1Liver failure and liver cancer from chronic hepatitis C are the most common indications for liver transplantation and numbers of both are projected to double over the next 20 years.
2Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation and associated with accelerated progression to cirrhosis, graft loss and death.
3Graft and patient survival is reduced in liver transplant recipients with recurrent HCV infection compared to HCV-negative recipients.
4The natural history of chronic hepatitis C is accelerated following liver transplantation compared C, with 20% progressing to cirrhosis by 5 years. However, the rate of fibrosis progression is not uniform and may increase over time.
5The rates of progression from cirrhosis to decompensation and from decompensation to death are also accelerated following liver transplantation.
6Multiple host, donor and viral factors are associated with rapid fibrosis progression and HCV-related graft failure.
7Over the last decade, graft and patient survival rates have improved following liver transplantation for non-HCV disease but not for HCV-cirrhosis. This may reflect worsening donor quality and changes in immunosuppression strategies over recent years.
8Viral eradication by antiviral therapy prevents disease progression and improves survival.
9The severity of recurrent hepatitis C at one year post-transplant predicts subsequent progression to cirrhosis. Annual protocol biopsies are recommended to help determine need for antiviral therapy.
10The projected impact of recurrent hepatitis C on graft and patient survival can only be avoided by the development of safe and effective antiviral strategies which can both prevent initial graft infection and eradicate established hepatitis C recurrence.
Chronic hepatitis C has become the global “epidemic” of the new millennium, with an estimated 180 million people currently infected.1 However, there are encouraging epidemiologic data suggesting that the incidence of hepatitis C virus (HCV) infections is now falling: the number of notified cases of acute hepatitis C has decreased by more than 50% in both Australia and the United States over the last decade, reflecting reduced exposure risk.2, 3 Transfusion-acquired infection has been rare since the introduction of routine screening of blood donors in 1992. The incidence of intravenous drug use–associated HCV has also dropped dramatically, reflecting both reduced numbers of injecting drug users and safer injecting practices.2 Vertical transmission and immigration from countries of high prevalence (Middle East, Eastern Europe, and Southeast Asia) are expected to become increasingly important sources of new infections in the West.
Serial community surveys have demonstrated that the prevalence of chronic HCV infection has been stable in the United States since 2000.4 However, this is an aging cohort, with increasing duration of infection, progression to cirrhosis, and associated complications.5 The annual rate of both HCV-related hepatocellular carcinoma and HCV-related mortality has doubled since 1990 and is projected to double again over the next decade.6–8 HCV-related end-stage liver disease already accounts for more than 40% of adult elective liver transplants performed in Europe and North America,9 and the number of referrals for transplantation is projected to double within the next decade.10
ALG, anti-lymphocyte globulin; ALT, alanine aminotransferase; ATG, anti-thymocyte globulin; CMV, cytomegalovirus; HCV, hepatitis C virus; HHV6, human herpesvirus 6; HIV, human immunodeficiency virus; MELD, model for end-stage liver disease; mTOR, mammalian target of rapamycin; NK, natural killer; NKT, natural killer T; STAT-1, signal transducer and activator of transcription-1; STAT-C, specifically targeted antiviral therapies for hepatitis C; UNOS, United Network for Organ Sharing.
NATURAL HISTORY OF RECURRENT HEPATITIS C
Recurrent HCV infection of the allograft is universal in the anti-HCV–positive candidate who is HCV RNA–positive at the time of transplantation but is rare if HCV RNA has been eradicated prior to transplantation.11, 12
Early studies of recurrent hepatitis C following liver transplantation underestimated both the incidence and severity of recurrence because of retrospective design, small numbers, and short follow-up. Most relied on serum transaminases elevations rather than histology for the diagnosis of recurrence, despite a lack of correlation between these.13, 14 The incidence and natural history of recurrent hepatitis C can be determined accurately only through prospective, longitudinal studies with frequent serial, protocol allograft biopsies.
The graft is infected at reperfusion, and histologic features of liver injury can be demonstrated as early as 9 days post-transplant.11, 15 Most patients will develop histologic features of acute hepatitis C between 4 and 12 weeks post-transplant, which are accompanied by a steep rise in the HCV viral load.16–20 Serum transaminase and HCV RNA levels usually settle spontaneously, but spontaneous viral clearance has not been observed. A “healthy HCV carrier” state does not ensue, and histologic features of chronic hepatitis C can be demonstrated in 70% to 90% of recipients after 1 year and in 90% to 95% after 5 years.
The natural history of chronic hepatitis C is accelerated in liver transplant recipients, with 10% to 30% progressing to cirrhosis within 5 years of transplantation and more than 40% after 10 years (see Fig. 1).13, 14, 19, 21–30 Serial biopsies in patients with recurrent hepatitis C have demonstrated annual rates of fibrosis progression between 0.3 and 0.6 stages/year (score F0-F4)13, 19, 24, 25, 31–36 versus 0.1 to 0.2 stages/year in immunocompetent patients with chronic hepatitis C.21, 37, 38 The median interval from transplantation to cirrhosis is 9.5 years (7-12) versus 30 years (20-50) from infection until cirrhosis in immunocompetent patients.
The best predictor of risk of cirrhosis at 5 years is the severity of necroinflammatory activity in the allograft at 12 months post-transplant (see Fig. 2).14, 22, 25, 35 The relationship between the fibrosis stage and time elapsed since transplantation appears to be linear for the first 5 years. However, longer term longitudinal studies have observed accelerated fibrosis progression beyond 5 years.33 Therefore, protocol biopsies should be continued in all patients unless cirrhosis has been identified.
The natural history of HCV cirrhosis is also accelerated after liver transplantation. The rate of decompensation is >40% at 1 year and >70% at 3 years in liver transplant recipients with established cirrhosis39, 40 versus <5% and <10%, respectively, in immunocompetent patients.41 The rate of progression from decompensation to death is also accelerated after liver transplantation, with 3-year survival of <10% following the onset of HCV-related allograft failure39 versus >60% following decompensation in immunocompetent patients.41
CHOLESTATIC HEPATITIS C SYNDROME
A small number of patients (2%-5%) will develop severe cholestatic hepatitis C, which is characterized by serum bilirubin greater than 6 mg/dL and serum alkaline phosphatase and γ-glutamyltransferase greater than 5 times the upper limit of normal, without biliary obstruction. Typical histological features are severe hepatocyte ballooning, intrahepatic cholestasis, and biliary ductular proliferation without significant lobular inflammation or lymphoid aggregates. This syndrome is also characterized by extremely high levels of serum and intrahepatic HCV RNA, a stable quasispecies pattern, and a deviation from a T helper 1 type intrahepatic cytokine response to a T helper 2 type intrahepatic cytokine response, all of which suggest immune escape and direct cytopathic injury from HCV in this syndrome.19, 42 Despite anecdotal reports of rescue with antiviral therapy and immunosuppression reduction, most cases rapidly progress to graft failure and death within the first year after transplantation. Retransplantation for this syndrome has usually resulted in rapid recurrence and death.
RETRANSPLANTATION FOR RECURRENT HCV
Although more than 10% of patients transplanted for chronic hepatitis C will eventually develop HCV-related graft failure, few will ever undergo retransplantation. Many centers are reluctant to relist patients with graft failure from recurrent hepatitis C because of reported disappointing outcomes.43–45 Even in those who are relisted, waiting list mortality is extremely high (50%-80%) because of rapid deterioration following decompensation.39, 46 Recent series have reported outcomes following retransplantation for recurrent hepatitis C similar to those achieved for other causes of graft loss.46, 47 In the recent United Network for Organ Sharing study of 2283 retransplants, HCV infection was associated with reduced outcome only in those undergoing retransplantation between 90 and 365 days after primary transplantation. These were largely patients with cholestatic hepatitis C who were sicker than their HCV-negative counterparts at relisting, with higher MELD scores and intensive care unit status.48 Recipient age, donor age, and MELD score at relisting, but not HCV status, were independent predictors of death post-retransplant. Taken together, these reports suggest that retransplantation for recurrent hepatitis C should be considered in patients < 60 years old, with onset of graft failure later than 1 year, when renal failure is absent and the MELD score is less than 30.
PATIENT AND GRAFT SURVIVAL
The earliest studies of the outcome of transplantation for chronic hepatitis C reported posttransplant patient survival and graft survival similar to those achieved following transplantation for other chronic liver diseases.30, 49, 50 However, these were usually single-center reports limited by small numbers and short follow-up. The 2 largest single-center studies did observe a trend toward reduced survival in HCV-positive recipients beyond 5 years.14, 51 Several recent large registry analyses have reported reduced graft and patient survival in recipients with recurrent hepatitis C.29, 52–54 In the most recent United Network for Organ Sharing study, the 3-year patient survival was 78% in 7459 anti-HCV+ recipients versus 82% in 20,734 anti-HCV–negative recipients (hazard ratio, 1.14; confidence interval, 1.05-1.23; P < 0.001; see Fig. 3).52 In a large European study, 7-year graft and patient survival was 51% and 55% in 283 HCV-positive recipients versus 67% and 70%, respectively, in 239 HCV-negative recipients.27
Since 1990, graft and patient survival rates have improved steadily in HCV-negative recipients, reflecting advances in immunosuppression, organ preservation, surgical techniques, and intensive care. However, outcomes have not improved in HCV-positive recipients during this period and, in some series, have deteriorated.31, 52, 53, 55 This phenomenon has been attributed to an adverse effect of deteriorating donor quality (increasing age and steatosis) and new immunosuppressive regimens on the natural history of recurrent hepatitis C (discussed later).
More than one-third of patients transplanted for hepatitis C cirrhosis will have an associated hepatocellular carcinoma.56–58 A pretransplant diagnosis of hepatocellular carcinoma has a negative impact on posttransplant survival following transplantation for HCV cirrhosis because of mortality from tumor recurrence.57–60 In a recent large study, this corollary was also true: pretransplant HCV infection had a negative impact on posttransplant survival following transplantation for hepatocellular carcinoma because of death from both tumor recurrence and HCV-related allograft failure.61 In this multivariate analysis, HCV infection was an independent predictor of tumor recurrence, and this finding remains unexplained.
RISK FACTORS FOR SEVERE RECURRENCE
Longitudinal natural history studies have identified a number of pretransplant and posttransplant factors associated with more rapid progression to cirrhosis. These include pretransplant host and viral factors, transplant donor factors, and posttransplant factors including immunosuppression and complications of transplantation (see Table 1). Specific donor factors are discussed in the next chapter.
Table 1. Factors Associated with an Accelerated Rate of Fibrosis Progression in Patients with Recurrent Hepatitis C Infection
Abbreviations: ALG, anti-lymphocyte globulin; ALT, alanine aminotransferase; ATG, anti-thymocyte globulin; CMV, cytomegalovirus; HCV, hepatitis C virus; HHV6, human herpesvirus 6; HIV, human immunodeficiency virus; NK, natural killer; NKT, natural killer T.
A. Pretransplant factors
1. Viral factors
i. HCV genotype 1
ii. High HCV RNA level
iii. HIV coinfection
2. Host factors
i. Reduced multispecific T-cell (CD4+, CD8+) responses
ii. Reduced innate NK/NKT (CD56+) responses
B. Transplant factors
1. Year of transplant
2. Donor factors
iii. Diabetes Mellitus
C. Posttransplant factors
1. Adjuvant immunosuppression
i. Pulse corticosteroids for rejection
ii. ATG/ALG/OKT3 for rejection
2. Maintenance immunosuppression
i. Prednisone withdrawal within 1 year
ii. Azathioprine withdrawal within 1 year
3. Pattern of recurrence
i. Cholestatic hepatitis
ii. Severe inflammation/fibrosis at 1 year
iii. Persistently elevated ALT
4. Posttransplant diabetes mellitus
5. Herpesvirus infection (CMV and HHV6)
Higher HCV RNA levels in both serum and liver at the time of transplantation are associated with increased risk of progression to cirrhosis, graft loss, and death.62 Higher levels in the early posttransplant period have also been associated with more rapid progression.63 These observations have encouraged studies of early pre-emptive antiviral therapy in an attempt to delay HCV recurrence in the allograft. However, any potential benefit of early viral suppression has been outweighed by the poor tolerability of current therapies in the immediate posttransplant period.
There are conflicting reports on the relationship between viral genotype and recurrent hepatitis C infection. Genotype 1b has been associated with more severe recurrent hepatitis C in European centers14, 64–66 but not in US centers.31, 67, 68 Certainly, transatlantic differences in genotype distribution do exist: only 20% of HCV-patients with cirrhosis in the United States are infected with HCV genotype 1b versus almost 50% in Europe.69 Also, patients with genotype 1b are less likely to have been infected through injecting drug use and are older, with longer disease duration, which may confound any direct effect of genotype. Suggested putative mechanisms for genotype effects include increased antigen expression, immunogenicity, and Fas-mediated apoptosis.70–72 Of note, 2 recent studies have also observed more rapid fibrosis progression in liver transplant recipients with HCV genotype 4.54, 73
Viral Genomic Heterogeneity (Quasispecies)
Quasispecies diversity increases with the duration of chronic HCV infection and is greatest in end-stage liver disease.74 Following liver transplantation, diversity falls during the early period of maximal immunosuppression and remains low in those cases with rapidly progressive cholestatic hepatitis C.75, 76 Diversity subsequently increases in those who develop mild chronic hepatitis, reflecting increased selective pressure during maintenance immunosuppression.77
Both cytomegalovirus and human herpesvirus 6 infection have been associated with accelerated fibrosis in patients with recurrent hepatitis C.78, 79 However, eloquent studies have not demonstrated any virologic interaction between HCV and cytomegalovirus.80, 81 In the future, the widespread use of highly effective cytomegalovirus prophylaxis regimens after liver transplantation is likely to conceal any potential impact of herpesvirus reactivation on recurrent hepatitis C.
Human Leukocyte Antigen Matching
Because both major histocompatibility complex class I and class II–restricted cellular immune responses are involved in the recognition of HCV peptides, human leukocyte antigen donor/recipient matching could potentially increase liver injury from recurrent hepatitis C by facilitating host recognition of viral antigens. However, human leukocyte antigen matching could also potentially reduce HCV-related liver injury by reducing the incidence of rejection and the associated need for adjuvant immunosuppression. In a study of 125 patients with recurrent HCV infection after liver transplantation, no relationship was found between the number of class II mismatches and the severity of HCV-related graft damage.14 In 2 recent studies, however, class I and II matching increased the rate of fibrosis progression despite a reduction in the incidence of rejection.82, 83 Further larger multicenter studies are needed to confirm this finding.
In a recent large multicenter study of more than 500 HCV-positive recipients, the risk of severe hepatitis C recurrence following transplantation from a donor older than 60 years was doubled in female recipients compared to male recipients. However, this gender impact on outcome was not observed with younger donors and remains unexplained.34
Host Immune Responses
Strong multispecific CD4+ and CD8+ T-cell responses have been associated with HCV eradication in nontransplanted patients, both in self-limited acute HCV infection and after antiviral therapy, and may also provide protection against severe liver injury in patients with chronic hepatitis C. The blunting of these adaptive immune responses by immunosuppression may contribute to the universal reinfection and accelerated disease progression observed following transplantation. The detection of vigorous multispecific CD4+ T-cell responses in the early posttransplant period may predict mild graft injury and a greater response to antiviral therapy.84, 85 A recent study has also reported that a strong innate immune response (natural killer/natural killer T) prior to transplantation may also provide protection from severe graft injury following liver transplantation.86
The prevalence of cryoglobulinemia increases with the duration of HCV infection and severity of liver disease, reaching 15% to 20% in patients with end-stage liver disease and almost 30% in liver transplant recipients with recurrent hepatitis C. Clinical vasculitis (glomerulonephritis and rash) may first present following transplantation, when levels of cryoprecipitate increase secondary to both an immunosuppression-induced increase in viral replication and impaired clearance of immune complexes by the allograft. HCV-related cryoglobulinemia is associated with reduced graft survival from both more severe HCV recurrence and increased incidence of hepatic artery thrombosis.87–89
ROLE OF IMMUNOSUPPRESSION
The effects of steroids on recurrent hepatitis C appear complex. In transplant recipients without HCV infection, an episode of steroid-responsive rejection is associated with increased patient and graft survival.90 In contrast, steroid-responsive rejection is associated with reduced survival in recipients with HCV infection, and this suggests an adverse effect of corticosteroids on the natural history of recurrent hepatitis C.62 High-dose intravenous steroid therapy for acute rejection leads to an early and massive increase in the hepatitis C viremia following liver transplantation and is associated with earlier onset and more rapid progression of recurrent hepatitis C.62, 91-94 These observations suggest that steroid-sparing immunosuppressive protocols may be beneficial in patients with recurrent hepatitis C.95 To date, however, steroid-sparing protocols have failed to demonstrate any benefit.96, 97 Recent data suggest that maintaining patients on low-dose prednisone over the long term may actually protect against rapid progression of recurrent hepatitis C.98–100 The addition of azathioprine to maintenance immunosuppression therapy may also reduce this risk.95, 101 This agent exhibits potent in vitro antiviral activity against Flaviviridae, including HCV.102
The popular practices of early discontinuation of steroids and avoidance of maintenance azathioprine have been implicated in the observed worsening outcomes for HCV during the past decade.100
The impact of calcineurin inhibitors on the natural history of recurrent hepatitis C is controversial. Cyclosporine may offer two potential advantages over tacrolimus in liver transplant recipients with recurrent hepatitis C. First, cyclosporine directly suppresses HCV replication in vitro by binding to cyclophyllin B and inhibiting HCV RNA polymerase. However, this antiviral effect is weak and limited to HCV genotype 1b.103 Second, tacrolimus but not cyclosporine indirectly enhances HCV replication in vitro through inhibition of phosphorylation and nuclear translocation of STAT-1, thereby blocking interferon signaling pathways.104
However, several randomized, controlled studies of primary immunosuppression have observed no differences in graft or patient survival in HCV-positive liver transplant recipients randomized to either tacrolimus or conventional cyclosporine,105 microemulsified cyclosporine,106 or microemulsified cyclosporine with C2 monitoring.107
Induction antibody therapy (anti-thymocyte globulin, OKT3, daclizumab, or basiliximab) has little effect on recurrent hepatitis C. Adjuvant antibody therapy for steroid-resistant rejection with anti-thymocyte globulin or OKT3, however, is associated with more rapid progression to cirrhosis.91, 92, 108
mTOR inhibition has no direct effect on HCV replication. Current long-term studies will determine whether the inhibitory effects of sirolimus/everolimus on transforming growth factor β and procollagen will delay allograft fibrosis in patients with recurrent hepatitis C.
ROLE OF OTHER POSTTRANSPLANT FACTORS
Earlier onset of biochemical hepatitis and persistently elevated serum transaminases are both associated with more rapid progression to cirrhosis.13, 109, 110
The relationship between recurrent HCV infection and de novo diabetes mellitus is complex. The risk of de novo diabetes mellitus is increased in patients with recurrent HCV infection. In addition, the presence of diabetes in patients with recurrent hepatitis C is associated with more rapid fibrosis progression.111
Liver failure and hepatocellular carcinoma due to chronic hepatitis C infection are already the leading indications for liver transplantation, and the demand for transplantation is projected to double by 2020. Reinfection is universal, and the natural history of recurrent hepatitis C is accelerated, with 20% to 40% progressing to cirrhosis within 5 years. Recurrent hepatitis C is now the most common cause of graft failure in HCV-positive recipients, and management of recurrent hepatitis C has become the greatest challenge facing adult liver transplant programs.
Because serum transaminases lack sensitivity and specificity for disease severity, all transplant recipients with recurrent hepatitis C infection should undergo annual liver biopsies both to determine prognosis and to provide further data on the natural history. Biopsies should continue beyond 5 years post-transplant as the fibrosis may accelerate after this time. Those with significant fibrosis (>F1) should be considered for pegylated interferon–ribavirin combination antiviral therapy, and those with established cirrhosis should be monitored closely for signs of decompensation.
Immunosuppression is the only factor associated with severe recurrence that can be modified following reinfection of the allograft. Changes in immunosuppression protocols during the past decade may have had an adverse impact on the natural history of recurrent hepatitis C. The increasingly potent induction regimens may enhance HCV replication, whereas rapid weaning of steroids and azathioprine may precipitate rapid immune reconstitution and immune-mediated graft injury. Avoidance of adjuvant pulse steroids and antilymphocyte antibodies for acute rejection and continuation of low-dose steroids and/or azathioprine beyond 12 months would seem reasonable, but further large randomized controlled studies are needed to identify the optimal immunosuppression protocol.
Ultimately, however, the only solution to the problem of recurrent hepatitis C will be the development of safe and effective antiviral strategies, both in the peritransplant period to prevent HCV infection of the allograft and in the late posttransplant period to treat established recurrence and prevent progression to graft failure. Combination STAT-C regimens may provide such opportunities in the future.