Recurrent Hepatitis C Virus Disease Research Articles

The road map toward an hepatitis C virus-free transplant population.

Antiviral therapy to eradicate hepatitis C virus (HCV) infection improves outcomes in patients undergoing liver transplantation (LT) for advanced chronic HCV with or without hepatocellular carcinoma. Traditionally, antiviral therapy focused on the use of interferon (IFN)-based regimens, with antiviral treatment initiated in the posttransplant period once recurrent HCV disease with fibrosis in the allograft was identified. The use of IFN-based therapy was limited in pretransplant patients with advanced liver disease. Earlier intervention, either before transplantation or early after LT, is now feasible with the advent of second-generation direct-acting antiviral agents (DAAs) with superior tolerability and efficacy to IFN-based therapy. These agents have the potential to reduce the number of patients developing HCV-related complications requiring LT and retransplantation, as well as reducing the demand for donor organs. We discuss the pros and cons of pretransplant, peritransplant, and posttransplant therapy with current DAAs, citing available data from clinical trials and real-world experience.

Analysis of Post-Liver Transplant Hepatitis C Virus Recurrence Using Serial Cluster of Differentiation Antibody Microarrays.

Hepatitis C virus (HCV) reinfection of the liver allograft after transplantation is universal, with some individuals suffering severe disease recurrence. Predictive markers of recurrent disease severity are urgently needed. In this study, we used a cluster of differentiation (CD) microarray to predict the severity of HCV recurrence after transplantation. The CD antibody microarray assays of live leukocytes were performed on peripheral blood taken in the first year after transplantation. The results were grouped into phases defined as; Pre-transplant (day 0), Early (day 3 to week 2), Mid (week 4 to week 10), and Late (week 12 to week 26). Hepatitis C virus severity was based on fibrosis stages in the first 2 years (F0-1 mild and F2-4 severe). Serial blood samples from 16 patients were taken before and after liver transplantation. A total of 98 assays were performed. Follow-up was 3 years or longer. Comparing recurrence severity, significantly greater numbers of CD antigens were differentially expressed on the pretransplant samples compared to any posttransplant timepoints. Five differentially expressed CD antigens before transplantation (CD27 PH, CD182, CD260, CD41, and CD34) were significantly expressed comparing severe to mild recurrence, whereas expression of only CD152 was significant in the late phase after transplantation. No relationship was observed between the donor or recipient interleukin-28B genotypes and HCV recurrence severity. This study shows that circulating leukocyte CD antigen expression has utility in assessing recurrent HCV disease severity after liver transplantation and serves as a proof of principle. Importantly, pretransplant CD antigen expression is most predictive of disease outcome.

Impact of new treatment options for hepatitis C virus infection in liver transplantation.

Liver transplant candidates and recipients with hepatitis C virus (HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens (e.g., pegylated-interferon plus ribavirin with or without first generation protease inhibitors, boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents (DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir, daclatasvir, and combination of other DAA. Possible interactions should be monitored, especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals.

Advances in therapy for HIV/hepatitis C virus-coinfected patients in the liver transplant setting.

Complications of cirrhosis due to hepatitis C virus (HCV) are increasing, and liver transplantation (LT) is the most effective treatment for those with liver decompensation or small hepatocellular carcinoma. However, for patients with human immunodeficiency virus (HIV) coinfection, barriers to LT exist. This is related to the poorer survival rates post-LT (55% at 5 years) and, up until this year, the limited options for treating those coinfected LT recipients with progressive recurrent HCV disease, the commonest reason for reduced survival. The newly approved antiviral therapies sofosbuvir and simeprevir, with significantly improved efficacy and markedly better safety and tolerability in HIV and transplant patients, offer the opportunity to transform the outcomes of HIV/HCV-coinfected patients with liver complications. Additional new therapies, anticipated within the year, are expected to further simplify the management of coinfected patients in the transplant setting.

Early viral load and recipient interleukin-28B rs12979860 genotype are predictors of the progression of hepatitis C after liver transplantation

There have been few detailed studies of viral kinetics after liver transplantation (LT), and conflicting data have been reported on viral loads and the severity of recurrent hepatitis C virus (HCV) disease. This long-term study aimed to examine (1) the impact of HCV RNA levels at specific points in time within the first year and (2) the influence of interleukin-28B (IL-28B) genotypes on patient outcomes and the severity of recurrent HCV disease. The viral loads were measured 2, 4, 12, 24, and 48 weeks after LT, and the recipient/donor IL-28B genotypes of 164 patients were determined. A Cox regression analysis showed that the viral load at week 2 was an independent negative predictor of recipient outcomes. A week 2 viral load ≥ 6.0 log(10) IU/mL was significantly associated with reduced patient survival. After a mean follow-up of 6.5 years, 21 of 164 patients (12.8%) developed a cholestatic type of HCV recurrence and/or rapidly progressed to cirrhosis within 1 year. A multivariate binary regression analysis showed that HCV viremia at week 2 and a non-C/C recipient IL-28B genotype were independent risk factors for cholestatic recurrent HCV. No predictive factors could be found for the occurrence of recurrent liver cirrhosis 5 and 10 years after LT. Our study shows that the HCV RNA level at week 2 and the recipient IL-28B genotype are independent, statistically significant risk factors for post-LT cholestatic HCV, and it emphasizes the importance of viral load monitoring and IL-28B genotyping for identifying HCV recipients at risk for severe HCV recurrence.

Human herpesvirus 6 in donor biopsies associated with the incidence of clinical cytomegalovirus disease and hepatitis C virus recurrence

Reactivation of cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6), as well as the recurrence of hepatitis C virus (HCV), occurs in the post liver transplantation period. However, their correlations remain questionable. The objectives of this study were to analyze the presence of CMV DNA and HHV-6 DNA in pre-transplant and post-transplant liver graft biopsies and to determine any correlations with CMV disease and HCV recurrence. Forty-one liver transplant recipients were followed up in the post-transplant period. The presence of CMV DNA and HHV-6 DNA was detected by nested PCR. Four patients (4/41, 9.8%) were positive for CMV DNA in pre-transplant biopsies and three of them remained positive after transplantation; 11 patients became positive in the post-transplant biopsies (p=0.06). Fifteen (15/41, 36.6%) patients were positive for HHV-6 DNA in pre-transplant biopsies and 11 of these remained positive after transplantation. Another 11 patients became positive after the surgery (p=0.05). CMV disease occurred in 17 recipients; 10 of these 17 (58.8%) patients were positive for HHV-6 DNA in pre-transplant biopsies and they continued positive after transplantation (p=0.0128). Twenty-eight patients were transplanted due to hepatitis C; 12 of these patients had recurrence of the virus, and HHV-6 was positive in nine of the 12 (75%) patients (p=0.049). Recipients with HHV-6 DNA in pre-transplant graft biopsies remained positive post transplantation, showing a possible risk for post-transplant allograft loss because there was an association between HHV-6 and recurrent HCV and CMV disease.

Hepatitis C virus-infected women have a higher risk of advanced fibrosis and graft loss after liver transplantation than men

In natural history studies of hepatitis C virus (HCV) infection, women have a lower risk of disease progression to cirrhosis. Whether female sex influences outcomes of HCV in the posttransplantation setting is unknown. All patients transplanted for HCV-related liver disease from 2002-2007 at five United States transplantation centers were included. The primary outcome was development of advanced disease, defined as biopsy-proven bridging fibrosis or cirrhosis. Secondary outcomes included death, graft loss, and graft loss with advanced recurrent disease. A total of 1,264 patients were followed for a median of 3 years (interquartile range, 1.8-4.7), 304 (24%) of whom were women. The cumulative rate of advanced disease at 3 years was 38% for women and 33% for men (P=0.31), but after adjustment for recipient age, donor age, donor anti-HCV positivity, posttransplantation HCV treatment, cytomegalovirus infection and center, female sex was an independent predictor of advanced recurrent disease (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.02-1.70; P=0.04). Among women, older donor age and treated acute rejection were the primary predictors of advanced disease. The unadjusted cumulative 3-year rates of patient and graft survival were numerically lower in women (75% and 74%, respectively) than men (80% and 78%, respectively), and in multivariable analyses, female sex was an independent predictor for death (HR, 1.30; 95% CI, 1.01-1.67; P=0.04) and graft loss (HR, 1.31; 95% CI, 1.02-1.67; P=0.03). Female sex represents an underrecognized risk factor for advanced recurrent HCV disease and graft loss. Further studies are needed to determine whether modification of donor factors, immunosuppression, and posttransplantation therapeutics can equalize HCV-specific outcomes in women and men.

Hepatocellular MxA protein expression supports the differentiation of recurrent hepatitis C disease from acute cellular rejection after liver transplantation

Differentiation of recurrent hepatitis C virus (HCV) disease from acute cellular rejection (ACR) following liver transplantation can be difficult. Previously, we have found that MxA protein, a specific and sensitive marker for type 1 interferon production, is strongly expressed in chronic HCV disease. Here, we investigate MxA expression as a marker for recurrent HCV disease in the livers of 14 adult HCV patients who underwent liver transplantation. Serial liver biopsies available for 12 of these patients were stained for MxA protein and scored using a semi-quantitative approach. Hepatocellular MxA protein levels were significantly up-regulated (p = 0.025) in recurrent HCV disease in comparison to ACR. In biopsies that showed histological changes consistent with recurrent HCV disease, strong hepatocellular MxA staining was present in 14/18 (78%). In the liver biopsies with histological evidence of ACR, strong MxA hepatocellular staining was present in only three of 10 (30%). Thus, assessment of hepatocellular MxA protein expression can contribute to the differential diagnosis of ACR and recurrent HCV disease following liver transplantation. In conclusion, analysis of intrahepatic MxA levels has the potential to reduce the inappropriate use with high-dose pulsing of steroids post-operatively.

Natural killer cells play divergent roles in shaping the outcome of hepatitis C virus recurrence following liver transplantation

End-stage liver disease related to chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation (LT) in the United States. Recurrence is almost universal, and HCV infection significantly impairs patient and allograft survival following LT. The spectrum of histologic injury related to HCV recurrence is highly variable, ranging from mild histologic abnormalities to allograft cirrhosis in up to 30% of recipients by the fifth postoperative year. Although this is an active and promising area of research, we currently cannot reliably identify patients who will develop progressive HCV recurrence. Thus, identifying variables before LT that predict more aggressive HCV recurrence is of importance, particularly in the context of donor organ shortage. The immune response is a critical determinant of clinical outcome in both the acute and chronic phases of HCV infection. Liver injury secondary to HCV infection is thought to be immune-mediated and not to result from the direct cytopathic effects of the virus. Considerable gaps exist in our understanding of how the immune response influences HCV recurrence postLT. In this setting, the infection of an HCV-naive allograft in some ways resembles acute HCV infection, and this suggests a role for innate immune mechanisms in recurrent HCV disease outcome. In this issue of Liver Transplantation, Espadas de Arias and colleagues contribute to our understanding of the potential role of natural killer (NK) cells in the antiviral immune response of LT recipients, adding important information to an emerging area of research.

Cirrhosis of mixed etiology (hepatitis C virus and alcohol): Posttransplantation outcome-Comparison with hepatitis C virus-related cirrhosis and alcoholic-related cirrhosis

Hepatitis C virus (HCV)-related liver disease is enhanced by alcohol consumption. Of HCV-related liver transplantation (LT) recipients, 25% have a history of alcohol intake. The purpose of this research was to determine whether LT outcome differs between patients with cirrhosis of mixed etiology compared to HCV or alcohol alone. Of 494 LT (1997-2001), recipient/donor features, post-LT histological, metabolic complications [hypertension, diabetes-diabetes mellitus (DM)], and de novo tumors were compared in 3 groups [HCV-related cirrhosis = 170 (HCV group), alcohol-related cirrhosis (alcohol group) = 107, and cirrhosis of mixed etiology (mixed group) = 60]. Protocol biopsies were done in HCV patients. Severe recurrent HCV disease was defined as: 1-year fibrosis >1, cholestatic hepatitis, recurrent cirrhosis, or HCV-related liver retransplantation (reLT) within 5 years. Patients in the mixed group were younger (mean age: HCV group = 59 years; mixed group = 49 years; alcohol group = 53 years; P < 0.05) and mainly men (% men: HCV group = 51%; mixed group = 97%; alcohol group = 87%). Hepatocellular carcinoma (HCC) was more frequent in HCV patients (HCV group = 44%; mixed group = 35%; alcohol group = 18%; P = 0.05). Five-year survival was lowest in the HCV group (HCV group = 49% versus mixed group = 73% versus alcohol group = 76%; and P < 0.01 for the HCV group versus the alcohol group or the HCV group versus the mixed group; P = 0.74 for the alcohol group versus the mixed group). Metabolic complications and de novo tumors were more frequent in the alcohol groups. Severe HCV disease was similar in the HCV+ groups (HCV group = 45%; mixed group = 45%; P = 0.66). Patients with in the mixed group were more frequently treated with antivirals (32% versus HCV group = 18%; P = 0.03). In HCV patients, factors independently associated with lower survival were older donor age, LT indication (HCV alone), and increased body mass index (BMI). Antiviral therapy was a protective factor. Post-LT survival was lower in the isolated HCV group compared to the alcohol or mixed groups despite a similar recurrence of HCV disease. A greater use of antiviral therapy in the mixed group may explain these differences. The incidence of metabolic complications and de novo tumors was greater in the alcohol groups.

Antiviral treatment in patients with hepatitis C virus-related cirrhosis awaiting liver transplantation

End stage liver disease due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT) worldwide. Regretfully, infection of the graft by HCV occurs almost universally after LT, causing chronic hepatitis and early progression to cirrhosis in a significant proportion of recipients. Moreover, graft and patient survival are significantly worse in patients undergoing LT for HCV-related cirrhosis than in those transplanted for other indications. Therefore, many LT centers consider antiviral treatment with interferon and ribavirin the mainstay of managing recurrent HCV disease in LT recipients. The optimal time to start treatment is unclear. In most instances, treatment is initiated when histological evidence of disease recurrence, either at protocol or on-demand liver biopsies, is observed after LT. However, antiviral treatment initiated before LT is a potential option for some patients for two reasons: first, clearing or suppressing HCV before LT may reduce or eliminate the risk of recurrent hepatitis C in the transplanted liver and thereby improve survival; second, clearing HCV in cirrhotic patient may halt disease progression and avoid the need for transplantation. In this article, the results obtained by pre-transplant antiviral regimens administered to HCV-positive cirrhotic patients awaiting LT are discussed.

Immunopathogenesis of hepatitis C virus infection and hepatic fibrosis: New insights into antifibrotic therapy in chronic hepatitis C

Fibrosis and cirrhosis represent the consequences of a sustained wound-healing response to chronic liver injury of any cause. Chronic hepatitis C virus (HCV) has emerged as a leading cause of cirrhosis in the USA and throughout the world. HCV may induce fibrogenesis directly by hepatic stellate cell activation or indirectly by promoting oxidative stress and apoptosis of infected cells. The ultimate result of chronic HCV injury is the accumulation of extracellular matrix with high density type I collagen within the subendothelial space of Disse, culminating in cirrhosis with hepatocellular dysfunction. The treatment of hepatitis C with the combination of pegylated interferon and ribavirin is still both problematic and costly, has suboptimal efficacy, serious side effects and a high level of intolerance, and is contraindicated in many patients. Hence, new approaches have assumed greater importance, for which there is an urgent need. The sustained progress in understanding the pathophysiology of hepatic fibrosis in the past two decades has increased the possibility of developing drugs specifically targeting the fibrogenic process. Future efforts should identify genetic markers associated with fibrosis risk in order to tailor the treatment of HCV infection based on genetically regulated pathways of injury and/or fibrosis. Such advances will expand the arsenal to overcome liver fibrosis, particularly in patients with hepatic diseases who have limited treatment options, such as those patients with chronic hepatitis C who have a high risk of fibrosis progression and recurrent HCV disease after liver transplantation.

Recurrent hepatitis C virus disease after liver transplantation and concurrent biliary tract complications: poor outcome

Recurrent hepatitis C virus (HCV) infection is particularly aggressive in the post-liver transplantation setting, with rapid progression of liver fibrosis. Biliary complications remain a significant cause of morbidity following liver transplantation. Post-cholecystectomy biliary strictures are associated with advanced hepatic fibrosis. The aim of this retrospective study was to determine whether the presence of biliary complications affects survival in liver transplant recipients with recurrent HCV disease. The files of liver transplant recipients (53.7% male; mean age 52.7+/-10.3 yr) were reviewed for incidence, type and treatment of biliary complications, and findings were compared between those who developed recurrent HCV disease (n=47, 83.9%) and those who did not (n=9). Twenty-one biliary complications developed in 12 patients with recurrent HCV (25.5%). Treatment with endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography with balloon dilatation and stent placement or surgical revision was successful in nine (75%). Three biliary complications developed in three patients with no recurrence (p=NS). There was no statistically significant association between recurrent HCV disease and biliary complications. However, among those with recurrent disease, the recurrence was severe in nine of 12 recipients with biliary complications (75%) but in only nine of 35 without biliary complications (26%) (p=0.001). Death was documented in eight patients with severe recurrence (44.4%), including three (37.5%) with biliary complications and two (7%) with non-severe recurrence, neither of whom had biliary complications (p=0.003). Antiviral treatment was successful in nine of 25 patients (36%) who received it. On multivariate analysis, biliary complications were a significant predictor of severe recurrence (OR 27.0, 95% confidence interval 2.07-351.4) (p=0.012). Fibrosis stage in the second biopsy was significantly correlated with serum alanine aminotransferase (p=0.01) and with duration of biliary obstruction (p=0.07). In conclusion, biliary complications of liver transplantation strongly affect outcome in patients with recurrent HCV disease despite attempts to relieve the biliary obstruction and to treat the recurrent HCV disease.

Treatment of Recurrent Hepatitis C in Liver Transplant Recipients

The course of hepatitis C is accelerated after transplantation, with an average of 25% of patients developing cirrhosis within 5 years of transplantation. Consequently, the 5- and 10-year graft survival rates in hepatitis C virus (HCV)-infected patients are significantly lower than in HCV-uninfected patients. Therapeutic interventions to prevent HCV recurrence and/or alter the rate of disease progression after transplantation are desirable. Prophylactic therapy in the form of polyclonal HCV antibodies has not been effective at prevention of HCV re-infection, but one study suggests that higher-dose therapy may modify the severity of early disease recurrence. Pre-emptive antiviral therapy has modest efficacy and generally is poorly tolerated. Live donor liver transplant recipients and recipients with low model of end-stage liver disease scores pretransplantation may tolerate pre-emptive therapy best. The treatment of recurrent established disease with a combination of interferon and ribavirin has been the mainstay of management. Similar to pre-emptive therapy, tolerance is reduced and dose reductions are frequent. The sustained virologic response rates are less than 45% in studies to date. Histologic and biochemical improvements generally are more frequent than virologic responses. Overall, the treatment of HCV disease in transplant recipients leaves much to be desired and there is an urgent need of new HCV therapies in this patient population.

Positive Serum Cryoglobulin Is Associated with Worse Outcome after Liver Transplantation for Chronic Hepatitis C

Recurrent hepatitis C virus (HCV) infection in patients after liver transplantation is an important clinical problem. Because serum cryoglobulins (CG) are known to be associated with an increased incidence of cirrhosis in nontransplant patients, the authors tested the hypothesis that CG would also predict aggressive recurrent HCV in patients after liver transplantation. Using a longitudinal database, the outcomes of 105 allografts transplanted into 97 HCV-positive patients from 1991 through 2002 were analyzed on the basis of CG status using a retrospective cohort design. Fifty-nine CG-negative and 38 CG-positive patients were identified. Histologic outcomes and graft survival were analyzed using Kaplan-Meier estimates and Cox univariate and multivariate analyses. Both overall survival and HCV-specific survival (non-HVC-related deaths and graft losses censored) were analyzed. By Kaplan-Meier estimates, CG-positive patients showed earlier graft failure with decreased time to severe histologic activity and fibrosis as compared with CG-negative patients (P<0.05 for all outcomes). By univariate analysis, CG-positive patients had significantly higher risk ratios for shortened HCV-specific graft survival, severe activity-free survival, and severe fibrosis-free survival as compared with CG-negative patients (P<0.05 for all outcomes). In the multivariate model, CG was an independent predictor for severe activity-free, severe fibrosis-free, and HCV-specific graft survival (P<0.05 for all outcomes). CG-positivity is associated with severe recurrent HCV disease in liver transplant recipients.

Early HCV-associated stellate cell activation in aggressive recurrent HCV: What can liver allografts teach about HCV pathogenesis?

Early HCV-associated stellate cell activation in aggressive recurrent HCV: What can liver allografts teach about HCV pathogenesis?

Severe recurrent hepatitis C after liver retransplantation for hepatitis C virus–related graft cirrhosis

An increase in the number of hepatitis C virus (HCV)-infected transplant recipients at need for repeated liver transplantation is anticipated. To date, there is a certain reluctance to accept these patients because of an increased organ shortage, early reports suggesting a poor outcome, and uncertainty regarding the natural history of recurrent hepatitis C in the second graft. The aim of this study is to determine the outcome of patients undergoing retransplantation for HCV-related graft cirrhosis. Of 49 transplant recipients with HCV-related allograft cirrhosis, 31 patients developed decompensation with criteria for retransplantation. Thirteen patients were denied this option. Of the 18 patients accepted, 6 patients died while on the waiting list (5 patients died of graft cirrhosis at a median of 3.2 months of listing), and 12 patients have undergone retransplantation (median, 10 months since HCV cirrhosis). After retransplantation, 8 patients (67%) died at a median of 8 months, and 4 patients (33%) remain alive after 1.9 years of follow-up. Causes and times of death from retransplantation were: surgical complications, n = 3 (perioperative period); HCV cirrhosis of the second graft, n = 2 (at 9 and 54 months); fibrosing cholestatic hepatitis, n = 1 (at 2 years); lymphoproliferative disorder, n = 1 (at 7 months); and endocarditis, n = 1 (at 3.5 years, with underlying cirrhosis). Of the 4 patients alive, fibrosis stages in the last biopsy specimens are stage 1 (n = 1), stage 3 (n = 1), and stage 4 or cirrhosis (n = 1; one patient has not undergone biopsy), despite antiviral therapy. The outcome of retransplantation for HCV cirrhosis of the first graft is very poor because of multiple complications. The severity of recurrent HCV disease in the second graft seems to be related to that observed in the first graft. (Liver Transpl 2003;9:228-235.)

Liver transplantation for chronic hepatitis C: long-term results, role of antiviral therapy, and outcome of retransplantation

Hepatitis C virus (HCV)–related liver disease is the leading indication for orthotopic liver transplantation (OLT) worldwide. Recurrent HCV infection—defined by viremia after transplantation—is nearly universal, with histologic evidence of recurrent hepatitis present in the majority of patients. Although short-term survival is similar for patients transplanted for other causes of liver failure, approximately 20 to 25% of HCV-positive patients develop allograft cirrhosis by 5 years. Currently, there are no proven antiviral therapies that prevent HCV recurrence or development of allograft cirrhosis. Therefore, retransplantation is often the only viable option for patients with recurrent HCV-related liver disease. However, the outcome after retransplantation for HCV recurrence is poor, and whether organs should be offered to patients whose first allograft is failing because of recurrent HCV disease remains highly controversial. This review will highlight recent information regarding the long-term results of liver transplantation for HCV-related liver disease, the role of antiviral therapy, and the outcome after retransplantation.

Retransplantation for hepatitis C: implications of different policies.

Approximately 20% of hepatitis C virus (HCV)-positive liver transplant recipients develop evidence of allograft cirrhosis by year 5. 2. The prevalence of HCV infection in patients undergoing retransplantation has significantly increased since 1990. 3. Retransplantation for recurrent HCV is associated with poor long-term survival. 4. Preoperative hyperbilirubinemia (bilirubin > or =5 mg/dL) and renal failure predict poor outcome after retransplantation. 5. Retransplantation is the only viable option for patients in whom allografts fail because of recurrent HCV disease.

Involvement of the fas system in hepatitis C virus recurrence after liver transplantation.

To date, there have been no reports of the involvement of the Fas system in recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT). In 25 patients who underwent OLT for HCV-related liver cirrhosis, we evaluated the expression of the Fas antigen (FasAg) on hepatocytes, apoptic hepatocytes, and serum levels of soluble Fas (sFas). The level of HCV viremia and HCV genotype were determined by polymerase chain reaction. Serum sFas levels were determined by an enzyme immunoassay procedure. DNA fragmentation was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) technique on deparaffinized liver samples. FasAg expression was evaluated by an immunoperoxidase method. Sixteen patients had evidence of recurrent HCV disease. The number of hepatocytes expressing FasAg and the percentage of apoptotic hepatocytes was greater among patients who developed recurrent hepatitis than among those who did not (P <.01 and P <.0001, respectively). There was a correlation between hepatic expression of FasAg, intensity of lobular inflammation (P =.007), and TUNEL index (P <.001). The levels of sFas were greater among the patients with recurrent HCV hepatitis than those without recurrent hepatitis (P <.04). We conclude that (1) Fas expression is up-regulated in recurrent HCV after OLT and is related to the grading of liver disease; likewise, levels of sFas were greater in the patients with recurrent HCV hepatitis; and (2) the demonstration of hepatocytes with FasAg expression and the labeling of the nuclei by TUNEL assay suggest that hepatic apoptosis mediated by the Fas system may have a role in the pathogenesis of recurrent HCV hepatitis after OLT.