression of HIV disease under antiretroviral therapy. However, in our study three out of five patients died due to graft failure. Therefore, prognostic criteria have to be defined for the selection of HIV-infected patients, who may benefit from OLT.     

Fulminant hepatitis B virus: Recurrence after liver transplantation in two patients also infected with hepatitis delta virus

Liver transplantation for hepatitis B virus (HBV)-related liver disease is complicated by HBV recurrence and, consequently, poor patient and graft survival. Patients transplanted for hepatitis delta virus (HDV)- related cirrhosis are reported to have a diminished incidence of HBV recurrence and improved graft survival. However, only a few reported HDV-infected patients had active HBV replicative disease before liver transplantation. In our experience, we transplanted two HDV-infected patients, both of whom had active HBV replication before liver transplantation. In one patient, hepatitis B surface antigen (HBsAg) recurred four months after transplantation. Two months later, Hepatitis Be antigen (HBeAg) and HBV-DNA became positive, and the patient died of fulminant recurrent hepatitis B and hepatitis delta. In the other patient, HBV persisted after transplantation, and 2 months later the patient required retransplantation for fulminant recurrent hepatitis B and hepatitis delta. With the second graft, the patient remained free of HBV infection for 1 year. Thereafter, the patient experienced HBV recurrence with active replication and died of fulminant hepatitis B and delta recurrence. In the first case and in the second graft of the second case, hepatitis B immunoglobulin (HBIG) immunoprophylaxis was administered in an attempt to prevent recurrence of HBV. The literature suggests that an HDV infection inhibits the replication of HBV and therefore plays a role in preventing the recurrence of HBV and improving survival. Our experience with two patients suggests that HDV infection, in the presence of active HBV replication, may not play a protective role.(Hepatology 1997 Feb;25(2):434-8)     

Prophylaxis against recurrent hepatitis B virus infection after liver transplantation

Over the past two decades, there have been significant improvements in the outcomes of liver transplantation for all indications. Liver transplantation for hepatitis B virus (HBV) infection, once considered a contraindication to transplantation, now achieves survival rates of 91% at 1 year, 81% at 5 years, and 73% at 10 years. This improvement in outcome has occurred largely with the introduction of therapies that prevent reinfection of the hepatic allograft and thus recurrent hepatitis B, cirrhosis, and graft failure. In the United States, it is estimated that 1.25 million people are chronically infected with HBV, resulting in approximately 5000 liver-related deaths and 250 liver transplantations annually. This review summarizes the important accomplishments in the successful application of liver transplantation for liver disease related to HBV infection.     

Immunosuppression, liver injury and post-transplant HCV recurrence

Hepatitis C virus (HCV) infection is a major cause for liver transplantation worldwide. Still, HCV re-infection of the graft occurs in almost all cases. Most liver transplant recipients experience episodes of graft hepatitis associated with fibrosis progression and graft failure. Clinical management of graft hepatitis can be challenging as in addition to rejection and HCV-induced hepatitis various other factors might be involved including toxic liver injury, steatohepatitis, ischaemic bile duct lesions or infections with other pathogens. Treatment options are often contradictory for different causes of graft hepatitis, and the role of distinct immunosuppressive drugs has been discussed controversially. Corticosteroids increase the infectivity of HCV by altering expression levels of entry factors and other immunosuppressive agents may have diverse effects on HCV replication and fibrosis progression. Interferon alpha-therapy of hepatitis C shows limited efficacy and tolerability in liver transplant recipients and may also cause rejection. In this review we summarize the current knowledge on mechanisms of liver injury in post-transplant hepatitis C, discuss the pros and cons of immunosuppressive agents in this specific setting and describe potential novel approaches to prevent HCV reinfection.     

Liver Transplantation for Viral Hepatitis: Current Status

Liver transplantation is now considered definitive therapy for end-stage liver disease and has been playing an increasingly important role in the management of fulminant hepatic failure. With the advent of effective immunosuppression and improved surgical techniques, high survival rates can be expected for most transplanted patients. It has become apparent, however, that transplantation for patients with viral hepatitis is associated with some unique problems because of the propensity for viral reinfection of the grafted liver. Patients with actively replicating hepatitis B viral infection pretransplantation appear to be most likely to experience clinically significant recurrent hepatitis. Recurrent hepatitis D (delta) and hepatitis C appear to be relatively less serious in the transplanted liver. Interventions to prevent or treat graft reinfection have thus far met with limited success. Further studies are needed to define more precisely which patients with viral hepatitis are likely to do poorly after liver transplantation, and to develop strategies for treating recurrent hepatitis in transplant recipients.     

Indications for liver transplantation for chronic viral hepatitis,and therapies for controlling hepatitis B virus infection before and after transplantation

The general indications for liver transplantation in hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and the issues surrounding treatment for HBV infection in the pre‐ and post‐transplant periods, are discussed. In general, transplantation is reserved for patients with end‐stage liver failure secondary to cirrhosis and a small population with acute liver failure. It is proposed that certain guidelines can be developed and that these should include any one of the following: a Child‐Pugh score ≥ 9, diuretic resistant ascites, recurrent portal hypertensive bleeding, recurrent encephalopathy, spontaneous bacterial peritonitis and the development of a small hepatocellular cancer (≤ 5 cm in diameter). Treatment for HBV infection now includes lamivudine therapy pre and post transplantation together with hepatitis B immunoglobulin. Such an approach has virtually abolished recurrence of HBV infection following liver transplantation.     

Hepatitis C virus and liver transplantation.

Advances in immunosuppressive therapy, operative techniques, and perioperative management have resulted in long-term patient survival rates approaching 90% following liver transplantation for chronic viral hepatitis. The increasing number of referrals for liver transplantation reflects the impact of chronic HCV infection as a cause of end-stage liver disease. Unlike hepatitis B, there is still no effective treatment in preventing recurrent hepatitis C after liver transplantation. The spectrum of allograft injury related to universal HCV infection recurrence ranges from no evidence of histologic injury to mild inflammation to severe disease with allograft failure in small proportion of patients. Various factors may explain these differing outcomes, including degree of pretransplantation viremia, HLA compatibility, presence of more pathogenic HCV genotypes, integrity of cellular immune response, and type of immunosuppression. Fortunately, patient survival does not seem to be affected short-term; the long-term outcome of liver transplantation for chronic hepatitis C is unclear but is likely to be decreased. Combination therapy with interferon plus ribavirin seems to be a promising treatment strategy for posttransplantation recurrent hepatitis C, and the use of pegylated interferon plus ribavirin may improve these results. Patients with moderate to severe allograft hepatitis are appropriate candidates for combination antiviral therapy. Histopathologically documented recurrent hepatitis C in liver transplant recipients is associated with impaired quality of life, inferior physical condition, and a higher incidence of depression compared with patients who did not have HCV and in those without HCV recurrence. In conclusion, it is possible that the continued improvements in antiviral therapy against HCV infection may ultimately decrease the number of patients needing liver transplantation. Suitable candidates with chronic HCV infection thus warrant treatment with pegylated interferon plus ribavirin combination therapy in the hope of decreasing disease progression. Recent studies, which require confirmation, suggest that nonresponders to standard antiviral therapy may benefit from maintenance therapy. The donor pool for patients with chronic hepatitis C and decompensated cirrhosis can be improved by using HCV-positive donors and by increasing utilization of newer surgical techniques, including adult-to-adult living-donor liver transplantation and split-liver transplantation.     

Cholestatic Hepatitis C in Immunocompromised Settings

The hepatitis C virus (HCV) is a major public health concern and a leading cause of chronic liver disease and liver transplantation. If the virus is not eradicated before liver transplantation, HCV infection recurs in almost all patients. Recurrent HCV after liver transplantation has a variable clinical course. Rarely, a severe cholestatic form of recurrent HCV can occur, better known as fibrosing cholestatic hepatitis (FCH). This type of cholestasis can lead to fibrosis and graft dysfunction in an accelerated fashion and is associated with a high morbidity and mortality. It has been described in other organ transplant recipients and patients with HIV/HCV coinfection, suggesting that an immunocompromised state is necessary to develop FCH.     

De novo autoimmune hepatitis after liver transplantation

Allograft dysfunction with clinical, serologic, and histologic features resembling autoimmune hepatitis (AIH) may develop in pediatric and adult patients who have received a liver transplant (LT) for end-stage diseases other than AIH. This condition is now known as de novo AIH, although its pathophysiology is still uncertain and whether it represents a specific type of rejection or a genuine form of AIH is under debate. The occurrence of de novo AIH seems to be unrelated to the etiology of the disease necessitating liver transplantation, but it has been correlated with antiviral treatment in cases of hepatitis C virus (HCV) infection recurring after LT. Several investigators have reported adverse outcome of de novo AIH, including graft failure, particularly in cases with late diagnosis. Prompt treatment with prednisone, with or without azathioprine (in addition to the basic immunosuppressive regimen), seems to be the best option. The histology of de novo AIH is characterized by an infiltrate rich in plasma cells with significant interface hepatitis and perivenular necro-inflammatory activity. These features are not specific for autoimmune damage; therefore, other causes of graft dysfunction must be excluded. The final diagnosis may be a challenge in patients with recurrent hepatitis C, and requires careful clinical and pathologic assessment.     

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.