Mortality Predictors in Liver Transplant Recipients With Recurrent Hepatitis C

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From Liver International
Mortality Predictors in Liver Transplant Recipients With Recurrent Hepatitis C Cirrhosis
Posted 09/21/2005
Sammy Saab; Henry Niho; Scott Comulada; Jonathan Hiatt; Francisco Durazo; Steven Han; Douglas G. Farmer; Curtis Holt; Hasan Yersiz; Leonard I. Goldstein; R. Mark Ghobrial; Ronald W. Busuttil
Abstract and Introduction
Abstract

Background/Aim: Recipients of orthotopic liver transplant for hepatitis C (HCV) invariably develop recurrent disease. The risk factors for death and retransplantation following the development of cirrhosis from HCV are unclear. The aim of this study was to identify predictors of survival in liver transplant recipients who develop cirrhosis from recurrent HCV.
Methods: We reviewed records of patients who underwent liver transplantation for cirrhosis due to HCV between January 1990 and December 2001. Prognostic factors of patient survival following the development of recurrent cirrhosis were identified through multivariate analysis.
Results: During the study period, 511 patients underwent transplantation for HCV cirrhosis. Of these, 65 patients (13%) developed biopsy proven recurrent cirrhosis from HCV; 43 (8%) were relisted for transplantation, and 24 (5%) underwent retransplantation. The overall Kaplan–Meier patient survival rates after the histologic diagnosis of cirrhosis at 1 and 5 years were 66% and 30%, respectively. A multivariate Cox proportional hazards model showed patients with higher last (i.e. at follow-up or prior to retransplantation) International normalized ratio (INR) values (hazard ratios (HR) = 2.02, 95% confidence interval 1.26, 3.24, P < 0.01) to have an increased risk of death.
Conclusion: Our Results suggested survival was decreased after the diagnosis of cirrhosis from recurrent HCV. Higher INR was associated with an increased risk of death following the development of cirrhosis.
Introduction

Hepatitis C (HCV) is currently the leading indication for orthotopic liver transplantation (OLT) in the United States.[1] In 1997, between 8000 and 10 000 patients died of HCV cirrhosis.[2,3] The number of deaths per year is projected to increase to 17 000 between 2010 and 2019.[4] The absolute number and relative proportion of transplants for HCV are likely to increase in the next decade, as a large cohort of infected individuals begin to seek medical care.[2]

Recurrent HCV disease is accelerated following OLT. After the first year, more than a quarter of patients show some degree of histologic damage;[5,6] at 3 years, the percentage increases to 80%.[7] Cirrhosis can develop in 10% to 20% of liver transplant recipients after 5 years.[7,8] In contrast, 20% of individuals from the general population develop cirrhosis after two decades of infection.[3] There are a number of factors associated with fibrosis progression after liver transplantation, including donor age and multiple steroid pulses.[9–12] Decompensation also appears to be accelerated after the development of cirrhosis. The probabilities of decompensation at 6 and 12 months are 17% and 42%, respectively.[11]

However, the mortality predictors after the development of cirrhosis are unclear. Thus, in the current study we identify predictive factors of patient survival in liver transplant recipients who developed cirrhosis. The Results may help estimate prognosis in patients with cirrhosis from recurrent HCV after liver transplantation.

Sammy Saab,1,2 Henry Niho,1 Scott Comulada,3 Jonathan Hiatt,2 Francisco Durazo,1,2 Steven Han,1,2 Douglas G. Farmer,2 Curtis Holt,2 Hasan Yersiz,2 Leonard I. Goldstein,2 R. Mark Ghobrial,2 and Ronald W. Busuttil2

1Division of Digestive Diseases, Department of Medicine, Los Angeles, CA, USA
2Department of Surgery, Dumont-UCLA Liver Transplant Center, Los Angeles, CA, USA
3Department of Biostatistics, University of California Los Angeles, Los Angeles, CA, USA

Patients and Methods

A retrospective review was performed for patients who developed cirrhosis from recurrent HCV between January 1990 and December 2001. These patients were previously described in an earlier study.[5] The current report provides longer follow-up (extended to June 2003) and more complete information regarding patients specifically with cirrhosis from recurrent HCV. Variables selected for analysis included recipient age (at time of transplantation), history and number of rejection episodes, donor age, laboratory values, time from transplant until date of cirrhosis diagnosis. Laboratory values were those before the first transplant (pretransplant) and either the value available at last follow-up or before retransplantation (last). Data were collected in accordance with requirements of our Institutional Review Board.

Patients undergoing OLT were stratified as urgent or nonurgent recipients according to UNOS status. Between 1990 and 1994, status 1, 2, and 3 patients were classified as nonurgent recipients, while status 4 patients were categorized as urgent. Between November 1994 and February 2002, UNOS altered its status designation, and status 2, 2B, 3, or 4 patients were designated as nonurgent recipients while status 1 or 2A patients were deemed urgent.

Immunosuppression regimens after OLT included combination therapy with tacrolimus, cyclosporine, and/or prednisone. According to our protocol, patients initially received 1 gm of methyprednisolone intravenously on the day of transplantation, followed by a taper to 20 mg/day over the first week. Oral prednisone was subsequently begun at 20 mg/day and tapered over 2 to 3 months as tolerated. Mycophenolate mofetil was used in patients with renal insufficiency or with intolerance to standard doses of cyclosporine or tacrolimus.

Cirrhosis was defined based upon histological findings. Biopsies were performed for the evaluation of elevated liver enzymes or clinical suspicion of cirrhosis such as ascites, jaundice and encephalopathy. Protocol biopsies were not performed. Survival was defined as the interval between the diagnosis of cirrhosis and death or last follow-up.
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Statistical Methods

Clinically relevant prognostic factors were chosen and compared between patients receiving and not receiving a second transplant (transplant status); proportions and medians were compared using the 2 and Wilcoxon rank-sum tests, respectively. The Wilcoxon rank-sum test was performed on continuous prognostic factors because the distributions were skewed.

The Kaplan–Meier method[13] was used to calculate 1- and 5-year survival rates after the diagnosis of cirrhosis. Cox proportional hazard regressions[14]were performed to investigate risk of death after the histologic diagnosis of cirrhosis, postfirst transplant. Predictors included transplant status and prognostic factors, except for gender. Separate Cox regressions were performed for each predictor (univariate analyses) and stepwise procedures were used to build final models. Predictors entered into models with significance levels of 0.10 or less and retained with significance levels of 0.05 or less. Transplant status and time from first transplant until cirrhosis were included in all final models, regardless of significance level, because they were thought to be clinically important. Hazard ratios are calculated by exponentiating Cox parameter estimates.

Transplant status was included as a time-dependent predictor in Cox regressions to adjust for waiting time from cirrhosis diagnosis until a second transplant was received. Adjusting for waiting time was important because patients may have expired while waiting for a second transplant, leading to a higher risk of death in patients not receiving a second transplant, compared with patients receiving a second transplant. We incorporated transplant status as a time-dependent predictor using methodology described in Allison.[15] All analyses were carried out using the SAS system, version 8.01 (SAS Institute Inc., Cary, NC).

Results
Baseline Characteristics

Between January 1990 and December 2001, 511 patients were identified who underwent transplantation for cirrhosis because of hepatitis C. Of the 511 patients, 65 developed recurrent hepatitis C with biopsy proven cirrhosis (12.7%) and comprise the current study group.

Of the 65 patients, 44 (68%) were male, and 21 (32%) were female, with a mean age of 55 ± 9.1 years. Their baseline laboratory values are shown in Table 1 . Of the 65 patients, 12 (18%) were diagnozed before the onset of clinical decompensation. Thirty-three (51%) recipients had at least episode of acute cellular rejection.

Decompensation occurred in 60 of the 65 patients (92.3%). The mean (±SD) time to decompensation was 1.8 (±2.1) years after the diagnosis of cirrhosis, in patients who did not have any clinical manifestation of liver disease at the time of the liver biopsy. The mean and median time after liver transplantation to the histological diagnosis of cirrhosis was 2.6 and 2.0 years, respectively.
Immunosuppression

Forty (62%) of our patients received tacrolimus, and 25 (38%) cyclosporine as the primary immunosuppressant agent. Fifteen (23%) patients were also administered mycophenolate mofetil. Of the 40 patients on tacrolimus, 10 also received mycophenolate mofetil. Of the 25 patients on cyclosporine, five patients also received mycophenolate mofetil. No patients required OKT-3 for acute rejection.
Follow-up

Forty-three of the 65 patients were listed for retransplantation, and 24 of them received a second transplant. The mean (±SD) interval between original liver transplantation and retransplantation was 33.3 ± 27.1 months. The UNOS status of one patient undergoing retransplantation was 1 and another was 2A. Six patients were status 2, three patients were status 2B, and 10 patients were status 3. The status was not available in three. Of the 24 patients who underwent retransplantation, 12 patients expired after a mean (±SD) of 14.6 (±19.5) months. Of the remaining 19 patients who were listed for retransplantation, 14 expired while awaiting liver transplant, while five are still alive awaiting a second graft. Of the 22 patients not listed for retransplantation, 12 are currently alive; four of them are compensated and were not believed to require retransplantation at this time. These data are summarized in the Fig. 1.

     
Click to zoom   
Figure 1.  (click image to zoom) http://images.medscape.com/images/512/989/thumb-liv512989.fig1.gif

Outcome of patients with cirrhosis from recurrent hepatitis C. Of the 65 patients in our cohort, 24 underwent retransplantation. One patient underwent a third transplant. HCV, hepatitis C virus; reOLT, reorthotopic liver transplantation; GIB, gastrointestinal bleed.

Prognostic Factors

Prognostic factors are summarized by transplant status in Table 2 . Patients receiving a second transplant were more likely to experience rejections (2 = 4.16, df = 1, P = 0.04), had a higher median pretransplant serum creatinine level (Wilcoxon test, P = 0.03), had a higher median Model for end-stage liver disease (MELD) score at cirrhosis diagnosis (Wilcoxon test, P = .01), and had higher median current total bilirubin, serum creatinine, and MELD scores (Wilcoxon tests, all P < 0.01) than patients not receiving a second transplant. This suggests that sicker patients may be more likely to receive second transplants. Other transplant status differences were not statistically significant.
Survival Rates

The overall Kaplan–Meier patient survival rates at 1- and 5-years after the diagnosis of cirrhosis were 66% and 30%, respectively. An adjustment for waiting time was incorporated into the Cox regressions.
Cox Regressions

Results from the univariate Cox regression models are shown in Table 2 . Univariate analyses help to determine which prognostic factors to consider when analyzing patient survival by transplant status. Risk of death was higher for patients with higher values of last creatinine and International normalized ratio (INR). Donor age was not associated with higher risk of death.

Results from the final Cox models, chosen by stepwise selection, are shown in Table 3 . Transplant status and time to cirrhosis were not significant predictors of risk of death in any of the Cox models, but retained because we felt they were clinically important.

Risk of death was found to double per unit increase in INR in the final Cox regression model.
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Discussion

Allocation of organs is beset with ethical and practical considerations. It is an essential premise of liver transplantation to allocate organs in a productive and non-futile approach. Recurrent HCV has become an important and controversial issue in liver transplantation. As the number and proportion of patients transplanted for HCV increases, recurrent HCV disease is likely to become a substantial problem. Many of these patients are likely to return to their transplant centers requiring retransplantation. However, retransplantation may not necessarily be the best option for all patients. For most indications, clinical outcome is generally worse following retransplantation than primary transplantation for the original disease.[16]

Several investigators have created models to predict survival after the development of graft dysfunction. Using variables identified in univariate and multivariate analyses, several recipient variables have been consistently identified to have prognostic significance, including age, high UNOS status, serum creatinine level, serum bilirubin level, and coagulopathy.[17, 18] Arguably, the most important among these appear to be serum creatinine level and serum bilirubin.[17] In our study, the risk of death was found to double per unit increase in INR in the final Cox regression model.

Time to recurrent HCV cirrhosis was not found to be an important predictor of survival. The effect of early recurrent cirrhosis may reflect both host and viral factors. Previous studies have suggested that treatment of rejection may lead to early disease and graft failure. The association between death was independent of the history or number of rejection episodes. The association also showed little difference, whether or not severity of liver disease, as measured by bilirubin, creatinine, and INR, was considered. Donor age was also not found to be predictive of death after the diagnosis of cirrhosis. This is in contrast to several studies where donor age was predictive of posttransplant outcome.[9–12] Although donor age may be a risk factor for hepatitis C progression, its utility in predicting mortality after the development of cirrhosis may be limited. Furthermore, the cause of graft failure and/or death was not discussed or identified in several studies.[9,10,12] It may also be than in our select population of patients with a histologic diagnosis of cirrhosis factors other than donor age were more predictive of survival.

Our study has several important limitations. First, since protocol biopsies were not performed in our study cohort, we may have underestimated the frequency, and thus the survival, of patients with histologic cirrhosis. However, it is our practice to perform liver biopsies on all patients with abnormal liver tests. Since only patients with histologic diagnosis of cirrhosis were included, we have overestimated survival since patients with more advanced liver disease may be less likely to undergo a liver biopsy. Changes in the allocation policy, immunosuppression schedule, and selection of transplant recipients over time may have biased our Results. Moreover, we did not include viral load as a predictor model. Many recipients had their viral loads measured at different laboratories using a variety of assays making any conclusions regarding comparison within and between patients suspect.

Our study cohort was likely a select population. Our patient survival was higher than that reported elsewhere.[13, 19] An important predictor of survival in our study, and others, is preretransplant liver disease severity: the greater the severity of liver disease, the worse the expected outcome.[20] The trend in our institution has been to avoid retransplantation of patients with severely impaired synthetic function and/or respiratory failure.[21, 22] This potential limitation was taken into account by allowing pretransplant measures of liver severity to be included in our final Cox regression models. However, posttransplant measures, including INR, had greater effects on survival. In the liver allocation of MELD-era, where retransplantation is inherently dependent on INR, substantial lower survival is expected.

The current study focuses upon readily available clinical variables to identify independent predictive variables of death and liver retransplantation following the development of cirrhosis. We did not include donor or operative specific variables, such as age or ischemic time, since these factors may not be modifiable. Confronted with the decision of whether to transplant in patients who are unlikely to survive without transplantation, expanded donor grafts remain an attractive option.

We chose to include the last and most current set of potential predictors because of the fact that most clinical decisions are based on this information. Future studies using protocol biopsies, and with a greater number of patients, should assess predictor variables at different time points in the natural history of patients with cirrhosis from recurrent HCV.

The Results of our study indicate that development of coagulopathy is an important independent risk factor of mortality. Patients with recurrent HCV and who develop coagulopathy should be considered for retransplantation. Because of the small number of patients who were transplanted a second time and the limited follow-up, we are unable to comment on subgroups who benefit from retransplantation. Decisions regarding retransplantation need to take into account the needs of an individual with the ethics of allocating organs to recipients with the greatest outcome.

In summary, recipients transplanted for HCV are at risk of recurrent disease. The clinical impact of recurrent disease is likely to increase with longer follow-up. Our Results suggest higher levels of INR is an important predictor of death following the development of cirrhosis from recurrent HCV. This study emphasizes the importance of further investigation of the utility of retransplantation in recipients with recurrent HCV disease.

Figures for:
Mortality Predictors in Liver Transplant Recipients With Recurrent Hepatitis C Cirrhosis

[Liver Int.  2005;25(5):940-945.  ©2005 Blackwell Publishing]

    Figure 1.Outcome of patients with cirrhosis from recurrent hepatitis C. Of the 65 patients in our cohort, 24 underwent retransplantation. One patient underwent a third transplant. HCV, hepatitis C virus; reOLT, reorthotopic liver transplantation; GIB, gastrointestinal bleed.

http://images.medscape.com/images/512/989/art-liv512989.fig1.gif

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 Tables for:
Mortality Predictors in Liver Transplant Recipients With Recurrent Hepatitis C Cirrhosis

[Liver Int.  2005;25(5):940-945.  ©2005 Blackwell Publishing]

Table 1. Demographics and Laboratory Values


    Table 1 http://images.medscape.com/images/512/989/art-liv512989.tab1.gif


Table 2. Risk of Death After Cirrhosis Diagnosis


    Table 2 http://images.medscape.com/images/512/989/art-liv512989.tab2.gif


Table 3. Results for Final Cox Regression Models of Risk of Death After Cirrhosis Diagnosis of Cirrhosis


    Table 3 http://images.medscape.com/images/512/989/art-liv512989.tab3.gif

References for:
Mortality Predictors in Liver Transplant Recipients With Recurrent Hepatitis C Cirrhosis

[Liver Int.  2005;25(5):940-945.  ©2005 Blackwell Publishing]

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