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Report of the First International Liver Transplantation Society Expert Panel Consensus Conference on liver transplantation and hepatitis C
Report of the First International Liver Transplantation Society Expert Panel Consensus Conference on Liver Transplantation and Hepatitis C Russell H. Wiesner, Michael Sorrell, Federico Villamil, and the International Liver Transplantation Society Expert Panel
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epatitis C virus (HCV) is one of the leading causes of chronic liver disease worldwide. In addition, cirrhosis secondary to chronic HCV infection is the most common indication for liver transplantation throughout the world. At present in the United States, more than 16,000 patients are listed for liver transplantation on the United Network for Organ Sharing (UNOS) list, whereas approximately 5,000 liver transplantations are performed per year. In adults, 40% of liver transplantations are performed for HCV cirrhosis. Thus, the preponderance of HCV as the primary indication for liver transplantation, the reported worsening of patient and graft survival in HCV liver transplant recipients, and the growing demand for retransplantation in recipients with recurrent HCV disease has stimulated the need for an overview of the present state of the art concerning liver transplantation and HCV disease. Conference participants examined the following issues: (1) the definition of recurrent HCV disease, (2) the natural history of HCV infection after liver transplantation, (3) potential clinical predictors of adverse outcomes, (4) treatment and managerial strategies, the contribution of immunosuppression to outcome, and the role of retransplantation for recurrent HCV disease in the face of an increasing donor shortage. Consensus was reached by the conference participants by assessing current medical knowledge and personal experience, which formed the basis for the proposal of future studies thought to be important to further improve the outcome of liver transplantation for HCV liver recipients. It is important to note that as new information accrues, these assessments and recommendations inevitably will change.
What Are the Best Ways to Classify Recurrent Hepatitis C? It is recognized that recurrence of HCV infection after liver transplantation is immediate and universal, based on the presence of HCV RNA in serum and liver. However, the recurrence of HCV disease requires protocol and/or clinically indicated liver biopsies that report both grade and stage of disease.
Recurrence of HCV disease after liver transplantation occurs at various time points and shows a wide spectrum of histological findings, which may occur through different mechanisms of hepatocyte damage. This heterogeneity, based on time of recurrence and morphological pattern of damage, may be important regarding prognosis and for the selection of patients for treatment. Therefore, the standardization of definitions to define post–liver transplantation HCV recurrence is believed to be an important first step. Recurrent HCV Infection Recurrent HCV infection occurs immediately and universally in patients undergoing liver transplantation for chronic HCV disease. The diagnosis of recurrent HCV infection is based entirely on the presence of HCV RNA in serum and/or liver alone. Acute Recurrent HCV Disease Acute recurrent HCV disease usually occurs within 6 months after liver transplantation, but can occur at any time posttransplantation, and typically is associated with increasing transaminase levels. Liver biopsy, From the International Liver Transplantation Society Expert Panel on Liver Transplantation and HCV. Chairmen: Russell H. Wiesner, MD; Michael Sorrell, MD; Federico Villamil, MD; and the International Liver Transplant Society Expert Panel: Vijayan Balan, MD; Marina Berenguer, MD; Robert S. Brown, MD; Michael R. Charlton, MD; Gary I. Davis, MD; Rolland C. Dickson, MD; Gregory T. Everson, MD; Richard B. Freeman, MD; Edward J. Gane, MD; R. Mark Ghobrial, MD; Fredric Gordon, MD; Paul Kuo, MD; John R. Lake, MD; Amadeo Marcos, MD; Andrew Mason, MD; Timothy McCashland, MD; Geoffrey W. McCaughan, MD; Charles Miller, MD; James Neuberger, MD; Peter Neuhaus, MD; John J. Poterucha, MD; Jorge L. Rakela, MD; Juan Rodes, MD; Hugo R. Rosen, MD; Eugene R. Schiff, MD; Byers W. Shaw, Jr, MD; Mitchell L. Shiffman, MD; Norah Terrault, MD, MPH; James Trotter, MD; John M. Vierling, MD; William J. Wall, MD, FRCS; Teresa L. Wright, MD. Address reprint requests to the International Liver Transplantation Society, 17000 Commerce Parkway, Suite C, Mt. Laurel, NJ 08054. Telephone: 856-439-0500; FAX: 856-439-0525; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0911-0019$30.00/0 doi:10.1053/jlts.2003.50268
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required to determine the incidence and time of onset of recurrent acute hepatitis C, is characterized pathologically by a predominant pattern of lobular hepatitis, focal liver cell necrosis, acidophilic bodies, and macrovesicular fatty change. Chronic Recurrent HCV Disease Chronic recurrent HCV disease often develops after acute recurrent HCV disease and typically is characterized histologically by chronic hepatitis with variable degrees of mixed portal, periportal, and lobular inflammation with or without variable degrees of portal and/or periportal fibrosis. Severity of Recurrent HCV Disease It must be recognized that there are two distinct forms of severe HCV recurrence: chronic HCV disease and cholestatic HCV disease. Because these two entities appear to differ in pathogenesis, prognosis, and outcome, both clinical variants should be analyzed separately when reporting outcomes. Severity of chronic hepatitis C disease should be defined by grade of necroinflammation and stage of fibrosis on liver biopsy. Recurrent cholestatic HCV disease can occur as the initial manifestation of recurrent HCV disease, or less frequently, it can emerge on a background of chronic HCV disease. A definition of cholestatic HCV disease after liver transplantation should include all of the following criteria: (1) longer than 1 month posttransplantation (usually ⱕ 6 months); (2) serum bilirubin level greater than 6 mg/dL; (3) serum alkaline phosphatase and ␥-glutamyltransferase levels greater than five times the upper limits of normal; (4) characteristic histological state with ballooning of hepatocytes predominantly in the perivenular zone (not necrosis or fallout), paucity of inflammation, and variable degrees of cholangiolar proliferation without bile duct loss; (5) very high serum HCV RNA levels; and (6) absence of surgical biliary complications (normal cholangiogram) and absence of evidence for hepatic artery thrombosis. Allograft Rejection Allograft rejection may occur in the setting of pathological changes associated with recurrent HCV disease. Therefore, the distinction is not simply between allograft rejection and hepatitis C, but rather has to be made between allograft rejection with hepatitis C versus hepatitis C alone. Furthermore, histological features of the Banff criteria that define severity of allograft rejection use interface
hepatitis and bile duct damage as key parameters. However, both these histological findings can be present in recurrent chronic HCV disease. Hence, the diagnosis and severity of allograft rejection should not rely solely on Banff criteria in this setting. An accurate diagnosis of allograft rejection in the presence of HCV disease is likely to depend on the presence of endotheliitis, severe bile duct damage, and characteristics of the portal tract infiltrate (predominately mixed in allograft rejection versus mononuclear in chronic HCV disease).
What Is the Natural History of Recurrent HCV Disease? Recurrence of HCV infection after liver transplantation is immediate and universal and, in most studies, associated with a reduction in patient and graft survival in HCV-positive compared with HCV-negative liver recipients. Furthermore, the natural history of chronic HCV disease after liver transplantation often is accelerated compared with nontransplantation patients with HCV disease. Reports indicated that 20% to 40% of liver transplant recipients with recurrent HCV disease progress to allograft cirrhosis within 5 years compared with less than 5% of nontransplantation patients with chronic HCV disease. In addition, it has been shown that the median rate of fibrosis progression is between 0.3 and 0.6 stage per year in HCV-infected liver recipients compared with 0.1 to 0.2 stage per year in immune-competent HCV-infected patients. It remains unclear whether all HCV-infected liver recipients develop progressive fibrosis, whether the rate of fibrosis is constant or changes over time, and the relationship between degrees of fibrosis and immunosuppression levels. Recent estimates suggest that the median interval from liver transplantation to graft cirrhosis is approximately 9.5 years (range, 7 to 12 years) in HCV-infected liver recipients compared with 30 years (range, 20 to 35 years) in immunocompetent HCV-infected patients. Moreover, the rate of progression from cirrhosis to hepatic decompensation also is accelerated after liver transplantation. The rate of development of decompensated liver disease in HCV liver recipients with cirrhosis is greater than 40% at 1 year and greater than 60% at 3 years compared with less than 5% and 10% in immunocompetent HCV patients with cirrhosis, respectively. Similarly, the rate of progression from hepatic decompensation to death is accelerated after liver transplantation, with a 3-year survival rate less than 10% in decompensated HCV liver recipients
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compared with 60% after decompensation in immunocompetent HCV patients. Based on these findings, the consensus group made the following recommendation: because serum aminotransferase levels have poor sensitivity and specificity for assessing severity of recurrent HCV disease, all liver transplant recipients with recurrent HCV infection should undergo annual liver biopsies to determine histological progression and provide additional data on the natural history of the disease. The group particularly suggested that yearly biopsies be continued beyond 5 years posttransplantation unless cirrhosis is diagnosed. It was suggested further that long-term longitudinal histological studies be considered in patients with recurrent hepatitis C to assess the following issues: (1) incidence of cirrhosis at 10 years posttransplantation; (2) whether some transplant recipients with recurrent hepatitis C evolve without developing significant hepatic fibrosis; (3) whether the rate of fibrosis in an individual patient may change with time and is dependent on overall immunosuppression; (4) whether more recent liver transplantation for HCV infection is associated with more rapid histological progression, including an assessment of why this may occur; and (5) these studies should record immunosuppressive therapy from the time of transplantation to allow further analysis of the effects of specific immunosuppressive regimens on severity of recurrent HCV disease.
What Are the Risk Factors for Severity of HCV Recurrence? The consensus group reviewed clinical risk factors that predict severity of recurrence of posttransplantation HCV disease. Based on the consensus group’s interpretation of published data for each risk factor, the strength of association with recurrent HCV disease is classified as “established,” “controversial,” or “unknown” because of insufficient data (Table 1). Risk factors are classified further by “pretransplantation,” “posttransplantation and/or recipient,” “virological,” and “other risk factors.” Pretransplantation Factors Several pretransplantation factors associated with severity of recurrence of HCV disease are listed in Table 1. Donor age is an established risk factor for severity of HCV recurrence. As a result, under ideal circumstances, HCV-infected transplant recipients should receive organs from donors younger than 50 years, if
Table 1. Factors Associated With Increased Severity of Recurrent Hepatitis C and Patient and Graft Survival Factors Recipient-related factors Female gender Age Nonwhite race Severity of illness Donor factors Donor age Living donor Donor-recipient HLA matching Donor genetic factors Other posttransplantation factors Cold ischemia time Time to recurrence Treatment of rejection (OKT3, corticosteroids) Virological variables Genotype 1b Pretransplantation viral load Early posttransplantation viral load CMV infection
Association Established (survival) Established (survival) Established (severity, survival) Established (survival) Established (severity, survival) Unknown, insufficient data Controversial Unknown, insufficient data
Unknown, insufficient data Established (severity) Established (severity)
Controversial Established (severity) Established (severity) Established (severity)
possible. However, because of the vast number of HCV-infected patients awaiting liver transplantation, exclusion of older donors may not be feasible for many programs. Preliminary data suggest that severity of HCV recurrence in living donor liver transplantation (LDLT) in HCV-infected recipients is worse than with cadaveric donors. However, the number of HCV-infected living donor liver transplant recipients to date is very small, the posttransplantation follow-up interval is limited, and reports to date lack protocol liver biopsies. As a result, data regarding the impact of LDLT on severity of HCV recurrence were deemed inconclusive by the consensus group because of insufficient data. Additional studies are required with larger numbers of patients with longer follow-up, including protocol liver biopsies to determine the impact of living donation on severity of HCV recurrence. Data also are conflicting on the impact of donorrecipient HLA matching on severity of recurrent hepatitis C. Other important pretransplantation factors with insufficient data to determine their effect on HCV
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recurrence include the effect of donor steatosis, cold ischemia time, and donor genetic factors mediating the inflammatory response. Additional studies are necessary to clarify the role of each of these factors on HCV recurrence. Posttransplantation and/or Recipient Factors Several posttransplantation and/or recipient factors may impact on the severity of recurrent hepatitis C. Female gender is identified as a risk factor for diminished patient survival in HCV-infected liver transplant recipients. However, there are no data on gender as a risk factor for severity of recurrence of HCV. Similarly, increasing recipient age in general is a significant risk factor for decreased patient and graft survival in all liver recipients regardless of reason for transplantation, but has not been identified as a specific significant risk factor for severity of HCV recurrence. Rates of fibrosis progression and patient survival appear to be worse for non-Caucasian HCV-infected liver recipients compared with Caucasian transplant recipients. The basis for these findings is not known and could include increased severity of recurrence, access to medical care, or other unidentified factors. Pretransplantation severity of illness, measured by a Child-Pugh score higher than 10 and UNOS status, is a risk factor for patient and graft loss independent of severity of HCV recurrence. Another recipient variable that potentially could have a negative impact on outcome is previous interferon treatment in HCV-infected liver recipients, although currently, data are inconclusive. Other established posttransplantation factors associated with increased severity of hepatitis recurrence include early time to recurrence and treatment of rejection with bolus intravenous corticosteroids and/or antilymphocyte preparations. Finally, cytomegalovirus (CMV) infection has been identified as an established risk factor for severity of HCV recurrence. The mechanisms of CMV infection leading to increased severity of recurrent HCV disease remain undefined. Whether CMV infection is a surrogate marker for overimmunosuppression or the inherent immunosuppressive properties of the CMV virus itself are the cause for increased severity of recurrent HCV disease remains undetermined. Virological Factors Virological factors also are potentially important determinants of severity of recurrent hepatitis C. HCV genotype in a transplant recipient remains a controversial factor for severity of HCV recurrence. European cen-
ters have reported worse outcome in transplant recipients infected with genotype 1b, but this association was not confirmed in US studies. A clear association was found between elevated pretransplantation HCV viral load and both severity of HCV recurrence and patient survival. However, there are no data directly showing that reduction in pretransplantation viral load reduces the risk for progressive hepatitis C after transplantation. Future Studies Future studies for predicting or reducing the severity of recurrent posttransplantation hepatitis C should focus on the role of reducing pretransplantation and posttransplantation viral loads. In addition, treatment of mild rejection must be weighed carefully against the potential detriments of the administration of intravenous bolus corticosteroid and antilymphocyte therapy. Finally, the impact of prophylactic therapy to prevent CMV infection must be assessed with regard to its overall impact on severity of HCV recurrence.
What Is the Role of Immunosuppression in Severity of HCV Recurrence? There is evidence from liver transplant recipients and other immunosuppressed patient populations that excess immunosuppression has a deleterious effect on outcome of HCV infection. Recent advances in immunosuppression have lead to improved outcomes after orthotopic liver transplantation in HCV-negative, but not HCV-positive, liver transplant recipients. The impact of high-dose maintenance corticosteroid therapy for the prevention of acute cellular rejection has been associated with decreased patient and graft survival in HCV-infected transplant recipients, but not non–HCV-infected transplant recipients. However, the optimal approach to tapering corticosteroid therapy (rapidly versus slowly) remains unknown. Use of OKT3 is associated with even greater rates of graft loss and mortality, but the risk versus benefit of using OKT3 to treat steroid-resistant rejection in HCV-infected transplant recipients currently is not known. Few data are available yet on the effects of polyclonal anti– T-cell preparations on recurrent hepatitis C. The use of anti-CD25 antibodies for induction immunosuppression appears to have minimal impact on severity of HCV recurrence compared with other immunosuppression regimens. With regard to calcineurin inhibitors, no significant differences in outcome have been observed in HCVinfected transplant recipients treated with tacrolimus
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versus cyclosporine-based immunosuppression. The impact of mycophenolate mofetil (MMF) on HCV recurrence also remains unclear. The effect of sirolimus on HCV recurrence has not been studied. Long-term use of triple therapy with full doses of calcineurin inhibitors, MMF, and prednisone may produce excess immunosuppression and thus be deleterious to HCV-infected liver recipients. The addition of T-cell– depleting agents has the potential to dramatically increase viral replication, which could result in progressive HCV disease. The optimal strategy therefore is to achieve a balance between prevention of acute and chronic rejection while minimizing the potential negative effects of immunosuppression on recurrent hepatitis C. Additional studies are needed to define the optimal immunosuppressive strategy in HCV-infected liver recipients.
Is There a Role for Pretransplantation Antiviral Treatment of HCV Disease? Defining the Treatment Population: Who Should be Treated? HCV cirrhosis has been the leading indication for liver transplantation worldwide. More than 5,000 patients in the United States on the liver waiting list have a primary diagnosis of hepatitis C, and more than 1,000 additional patients have HCV as a co-cause of liver disease (UNOS Transplant Registry, January 2003). Some have suggested that patients with hepatitis C on the waiting list are too sick to consider treatment. However, 93% of HCV-infected listed patients have Model for End-Stage Liver Disease (MELD) scores of 18 or less, which corresponds to a Child-Turcotte-Pugh (CTP) score of 7 or less. For example, a bilirubin level of 2.5 mg/dL with an international normalized ratio of 1.5 and creatinine level of 1.5 mg/dL corresponds to a MELD score of 18. This suggests that the majority of patients with chronic hepatitis C on the waiting list have reasonably stable hepatic function and therefore might be suitable candidates for antiviral therapy. Existing experience indicates reasonable safety and efficacy of interferon-based antiviral therapy in patients with CTP scores of 7 or less or a MELD score of 18. Conversely, one published report suggests that patients with very advanced liver disease (CTP score ⬎ 11 or MELD score ⬎ 25) may not tolerate interferon-based antiviral therapy. The committee recommended the guidelines listed in Table 2 for selection of patients with HCV cirrhosis for treatment with interferon-based therapy.
Table 2. Proposed Guidelines for Selection of Patients With HCV Cirrhosis for Interferon-Based Treatment Consider Treatment Strongly consider In select cases Treatment not advised
CTP Score
MELD Score
ⱕ7 8-11 ⬎11
ⱕ18 18-25 ⬎25
Decision to Treat Randomized controlled trials of interferon-based antiviral therapy have supported the concept of treatment of patients with stable or compensated cirrhosis. The best response rates have been reported with the use of peginterferon plus ribavirin; overall sustained virological responses (SVRs) have been reported in up to 50% of patients. Entry criteria for these trials excluded patients with clinical, biochemical, or hematologic decompensation. Patients with ascites, variceal hemorrhage, spontaneous bacterial peritonitis, or encephalopathy also were excluded from treatment. Recent experience from one US center suggests that sicker patients, even those who have a history of clinical decompensation, may benefit from treatment. In this study, 102 patients were treated with the combination of nonpegylated interferon plus ribavirin using an initially low, accelerating, dose regimen (LADR). Thirtynine percent of patients experienced clearance of HCV RNA on treatment, and 21% achieved an SVR (11% with genotype 1, 50% with genotypes 2 and 3). Although genotype was the major determinant, response to therapy also was related to the ability of achieving full-dose treatment, particularly in patients infected with genotype 1. Of patients who achieved an SVR, none relapsed after liver transplantation despite the use of high-dose immunosuppressive therapy. Data were particularly encouraging for patients with genotypes 2 and 3, and the recommendation is to strongly consider these patients for pretransplantation antiviral therapy. Conversely, the risk-benefit ratio of treating patients with genotype 1 infection remains to be defined by randomized controlled trials. Of particular importance is assessing the degree of toxicity associated with treating such patients. The committee stressed the need for close monitoring during treatment and that therapy should be administered in liver clinics affiliated with liver transplant programs. These centers should have extensive experience in the management of advanced liver dis-
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ease, hepatitis C, and complications of end-stage liver disease. Treatment Regimen Large proportions of liver transplant candidates with chronic liver disease have neutropenia, thrombocytopenia, and anemia before the institution of treatment. Use of interferon and ribavirin in this population will tend to worsen or precipitate cytopenias. Treatment-related neutropenia and thrombocytopenia may be more common and severe with pegylated compared with nonpegylated interferons. The potential benefit of greater virological response rates with pegylated interferon therapy may be counterbalanced by complications related to cytopenias. There was a general consensus that an LADR of therapy is preferred in the treatment of this patient population. Suggested starting doses were as follows: interferon alfa-2b, 1.5 million units thrice weekly; peginterferon alfa-2b, 0.5 g/kg/wk; or peginterferon alfa-2a, 90 g/wk, plus ribavirin, 600 mg/d. Patients with a creatinine clearance less than 50 mL/min should be started at a lower dose of ribavirin, 400 mg/d. Dose adjustments are made every 2 weeks. Interferon dose first is increased as tolerated to achieve full-dose treatment within 2 to 4 weeks. Ribavirin dose subsequently is increased in increments of 200 mg every 2 weeks as tolerated to achieve an estimated optimal effective dose of 10.6 mg/kg/d. Patients on this therapy require hematologic and biochemistry studies at 2-week intervals until stabilization of dose and then monthly thereafter. HCV RNA should be measured every 3 months. Patients who fail to respond to 12 weeks of treatment with at least a 2-log decrease in HCV RNA levels should have treatment discontinued. Expected duration of initial treatment after a patient achieves optimal doses of both interferon and ribavirin would be 6 months for genotypes 2 and 3 and 12 months for genotype 1; however, additional data are needed to support these timelines. The desired outcome of this therapy is an SVR. However, relapse rates in liver transplant candidates with advanced cirrhosis may be greater than those in noncirrhotic patients with HCV, particularly with genotype 1, because of the inability to achieve optimal doses of both interferon and ribavirin. If treatment is stopped and relapse occurs, one might consider reinstitution of antiviral therapy. An alternative approach could be continuation of antiviral therapy for patients with genotype 1 with on-treatment viral clearance up to the time of transplantation. The impact of such an approach needs to be further assessed.
Management of Side Effects of Treatment Interferon is associated with neutropenia, thrombocytopenia, and mild anemia, primarily because of bone marrow suppression. Ribavirin is associated with anemia caused by both hemolysis and bone marrow suppression. Development or exacerbation of cytopenia in patients with cirrhosis may increase the risk for infection, bleeding, and anemia-related fatigue, poor stamina, or exercise intolerance. Two strategies have been used to control these side effects: dose reduction or use of hematologic growth factors (granulocyte colony-stimulating factor and erythropoietin analogues). The value of either granulocyte colony-stimulating factor or erythropoietin in preventing complications or enhancing virological response is unknown. However, the alternative strategy, dose reduction, has the potential to compromise the primary objective of achieving the greatest rate of virological response. The extent to which dose reductions compromise response and the relative importance of interferon plus ribavirin dose reductions affecting an SVR remain under evaluation. Because of this uncertainty, use of growth factors was favored by the consensus group over dose reduction in the management of cytopenias associated with pretransplantation patients. However, the consensus group pointed out that data concerning this dilemma are needed. Posttreatment Follow-Up of Responders Posttreatment follow-up should include the following steps: (1) evaluation of hepatitis C recurrence with HCV RNA measurements at minimum at 3 and 6 months posttreatment; reinstitution of treatment should be considered in patients who relapse, and those with an SVR beyond 6 months posttreatment should be retested at 12 months posttreatment to ensure longterm response; (2) screening for hepatocellular carcinoma should be performed for the life of the patient; and (3) monitoring for maintenance of alcohol abstinence; approximately 50% of patients with HCV cirrhosis have current or past histories of significant alcohol use, and maintenance of abstinence must be emphasized. Suggested Research Studies The consensus group believes strongly that there should be a large multicenter study using interferon in the LADR, particularly in patients with HCV genotype 1 infection. This is needed to verify previous findings and optimize response rates. The group supported the study of treatment of pre-
Report of the First ILTS Expert Panel Consensus Conference
transplantation HCV infection in the setting of LDLT. The ability to time transplantation in relation to clearance of HCV RNA is a unique advantage of LDLT and may lead to improved clinical outcomes after transplantation. In this setting, at least 12 weeks, and preferably 24 weeks, of treatment should be administered before transplantation. The population of nonresponders to interferon plus ribavirin therapy is heterogeneous. Some partially respond and show a greater than 1-log reduction in HCV RNA levels, whereas others fail to suppress HCV RNA at all. The existing literature suggests that lower HCV RNA levels before transplantation may be associated with less severe recurrence. Two US trials, HALT-C and COPILOT, and a European trial are examining the effectiveness of maintenance therapy in nonresponders in immune-competent HCV-infected individuals. Neither will address the question of such therapy for posttransplantation recurrence. A study of low-dose maintenance interferon therapy in modifying the severity of posttransplantation recurrent HCV disease should be considered. In such a study, the impact of maintenance therapy on fibrogenesis must be assessed. There also was a concern that pretransplantation antiviral therapy might select host and viral resistance factors that may adversely affect the posttransplantation course of allograft infection. Studies to examine these potentially deleterious effects should be considered.
Is There a Role for Prophylactic and Preemptive Therapy to Prevent HCV Recurrence After Liver Transplantation? Prophylaxis of HCV Recurrence Limited data are available regarding the efficacy of hepatitis C immunoglobulin (HCIg) preparations to prevent recurrence of HCV infection. HCIg was ineffective in a Canadian study; however, two additional trials using different preparations of HCIg are ongoing at this time. Based on available data, the group concluded that there is no clear role for prophylactic therapy with HCIg at this time, pending the evaluation of ongoing studies. Preemptive Antiviral Therapy To date, no study has compared preemptive therapy with treatment of established recurrent HCV disease. In addition, there are no data to suggest that treatment
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during acute recurrent HCV disease influences the natural history of the disease. Although limited data are available concerning the efficacy of specific therapies, combined interferon and ribavirin treatment appears to be superior to interferon monotherapy. However, early use of interferon and ribavirin combination therapy seems to be associated with increased toxicity. Based on available information, the committee made the following recommendations: 1. Preemptive therapy should be considered in patients who undergo retransplantation for rapidly progressive recurrent hepatitis C and HCV-negative transplant recipients who receive organs from HCV-positive donors because of great clinical need. However, demonstration of efficacy is lacking at this time. 2. When preemptive therapy is used, the following factors should be considered: stability of clinical condition (not in the intensive care unit), satisfactory renal function, adequate hematologic parameters, and no contraindications to interferon or ribavirin therapy, and the end point for discontinuation of therapy should be defined. It is important to consider that in many circumstances, adverse events associated with treatment outweigh the theoretical benefits of preemptive therapy. 3. Extreme caution is advised in using preemptive therapy for liver transplant recipients who receive another organ, such as a kidney or heart, because of the reported increase in incidence of rejection. The consensus panel concluded that based on available data, the role for prophylactic and preemptive antiviral therapy remains to be defined, and should be used only in unusual circumstances. Future recommendation. A future recommendation is to compare results of preemptive antiviral therapy with treatment of established disease with regard to longterm benefits.
Should Patients With Recurrent HCV Disease Be Treated With Interferon and Ribavirin? A number of recent reports have shown that combination therapy with standard interferon and ribavirin is associated with an SVR rate of 20% to 30% in liver recipients with recurrent HCV disease. However, most of these studies are single-center reports and uncontrolled. Furthermore, there appears to be significant variability in patient selection and immunosuppressive approach, making interpretation of these studies difficult.
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Nevertheless, the SVR rate is far less than that reported for immunocompetent HCV-infected patients and the toxicity is greater, leading to more frequent dose reductions and discontinuation of therapy. Interferon-induced rejection, a concern that resulted from experience in renal transplant recipients, seems to occur uncommonly. It is evident that there are many unknowns with regard to the treatment of post–liver transplantation HCV disease, including: (1) optimal timing of treatment, (2) optimal treatment regimen, (3) duration of therapy, and (4) optimal immunosuppression regimen. Furthermore, there remains substantial uncertainty regarding the risk-benefit ratio of treating patients after liver transplantation. Therefore, the group reached a consensus that it would be appropriate to use an observation or control arm in prospective studies evaluating the treatment of recurrent HCV disease. There also remains uncertainty regarding the optimal dosing of interferon and ribavirin because renal dysfunction commonly is related to calcineurin therapy and renal dysfunction increases ribavirin toxicity. In view of the multiple unknowns concerning the natural history of recurrent HCV disease, two approaches to treatment were suggested. One approach is to intervene with the first evidence of acute allograft injury (acute recurrent HCV disease), which typically occurs in the first 6 months posttransplantation and usually is associated with a significant increase in serum alanine aminotransferase and HCV RNA levels. The second approach is to initiate antiviral therapy when the patient has histological evidence of established liver disease, with inflammation and/or fibrosis of the graft. Because disease progression from these two time points may differ, it is attractive to examine prospectively the risks and benefits of treatment in both patients with acute recurrent HCV disease and those with established chronic HCV disease with fibrosis. Finally, the consensus group addressed the potential benefits of long-term maintenance therapy in patients with recurrent HCV disease. It was agreed that there were no data to recommend maintenance therapy as an approach, and additional information regarding the potential relationship between biochemical, virological, and histologic end points would be valuable in designing control trials to address this issue. Although no firm recommendations can be made based on data, there are enough anecdotal and singlecenter reports that suggest that a patient with recurrent HCV disease who has grade II fibrosis or higher should be given a trial of combination therapy with interferon
and ribavirin. Although safety and toxicity data are available with the use of standard interferon and ribavirin, more data are needed with regard to the use of pegylated interferon in the post–liver transplantation setting.
What Is the Role of Retransplantation in Patients With Recurrent HCV Disease? The growing cohort of patients with end-stage liver disease secondary to recurrent HCV disease in the present era of increasing donor shortage has led to reexamination of the wisdom of retransplantation for recurrent HCV infection. In the absence of totally effective antiviral therapy and based on the present available evidence, the consensus group made the following recommendations: 1. It is reasonable to consider that some patients with recurrent HCV disease will benefit from repeat liver grafting. 2. Variables associated with the worst outcomes include serum bilirubin level of 10 mg/dL or greater, serum creatinine level of 2.0 mg/dL or greater, creatinine clearance less than 40 mL/min, recipient age older than 55 years, early HVC recurrence with the development of cirrhosis at less than 1 year, and donor age older than 40 years. 3. Selection for retransplantation should be made before the development of decompensation. When decompensation is present, a 1-year mortality rate of 50% can be expected. 4. The presence of cholestatic HCV disease should preclude retransplantation. 5. Additional transplantation beyond the second graft for recurrent hepatitis should be discouraged, except under the most unusual circumstances. 6. There are minimal data concerning the role of retransplantation in living donor transplant recipients with recurrent HCV disease. No consensus could be reached about the advisability of retransplantation in these patients at this time. 7. When retransplantation for recurrent HCV is anticipated, a target 1-year survival rate of at least 60% should be achievable at the time of listing. This recommendation is based on the lowest acceptable 1-year survival for primary liver transplantation, i.e., fulminant liver failure and primary liver cancer. Recommendation for future studies. Present survival models using clinical risk factors to predict survival need to be validated to more accurately predict survival after retransplantation for recurrent HCV disease.
Report of the First ILTS Expert Panel Consensus Conference
Should HCV-Infected Grafts Be Used in Liver Transplantation? The increasing shortage of donor organs has prompted the use of HCV-positive donor organs in HCV-positive recipients. Based on available evidence, the following statements represent the consensus group’s opinion: 1. Liver allografts from HCV-positive donors have been used successfully in HCV-positive recipients (HCV RNA positive). Short-term patient and graft survival are similar compared with a cohort of HCV-positive patients who received an organ from an HCVnegative donor. 2. Special attention should be given to histological evaluation of the HCV-positive organ. Normal macroscopic appearance, minimal or no fibrosis, and minimal inflammatory changes should be present.
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3. HCV-positive grafts should only be used in HCV RNA–positive recipients. As a corollary, an HCV-positive allograft should not be used in a recipient who is HCV-antibody positive, but HCV RNA negative. Exceptions can be made in emergency life-saving circumstances. 4. A recipient of an organ from an HCV-positive donor should be fully informed before transplantation, and an informed consent should be obtained according to local procedures. Recommendation for future studies. HCV-positive recipients of an HCV-positive donor organ should be followed up closely. Data should be gathered concerning such issues as the influence of donor age, degree of steatosis, and overtake of donor and recipient genotype on clinical outcome.
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epatitis C virus (HCV) is one of the leading causes of chronic liver disease worldwide. In addition, cirrhosis secondary to chronic HCV infection is the most common indication for liver transplantation throughout the world. At present in the United States, more than 16,000 patients are listed for liver transplantation on the United Network for Organ Sharing (UNOS) list, whereas approximately 5,000 liver transplantations are performed per year. In adults, 40% of liver transplantations are performed for HCV cirrhosis. Thus, the preponderance of HCV as the primary indication for liver transplantation, the reported worsening of patient and graft survival in HCV liver transplant recipients, and the growing demand for retransplantation in recipients with recurrent HCV disease has stimulated the need for an overview of the present state of the art concerning liver transplantation and HCV disease. Conference participants examined the following issues: (1) the definition of recurrent HCV disease, (2) the natural history of HCV infection after liver transplantation, (3) potential clinical predictors of adverse outcomes, (4) treatment and managerial strategies, the contribution of immunosuppression to outcome, and the role of retransplantation for recurrent HCV disease in the face of an increasing donor shortage. Consensus was reached by the conference participants by assessing current medical knowledge and personal experience, which formed the basis for the proposal of future studies thought to be important to further improve the outcome of liver transplantation for HCV liver recipients. It is important to note that as new information accrues, these assessments and recommendations inevitably will change.
What Are the Best Ways to Classify Recurrent Hepatitis C? It is recognized that recurrence of HCV infection after liver transplantation is immediate and universal, based on the presence of HCV RNA in serum and liver. However, the recurrence of HCV disease requires protocol and/or clinically indicated liver biopsies that report both grade and stage of disease.
Recurrence of HCV disease after liver transplantation occurs at various time points and shows a wide spectrum of histological findings, which may occur through different mechanisms of hepatocyte damage. This heterogeneity, based on time of recurrence and morphological pattern of damage, may be important regarding prognosis and for the selection of patients for treatment. Therefore, the standardization of definitions to define post–liver transplantation HCV recurrence is believed to be an important first step. Recurrent HCV Infection Recurrent HCV infection occurs immediately and universally in patients undergoing liver transplantation for chronic HCV disease. The diagnosis of recurrent HCV infection is based entirely on the presence of HCV RNA in serum and/or liver alone. Acute Recurrent HCV Disease Acute recurrent HCV disease usually occurs within 6 months after liver transplantation, but can occur at any time posttransplantation, and typically is associated with increasing transaminase levels. Liver biopsy, From the International Liver Transplantation Society Expert Panel on Liver Transplantation and HCV. Chairmen: Russell H. Wiesner, MD; Michael Sorrell, MD; Federico Villamil, MD; and the International Liver Transplant Society Expert Panel: Vijayan Balan, MD; Marina Berenguer, MD; Robert S. Brown, MD; Michael R. Charlton, MD; Gary I. Davis, MD; Rolland C. Dickson, MD; Gregory T. Everson, MD; Richard B. Freeman, MD; Edward J. Gane, MD; R. Mark Ghobrial, MD; Fredric Gordon, MD; Paul Kuo, MD; John R. Lake, MD; Amadeo Marcos, MD; Andrew Mason, MD; Timothy McCashland, MD; Geoffrey W. McCaughan, MD; Charles Miller, MD; James Neuberger, MD; Peter Neuhaus, MD; John J. Poterucha, MD; Jorge L. Rakela, MD; Juan Rodes, MD; Hugo R. Rosen, MD; Eugene R. Schiff, MD; Byers W. Shaw, Jr, MD; Mitchell L. Shiffman, MD; Norah Terrault, MD, MPH; James Trotter, MD; John M. Vierling, MD; William J. Wall, MD, FRCS; Teresa L. Wright, MD. Address reprint requests to the International Liver Transplantation Society, 17000 Commerce Parkway, Suite C, Mt. Laurel, NJ 08054. Telephone: 856-439-0500; FAX: 856-439-0525; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0911-0019$30.00/0 doi:10.1053/jlts.2003.50268
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required to determine the incidence and time of onset of recurrent acute hepatitis C, is characterized pathologically by a predominant pattern of lobular hepatitis, focal liver cell necrosis, acidophilic bodies, and macrovesicular fatty change. Chronic Recurrent HCV Disease Chronic recurrent HCV disease often develops after acute recurrent HCV disease and typically is characterized histologically by chronic hepatitis with variable degrees of mixed portal, periportal, and lobular inflammation with or without variable degrees of portal and/or periportal fibrosis. Severity of Recurrent HCV Disease It must be recognized that there are two distinct forms of severe HCV recurrence: chronic HCV disease and cholestatic HCV disease. Because these two entities appear to differ in pathogenesis, prognosis, and outcome, both clinical variants should be analyzed separately when reporting outcomes. Severity of chronic hepatitis C disease should be defined by grade of necroinflammation and stage of fibrosis on liver biopsy. Recurrent cholestatic HCV disease can occur as the initial manifestation of recurrent HCV disease, or less frequently, it can emerge on a background of chronic HCV disease. A definition of cholestatic HCV disease after liver transplantation should include all of the following criteria: (1) longer than 1 month posttransplantation (usually ⱕ 6 months); (2) serum bilirubin level greater than 6 mg/dL; (3) serum alkaline phosphatase and ␥-glutamyltransferase levels greater than five times the upper limits of normal; (4) characteristic histological state with ballooning of hepatocytes predominantly in the perivenular zone (not necrosis or fallout), paucity of inflammation, and variable degrees of cholangiolar proliferation without bile duct loss; (5) very high serum HCV RNA levels; and (6) absence of surgical biliary complications (normal cholangiogram) and absence of evidence for hepatic artery thrombosis. Allograft Rejection Allograft rejection may occur in the setting of pathological changes associated with recurrent HCV disease. Therefore, the distinction is not simply between allograft rejection and hepatitis C, but rather has to be made between allograft rejection with hepatitis C versus hepatitis C alone. Furthermore, histological features of the Banff criteria that define severity of allograft rejection use interface
hepatitis and bile duct damage as key parameters. However, both these histological findings can be present in recurrent chronic HCV disease. Hence, the diagnosis and severity of allograft rejection should not rely solely on Banff criteria in this setting. An accurate diagnosis of allograft rejection in the presence of HCV disease is likely to depend on the presence of endotheliitis, severe bile duct damage, and characteristics of the portal tract infiltrate (predominately mixed in allograft rejection versus mononuclear in chronic HCV disease).
What Is the Natural History of Recurrent HCV Disease? Recurrence of HCV infection after liver transplantation is immediate and universal and, in most studies, associated with a reduction in patient and graft survival in HCV-positive compared with HCV-negative liver recipients. Furthermore, the natural history of chronic HCV disease after liver transplantation often is accelerated compared with nontransplantation patients with HCV disease. Reports indicated that 20% to 40% of liver transplant recipients with recurrent HCV disease progress to allograft cirrhosis within 5 years compared with less than 5% of nontransplantation patients with chronic HCV disease. In addition, it has been shown that the median rate of fibrosis progression is between 0.3 and 0.6 stage per year in HCV-infected liver recipients compared with 0.1 to 0.2 stage per year in immune-competent HCV-infected patients. It remains unclear whether all HCV-infected liver recipients develop progressive fibrosis, whether the rate of fibrosis is constant or changes over time, and the relationship between degrees of fibrosis and immunosuppression levels. Recent estimates suggest that the median interval from liver transplantation to graft cirrhosis is approximately 9.5 years (range, 7 to 12 years) in HCV-infected liver recipients compared with 30 years (range, 20 to 35 years) in immunocompetent HCV-infected patients. Moreover, the rate of progression from cirrhosis to hepatic decompensation also is accelerated after liver transplantation. The rate of development of decompensated liver disease in HCV liver recipients with cirrhosis is greater than 40% at 1 year and greater than 60% at 3 years compared with less than 5% and 10% in immunocompetent HCV patients with cirrhosis, respectively. Similarly, the rate of progression from hepatic decompensation to death is accelerated after liver transplantation, with a 3-year survival rate less than 10% in decompensated HCV liver recipients
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compared with 60% after decompensation in immunocompetent HCV patients. Based on these findings, the consensus group made the following recommendation: because serum aminotransferase levels have poor sensitivity and specificity for assessing severity of recurrent HCV disease, all liver transplant recipients with recurrent HCV infection should undergo annual liver biopsies to determine histological progression and provide additional data on the natural history of the disease. The group particularly suggested that yearly biopsies be continued beyond 5 years posttransplantation unless cirrhosis is diagnosed. It was suggested further that long-term longitudinal histological studies be considered in patients with recurrent hepatitis C to assess the following issues: (1) incidence of cirrhosis at 10 years posttransplantation; (2) whether some transplant recipients with recurrent hepatitis C evolve without developing significant hepatic fibrosis; (3) whether the rate of fibrosis in an individual patient may change with time and is dependent on overall immunosuppression; (4) whether more recent liver transplantation for HCV infection is associated with more rapid histological progression, including an assessment of why this may occur; and (5) these studies should record immunosuppressive therapy from the time of transplantation to allow further analysis of the effects of specific immunosuppressive regimens on severity of recurrent HCV disease.
What Are the Risk Factors for Severity of HCV Recurrence? The consensus group reviewed clinical risk factors that predict severity of recurrence of posttransplantation HCV disease. Based on the consensus group’s interpretation of published data for each risk factor, the strength of association with recurrent HCV disease is classified as “established,” “controversial,” or “unknown” because of insufficient data (Table 1). Risk factors are classified further by “pretransplantation,” “posttransplantation and/or recipient,” “virological,” and “other risk factors.” Pretransplantation Factors Several pretransplantation factors associated with severity of recurrence of HCV disease are listed in Table 1. Donor age is an established risk factor for severity of HCV recurrence. As a result, under ideal circumstances, HCV-infected transplant recipients should receive organs from donors younger than 50 years, if
Table 1. Factors Associated With Increased Severity of Recurrent Hepatitis C and Patient and Graft Survival Factors Recipient-related factors Female gender Age Nonwhite race Severity of illness Donor factors Donor age Living donor Donor-recipient HLA matching Donor genetic factors Other posttransplantation factors Cold ischemia time Time to recurrence Treatment of rejection (OKT3, corticosteroids) Virological variables Genotype 1b Pretransplantation viral load Early posttransplantation viral load CMV infection
Association Established (survival) Established (survival) Established (severity, survival) Established (survival) Established (severity, survival) Unknown, insufficient data Controversial Unknown, insufficient data
Unknown, insufficient data Established (severity) Established (severity)
Controversial Established (severity) Established (severity) Established (severity)
possible. However, because of the vast number of HCV-infected patients awaiting liver transplantation, exclusion of older donors may not be feasible for many programs. Preliminary data suggest that severity of HCV recurrence in living donor liver transplantation (LDLT) in HCV-infected recipients is worse than with cadaveric donors. However, the number of HCV-infected living donor liver transplant recipients to date is very small, the posttransplantation follow-up interval is limited, and reports to date lack protocol liver biopsies. As a result, data regarding the impact of LDLT on severity of HCV recurrence were deemed inconclusive by the consensus group because of insufficient data. Additional studies are required with larger numbers of patients with longer follow-up, including protocol liver biopsies to determine the impact of living donation on severity of HCV recurrence. Data also are conflicting on the impact of donorrecipient HLA matching on severity of recurrent hepatitis C. Other important pretransplantation factors with insufficient data to determine their effect on HCV
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recurrence include the effect of donor steatosis, cold ischemia time, and donor genetic factors mediating the inflammatory response. Additional studies are necessary to clarify the role of each of these factors on HCV recurrence. Posttransplantation and/or Recipient Factors Several posttransplantation and/or recipient factors may impact on the severity of recurrent hepatitis C. Female gender is identified as a risk factor for diminished patient survival in HCV-infected liver transplant recipients. However, there are no data on gender as a risk factor for severity of recurrence of HCV. Similarly, increasing recipient age in general is a significant risk factor for decreased patient and graft survival in all liver recipients regardless of reason for transplantation, but has not been identified as a specific significant risk factor for severity of HCV recurrence. Rates of fibrosis progression and patient survival appear to be worse for non-Caucasian HCV-infected liver recipients compared with Caucasian transplant recipients. The basis for these findings is not known and could include increased severity of recurrence, access to medical care, or other unidentified factors. Pretransplantation severity of illness, measured by a Child-Pugh score higher than 10 and UNOS status, is a risk factor for patient and graft loss independent of severity of HCV recurrence. Another recipient variable that potentially could have a negative impact on outcome is previous interferon treatment in HCV-infected liver recipients, although currently, data are inconclusive. Other established posttransplantation factors associated with increased severity of hepatitis recurrence include early time to recurrence and treatment of rejection with bolus intravenous corticosteroids and/or antilymphocyte preparations. Finally, cytomegalovirus (CMV) infection has been identified as an established risk factor for severity of HCV recurrence. The mechanisms of CMV infection leading to increased severity of recurrent HCV disease remain undefined. Whether CMV infection is a surrogate marker for overimmunosuppression or the inherent immunosuppressive properties of the CMV virus itself are the cause for increased severity of recurrent HCV disease remains undetermined. Virological Factors Virological factors also are potentially important determinants of severity of recurrent hepatitis C. HCV genotype in a transplant recipient remains a controversial factor for severity of HCV recurrence. European cen-
ters have reported worse outcome in transplant recipients infected with genotype 1b, but this association was not confirmed in US studies. A clear association was found between elevated pretransplantation HCV viral load and both severity of HCV recurrence and patient survival. However, there are no data directly showing that reduction in pretransplantation viral load reduces the risk for progressive hepatitis C after transplantation. Future Studies Future studies for predicting or reducing the severity of recurrent posttransplantation hepatitis C should focus on the role of reducing pretransplantation and posttransplantation viral loads. In addition, treatment of mild rejection must be weighed carefully against the potential detriments of the administration of intravenous bolus corticosteroid and antilymphocyte therapy. Finally, the impact of prophylactic therapy to prevent CMV infection must be assessed with regard to its overall impact on severity of HCV recurrence.
What Is the Role of Immunosuppression in Severity of HCV Recurrence? There is evidence from liver transplant recipients and other immunosuppressed patient populations that excess immunosuppression has a deleterious effect on outcome of HCV infection. Recent advances in immunosuppression have lead to improved outcomes after orthotopic liver transplantation in HCV-negative, but not HCV-positive, liver transplant recipients. The impact of high-dose maintenance corticosteroid therapy for the prevention of acute cellular rejection has been associated with decreased patient and graft survival in HCV-infected transplant recipients, but not non–HCV-infected transplant recipients. However, the optimal approach to tapering corticosteroid therapy (rapidly versus slowly) remains unknown. Use of OKT3 is associated with even greater rates of graft loss and mortality, but the risk versus benefit of using OKT3 to treat steroid-resistant rejection in HCV-infected transplant recipients currently is not known. Few data are available yet on the effects of polyclonal anti– T-cell preparations on recurrent hepatitis C. The use of anti-CD25 antibodies for induction immunosuppression appears to have minimal impact on severity of HCV recurrence compared with other immunosuppression regimens. With regard to calcineurin inhibitors, no significant differences in outcome have been observed in HCVinfected transplant recipients treated with tacrolimus
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versus cyclosporine-based immunosuppression. The impact of mycophenolate mofetil (MMF) on HCV recurrence also remains unclear. The effect of sirolimus on HCV recurrence has not been studied. Long-term use of triple therapy with full doses of calcineurin inhibitors, MMF, and prednisone may produce excess immunosuppression and thus be deleterious to HCV-infected liver recipients. The addition of T-cell– depleting agents has the potential to dramatically increase viral replication, which could result in progressive HCV disease. The optimal strategy therefore is to achieve a balance between prevention of acute and chronic rejection while minimizing the potential negative effects of immunosuppression on recurrent hepatitis C. Additional studies are needed to define the optimal immunosuppressive strategy in HCV-infected liver recipients.
Is There a Role for Pretransplantation Antiviral Treatment of HCV Disease? Defining the Treatment Population: Who Should be Treated? HCV cirrhosis has been the leading indication for liver transplantation worldwide. More than 5,000 patients in the United States on the liver waiting list have a primary diagnosis of hepatitis C, and more than 1,000 additional patients have HCV as a co-cause of liver disease (UNOS Transplant Registry, January 2003). Some have suggested that patients with hepatitis C on the waiting list are too sick to consider treatment. However, 93% of HCV-infected listed patients have Model for End-Stage Liver Disease (MELD) scores of 18 or less, which corresponds to a Child-Turcotte-Pugh (CTP) score of 7 or less. For example, a bilirubin level of 2.5 mg/dL with an international normalized ratio of 1.5 and creatinine level of 1.5 mg/dL corresponds to a MELD score of 18. This suggests that the majority of patients with chronic hepatitis C on the waiting list have reasonably stable hepatic function and therefore might be suitable candidates for antiviral therapy. Existing experience indicates reasonable safety and efficacy of interferon-based antiviral therapy in patients with CTP scores of 7 or less or a MELD score of 18. Conversely, one published report suggests that patients with very advanced liver disease (CTP score ⬎ 11 or MELD score ⬎ 25) may not tolerate interferon-based antiviral therapy. The committee recommended the guidelines listed in Table 2 for selection of patients with HCV cirrhosis for treatment with interferon-based therapy.
Table 2. Proposed Guidelines for Selection of Patients With HCV Cirrhosis for Interferon-Based Treatment Consider Treatment Strongly consider In select cases Treatment not advised
CTP Score
MELD Score
ⱕ7 8-11 ⬎11
ⱕ18 18-25 ⬎25
Decision to Treat Randomized controlled trials of interferon-based antiviral therapy have supported the concept of treatment of patients with stable or compensated cirrhosis. The best response rates have been reported with the use of peginterferon plus ribavirin; overall sustained virological responses (SVRs) have been reported in up to 50% of patients. Entry criteria for these trials excluded patients with clinical, biochemical, or hematologic decompensation. Patients with ascites, variceal hemorrhage, spontaneous bacterial peritonitis, or encephalopathy also were excluded from treatment. Recent experience from one US center suggests that sicker patients, even those who have a history of clinical decompensation, may benefit from treatment. In this study, 102 patients were treated with the combination of nonpegylated interferon plus ribavirin using an initially low, accelerating, dose regimen (LADR). Thirtynine percent of patients experienced clearance of HCV RNA on treatment, and 21% achieved an SVR (11% with genotype 1, 50% with genotypes 2 and 3). Although genotype was the major determinant, response to therapy also was related to the ability of achieving full-dose treatment, particularly in patients infected with genotype 1. Of patients who achieved an SVR, none relapsed after liver transplantation despite the use of high-dose immunosuppressive therapy. Data were particularly encouraging for patients with genotypes 2 and 3, and the recommendation is to strongly consider these patients for pretransplantation antiviral therapy. Conversely, the risk-benefit ratio of treating patients with genotype 1 infection remains to be defined by randomized controlled trials. Of particular importance is assessing the degree of toxicity associated with treating such patients. The committee stressed the need for close monitoring during treatment and that therapy should be administered in liver clinics affiliated with liver transplant programs. These centers should have extensive experience in the management of advanced liver dis-
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ease, hepatitis C, and complications of end-stage liver disease. Treatment Regimen Large proportions of liver transplant candidates with chronic liver disease have neutropenia, thrombocytopenia, and anemia before the institution of treatment. Use of interferon and ribavirin in this population will tend to worsen or precipitate cytopenias. Treatment-related neutropenia and thrombocytopenia may be more common and severe with pegylated compared with nonpegylated interferons. The potential benefit of greater virological response rates with pegylated interferon therapy may be counterbalanced by complications related to cytopenias. There was a general consensus that an LADR of therapy is preferred in the treatment of this patient population. Suggested starting doses were as follows: interferon alfa-2b, 1.5 million units thrice weekly; peginterferon alfa-2b, 0.5 g/kg/wk; or peginterferon alfa-2a, 90 g/wk, plus ribavirin, 600 mg/d. Patients with a creatinine clearance less than 50 mL/min should be started at a lower dose of ribavirin, 400 mg/d. Dose adjustments are made every 2 weeks. Interferon dose first is increased as tolerated to achieve full-dose treatment within 2 to 4 weeks. Ribavirin dose subsequently is increased in increments of 200 mg every 2 weeks as tolerated to achieve an estimated optimal effective dose of 10.6 mg/kg/d. Patients on this therapy require hematologic and biochemistry studies at 2-week intervals until stabilization of dose and then monthly thereafter. HCV RNA should be measured every 3 months. Patients who fail to respond to 12 weeks of treatment with at least a 2-log decrease in HCV RNA levels should have treatment discontinued. Expected duration of initial treatment after a patient achieves optimal doses of both interferon and ribavirin would be 6 months for genotypes 2 and 3 and 12 months for genotype 1; however, additional data are needed to support these timelines. The desired outcome of this therapy is an SVR. However, relapse rates in liver transplant candidates with advanced cirrhosis may be greater than those in noncirrhotic patients with HCV, particularly with genotype 1, because of the inability to achieve optimal doses of both interferon and ribavirin. If treatment is stopped and relapse occurs, one might consider reinstitution of antiviral therapy. An alternative approach could be continuation of antiviral therapy for patients with genotype 1 with on-treatment viral clearance up to the time of transplantation. The impact of such an approach needs to be further assessed.
Management of Side Effects of Treatment Interferon is associated with neutropenia, thrombocytopenia, and mild anemia, primarily because of bone marrow suppression. Ribavirin is associated with anemia caused by both hemolysis and bone marrow suppression. Development or exacerbation of cytopenia in patients with cirrhosis may increase the risk for infection, bleeding, and anemia-related fatigue, poor stamina, or exercise intolerance. Two strategies have been used to control these side effects: dose reduction or use of hematologic growth factors (granulocyte colony-stimulating factor and erythropoietin analogues). The value of either granulocyte colony-stimulating factor or erythropoietin in preventing complications or enhancing virological response is unknown. However, the alternative strategy, dose reduction, has the potential to compromise the primary objective of achieving the greatest rate of virological response. The extent to which dose reductions compromise response and the relative importance of interferon plus ribavirin dose reductions affecting an SVR remain under evaluation. Because of this uncertainty, use of growth factors was favored by the consensus group over dose reduction in the management of cytopenias associated with pretransplantation patients. However, the consensus group pointed out that data concerning this dilemma are needed. Posttreatment Follow-Up of Responders Posttreatment follow-up should include the following steps: (1) evaluation of hepatitis C recurrence with HCV RNA measurements at minimum at 3 and 6 months posttreatment; reinstitution of treatment should be considered in patients who relapse, and those with an SVR beyond 6 months posttreatment should be retested at 12 months posttreatment to ensure longterm response; (2) screening for hepatocellular carcinoma should be performed for the life of the patient; and (3) monitoring for maintenance of alcohol abstinence; approximately 50% of patients with HCV cirrhosis have current or past histories of significant alcohol use, and maintenance of abstinence must be emphasized. Suggested Research Studies The consensus group believes strongly that there should be a large multicenter study using interferon in the LADR, particularly in patients with HCV genotype 1 infection. This is needed to verify previous findings and optimize response rates. The group supported the study of treatment of pre-
Report of the First ILTS Expert Panel Consensus Conference
transplantation HCV infection in the setting of LDLT. The ability to time transplantation in relation to clearance of HCV RNA is a unique advantage of LDLT and may lead to improved clinical outcomes after transplantation. In this setting, at least 12 weeks, and preferably 24 weeks, of treatment should be administered before transplantation. The population of nonresponders to interferon plus ribavirin therapy is heterogeneous. Some partially respond and show a greater than 1-log reduction in HCV RNA levels, whereas others fail to suppress HCV RNA at all. The existing literature suggests that lower HCV RNA levels before transplantation may be associated with less severe recurrence. Two US trials, HALT-C and COPILOT, and a European trial are examining the effectiveness of maintenance therapy in nonresponders in immune-competent HCV-infected individuals. Neither will address the question of such therapy for posttransplantation recurrence. A study of low-dose maintenance interferon therapy in modifying the severity of posttransplantation recurrent HCV disease should be considered. In such a study, the impact of maintenance therapy on fibrogenesis must be assessed. There also was a concern that pretransplantation antiviral therapy might select host and viral resistance factors that may adversely affect the posttransplantation course of allograft infection. Studies to examine these potentially deleterious effects should be considered.
Is There a Role for Prophylactic and Preemptive Therapy to Prevent HCV Recurrence After Liver Transplantation? Prophylaxis of HCV Recurrence Limited data are available regarding the efficacy of hepatitis C immunoglobulin (HCIg) preparations to prevent recurrence of HCV infection. HCIg was ineffective in a Canadian study; however, two additional trials using different preparations of HCIg are ongoing at this time. Based on available data, the group concluded that there is no clear role for prophylactic therapy with HCIg at this time, pending the evaluation of ongoing studies. Preemptive Antiviral Therapy To date, no study has compared preemptive therapy with treatment of established recurrent HCV disease. In addition, there are no data to suggest that treatment
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during acute recurrent HCV disease influences the natural history of the disease. Although limited data are available concerning the efficacy of specific therapies, combined interferon and ribavirin treatment appears to be superior to interferon monotherapy. However, early use of interferon and ribavirin combination therapy seems to be associated with increased toxicity. Based on available information, the committee made the following recommendations: 1. Preemptive therapy should be considered in patients who undergo retransplantation for rapidly progressive recurrent hepatitis C and HCV-negative transplant recipients who receive organs from HCV-positive donors because of great clinical need. However, demonstration of efficacy is lacking at this time. 2. When preemptive therapy is used, the following factors should be considered: stability of clinical condition (not in the intensive care unit), satisfactory renal function, adequate hematologic parameters, and no contraindications to interferon or ribavirin therapy, and the end point for discontinuation of therapy should be defined. It is important to consider that in many circumstances, adverse events associated with treatment outweigh the theoretical benefits of preemptive therapy. 3. Extreme caution is advised in using preemptive therapy for liver transplant recipients who receive another organ, such as a kidney or heart, because of the reported increase in incidence of rejection. The consensus panel concluded that based on available data, the role for prophylactic and preemptive antiviral therapy remains to be defined, and should be used only in unusual circumstances. Future recommendation. A future recommendation is to compare results of preemptive antiviral therapy with treatment of established disease with regard to longterm benefits.
Should Patients With Recurrent HCV Disease Be Treated With Interferon and Ribavirin? A number of recent reports have shown that combination therapy with standard interferon and ribavirin is associated with an SVR rate of 20% to 30% in liver recipients with recurrent HCV disease. However, most of these studies are single-center reports and uncontrolled. Furthermore, there appears to be significant variability in patient selection and immunosuppressive approach, making interpretation of these studies difficult.
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Nevertheless, the SVR rate is far less than that reported for immunocompetent HCV-infected patients and the toxicity is greater, leading to more frequent dose reductions and discontinuation of therapy. Interferon-induced rejection, a concern that resulted from experience in renal transplant recipients, seems to occur uncommonly. It is evident that there are many unknowns with regard to the treatment of post–liver transplantation HCV disease, including: (1) optimal timing of treatment, (2) optimal treatment regimen, (3) duration of therapy, and (4) optimal immunosuppression regimen. Furthermore, there remains substantial uncertainty regarding the risk-benefit ratio of treating patients after liver transplantation. Therefore, the group reached a consensus that it would be appropriate to use an observation or control arm in prospective studies evaluating the treatment of recurrent HCV disease. There also remains uncertainty regarding the optimal dosing of interferon and ribavirin because renal dysfunction commonly is related to calcineurin therapy and renal dysfunction increases ribavirin toxicity. In view of the multiple unknowns concerning the natural history of recurrent HCV disease, two approaches to treatment were suggested. One approach is to intervene with the first evidence of acute allograft injury (acute recurrent HCV disease), which typically occurs in the first 6 months posttransplantation and usually is associated with a significant increase in serum alanine aminotransferase and HCV RNA levels. The second approach is to initiate antiviral therapy when the patient has histological evidence of established liver disease, with inflammation and/or fibrosis of the graft. Because disease progression from these two time points may differ, it is attractive to examine prospectively the risks and benefits of treatment in both patients with acute recurrent HCV disease and those with established chronic HCV disease with fibrosis. Finally, the consensus group addressed the potential benefits of long-term maintenance therapy in patients with recurrent HCV disease. It was agreed that there were no data to recommend maintenance therapy as an approach, and additional information regarding the potential relationship between biochemical, virological, and histologic end points would be valuable in designing control trials to address this issue. Although no firm recommendations can be made based on data, there are enough anecdotal and singlecenter reports that suggest that a patient with recurrent HCV disease who has grade II fibrosis or higher should be given a trial of combination therapy with interferon
and ribavirin. Although safety and toxicity data are available with the use of standard interferon and ribavirin, more data are needed with regard to the use of pegylated interferon in the post–liver transplantation setting.
What Is the Role of Retransplantation in Patients With Recurrent HCV Disease? The growing cohort of patients with end-stage liver disease secondary to recurrent HCV disease in the present era of increasing donor shortage has led to reexamination of the wisdom of retransplantation for recurrent HCV infection. In the absence of totally effective antiviral therapy and based on the present available evidence, the consensus group made the following recommendations: 1. It is reasonable to consider that some patients with recurrent HCV disease will benefit from repeat liver grafting. 2. Variables associated with the worst outcomes include serum bilirubin level of 10 mg/dL or greater, serum creatinine level of 2.0 mg/dL or greater, creatinine clearance less than 40 mL/min, recipient age older than 55 years, early HVC recurrence with the development of cirrhosis at less than 1 year, and donor age older than 40 years. 3. Selection for retransplantation should be made before the development of decompensation. When decompensation is present, a 1-year mortality rate of 50% can be expected. 4. The presence of cholestatic HCV disease should preclude retransplantation. 5. Additional transplantation beyond the second graft for recurrent hepatitis should be discouraged, except under the most unusual circumstances. 6. There are minimal data concerning the role of retransplantation in living donor transplant recipients with recurrent HCV disease. No consensus could be reached about the advisability of retransplantation in these patients at this time. 7. When retransplantation for recurrent HCV is anticipated, a target 1-year survival rate of at least 60% should be achievable at the time of listing. This recommendation is based on the lowest acceptable 1-year survival for primary liver transplantation, i.e., fulminant liver failure and primary liver cancer. Recommendation for future studies. Present survival models using clinical risk factors to predict survival need to be validated to more accurately predict survival after retransplantation for recurrent HCV disease.
Report of the First ILTS Expert Panel Consensus Conference
Should HCV-Infected Grafts Be Used in Liver Transplantation? The increasing shortage of donor organs has prompted the use of HCV-positive donor organs in HCV-positive recipients. Based on available evidence, the following statements represent the consensus group’s opinion: 1. Liver allografts from HCV-positive donors have been used successfully in HCV-positive recipients (HCV RNA positive). Short-term patient and graft survival are similar compared with a cohort of HCV-positive patients who received an organ from an HCVnegative donor. 2. Special attention should be given to histological evaluation of the HCV-positive organ. Normal macroscopic appearance, minimal or no fibrosis, and minimal inflammatory changes should be present.
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3. HCV-positive grafts should only be used in HCV RNA–positive recipients. As a corollary, an HCV-positive allograft should not be used in a recipient who is HCV-antibody positive, but HCV RNA negative. Exceptions can be made in emergency life-saving circumstances. 4. A recipient of an organ from an HCV-positive donor should be fully informed before transplantation, and an informed consent should be obtained according to local procedures. Recommendation for future studies. HCV-positive recipients of an HCV-positive donor organ should be followed up closely. Data should be gathered concerning such issues as the influence of donor age, degree of steatosis, and overtake of donor and recipient genotype on clinical outcome.