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Recurrent Hepatitis C Cirrhosis after Liver Transplantation

Permanent Link: http://ufdc.ufl.edu/UFE0022186/00001

Material Information

Title: Recurrent Hepatitis C Cirrhosis after Liver Transplantation A Natural History Study
Physical Description: 1 online resource (48 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: cirrhosis, hepatitis, liver
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Hepatitis C virus infection is a significant public health problem. Chronic infection leads to cirrhosis and liver failure. Over the last 15 years, hepatitis C has become the most common cause of liver failure requiring liver transplantation in the United States. Hepatitis C virus re-infects the transplanted liver immediately, which causes hepatitis in the new allograft. Recurrent infection can lead to graft cirrhosis in up to 30% of patients within 5 years, which is much shorter than the time to cirrhosis in the immunocompetent population. The natural history of recurrent hepatitis C cirrhosis in the transplant population is not well defined. Limited data available are from Europe and suggest that after development of graft cirrhosis, decompensation and death occur rapidly. Therefore, the aim of this study is to define the natural history of recurrent HCV cirrhosis after LT in a US population and to identify risk factors for decompensation and survival. All adult patients undergoing liver transplant for hepatitis C from 1991 to 2007 were prospectively monitored with protocol liver biopsies at month 4 and annually post-transplant. Cirrhosis was defined as fibrosis score 5 or 6 (modified Ishak scale) on biopsy. Antiviral therapy for hepatitis C was initiated when fibrosis score was > 2. Demographic, clinical and histologic data were collected at time of cirrhosis and decompensation. Kaplan-Meier curves were used to estimate probability of decompensation and patient survival. Cox regression analysis was used to determine risk factors of decompensation and survival. Of the 1,085 adult liver transplants performed at the University of Florida from 1991 to 2007, 502 were performed for HCV cirrhosis. Eighty-eight patients had biopsy proven cirrhosis by a median time of 3.7 years after transplant, and 71 were clinically compensated at diagnosis. 26 patients had at least one episode of decompensation during follow up. The median time to the first decompensation event was 6 months. The cumulative probability of clinical decompensation after cirrhosis was 30% at 1 year and 39% at 3 years. A MELD score of ?17 was predictive of decompensation (RR 7.28, 95%CI 2.58?16.9). A sustained virologic response to interferon treatment reduced the risk of decompensation (RR 0.03, 95%CI 0.006?0.4). Overall survival was 83% at 1 year, 61% at 3 years, and 41% at 5 years with a median survival time of 47.8 months. Survival was negatively affected by decompensation. Once decompensation occurred, 1 year survival was only 46%. Poor survival was predicted by MELD score ?17, (RR 7.28; 95% CI 2.58?16.9), HCC (RR 4.14; 95% CI 1.42?14.9). The results confirm a previous report of the accelerated natural history of hepatitis C cirrhosis in an immunosuppressed population. Successful antiviral therapy may protect against decompensation; however, once decompensation occurs, survival is negatively effected. Clinically, MELD is useful to predict decompensation events and survival. The finding that HCC negatively impacts survival is surprising, and deserves further study.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis: Thesis (M.S.)--University of Florida, 2008.
Local: Adviser: Asal, Nabih R.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022186:00001

Permanent Link: http://ufdc.ufl.edu/UFE0022186/00001

Material Information

Title: Recurrent Hepatitis C Cirrhosis after Liver Transplantation A Natural History Study
Physical Description: 1 online resource (48 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: cirrhosis, hepatitis, liver
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Hepatitis C virus infection is a significant public health problem. Chronic infection leads to cirrhosis and liver failure. Over the last 15 years, hepatitis C has become the most common cause of liver failure requiring liver transplantation in the United States. Hepatitis C virus re-infects the transplanted liver immediately, which causes hepatitis in the new allograft. Recurrent infection can lead to graft cirrhosis in up to 30% of patients within 5 years, which is much shorter than the time to cirrhosis in the immunocompetent population. The natural history of recurrent hepatitis C cirrhosis in the transplant population is not well defined. Limited data available are from Europe and suggest that after development of graft cirrhosis, decompensation and death occur rapidly. Therefore, the aim of this study is to define the natural history of recurrent HCV cirrhosis after LT in a US population and to identify risk factors for decompensation and survival. All adult patients undergoing liver transplant for hepatitis C from 1991 to 2007 were prospectively monitored with protocol liver biopsies at month 4 and annually post-transplant. Cirrhosis was defined as fibrosis score 5 or 6 (modified Ishak scale) on biopsy. Antiviral therapy for hepatitis C was initiated when fibrosis score was > 2. Demographic, clinical and histologic data were collected at time of cirrhosis and decompensation. Kaplan-Meier curves were used to estimate probability of decompensation and patient survival. Cox regression analysis was used to determine risk factors of decompensation and survival. Of the 1,085 adult liver transplants performed at the University of Florida from 1991 to 2007, 502 were performed for HCV cirrhosis. Eighty-eight patients had biopsy proven cirrhosis by a median time of 3.7 years after transplant, and 71 were clinically compensated at diagnosis. 26 patients had at least one episode of decompensation during follow up. The median time to the first decompensation event was 6 months. The cumulative probability of clinical decompensation after cirrhosis was 30% at 1 year and 39% at 3 years. A MELD score of ?17 was predictive of decompensation (RR 7.28, 95%CI 2.58?16.9). A sustained virologic response to interferon treatment reduced the risk of decompensation (RR 0.03, 95%CI 0.006?0.4). Overall survival was 83% at 1 year, 61% at 3 years, and 41% at 5 years with a median survival time of 47.8 months. Survival was negatively affected by decompensation. Once decompensation occurred, 1 year survival was only 46%. Poor survival was predicted by MELD score ?17, (RR 7.28; 95% CI 2.58?16.9), HCC (RR 4.14; 95% CI 1.42?14.9). The results confirm a previous report of the accelerated natural history of hepatitis C cirrhosis in an immunosuppressed population. Successful antiviral therapy may protect against decompensation; however, once decompensation occurs, survival is negatively effected. Clinically, MELD is useful to predict decompensation events and survival. The finding that HCC negatively impacts survival is surprising, and deserves further study.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis: Thesis (M.S.)--University of Florida, 2008.
Local: Adviser: Asal, Nabih R.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022186:00001


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RECURRENT HEPATITIS C CIRRHOSIS AFTER LIVER TRANSPLANTATION: A NATURAL HISTORY STUDY By VIRGINIA C. CLARK A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2008 1

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2008 Virginia C. Clark 2

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To Joe 3

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ACKNOWLEDGMENTS I would like to express my a ppreciation for the support of the Gastroenterology Division during the time of my fellows hip which provided the needed time for completion of the requirements of this Masters of Science degree. I am especially grateful to Charou Chen for all of her assistance as this could not have been co mpleted without her. In addition, I would like to thank Nabih Asal, David Nelson, an d Roberto Firpi for their guidan ce, mentorship, and patience. Finally, I would like to thank C onsuelo Soldevila-Pico whose de dication to liver transplant patients is unequaled. 4

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TABLE OF CONTENTS page ACKNOWLEDGMENTS ...............................................................................................................4 LIST OF TABLES ...........................................................................................................................6 LIST OF FIGURES .........................................................................................................................7 LIST OF ABBREVIATIONS ..........................................................................................................8 ABSTRACT .....................................................................................................................................9 CHAPTER 1 INTRODUCTION................................................................................................................. .11 Epidemiology of Hepatitis C ..................................................................................................11 Cirrhosis ..................................................................................................................................12 Liver Transplantation for Hepatitis C Cirrhosis .....................................................................13 Recurrent Hepatitis C Infection ..............................................................................................14 Study Aims .............................................................................................................................17 2 MATERIALS AND METHODS...........................................................................................18 Patients ....................................................................................................................................18 Follow-up ................................................................................................................................18 Interferon Therapy for Recurrent Hepatitis C ........................................................................19 Study Design and Data Collection ..........................................................................................19 Outcomes ................................................................................................................................20 Prognostic Factors for Morbidity and Mortality .....................................................................21 Statistical Analysis ..................................................................................................................21 3 RESULTS...................................................................................................................... .........22 Patient Characteristics ............................................................................................................22 Patients with Compensated Cirrhosis at Baseline ..................................................................23 Patients with Decompensated Cirrhosis at Baseline ...............................................................25 MELD Score as a Predictor of Mortality ................................................................................26 4 DISCUSSION................................................................................................................... ......37 LIST OF REFERENCES ...............................................................................................................42 BIOGRAPHICAL SKETCH .........................................................................................................48 5

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LIST OF TABLES Table page 3-1 Baseline characteristics of patients with compensated and decompensated recurrent HCV graft cirrhosis ............................................................................................................28 3-2 Univariate analysis of predictors of decompensation after recurrent graft cirrhosis .........34 3-3 Univariate analysis of predictors of survival after recurrent graft cirrhosis ......................36 6

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LIST OF FIGURES Figure page 3-1 Exclusion criteria. 502 patients were transplanted for HCV. Only 88 patients developed cirrhosis and were included in the study. .........................................................27 3-2 Clinical outcome from time of st udy entry until death or last follow-up. .........................29 3-3 Overall survival of the entire cohort (n=88) from time of study entry stratified into compensated cirrhosis (n=71) and decompensated cirrhosis (n=17). Survival is significantly worse in those who are decomp ensated at diagnosis (41% vs. 83% at 1 year). Median survival is also shorter (6.8 months vs. 47.8 months). ...............................30 3-4 The cumulative probability of decompensati on is 30% one year after the diagnosis of cirrhosis. The probability of d ecompensation at 5 years is 47%. ......................................31 3-5 Overall survival from diagnosis of cirrhosis. Survival is signifi cantly better in those who remain compensated (p<0.001). .................................................................................32 3-6 Cumulative survival from time of decompensation. The median time from decompensation to death is 11.8 months. Proba bility of survival once signs of liver decompensation develop is 46% at 1 year. ........................................................................33 3-7 Decompensation by MELD score. As the MELD score increases, the probability of clinical decompensation become s significantly higher (p<0.001). ....................................35 7

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LIST OF ABBREVIATIONS CBC Complete Blood Count CSA Cyclosporin HAI Hepatic Activity Index HCC Hepatocellular Carcinoma HCV Hepatitis C Virus IFN Interferon INR International Normalized Ratio IVDU Intravenous Drug Use LT Liver Transplantation MELD Model for End Stage Liver Disease NR Non-Responder to Interferon Therapy PMN Polymorphonuclear Leukocyte RAPA Sirolimus RL Relapse to Interferon Therapy ROC Receiver Operating Curve SVR Sustained Virologic Response TAC Tacrolimus US United States 8

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Abstract of Thesis Presen ted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science RECURRENT HEPATITIS C CIRRHOSIS AFTER LIVER TRANSPLANTATION: A NATURAL HISTORY STUDY By Virginia C. Clark May 2008 Chair: Nabih R. Asal Major: Medical SciencesClinical Investigation Hepatitis C virus infection is a significant publ ic health problem. Chr onic infection leads to cirrhosis and liver failure. Over the last 15 year s, hepatitis C has become the most common cause of liver failure requiring liver transplantation in the United States. Hepatitis C virus re-infects the transplanted liver immediately, which causes hepati tis in the new allograft. Recurrent infection can lead to graft cirrhosis in up to 30% of patients within 5 years, which is much shorter than the time to cirrhosis in the immunocom petent population. The natural hi story of recurrent hepatitis C cirrhosis in the transplant population is not well defined. Limited data available are from Europe and suggest that after development of graft cirrhosis, decompensation and death occur rapidly. Therefore, the aim of this study is to define the natural hi story of recurrent HCV cirrhosis after LT in a US population and to id entify risk factors for decompensation and survival. All adult patients undergoing liver transp lant for hepatitis C from 1991 to 2007 were prospectively monitored with protocol liver biopsies at month 4 and annually post-transplant. Cirrhosis was defined as fibrosis score 5 or 6 (modified Ishak scale) on biopsy. Antiviral therapy for hepatitis C was initiated when fibrosis scor e was >2. Demographic, clinical and histologic data were collected at time of cirrhosis and d ecompensation. Kaplan-Meier curves were used to 9

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estimate probability of decompensation and patient survival. Cox regression analysis was used to determine risk factors of decompensation and survival. Of the 1,085 adult liver transplants performed at the University of Florida from 1991 to 2007, 502 were performed for HCV cirrhosis. Eight y-eight patients had biopsy proven cirrhosis by a median time of 3.7 years after transplant, and 71 were clinica lly compensated at diagnosis. 26 patients had at least one episode of decomp ensation during follow up. The median time to the first decompensation event was 6 months. The cumulative probability of clinical decompensation after cirrhosis was 30% at 1 year and 39% at 3 years. A MELD score of 17 was predictive of decompensation (RR 7.28, 95%CI 2.58.9). A sustained virologic response to interferon treatment reduced the risk of decompensa tion (RR 0.03, 95%CI 0.006.4). Overall survival was 83% at 1 year, 61% at 3 ye ars, and 41% at 5 years with a median survival time of 47.8 months. Survival was negatively affected by decompensation. Once decompensation occurred, 1 year survival was only 46%. Poor survival was predicted by MELD score 17, (RR 7.28; 95% CI 2.58.9), HCC (RR 4.14; 95% CI 1.42.9). The results confirm a previous report of th e accelerated natural history of hepatitis C cirrhosis in an immunosuppressed population. Succe ssful antiviral thera py may protect against decompensation; however, once decompensation o ccurs, survival is ne gatively effected. Clinically, MELD is useful to predict decompensation events a nd survival. The finding that HCC negatively impacts survival is su rprising, and deserves further study. 10

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CHAPTER 1 INTRODUCTION Hepatitis C viral infection is a significant public heath problem worldwide. The primary mode of transmission varies by location of cohort studi ed, but in general, it is transmitted by sharing infected blood.1 In the United States, the most common mode of transmission is by intravenous drug use (IVDU), which is followed by those who were infected by contaminated blood products prior to blood bank screening. Sexual transmissi on is uncommon. Infection with hepatitis C (HCV) is largely asymptomatic, and many of those infected are diagnosed after only after routine blood chemistries are noted to be abnormal. S till others are not diagnosed until symptoms of liver damage become apparent. Epidemiology of Hepatitis C Approximately 3.2 million people in the US are chronically infected for an estimated 1.6% prevalence.2 Data from NHANES III, which covered the years of 1988-1994, indicated the peak prevalence of infection occurred in those 30-39 year s of age. The peak prevalence of infection shifted to ages 40-49 in a later NHANES cohor t (1999). When the prevalence of HCV was evaluated by year of birth in the early and late cohorts, the results were similar. The majority of people were born between 1945 and 1964, suggesting th e shift in peak prevalence over time represented an aging cohort with a longer duratio n of infection. The prevalent cases are anticipated to decrease from 3 million to 2 million over the next 40 years.3 The number of incident cases is also projected to decline largely because of a decrease in IVDU and in some small part because of blood bank screening. Howe ver, the damage to the liver from HCV is cumulative and slowly progressive. As a result of the long lag time from infection to the clinical manifestations of cirrhosis, the burden of end stag e liver disease from HCV is just starting to be felt by the medical community. In 2000, there were less than 500,000 cases of cirrhosis in the 11

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U.S. as a result of HCV. By 2020, the projected number of cases of cirrhosis from HCV will approach 720,000 and peak at 900,000 cases by 2030.3 Cirrhosis The healthy liver is responsible for mainta ining the bodys metabolic homeostasis. This includes bile synthesis and excre tion, which is important for dige stion and absorption of dietary fats and vitamins. The liver also synthesizes pr oteins necessary for regul ation of blood clotting, cholesterol levels, and clearance of metabolic waste products from the body. Cirrhosis is the final common pathway for all diseases that da mage the liver and is not specific for HCV. Cirrhosis is a pathologic dia gnosis based on liver histology wh ere discrete nodules of liver parenchyma are surrounded by dense fibrous ti ssue. The parenchymal injury and resulting fibrosis extend throughout th e entire liver creating a sh runken and hard organ. The liver is able to maintain normal synthe tic function in the early stages of cirrhosis despite having a significant amount of scar tissu e present. The clinical consequences of the deranged metabolism are masked to some degree b ecause of the large functional reserve of the liver. It is during this phase that patients are considered compensated. As progressive liver injury accumulates, the synthetic capabilities diminish and the consequences of portal hypertension become evident. A transition occurs to a decompensated state once symptoms of liver failure are present, which include ja undice, ascites, encepha lopathy, and esophageal variceal bleeding or hepatocellular carcinoma (HCC) develops. Ja undice is apparent clinically by yellowing of the skin and eyes and occurs as bilirubin accumulates to levels > 3mg/dL. Ascites is the accumulation of fluid in the perito neal cavity as a result of portal hypertension and is clinically apparent by a swo llen, often tense, distended abdome n. Esophageal varices are also a result of portal hypertension and are defined as abnormally dist ended veins in the esophagus. They pose a risk to rupture and cause catastroph ic and life threatening hemorrhage. Hepatic 12

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encephalopathy can be defined broadly as changes in mental status related to the inability of the liver to clear toxic metabolites from the blood. The clinical presentation of encephalopathy can be as subtle as insomnia or as overt as coma. The rate of transition from compensated cirrhos is to decompensated cirrhosis is slow. As demonstrated by natural history studies of HCV cirrhosis, the cumulative probability of decompensation at 3 years is 12%. After 5 years from the diagnosis of cirrhosis, the probability of remaining compensated is approximately 80%.4-6 The development of decompensation is clinically important because the prognosis is worse once this occurs. For those who remain compensated, survival 3 years from the diagnosis of cirrhosis ranges from 92% to 96%.4-6 At 5 years, survival ranges from 82% to 90%.4-6 Once an episode of decompensation occurs, survival deteriorates. Th e probability of remain ing alive 3 years after decompensation is 57% and further decreases to 50% by 5 years.4-6 Evaluation for liver transplantation is appropriate after the first ep isode of decompensation because of the expected decrease in survival related to liver failure. Liver Transplantation for Hepatitis C Cirrhosis As may be expected based on the epidemiol ogy and natural history of the infection, HCV induced liver disease has become the most common indication for liver transplantation in the US. In 1991, only 16% of LT were performed for HCV, but by 2001, HCV was the indication for 55% of all LT.7 The number of patients with decompen sated disease who could be considered for liver transplantation will double over the next 30 years from 65,000 in 2000 to 145,000 in 2030.3 In addition, the number of cases of H CC will also double from 7000 to 14000. To put these numbers in perspective, approximately 6000 liv er transplants are performed annually in the U.S., and that number has not increased si gnificantly over the past several years.8 The rate limiting factor is the number of available donor organs. The increasing burden of HCV cirrhosis 13

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with or without HCC will further pressure th e already limited donor pool. In this light, the outcomes for LT for HCV will be carefully scrutini zed as the transplant community decides the most ethical balance for organ al location and distribution. Recurrent Hepatitis C Infection Transplantation relieves the symptoms of liver fa ilure and cirrhosis, but it is not a cure for HCV. In fact, recurrence of HCV in the transp lanted liver is expected, and most patients establish some degree of chronic hepatitis in the liver allograft.9 The natural history of recurrent hepatitis C after LT is variable. An acute hepa titis occurs within 1 months of LT and is characterized by increased serum transami nases and levels of circulating virus.10 Chronic hepatitis becomes established as HCV infection pe rsists, which leads to pr ogressive fibrosis in some patients. The development of fibrosis in the transplant population oc curs at an accelerated rate (0.3.8 stage/year) compared to an non-immune compromised patient population.11, 12 As a result, the estimated time from recurrent HCV inf ection to graft cirrhosis falls between 5 and 12 years, which is much faster than the >20 year progression to cirrhosis described in the nontransplant population.1 Multiple factors have been identified that ar e associated with disease progression, severity, and worse outcomes. As the demand for LT has increased, the donor pool of organs has not likewise expanded. Use of marginal organs, including those from donors >50 years old, has increased in order to meet demand. Multiple studies have now demonstrated that this may not be the best practice for patients with HCV since older donor age is a str ong predictor of rapid fibrosis progression after transplant.12-17 Immunosuppression management after transplant has also been implicated in progressive disease.18, 19 Corticosteroids boluses used to treat acute cellular rejection in HCV patients lead to early disease recurrence and higher risk of progression to graft cirrhosis.20, 21 The data on cumulative doses of co rticosteroids used for maintaining 14

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immunosuppression is less clear. Some authors a dvocate rapid tapering of steroids early after transplant; however recent data would suggest a longer steroid tape r and lower overall immunosuppression may lead to better outcomes.22, 23 Another strategy employed has been the complete avoidance of steroids, although the ideal immunosuppression protocol has not been established to help modify recurr ence of HCV in the liver graft.24 Other variables that have been implicated to negatively impact HC V fibrosis progression include warm ischemia, graft preservation injury, presence of diabetes mellitus, donor steatosis, co-infection with CMV, and type of calcineurin inhibitor used.14, 21, 25-27 Given the breadth of these findings, any single factor will not likely differentiate patie nts at risk for rapid progression of disease. Rational manipulation of the risk fa ctors for fibrosis progression is important to prevent recurrent graft cirrhosis and graft failure since eradica tion of the virus after LT is challenging.28-30 Early data showed no negative im pact on survival in those tr ansplanted for HCV compared to other indications for transplant.31 As experience with transplantation matured, decreased survival in those who were tran splanted for HCV became evident.32 At 5 and 10 years after transplantation, survival after LT for HCV reaches 61% and 68% compared with 76% and 78% for other indications.33 The decreased survival after LT has been attributed to graft failure and cirrhosis from progressive HCV.33 By analyzing LT cohorts by year of transplant, researchers showed 3-year survival improve d for each consecutive time period for non-HCV indications. In contrast, survival in the HCV cohorts remained the same, and the survival benefit from improvements in immunosuppre ssion and post-transplant care was mitigated by recurrence of disease.34 15

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All patients transplanted for HCV cirrhosis face the prospect of recurrent disease and enduring treatment with interferon and ribavirin. Unfortunately, some of these patients also must cope with the eventual failure of the liver a llograft as a result of chronic HCV infection. Recurrent graft cirrhosis occurs in 8% of those transplanted for HCV by a median of 3 years, with a 30% cumulative probability of developing graft cirrhosis by year five.31, 35-39 The natural history of recurrent graft cirrhosis in the post-LT HCV patients is not well defined. A single study has shown survival one year after recurrent cirrhosis is 71%.40 Decompensation occurs rapidly after the diagnosis of recurrent graft cirrhosis, with a 42% cumulative probability of decompensation at 1 year.40 Furthermore, only 41% of pati ents are alive a year after decompensation in the post-LT population.40 The data from this study originated from a single center in Spain who has re ported poor outcomes in regards to recurrent HCV,11 which suggest the results may have limited applicability for ot her transplant centers who fare better. Other limitations include a small study population (n=39) and short term follow up (1.1 year) after the development of cirrhosis. To date these results have not been c onfirmed in a U.S. transplant population or by any other transplant center in Europe. If recurrent graft ci rrhosis has such an ominous pr ognosis, a better understanding of the natural history is important for both patients and clinicians as they face decisions in medical management and possibly even end of life care. In addition, the outcomes from recurrent HCV graft cirrhosis are meaningful to liver transplant centers as deci sions are made regarding if and when a second liver transplant should be offered. Liver re-transplantation for graft failure is the only life saving option patients may have; however th is practice is controversial. Initial single center reports of poor survival (mortality rates greater than 50 %) after re-trans plantation for HCV raised apprehension over the medical viability of this option.41-43 Ethical concerns 16

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regarding scarce resource utiliza tion were also voiced within th e liver transplant community. For these reasons and others, liver re-transplantati on for HCV currently only accounts for 2% of all transplants annually.44 A more recent multi-center st udy had equivalent 1 and 3 year survival in those re-transplante d for HCV compared to other indi cations for late graft failure, suggesting re-OLT may be an option in well selected patients.45 As this clinical story develops, understanding prognostic factors for decompensation and survival will be critically important to determine the optimal timing of re-transplantation for HCV. Study Aims Therefore, the aims of this study were to determine the clinical course of recurrent graft cirrhosis from HCV and to identify prognostic factors for both decompensation and survival once cirrhosis occurs. 17

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CHAPTER 2 MATERIALS AND METHODS Patients A total of 1,316 liver transplants were performe d at the University of Florida from July 1991 to April 2007. In 502 adult liver transplants, the primary indication was HCV cirrhosis. Per institutional protocol for HCV tr ansplant patients, liver biopsies were performed 4 months after LT and then yearly afterward. Biops ies were also done if clinica lly indicated. Each biopsy was scored for inflammation and fibrosis from r ecurrent HCV using the modified Knodell scoring system of Ishak46. All patients were evaluated for inclusion in the study if the following criteria were met: (1) at least one protocol biopsy following liver transplanta tion, (2) detectable HCV RNA after liver transplantation, a nd (3) biopsy proven cirrhosis defi ned by a fibrosis stage of 5 or 6. Patients were excluded for (1) evidence of cholestatic HCV, (2) fibrosis stage 4, (3) absence of a protocol liver biopsy, or (4) less than 4 months follow up after liver transplant. Follow-up All patients were evaluated in clinic once a year at the approximat e anniversary of liver transplantation. At that time, the protocol bi opsy was performed. Once cirrhosis was established by biopsy, a follow up liver ultrasound was performed, and at least one screening endoscopy was completed to evaluate for the presence of esophag eal or gastric varices. In all patients, liver chemistries were assessed at 3 month intervals, and at the time of biopsy, an INR, platelet count, complete metabolic profile, CBC and HCV RNA were collected. Pati ents were also evaluated in clinic for complications of liver tran splantation or recurrent disease. Prior to 1997, standard immunosuppression consisted of Cyclosporine (CSA) in combination with prednisone. Target trough c oncentrations for CSA were 200 ng/ml for the first month post-transplant followed by 150 ng/ml thereafter. Now tacrolimus is used as the 18

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primary calcineurin inhibitor for immunosuppre ssion with target trough concentrations of 10 ng/ml for the first month post-transplant followed by 5 ng/ml thereafter. Typically, immunosuppression was tapered to monotherapy (TAC or CSA) within 4-6 months of transplantation as tolerated. Sirolimus was used as part of a renal sparing regimen as necessary when chronic renal insufficiency occurred dur ing prolonged follow up after transplantation. Interferon Therapy for Recurrent Hepatitis C Protocol biopsies were used to monitor for the development of fibrosis from recurrent hepatitis C. Combination therapy with interf eron and ribavirin was initiated once patients developed significant fibrosis (Is hak fibrosis stage > 2) on protocol or indication liver biopsy. The duration of treatment was 48 weeks for genotype 1 and 24 weeks for genotype 2 and 3 if tolerated. Interferon (IFN) was initiated at half of standard dosing for 2 weeks, and if tolerated, a full dose was given. Ribavirin dosage was based on weight. Hemoglobin, wh ite blood cell, and platelet counts were monitored weekly for the fi rst four weeks and then monthly thereafter. Dose reductions for IFN were performed if PMN < 750 or platelets < 50,000/mL. If PMN < 500 or platelets < 30,000, therapy was st opped. If hemoglobin < 10 mg/dl, ribavirin was reduced to 600 mg/day. Ribavirin was discontinued if hemoglobin < 8 mg/dl. Th erapy was discontinued in any patient who developed moderate to severe re jection, systemic bacterial infection, severe neuropsychiatric symptoms, or symptomatic an emia. Serum HCV RNA values were measured six months after completion of interferon-based therapy to asses for a sustained virological response (SVR) in those patients with a negative HCV at the end of treatment. Subsequently, HCV RNA titers were obtained annually. Study Design and Data Collection The study is a description of the natural hi story a small group of patients from a larger cohort of post-transplant HCV patients. Patients who developed recurrent graft cirrhosis were 19

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identified from a post-LT database. Data was compiled retrospectively by reviewing computerized medical records, a separate electron ic transplantation database, and paper charts. Clinical, laboratory, and biopsy da ta were recorded at time of study entry, which was defined as recurrent graft cirrhosis from HCV. Based on available laboratory data, a MELD score47 (Model for Endstage Liver Disease) was ca lculated at study entry. Furthermore, patients were classified into one of four clinical stages of cirrhosis of increasing severity: (a) Stage 1 no varices, no ascites (b) Stage 2 varices, no ascites (c) Stag e 3 ascites varices (d) Stage 4 bleeding ascites. Stages 1 & 2 were considered compensa ted cirrhosis, and stages 3 & 4 were considered decompensated cirrhosis48. During the subsequent follow up time, the development of the following clinical events was recorded: ascite s, varices bleeding, encephalopathy, jaundice (bilirubin >3mg/dL), and hepatocellular carcinom a (HCC). Albumin, INR, platelets, creatinine, bilirubin, and MELD were also recorded at time of first decompensation. Outcomes The end points chosen were (a) clinical decompensation defined by ascites, bleeding esophageal varices, or encephal opathy, and (b) death or re-trans plantation from recurrent HCV cirrhosis. The total time of obser vation was calculated from the date of cirrhosis until date of death, re-transplantation for HCV, or the end of the observation period (2/13/2008). The time to development of decompensated cirrhosis was calcul ated from the time of cirrhosis to the first development of clinical decompensation. If patients had more than one clinical event, then the date of the first event was used for time dependent calculations. Cause of death was categorized as related to graft failure or not Patients were censored at time of death or end of the observation period. If patients were lost to follow up, they were censored at the date of last evaluation. Liver re-transplantation was considered as death for ca lculation of patient su rvival rates since the 20

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overall aim of the study was to de scribe the course of events l eading to the terminal event of either re-transplantation or death. Prognostic Factors for Morbidity and Mortality The following clinical and serologic variables at entry were evaluate d as predictors of decompensation: age at diagnosis of cirrhosis donor age, gender, MELD score, albumin, bilirubin, creatinine, INR, platelets, HCC at tim e of LT, Hepatic Activity Index (HAI), time from LT to cirrhosis, date of LT, immunosuppression regimen, and response to IFN treatment postLT. A similar analysis was performed for predictors of survival using age, gender, MELD score, albumin, bilirubin, creatinine, INR, platelets, ascites, encephalopathy, jaundice, varices, time from LT to cirrhosis, date of LT, immunosuppr ession regimen, and response to interferon treatment post-LT in the groups presen ted compensated and decompensated. Statistical Analysis Categorical data were expresse d as percentages, and continu ous variables were presented as median with a range. The Chi-Square ( 2) or Fishers exact test was used to compare categorical data when appropriate The Kaplan-Meier method was us ed to establish the actuarial decompensation and survival curves that were comp ared with the log rank test. Multivariate Cox regression analyses were used to identify risk factors for time to decompensation and overall survival. Variables that retained significance (p<0.05) in the univari ate analysis were retained in the multivariate analysis. ROC curves were gene rated to determine the accuracy of MELD at time of cirrhosis to predict 3 month and 1 year survival. 21

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CHAPTER 3 RESULTS A total of 1,316 liver transplants were performe d at the University of Florida from July 1991 to April 2007. The primary indication was HC V cirrhosis in 502 patients. Patients were excluded if the fibrosis stage was 4 (n=328), no biopsy data wa s available (n=68), or if cholestatic HCV was present on bi opsy (n=18). The final study c ohort consisted of 88 patients with recurrent graft cirrh osis (Figure 3-1), which is 17.5% of those transplanted for HCV. Because retrospective studies ar e subject to bias, an evaluation of completeness of data ascertainment was undertaken. Thirty eight (43.2%) individuals missed no protocol biopsies. Twenty-three (26.1%) missed one biopsy, and 15 (17.1%) missed two protocol biopsies. Twelve (13.6%) of patients missed 3 or more biopsies. Importantly, only 12.5% (n= 11) had greater than a 2 year period between a biopsy with fibrosis stage 4 prior to the biopsy with cirrhosis, suggesting that the timing of the onset of cirr hosis was captured with reasonable accuracy. Eleven patients (12.5%) were missing an INR, so a MELD score was not calculated. Nine patients (10.2%) were missing HAI grades. Otherwis e, complete data was available for all other clinical and laboratory values. Patient Characteristics At the time of histologic diagnosis of ci rrhosis, 80.7% of the patients (n=71) were clinically compensated. In this group, the median length of time from LT to recurrent graft cirrhosis was 3.7 years (range, 9 months.8 years). The averag e number of biopsies completed was 4.2, which is consistent with one pe r year. After the diagnosis of cirrhosis, the median follow up was 2 years (range, 0 years). At some point during the follow up after liver transplantation, treatment w ith IFN was attempted in a large proportion (71.8%) of the 22

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compensated patients. An SVR was achieved in only 12.7% (n=9). Advanced fibrosis was present at time of treatment in each of these patients. A smaller number of patients (19.3%) were d ecompensated at time of study entry. In this group, the length of time from LT to cirrhosis wa s 2.5 years (range, 4 months.1 years), and the number of biopsies completed was 3.4. After th e diagnosis of cirrhosis, median follow up time was 5.1 months (range 0.6 years). In over half (52.9%) of these patients, IFN treatment was tried prior to decompensation, although SVR was achieved by only one person. The baseline clinical features of these two groups are compar ed in Table 3-1. The only significant differences found between the two groups were in albumin a nd creatinine. Accordingly, MELD scores were also significantly different between groups (11.2 vs 15.3, p <0.0001). The clinical course for all patients with recurrent HCV graft cirrhosis (n=88) is summarized in Figure 3-2. For the overall cohort, the median time from LT to last follow up was 5.9 years (range 8 months years). Less than half of the patients eventually developed signs of decompensated liv er disease (n=26). At the end of follow up, 35 patients remained alive with compensated cirrhosis. The overall survival for both the compensated and decompensated patien ts at time of study en try is shown in Figure 3-3. Patients with Compensated Cirrhosis at Baseline Decompensation Over a median follow up of 2 years (range 0 months years) months, 63.4% (n=45) of the 71 compensated patients remained so. The other 26 patients developed signs of decompensated liver disease by a median time of 4.8 months (range 0.1 years) from the diagnosis of cirrhosis. The median MELD score and albumin at time of decompensation were 16 (range, 7) and 3.0 g/dL (range 2) respective ly. Development of ascites was the most common clinical event (30.0%), followed by jaundice (19.7%) and ence phalopathy (16.9%). 23

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Esophageal varices were present in 25.6% of patients, although onl y one bleeding event occurred. Only one patient developed de novo hepatocellular carci noma. The cumulative probability of clinical decompensation was 23% at 6 months, 30% at 1 year, and 39% at 3 years after cirrhosis developed (Figure 3-4). The proba bility of remaining compensated at 5 years was 53%. Death or re-transplantation Twenty three patients reached the outcome of death or re-LT. Nineteen patients died and four were re-transplanted for HCV. The median time from LT to re-LT was 3.9 years (range, 1.9.3 years). Three of the re-trans planted patients are still alive. The other patient died of a cerebrovascular accident after re -LT. In the other 19 patients, the most common cause of death was graft failure (79%) seconda ry to recurrent HCV. Patient survival From the time of diagnosis compensated cirrhos is, the cumulative probability of survival was 83% at 1 year, 61% at 3 ye ars, and 41% at 5 years with a median survival time of 47.8 months. As shown in Figure 3-5, cumulative surviv al is worse in those who decompensate when compared to patients who remain compensated (p <0.001). When considering survival from the time of decompensation, survival is poor as shown in Figure 3-6. The probability of survival one year after decompensation is 46%. The medi an time from decompensation to death was 11.1 months. Risk factors for decompensation and mortality Factors in a univariate analysis for predictors of decompensation are shown in Table 3-2. The factors with significance we re albumin, MELD score, and tw o of the individual components of the MELD, bilirubin and INR. In addition, in those who had a rapid course of recurrent HCV 24

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cirrhosis, the relative risk of decompensation was 3.20 (95% CI 1.31.80). The risk of decompensation increased as the MELD score increas ed with the highest risk in those with score MELD 17 (RR 7.28; 95% CI 2.41.0) as seen in Fi gure 3-7. A SVR to IFN decreased the risk for decompensation (RR 0.05; 95%CI 0.04.42). In the subsequent multivariate analysis, MELD 17 (RR 3.88; 95% CI 1.12.45) had the greatest risk for decompensation and was the only variable that retained significance. Albumin approach ed significance (p=0.54) and was protective (RR 0.49; 95%CI 0.24.01). The impact IF N treatment had on decreasing the risk of decompensation lost significance in the multivariate model (RR 0.37; 95%CI 0.5.0). Similar factors were used in a univariate analys is for overall survival as shown in Table 33. Two of those remained significant in the multiv ariate analysis. The largest risk for mortality was from a MELD 17 (RR 13.6; 95% CI 2.7.1). HCC at time of LT also conferred a risk for decreased survival (RR 4.14; 95% CI 1.42.9). Patients with Decompensated Cirrhosis at Baseline This small group of patients (n=17) presen ted initially with clinical signs of decompensation, and cirrhosis was confirmed by subsequent biopsy. Ascites was the presenting symptom in 15 patients (88.2%), whereas jaundice (n=1) and variceal bl eeding (n=1) accounted for the other patients. Four patients (24 %) developed encephalopathy and seven became jaundiced (41.2%). Nine (47.1%) pati ents had varices, but only two patients had a variceal bleed. Twelve patients reached the outcome of death or re-LT for HCV. Two patients were transplanted, and are still alive at time of last follow up. The cause of death was graft failure in 7 of 10 patients. Cumulative probabili ties of survival were 75% at 3 months, 55% at 6 months, and 41% at 1 year with a median survival time of 6.8 months. 25

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MELD Score as a Predictor of Mortality Complete laboratory data were available to calculate a MELD score at study entry in 77 of 88 (87.5%) patients. Overall, there were 43 deat hs; 7 occurred within 3 months and 19 occurred within one year. The c-statistic for predicti on of 3 month and 1 year survival by the MELD score was 0.84 (95% CI 0.69.99, p= 0.003) and 0.87 (95% CI 0.72.93, p<0.001), respectively. 26

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Liver Transplantation for Hepatitis C n=502 No cirrhosis on biopsy n=328 Inadequate biopsy data n=68 Cholestatic HCV n=18 Recurrent Hepatitis C Cirrhosis n=88 Figure 3-1. Exclusion criteria. 502 patients were transplanted for HCV. Only 88 patients developed cirrhosis and were included in the study. 27

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Table 3-1. Baseline characteristics of patients with compensated and decompensated recurrent HCV graft cirrhosis Patient Characteristics Variables Compensated n=71 Decompensated n=17 P value Age in years (mean) 53.5 50.5 ns Sex (%male) 63.4 52.9 ns Race % Caucasian % African American % Hispanic 77.5 7.0 15.5 88.2 5.9 5.9 ns Age at OLT (mean) 49.4 47.4 ns Donor Age (mean) 43.5 50.9 ns Donor Sex (%male) 47.9 47.1 ns HCC at OLT (%) 14.1 0.0 ns Genotype (%) 1 2/3 4 70.4 7.0 1.4 64.7 11.8 5.9 ns Albumin (g/dL) 3.6 2.9 0.0001 Bilirubin (mg/dL) 1.9 4.4 ns Platelets (1000/mm3) 115.7 117.2 ns Creatinine (mg/dL) 1.2 1.7 0.0001 INR 1.1 1.2 ns HAI at time of cirrhosis 5.1 5.0 ns HAI average from all biopsies 4.1 4.4 ns Steroid treatment for rejection 52.1 43.8 ns No IFN treatment post-OLT (%) 28.2 47.1 ns SVR to IFN (%) 12.7 5.9 ns Treatment Failure to IFN 59.2 47.1 ns Immunosuppression Cyclosporine Tacrolimus Rapa 40.8 74.6 8.5 23.5 82.4 5.9 ns OLT before 12/31/1998 43.7 35.3 ns 28

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Liver Transplantation Histologic Cirrhosis n = 88 Decompensated at diagnosis n=17 19.3% Compensated at diagnosis n= 71 Decompensated n=26 36.6% No decompensation n=45 63.4% Dead n= 10 Alive n= 5 Dead n= 8 Alive n= 35 Re-OLT n= 2 Alive n=3 Re-OLT n= 4 Dead n= 19 80.7% Figure 3-2. Clinical outcome from time of st udy entry until death or last follow-up. 29

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Months after cirrhosis120 108 96 84 72 60 48 36 24 12 0 Cum Survival1.0 0.8 0.6 0.4 0.2 0.0 compensated cirrhosis decompensated cirrhosis p<0.001 [log-rank test ] Figure 3-3. Overall survival of the entire cohort (n=88) from time of study entry stratified into compensated cirrhosis (n=71) and decompensated cirrhosis (n=17). Survival is significantly worse in those who are decomp ensated at diagnosis (41% vs. 83% at 1 year). Median survival is also shorter (6.8 months vs. 47.8 months). 30

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Months after cirrhosis120 108 96 8472 6048362412 0 Cumulative probability of decompensation1.0 0.8 0.6 0.4 0.2 0.0 Censored Survival Function Figure 3-4. The cumulative probability of decompensa tion is 30% one year after the diagnosis of cirrhosis. The probability of deco mpensation at 5 years is 47%. 31

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Months after cirrhosis120 108 96 84 72 60 48 36 24 12 0 Cumulative Survial1.0 0.8 0.6 0.4 0.2 0.0 decompensation free decom p ensated p=0.001 [log-rank test ] Figure 3-5. Overall survival from di agnosis of cirrhosis. Survival is significantly better in those who remain compensated (p<0.001). Figure 3-5. Overall survival from di agnosis of cirrhosis. Survival is significantly better in those who remain compensated (p<0.001). 32

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Months from decompensation96 84 72 60 48 36 24 12 0 Cum Survival1.0 0.8 0.6 0.4 0.2 0.0 Figure 3-6. Cumulative survival from time of decompensation. The median time from decompensation to death is 11.8 months. Proba bility of survival once signs of liver decompensation develop is 46% at 1 year. 33

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Table 3-2. Univariate analysis of predictors of decompensation after recurrent graft cirrhosis Predictors of Decompensation Variables RR 95% CI p Age at post-OLT cirrhosis 0.98 0.93-1.03 ns Age at OLT 1.00 0.95-1.05 ns Male gender 0.74 0.34-1.61 ns Donor gender male 1.67 0.77-3.63 ns Donor age at OLT 0.99 0.97-1.01 ns Genotype 1 0.94 0.41-2.20 ns HCC at OLT 1.30 0.38-4.43 ns MELD 1.28 1.13-1.45 0.0001 Albumin at cirrhosis (g/dL) 0.45 0.23-0.92 0.03 Bilirubin (mg/dL) 1.17 1.07-1.28 0.001 INR 3.51 1.44-8.60 0.006 Creatinine (mg/dL) 0.91 0.29-2.87 ns Platelets (1000/mm3) 1.00 0.99-1.01 ns HAI score at cirrhosis 1.06 0.77-1.47 ns OLT to cirrhosis < 2 yr 3.20 1.31-7.80 0.01 OLT before 12/31/1998 0.75 0.34-1.67 ns CSA 0.53 0.23-1.21 ns TAC 1.96 0.76-5.03 ns RAPA 0.98 0.29-3.38 ns Graft rejection 0.57 0.25-1.31 ns Steroid RX for graft rejection 0.87 0.40-1.89 ns Response for interferon post OLT Treatment failures 0.28 0.12-0.64 0.003 Sustained response 0.05 0.04-0.42 0.006 34

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Months from cirrhosis80 60 40 20 0 Cum probability of decompensation1.0 0.8 0.6 0.4 0.2 0.0 MELD > 16 MELD 13-16 MELD <13 Figure 3-7. Decompensation by MELD score. As th e MELD score increases, the probability of clinical decompensation becomes significantly higher (p<0.001). 35

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Table 3-3. Univariate analysis of predictors of survival afte r recurrent graf t cirrhosis Predictors of Survival Variables RR 95% CI p Age at post-OLT cirrhosis 1.00 0.96-1.05 ns Age at OLT 1.02 0.97-1.06 ns Male gender 0.70 0.34-1.46 ns Donor gender male 1.00 0.48-2.07 ns Donor age at OLT 1.00 0.98-1.03 ns Genotype 1 0.61 0.29-1.29 ns HCC at OLT 3.50 1.29-9.53 0.01 MELD 1.32 1.15-1.51 0.0001 Albumin at cirrhosis (g/dL) 0.36 0.16-0.77 0.009 Bilirubin (mg/dL) 1.21 1.10-1.33 0.0001 INR 1.78 1.41-2.26 0.0001 Creatinine (mg/dL) 0.61 0.21-1.70 ns Platelets (1000/mm3) 1.00 0.99-1.01 ns HAI score at cirrhosis 1.22 0.92-1.63 ns OLT to cirrhosis < 2 yr 2.02 0.89-4.73 ns OLT before 12/31/1998 1.20 0.56-2.53 ns CSA 0.52 0.25-1.12 ns TAC 1.11 0.51-2.41 ns RAPA 0.56 0.17-1.91 ns Graft rejection 0.56 0.24-1.27 ns Steroid RX for graft rejection 0.90 0.44-1.88 ns Decompensation in < 1 year 5.29 2.23-12.5 0.0001 Response for interferon post OLT Treatment failures 2.31 1.08-4.93 0.03 Sustained response 0.15 0.02-1.17 0.07 36

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CHAPTER 5 DISCUSSION At the University of Florida, Hepatitis C is the most common indication for liver transplantation, accounting for almost half of all transplantations that have been performed to date. HCV recurrence in the graft is inevitable. Treatment after transplant ation to eradicate HCV is often attempted, but it is poorly tolerated s econdary to side effects. Rates of SVR after transplant are approximately 30%, which is less than would be expected in a nonimmunocompromised population.49, 50 These factors combined with the increase in number of patients being transplanted for HCV cirrhosis le ave transplant centers faced with continued growth in the number of post LT patients with recurrent HCV gr aft cirrhosis. For this reason, better insight into the natural history of recurrent HCV graft cirrhosis is needed. Much of the current understanding is based on a single centers experience from Spain which reported a rapid progression to decompensation and death once cirrhosis is present.40 By focusing on a similar group of patients, the goal of this study was to evaluate th e long term outcomes after the development of cirrhosis in a U.S. population. Decompensation and survival were the primary outcomes and predictive factors for each of these events were also evaluated. The results reported here represent the larges t series to date of patients w ith recurrent HCV graft cirrhosis. The key findings in this study can be summarized as follows: (1) Short term survival one year after the diagnosis of cirrhosis is good (83%) but falls to 41% by 5 ye ars; (2) the probability of decompensation one year after cirrhosis is 30% and remains less than 50% at five years; (3) survival is poor once decompensation develops; (4) MELD score 17 and transplantation for HCC are predictors of poor surviv al. These results confirm the aggressive nature of HCV after LT as the probabilities of decompensation and su rvival are less than what is reported in immunocompetent HCV populations. 37

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Ascites was the most common decompensating event, occurring in 30% of patients. Encephalopathy, jaundice, and GI bleeding also occurred in sim ilar proportions to previous reports. Only one case of de novo HCC occurred, which is quite different from the reported natural history prior to transplant. In a large c ohort of patients with HCV cirrhosis, HCC was the most common complication. It occurred in 32% of the population, and was the major contributor to mortality.51 The reason for lack of observed HCC in this study population is unknown, but it can be postulated to partly be a time depende nt phenomenon. The probability of developing cancer increases with time. The estimated annual incidence of HCC is 3%, with the cumulative probability of 15% at five years.6, 51 The cumulative probability of survival in this study cohort at five years was 41%. Simply put, patients may not live long enough after recurrent graft cirrhosis to have time to devel op HCC. The small number of patients in the study may also be a factor in the lack of incident cases. Although the general conclusions made from th is study are similar to those of Berenguer et. al40, the results suggest differences in the tim e frame in which complications develop. The median time from LT to development of cirrhosis was longer (3 vs. 2 years), and survival at one year was higher (83% vs. 72%). The lower probability of decompensation is the likely explanation, since decompensati on negatively influences surviv al (Figure 3-5). Antiviral treatment with IFN is one possi ble explanation for the slower rate of decompensation, since roughly two thirds of the patients were treated in an attempt to eradicate HCV. In the univariate analysis, IFN treatment reduced the risk of d ecompensation in patients who achieved an SVR. This finding is consistent with the only random ized controlled trial of IFN treatment after LT.52 The investigators reported a reduc tion in the hepatic venous pressu re gradient (HVPG) in those who achieved an SVR. This study did not ev aluate the affect of decreased HVPG on 38

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decompensation or survival outcomes, but the investigators had previously showed an elevated HVPG is predictive of severe recurrent HCV and decompensation.53 The results of the current study provide evidence that SVR may improve clin ical outcomes, not just surrogate markers like fibrosis progression. The findings are comparable to a recent study that showed achieving an SVR significantly reduced the risk of liver failu re in patients with advanced fibrosis or cirrhosis.54 Although significance of IFN treatment was lo st in the multivariate analysis because the total number who achieved an SVR was so small, it is an interesting fi nding that needs to be confirmed by others in the post transplant setting. The results strengthen the argument for aggressive treatment of those with recurrent HCV after LT, even if advanced disease is already present. Other possible reasons for the lower probability of decompensation are related to baseline differences in the two cohorts of patients that cannot be measured. The ci rrhotic cohort in the Spanish study had a CP score of 5 (range, 5) and an albumin of 3.8g/L at baseline, whereas the patients in the current study had a MELD of 11 (range, 6) and an albumin of 3.6g/L. A direct comparison in the severity of illness ca nnot be made since we did not use Child-Pugh (CP) scores. Because of the retrospec tive nature of this st udy, an accurate assignment of CP scores was not possible. Instead, a MELD score was calculated based on objective lab data done at the time of the biopsy. If anything, the slightly lowe r albumin would suggest a higher probability of decompensation in the current study since it was identified as an inde pendent predictor of decompensation by the Spanish group and approach ed significance in the current analysis. Regardless of the overall probability of decompensation, this study confirms that decompensation is a watershed event in recurrent HCV graft cirrhosis. The one year survival after clinical decompensation was only 46%, whic h is very similar to the Spanish study. For 39

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comparison, the probability of surv ival after the onset of the first major complication in a general HCV population is 50% at 5 years.4 The influence decompensation has on survival is best seen when survival is stratified by decompensation. One year survival in compen sated patients is 91% compared to 71% in decompensated patients. The difference is more pronounced at 5 years, where cumulative survival is 69% in those th at remain compensated and only 24% in the decompensated group. Interestingly, a group of patients had clinical si gns of decompensation which led to a biopsy confirming cirrhosis. The wors t survival was seen in these patients, with a 41% one year survival rate, compared to 85% and 92% in the other two groups. Importantly, this survival at one year is similar to that seen after decompensation occurs in the compensated group. The focus of this study was not to identify th e factors associated with recurrent graft cirrhosis, but known risk like donor ag e, steroid treatment for rejec tion and others were included in the analysis for predictors of decompensati on and survival. None were significant predictors of risk. The MELD score was used as a cont inuous variable and was predictive of both decompensation and survival. A score 17 conferred the highest risk of decompensation and thus survival. The finding that HCC at time of transplant negatively impacted survival is unexpected. LT is widely accepted as therapy fo r HCC when stringent selection criteria are used. To qualify for transplanta tion, a single tumor nodule must be less than 5cm in size or up to three nodules can be present if all are less than 3 cm. The in itial study was followed by others that demonstrated excellent survival.55, 56 In this highly selected study population of those with the recurrent graft cirrhosis, the decreased survival is not relate d to recurrent cancer. In fact, since tumor is removed at time of transplant something about its absence may accelerate the progression of recurrent HCV. 40

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Limitations of this study are its retrospectiv e nature which potentially introduces several confounding factors. The patients were transp lanted over the course of many years, and immunosuppression regimens and othe r clinical management protocols have changed with time. To asses for any impact that changes in clinic al management may have occurred with time, the cohort was divided into two groups by year of transplantation. The later group was used as a referent for those transplanted prior to December 1998, and no significant differences were found. The only potential for selec tion bias was in those patients who were treated with IFN. By protocol, all patients were eligible, but some were d eemed to sick to tolerate the treatment. This could exaggerate the effect of IFN treatment on preventing decompensation and survival if at baseline those not treated were sick. For that reason, treatment failures were compared only to those who achieved an SVR. Lead time bias was minimized because of the nature of the protocol biopsies yearly. In conclusion, recurrent HCV cirrhosis is a growing problem faced by liver transplant centers. Survival short term after cirrhosis is excellent, but decreases over time related to decompensation and graft failure. Once decompensati on occurs, survival is poor and repeat liver transplantation should be considered to improve survival. 41

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LIST OF REFERENCES 1. Bialek, S. The Changing Epidemology and Natural History of Hepatitis C Viral Infection. Clinics in Liver Disease 2006;10:697-715. 2. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infecti on in the United Stat es, 1999 through 2002. Ann Intern Med 2006;144:705-14. 3. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl 2003;9:331-8. 4. Fattovich G, Giustina G, Degos F, Tremol ada F, Diodati G, Almasio P, Nevens F, Solinas A, Mura D, Brouwer JT, Thomas H, Nj apoum C, Casarin C, Bonetti P, Fuschi P, Basho J, Tocco A, Bhalla A, Galassini R, Noventa F, Schalm SW, Realdi G. Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology 1997;112:463-472. 5. Hu K, Tong M. The long-term outcomes of patients with compensated hepatitis C virusrelated cirrhosis and history of parenteral exposure in the United States. Hepatology 1999;29:1311-1316. 6. Serfaty L, Chazouillres O, Bonnand A, Rosmorduc O, Poupon R, Poupon R. Determinants of outcome of compensated he patitis C virus-relate d cirrhosis. Hepatology 1998;27:1435-1440. 7. Thuluvath P, Segev D, Yoo H. Trends in pos t-liver transplant survival in patients with hepatitis C between 1991 and 2001 in the United States. Liver Transplantation 2007;13:719-724. 8. OPTN/SRTR. 2006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Tr ansplant Recipients: Transplant Data 19962005. Health Resources and Services Admi nistration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD. 2006. 9. Berenguer M. Natural history of recurrent hepatitis C. Liver Transplantation 2002;8:s14s18. 10. Berenguer M. Management of hepatitis C in the transplant patie nt. Clinics in Liver Disease 2007;11:355-76. 11. Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, Rayon M, Cordoba J, Herola A, Ascher N, Mir J, Berenguer J, Wright TL. HCV-related fibrosis progression following liver transplantation: increase in recent years. Journal of Hepatology 2000;32:673-684. 42

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12. Firpi R, Abdamalek M, Soldevila-Pico C, Ca brera R, Shuster J, Theriaque D, Reed A, Hemming A, Liu C, Crawford J, Nelson D. On e-year protocol liver biopsy can stratify fibrosis progression in liver tr ansplant recipients with r ecurrent hepatitis C infection. Liver Transplantation 2004;10:1240-1247. 13. Wali M, Harrison RF, Gow PJ, Mutimer D. Ad vancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C. Gut 2002;51:248-252. 14. Burak KW, Kremers WK, Batts KP, Wiesne r RH, Rosen CB, Razonable RR, Paya CV, Charlton MR. Impact of cytomegalovirus in fection, year of transplantation, and donor age on outcomes after liver transplantation fo r hepatitis C. Liver Transpl 2002;8:362-9. 15. Berenguer M, Prieto M, San Juan F, Rayn JM, Martinez F, Carrasco D, Moya A, Orbis F, Mir J, Berenguer J. Contribution of donor ag e to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002;36:202-210. 16. Rifai K, Sebagh M, Karam V, Saliba F, Az oulay D, Adam R, Castaing D, Bismuth H, Reynes M, Samuel D, Feray C. Donor age influences 10-year liver graft histology independently of hepatitis C viru s infection. J Hepatol 2004;41:446-53. 17. Neumann UP, Berg T, Bahra M, Seehofer D, Langrehr JM, Neuhaus R, Radke C, Neuhaus P. Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J Hepatol 2004;41:830-6. 18. Samonakis DN, Triantos CK, Thalheimer U, Quaglia A, Leandro G, Teixeira R, Papatheodoridis GV, Sabin CA, Rolando N, Davies S, Dhillon AP, Griffiths P, Emery V, Patch DW, Davidson BR, Rolles K, Burroughs AK. Immunosuppression and donor age with respect to severity of HCV recurrence after liver transpla ntation. Liver Transpl 2005;11:386-95. 19. Lake JR. The role of immunosuppression in recurrence of hepatitis C. Liver Transpl 2003;9:S63-6. 20. Samuel D, Forns X, Berenguer M, Trautw ein C, Burroughs A, Rizzetto M, Trepo C. Report of the monothematic EASL conference on liver transplantati on for viral hepatitis (Paris, France, January 12-14, 2006). J Hepatol 2006;45:127-43. 21. Berenguer M. What determines the natural hi story of recurrent hepatitis C after liver transplantation? Journal of Hepatology 2005;42:448-456. 22. Berenguer M, Aguilera V, Prieto M, San Juan F, Rayon JM, Benlloch S, Berenguer J. Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression. J Hepatol 2006;44:717-22. 43

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BIOGRAPHICAL SKETCH Virginia Clark received her unde rgraduate degree from the Un iversity of Georgia in 1996. Her medical degree is from Emory Un iversity, and she completed trai ning in internal medicine at Vanderbilt University in 2003. She completed subs pecialty training in ga stroenterology at the University of Florida in 2007. Her masters degree in clinical investigat ion was completed during her time as a gastroenterology and hepatology fellow. She joined the College of Medicine at the University of Florida as faculty in the Division of Gastroente rology, Hepatology, and Nutrition. 48