Transplantation for Hepatitis C

Natural History of Hepatitis C Virus Infection

HCV infection is common in most developed countries; it affects 1.5% to 2% of the general population, with at least 2.7 million carriers in the United States and an estimated 170 million carriers worldwide. The natural history of this infection has been extensively evaluated. The condition is characterized by a high risk for chronic infection after viral exposure with progression to chronic hepatitis: this develops in 65% to 85% of those exposed to the virus. The progression of chronic hepatitis C is relatively slow, and the risk for developing cirrhosis ranges from 4% to 25% in infected persons over 20 to 30 years of follow-up. This risk is influenced by alcohol use, age at infection, sex, immune status, metabolic syndrome, and genetics. The prognosis of those who progress to HCV-related cirrhosis depends primarily on the development of two events, clinical decompensation (e.g., development of ascites) and hepatocellular carcinoma (HCC). Although the 10-year patient survival rate reaches 80% in the absence of these events, it drops to less than 50% once complications develop. The risk for decompensation unrelated to HCC has been estimated to be approximately 15% to 20% after 4 years of follow-up. The annual incidence of HCC in HCV-infected cirrhotic patients is estimated to be between 1.5% and 3.3%.

Indications for Liver Transplantation

Liver transplantation should be considered when the course of the disease is sufficiently advanced that medium-term (2 to 5 years) survival is unlikely without transplant. Because the prognosis of compensated HCV-related cirrhosis is good, cirrhosis per se should not be considered an indication for liver transplantation. In fact, patients with compensated cirrhosis can be successfully treated by antiviral therapy, with significant but manageable side effects. SVR often leads to disease stabilization and may even reverse cirrhosis. The risk for hepatic decompensation or HCC development diminishes significantly but does not disappear in the short term, and hence these patients should continue to be monitored periodically, including screening for HCC. An SVR can now be achieved with the use of triple therapy (PEG-IFN in combination with RBV and a protease inhibitor—telaprevir or boceprevir) in approximately 45% to 65% of patients with compensated cirrhosis; unfortunately, lower response rates are achieved in those who were previously nonresponders to antiviral therapy (14% in previous cirrhotic null responders).

Once decompensation occurs, liver transplantation is the treatment of choice. This is the case for patients with cirrhosis who have attained a Child-Turcotte-Pugh score greater than 7, Model for End-Stage Liver Disease (MELD) greater than 14, or those who have a history of spontaneous bacterial peritonitis, refractory ascites or encephalopathy, or recurrent variceal bleeding unresponsive to traditional endoscopic or radiological treatment.

The coexistence of HCC is an increasingly frequent complication of HCV-related cirrhosis. Initially the results of transplantation for HCC patients were disappointing, with high recurrence rates and dismal patient survival because of the advanced state of disease at the time of transplant. In 1996 Mazzaferro et al defined the Milan criteria (single HCC up to 5 cm; or up to three tumors, none larger than 3 cm; and without evidence of macrovascular invasion or extrahepatic spread). With these selection criteria, survival rates do not differ from those achieved by HCV-infected patients without HCC. (This topic will be covered in Chapter 15 .)

Source of Infection

The most common source of posttransplant HCV infection is pretransplantation infection. Recurrent infection, defined as the reappearance of HCV RNA in serum, is nearly universal. A rapid decrease in HCV RNA occurs immediately after removal of the infected liver, followed by an even sharper decline after implantation of the allograft, presumably representing virus uptake by the new liver. Selective HCV entry into recipient hepatocytes, early replication, and decreased clearance due to immunosuppression and major histocompatibility complex mismatching result in a “bottleneck” or decrease in viral diversity or quasispecies early after transplantation. This decline is followed by a progressive increase in serum HCV RNA levels such that pretransplantation levels are reached as soon as day 4 and increase up to tenfold to twentyfold higher 1 month after transplantation.

The virus may also be acquired from contaminated blood or donor organs. However, de novo acquisition of HCV infection has become extremely uncommon (<1% of HCV-negative recipients) as a result of routine and efficient screening for HCV in blood and organ donors.

In the current era of organ shortage and given the progressive increase in the number of HCV-infected patients in need of transplantation, some have advocated the use of organs from anti-HCV–positive donors. In these cases, viral transmission to the recipient depends primarily on the donor’s HCV RNA status. HCV RNA–positive donors invariably transmit HCV to recipients, whereas organs from anti-HCV–positive, HCV RNA–negative donors transmit infection at a much lower rate.

Definition of Viral Recurrence as Opposed to Histological Recurrence

Antibody assays for HCV are of little value after transplantation. The diagnosis of HCV reinfection should be established by testing for HCV RNA. Levels of viremia after transplantation are higher than pretransplant levels. Viral load, although not generally associated with the severity of liver disease in the nontransplant setting, may help to predict outcome in liver transplant recipients (e.g., the development of cholestatic hepatitis, progressive HCV disease) as well as to predict response and monitor therapy. In addition, viral titers generally peak at the time of acute hepatitis, a finding that may help to differentiate acute recurrent HCV hepatitis from cellular rejection. Whether higher pretransplant viremia predicts a poorer outcome after transplantation is less clear.

The diagnosis of recurrent HCV disease, in contrast to reinfection, is based on histological findings. Standard liver tests lack specificity and sensitivity in this setting and may underestimate the presence of liver damage. In particular, there is generally a poor correlation between the severity of histological disease and serum transaminase levels. Histologically, acute hepatitis typically develops between the second and fourth month after transplantation, whereas changes consistent with chronic hepatitis are usually seen after the third posttransplant month. The usual histopathological appearance and evolution of hepatitis C in liver allografts are similar to those seen in the general population, except that in allografts the acute phase shows less portal inflammation, whereas the chronic phase less often shows portal-based lymphoid aggregates, and there is more ductular type of interface activity. Early liver changes seen in the acute phase include mild lobular lymphocytic inflammation with scattered apoptotic bodies, minimal cell swelling, and steatosis. This lesion progresses within 2 to 4 weeks to a more fully developed hepatitis, with portal and lobular inflammation of varying degrees in association with hepatocyte necrosis and midzonal macrovesicular steatosis. The portal infiltrates are typically mononuclear cells but may be more mixed than in the nontransplant setting. Fatty change, bile duct injury, and patchy parenchymal lymphocytic infiltrates are also common. Fatty change alone may be an early marker of recurrence. Atypical histological findings, including marked bile duct epithelial injury, endotheliitis, profound cholestasis, bile duct proliferation, and perivenular ballooning of hepatocytes, can mimic other entities such as acute cellular rejection, obstruction, and ischemia. Exclusion of other causes such as cytomegalovirus (CMV) hepatitis, obstruction, ischemia, or drug toxicity may require serological, immunohistochemical, radiological, and endoscopic studies; drug discontinuation; or serial biopsy. Immunohistochemical and in situ methods to detect HCV antigens or HCV RNA, or both, in liver tissue have been evaluated as a means of differentiating recurrent hepatitis C from other conditions and as a predictor of disease severity. In general the results are conflicting, with relatively poor correlation with histological findings.

By 6 to 12 months after transplantation, chronic hepatitis dominates with portal and periportal changes, including chronic portal inflammation, occasional portal-based lymphoid aggregates, and necroinflammatory and ductular type of interface activity of varying severity. Focal inflammatory bile duct damage and “central perivenulitis" can be seen, but they are neither severe nor widespread, and bile duct loss is not generally a feature.

Atypical presentations of recurrent hepatitis C include cholestatic hepatitis and plasma cell–rich hepatitis. Cholestatic hepatitis is a unique and rare form of presentation (<10%) that portends a very poor prognosis. Graft failure occurs in more than half of patients within a few months of onset. Cholestatic hepatitis is likely a consequence of a direct cytopathic effect of HCV on hepatocytes due to massive viral replication in the context of a relatively inept cellular immune response against HCV. Indeed, such cases generally occur within the first year after transplant in patients overtly overimmunosuppressed. The histological findings include cholestasis, marked lobular disarray with spotty acidophilic hepatocyte necrosis and Kupffer cell hypertrophy, centrizonal hepatocyte ballooning and degeneration, and portal expansion due to prominent ductular type and fibrotic type of interface activity with mild mixed or even neutrophil-predominant portal inflammation. In 2003 the following diagnostic criteria were proposed by a consensus conference: (1) more than 1 month posttransplant (usually ≤6 months), (2) clinical cholestasis marked by striking elevations in serum alkaline phosphatase level and γ-glutamyltransferase activity (more than five times the upper limits of normal levels) and bilirubin levels (>6 mg/dL), (3) characteristic histological features, (4) high serum HCV RNA levels (generally higher than 30 to 50 million International Units/mL), and (5) absence of biliary complications (normal cholangiogram) or hepatic artery thrombosis. Unfortunately, a recent systematic review reported that only 3 of 12 studies published after 2003 used this definition, precluding accurate study of this entity.

The plasma cell variant of recurrent hepatitis C usually occurs in patients maintained on low-level immunosuppression and/or who are treated with IFN-based therapy. This entity is characterized by very low or even negative HCV RNA levels together with histopathological features that mimic those of autoimmune hepatitis (centrilobular necrosis with or without bridging necrosis and a prominent plasma cell–rich infiltrate). It remains controversial whether these cases represent a true “autoimmune” (alloimmune) process as opposed to an atypical manifestation of recurrent HCV disease, acute or chronic allograft rejection, or a combination of these entities. The differential diagnosis is, however, extremely relevant with potential risks associated with a misdiagnosis. For instance, treatment with steroids may reduce the severity of liver inflammation in cases of “autoimmunity/alloimmunity” at the expense of enhanced viral replication.

A major issue in clinical practice is distinguishing recurrent hepatitis from rejection with hepatitis, particularly at time points beyond 2 months after transplantation. However, one could argue that this dilemma has not been framed appropriately. The challenge should not be to differentiate recurrence of hepatitis C from rejection, but rather to determine whether alloimmunity is also playing a role in posttransplant hepatitis C and how it should best be treated. This issue is important because although the occurrence of acute cellular rejection does not have an important impact on long-term outcomes in HCV-negative liver recipients, this is not the case in patients who undergo liver transplantation for HCV disease. HCV-negative recipients who experience an episode of rejection have only half the mortality rate of HCV-negative recipients who do not experience an episode of rejection. By contrast, HCV-positive recipients have a threefold increased risk for death if they are treated with steroids for a single episode of rejection and more than a fivefold increased risk for death if they experience steroid-refractory acute cellular rejection. For this reason, many centers do not treat mild acute rejection, defined as Banff grade I rejection, in HCV-positive recipients, particularly when it occurs more than 2 months after transplantation. Key features suggestive of acute and chronic rejection in HCV-positive patients include (1) a mixed inflammatory infiltrate, significant bile duct injury, and/or biliary epithelial senescent changes and (2) terminal hepatic vein inflammation. Features more consistent with hepatitis C include the presence of lobular necroinflammatory activity and necroinflammatory ductular type of interface activity, features that are usually minimal or absent in acute and chronic rejection.

Natural History of Hepatitis C Virus Infection After Liver Transplantation

The natural history of recurrent HCV disease after liver transplantation ( Fig. 11-1 ) is highly heterogeneous. Besides different patterns of presentation, progression of fibrosis in those with a typical presentation is not uniform. In some patients, no or mild fibrosis progression is evident, even after several years of follow-up. In contrast, others progress rapidly to cirrhosis and allograft failure within months. In general the disease progresses more rapidly compared to the nonimmunosuppressed population, with a higher rate of yearly fibrosis progression (0.3 fibrosis units/yr [0.004 to 2.19] versus 0.2 fibrosis units/yr [0.09 to 0.8], P < .0001). As a consequence there is a shorter interval to the establishment of cirrhosis (9 to 12 years versus 20 to 30 years in immunocompetent patients). Fibrosis can progress linearly, present a delayed onset of rapid progression, or progress as a rapid increase in fibrosis during the first 3 years followed by slower progression over the long term. Interestingly, a recent non-Markov analysis based on 901 fibrosis measurements in 401 patients has shown that there is a decreasing risk for progression over time as duration in a specific fibrosis stage increases. However, a longer interval to reach that stage does not appear to predict a lower risk for further progression to a higher stage.

Based on published studies, by the fifth postoperative year, up to 30% of HCV recipients will progress to cirrhosis. ^∗

∗ References .

Once cirrhosis is established, the risk for clinical decompensation is higher (42% versus 5% to 10% in 1 year among nontransplanted patients with compensated HCV cirrhosis). Factors that predict decompensation include a Child-Turcotte-Pugh class B or C, a MELD score above 16, a serum albumin level of less than 3.4 g/dL, and a period from transplantation to a diagnosis of cirrhosis of less than 1 year. Survival after decompensation is less than 10% at 3 years, compared to 60% in nontransplanted patients.

Recent data have shown that the risk for severe HCV disease after transplantation has increased, at least in some centers. These trends have been attributed to a change in both immunosuppression protocols and donor quality. In fact, immunosuppression and donor age differences by center probably explain divergent outcomes in published series. ^†

† References .

The final consequence of recurrent hepatitis C is graft loss. Graft failure secondary to recurrent hepatitis C is now the most frequent cause of death, graft failure, and need for retransplantation in HCV-positive recipients. As a result, survival is significantly impaired when compared to other indications; an overall 10% difference at 10 years has been described in large series. In the most recent Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) report from the United States, the 3-year survival was 78% among 7459 anti-HCV–positive recipients compared to 82% in 20,734 anti-HCV–negative patients ( P < .0001) ( http://www.unos.org ). In addition, the more aggressive histological disease seen in recent years is beginning to translate into a further reduction in graft survival.

Factors Influencing Disease Severity and Progression or Survival

Factors that have shown an association with disease severity/progression or survival (or both) include those related to the host (demographics, genetic background, immune status, comorbidity, hepatic function at transplantation), the virus (genotype, HCV RNA levels, viral quasispecies), the environment (immunosuppression, alcohol, viral coinfection), the donor (age, degree of hepatic steatosis, liver volume, living versus deceased, donation after cardiac death [DCD], genetic background), and the surgery (ischemia time, biliary complications) ^∗

∗ References .

( Table 11-1 ). In the immunocompetent population the most powerful predictors of disease severity are those related to the host, including age at the time of infection, sex, the existence of any type of immunodeficiency, and alcohol use, whereas virus-related factors (e.g., genotype and HCV RNA) do not appear to play a major role in determining outcome. In the liver transplant setting the interactions are more complex, and the strongest determinants of outcome relate to the donor organ quality as well as the degree of immunosuppression ( Table 11-2 ).