Recurrence of hepatitis C virus (HCV) after orthotopic. Poor Survival After Liver Retransplantation: Is Hepatitis C to Blame?

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1 RAPID COMMUNICATION Poor Survival After Liver Retransplantation: Is Hepatitis C to Blame? Kymberly D.S. Watt, Elizabeth R. Lyden, and Timothy M. McCashland Data from 1990 to 1996 suggest that the prevalence of hepatitis C virus (HCV) infection in repeated orthotopic liver transplantation (re-olt) is increasing, and patient survival may be worse. Aims of the study are to: (1) assess the prevalence of HCV in re-olt, (2) compare survival between primary OLT and re-olt for HCV versus non- HCV diseases, and (3) evaluate Model for End-Stage Liver Disease (MELD) scores in re-olt. The United Network for Organ Sharing database for adult patients undergoing primary OLT or re-olt from January 1996 to June 2002 was analyzed. Patients with malignancy or those who underwent re-olt within 30 days of primary OLT were excluded. A total of 22,120 primary OLTs and 2,129 re- OLTs were performed. HCV was noted in 9,564 primary OLTs (43.2%) and 899 re-olts (42.2%). Overall 1, 3, and 5-year patient survival rates were 86%, 79%, and 73% for primary OLT, but 67%, 56%, and 52% for re-olt (P <.001). Survival rates of patients with HCV at 1, 3, and 5 years were 86%, 76%, and 68% for primary OLT and 61%, 50%, and 45% for re-olt (P <.001). Survival was less for patients with HCV compared with those with autoimmune hepatitis (AIH) and hepatitis B for re-olt (P <.01). However, survival after re-olt was no different for those with HCV than for those with all other causes. MELD scores between 11 and 20 were the most common for re-olt. A marked decreased in survival was noted in all patients who underwent re-olt with MELD scores greater than 25. HCV prevalence in OLT has reached a plateau in recent years. Survival after re-olt is inferior to that for primary OLT, but re-olt survival appears to have improved. Survival after re-olt is lower in patients with HCV compared with those with AIH and hepatitis B, but no different than for those with most other liver diseases. Survival appeared worse in patients who underwent re-olt with a MELD score greater than 25. (Liver Transpl 2003;9: ) Recurrence of hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) is almost universal. 1-4 Recent data suggest that in approximately 20% of HCV-related transplantations, allograft cirrhosis develops within 5 years. 5-9 HCV-related re-olt increased significantly throughout the early 1990s, 10 but there are no recent prevalence data to show if this trend continues. Patient survival after primary OLT for HCV infection throughout the 1990s was similar to that for most other indications for OLT However, a recent study by Forman et al 14 showed an increased rate of death and allograft failure in HCV-positive compared with HCV-negative transplant recipients. 14 In general, re-olt has a lower survival rate than primary OLT In small studies, patient survival after re- OLT for HCV was not different compared with re- OLT for other causes. 1,3,12,18 Conversely, several other studies suggested that survival after re-olt for HCV is significantly worse than that for non-hcv related indications. 10,19-21 These studies also suggested that survival is worse in patients with HCV irrespective of the cause of graft failure. Many studies of re-olt have attempted to identify risk factors associated with poor survival ,15,18-23 The most common risk factors cited have been age, renal dysfunction, hyperbilirubinemia, and United Network for Organ Sharing (UNOS) status. Prognostic models have been developed recently, but these studies predate the Model for End-Stage Liver Disease (MELD) scoring system, which incorporates many of these factors In the era of MELD scoring, one can speculate that patients undergoing OLT are sicker and have more risk factors for poor outcome than those who underwent OLT under the UNOS status scoring system. Considerable concern and debate surround the topic of re-olt in general and specifically in HCV-infected patients. Aims of the study are to determine the current prevalence of HCV-related liver disease in the re-olt population, survival after re-olt for patients with HCV versus other diseases, and whether pre-olt MELD scores are predictive of survival outcome. Patients and Methods We performed a retrospective cohort study using the UNOS registry. Data were accrued for all patients older than 17 years who underwent OLT or re-olt between January 1996 and From Internal Medicine/Hepatology, University of Nebraska Medical Center, Omaha, NE. Address reprint requests to Timothy M. McCashland MD, Nebraska Medical Center, Omaha, NE Telephone: ; FAX: ; tmccash@surgery.unmc.edu Copyright 2003 by the American Association for the Study of Liver Diseases /03/ $30.00/0 doi: /jlts Liver Transplantation, Vol 9, No 10 (October), 2003: pp

2 1020 Watt, Lyden, and McCashland the absolute MELD score less certain. To minimize this effect, we evaluated groups of MELD scores ( 10, 11 to 20, 21 to 25, 26 to 30, and 30), rather than single values. Figure 1. Prevalence of HCV in primary OLT and re- OLT according to year., 1st OLT;, Re OLT. June Because data before 1996 are available in previous reports, we chose 1996 as our starting date. For prevalence data, HCV status was determined using diagnostic codes provided in the database (4204, HCV postnecrotic cirrhosis; 4216, Laënnec s cirrhosis and HCV; 4104, acute hepatic necrosis and HCV; 4106 and 4206, hepatitis B virus [HBV] and HCV coinfection), as well as HCV antibody and recombinant immunoblot assay and RNA testing results. Patients with such comorbid liver disease as malignancy or HBV coinfection were analyzed as separate groups. These groups lacked statistical power (n 7 and n 8, respectively) and therefore were excluded from the survival analysis. Patients who underwent re-olt within 30 days of their primary OLT were excluded from the survival analysis because these likely represent primary nonfunction, hepatic artery thrombosis, or other surgically related causes for re-olt. Data were gathered on cohorts of patients who underwent re-olt for hepatitis C, hepatitis B, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), nonalcoholic steatohepatitis/cryptogenic cirrhosis, metabolic/genetic diseases, or alcohol-related liver disease. The metabolic/genetic group consisted of patients with hereditary hemochromatosis, 1 -antitrypsin, Wilson s disease, Budd-Chiari syndrome, or other vascular indications. MELD score was calculated using pre-olt serum bilirubin and creatinine levels and international normalized ratio (INR) according to Kamath et al 28 : log (serum creatinine in milligrams per deciliter) log (serum bilirubin in milligrams per deciliter) log (INR). Prothrombin time was converted to INR. Frequency distributions of data were analyzed. Survival estimates were calculated using the Kaplan-Meier method, and confidence intervals for specific estimates of time-to-event distributions were calculated using Greenwood s formula for the variance of estimates. Comparisons of outcome among different diagnostic groups and MELD groups were performed using log-rank test. P less than.05 is considered statistically significant. Although laboratory values for MELD calculation were available for only 1,235 of the 2,023 patients in our cohort, we believe it is a reasonable representative sample. The need to convert a prothrombin time to INR for many patients makes Results Patient Characteristics The study population included 24,249 transplant recipients. Of these, 10,463 patients (43.1%) had HCV infection. There were 22,120 primary OLTs and 2,129 re-olts, and HCV-positive patients totaled 9,564 (43.2%) and 899 (42.2%), respectively. The prevalence of HCV-related liver disease in re-olt increased from 1996 to 2000, but has since reached a plateau (Fig. 1). Re-OLT accounted for 9% of all OLTs performed during this time frame. HCV-infected patients had a mean age of 48.8 years. Mean ages for patients without HCV with various causes of liver disease were between 44 and 52 years, with the exception of patients with AIH, who had a mean age of 39.3 years. Patient Survival Overall survival rates for primary OLT were 86%, 79%, and 73% at 1, 3, and 5 years, respectively. Survival rates for re-olt ( 30 days from primary OLT) were significantly lower at 67%, 56%, and 52% at 1, 3, and 5 years (P.001), respectively. These survival rates were no different when re-olts within 30 days were included. Survival rates for HCV-infected transplant recipients were 86%, 76%, and 68% at 1, 3, and 5 years after primary OLT compared with 61%, 50%, and 45% after re-olt, respectively (P.001; Fig. 2). Survival rates after re-olt for all transplant recipients without HCV (70%, 60%, and 57% at 1, 3, and 5 years, respectively) were better than those for patients Figure 2. Survival after primary OLT and re-olt for patients with HCV and non-hcv diseases (N-HCV) in our cohort. *P <.001 comparing HCV with non-hcv in primary OLT. **P <.01 comparing HCV with non-hcv in re-olt.

3 Poor Survival After re-olt 1021 Table 1. Survival After Retransplantation According to Cause of Disease Group 1 Year Survival (%) 3 Year 5 Year pvhcv HCV (n 771) 61 (57 65) 50 (45 54) 45 (39 51) HBV (n 79) 73 (61 85) 70 (58 83) Same as 3-yr.032 Metabolic genetic (n 60) 62 (49 76) 48 (31 66) Same as 3-yr.97 Alcohol (n 115) 70 (60 80) 60 (48 71) 49 (34 64).37 Cryptogenic (n 102) 68 (57 79) 57 (44 70) 49 (31 67).35 AIH (n 61) 81 (71 93) 65 (50 81) 61 (44 78).037 PBC (n 86) 70 (59 81) 59 (45 73) Same as 3-yr.27 PSC (n 127) 68 (59 78) 63 (53 73) Same as 3-yr.10 Abbreviation: CI, confidence interval. with HCV (P.01; Fig. 2). Analyzed as individual groups, only patients with hepatitis B and AIH had significantly greater survival rates after re-olt than patients with HCV. Survival after re-olt was no different for those with HCV infection than for those with all other liver diseases (Table 1). One-year survival was similar for patients with HCV who underwent re-olt when analyzed according to year of OLT ( 1999, 1999 to 2000, 2000); however, long-term data are lacking. The most frequent causes of death in patients with and without HCV were sepsis (17.2% and 22.4%, respectively), multiorgan failure (10.8% and 12.6%, respectively), other infections (13.8% and 8.6%, respectively), and cardiovascular (7.5% and 10.9%, respectively). Graft failure accounted for 19.7% of deaths in HCV-infected patients, of which 10.8% were related to recurrent disease. Graft failure was the cause of 14.9% of deaths in patients without HCV. MELD Analysis Mean MELD scores for re-olt for patients with and without HCV were similar (21.7 and 21.5, respectively) and were constant from 1996 to 2002 (data not shown). MELD scores were analyzed in groups of 1 to 10, 11 to 20, 21 to 25, 26 to 30, and 30 and higher. Almost 40% of patients underwent re-olt with a preoperative MELD score between 11 and 20 (Fig. 3). Survival after re-olt in all groups decreased with increasing preoperative MELD scores. Survival was no different for those with HCV versus non-hcv diseases when analyzed according to MELD score groups (1 to 10, 11 to 20, 26 to 30, and 30 ; Table 2). However, patients with HCV had significantly decreased survival compared with those without HCV with MELD scores between 21 and 25 (P.001). Survival after re-olt was significantly lower than after primary OLT for each MELD group (P.001). Overall, a marked decrease in 5-year survival to less than 60% was noted in all re-olt patients with a MELD score higher than 25 and all re-olt patients with HCV with a MELD score higher than 20 (Table 2). Most concerning was the 5-year survival rate of 20% to 40% for those with a MELD score higher than 30. Discussion Our data show that the prevalence of HCV in both primary OLT and re-olt has increased. We again show that survival after re-olt is worse than after primary OLT for all patients, but the gap may be smaller than previously reported. Our results support previous findings showing that survival after re-olt for patients with HCV is less than combined survival for all other diagnoses. However, we show no difference Figure 3. Percentage of patients with HCV and non-hcv diseases who underwent re-olt according to MELD score groups., HCV;, non-hcv.

4 1022 Watt, Lyden, and McCashland Table 2. One- and 5-year Survival According to MELD Score Group Cause 1-Year Survival (%) 5 Year MELD 10 HCV (n 77) 83 (73 93) 55 (37 73).420 Non-HCV* (n 53) 81 (66 97) 74 (54 94) MELD HCV (n 262) 65 (58 72) 55 (46 64).600 Non-HCV* (n 225) 73 (66 80) 60 (50 70) MELD HCV (n 122) 62 (53 72) 47 (35 58).001 Non-HCV* (n 96) 81 (73 90) 66 (48 84) MELD HCV (n 100) 57 (46 68) 37 (23 52).490 Non-HCV* (n 81) 64 (52 75) 53 (39 66) MELD 30 HCV (n 126) 42 (32 53) 21 (6 36).073 Non-HCV* (n 93) 55 (44 66) 47 (36 59) NOTE. p obtained from log-rank test for overall survival. Abbreviation: CI, confidence interval. *Specified cohort including HBV, AIH, PBC, PSC, nonalcoholic steatohepatitis/cryptogenic cirrhosis, alcoholic liver disease, and metabolic/genetic diseases. p in re-olt survival for patients with HCV compared with those with most other causes of liver failure, with the exception of HBV and AIH. We also show that post-olt survival appears to decrease as preoperative MELD score increases. At each MELD score, survival is worse for re-olt than primary OLT, but is not disease specific. In 1998, Rosen and Martin 10 showed the prevalence of HCV in re-olt increased dramatically from 1990 to Two other studies documented a similar finding in primary OLT. 12,14 We show that the prevalence of HCV-related liver disease continued to increase in both primary OLT and re-olt through the 1990s and reached a plateau in recent years. Approximately 46% of primary OLTs and 43% of re-olts are performed in patients with HCV cirrhosis. Re-OLT accounts for 9% of all OLTs performed. However, given the retrospective nature of the study and inherent inconsistencies of the database, absolute prevalence cannot be established. To overcome these obstacles, extra effort was made in examining the database for repeated entries and other inconsistencies to increase the accuracy of our results. We show primary OLT survival rates consistent with those of previous investigators ,29,30 However, in 1997, Markmann et al 15 published single-center data and reported survival rates of 52% at 1 year and 42% at 5 years in adults undergoing re-olt between 1984 and In comparison, we show survival rates of 67% at 1 year and 52% at 5 years in adults undergoing re-olt between 1996 and These survival rates are similar to those reported in a recent European study. 31 This may suggest a small improvement in the overall survival rate of adults undergoing re-olt, but comparing single-center data with a large multicenter database may not be valid. Rosen and Martin 10 previously showed worse outcomes in patients who underwent re-olt between 1990 and 1996 for HCV-related liver disease compared with non-hcv diseases. Our data support this notion when comparisons are made between patients with HCV and all other re-olt patients combined. However, analyzed as subgroups, underlying HCV does not appear to portend worse survival than most other diagnoses we analyzed. Patients with hepatitis B and AIH were the only subgroups with significantly increased survival compared with those with HCV. Improved survival in patients with HBV infection can be explained easily by the advent of hepatitis B immunoglobulin and lamivudine therapies. Outcome in patients with AIH possibly is related to added advantages of immunosuppression in this disease compared with other diseases. Interestingly, survival of patients with HCV was similar to that of patients with cholestatic liver diseases after re-olt. Cox regression analysis showed no difference in survival between patients with HCV and PSC or PBC when adjusted for age and MELD score. Cholestatic diseases have always been thought to have better outcomes with OLT than other chronic liver disease. We can only speculate about why this would not occur in the case of re-olt. Pairwise comparisons

5 Poor Survival After re-olt 1023 between HCV and other diagnostic groups in this database may be underpowered, making interpretation of results difficult. One limitation of this type of study and studies like it is the inability to determine the exact cause of graft failure, whether disease recurrence, chronic rejection, vascular compromise, or primary nonfunction. This may impact on our findings, but previous studies have shown no difference in survival based on cause of graft failure Use of a multicenter database to provide mean survival statistics has both advantages and disadvantages. The obvious advantage is the number of patients analyzed and the power of the study. One disadvantage is that these statistics are not representative of individual centers. Previous studies have shown that the volume of OLTs in a center impacts on overall survival rates; highvolume centers have greater survival rates than lower volume centers. 31 Thus, statistics such as ours may not be applicable to individual centers. Several investigators have attempted to identify factors predictive of poor outcome post-olt ,15,18-23,27 They all identify similar variables, and many have attempted to develop prognostic models for survival after primary OLT and re-olt All these studies have shown recipient age, creatinine level, and bilirubin level to be predictive of survival after primary OLT or re-olt. UNOS status and intensive care unit requirements also were predictive in some of these studies. Given that many of these factors are incorporated into the MELD score, we chose to examine preoperative MELD scores associated with post-olt survival rates. Similar to other predictive models, higher scores were associated with lower post-olt survival rates. On average, HCV was associated with a lower survival rate compared with non-hcv diseases. Within each MELD group, this difference was not significant, except for MELD scores between 21 and 25. However, as listed in Table 2, this may represent an unexpected high survival rate for the non-hcv group in this MELD group as opposed to a lower survival rate in patients with HCV. There is no clear explanation for this finding, and it may represent aberrant data. Almost 40% of patients undergoing re-olt during the study years had MELD scores between 11 and 20. It is likely that mean MELD score will only increase in the coming years. Mean MELD score for OLT from February 2002 to December 2002 documented in the UNOS Web site was 25. Only recently has the MELD scoring system been validated as predictive of 3-month survival on the transplant waiting list. 32,33 There is a paucity of data assessing the predictability of pre-olt MELD score on post- OLT survival rate. 34,35 Although our study was not designed to evaluate the predictive capability of the MELD score for post-olt survival, our data suggest a MELD score higher than 25 may be associated with a decrease in survival after re-olt to less than 60%. This finding has significant implications and needs to be confirmed in prospective studies. Because organs are allocated based on MELD scores, most centers are performing OLT on patients with MELD scores higher than 25. The impact of higher MELD scores on survival may require such policy changes as awarding additional points to re-olt candidates to allow OLT to occur at a lower MELD score. Additionally, a predictive model used at the time of listing a patient for OLT would be invaluable to maximize the use of scarce organs. The transplant community needs to define acceptable 1- and 5-year survival rates. Certainly, survival rates 20% to 40% lower than those for primary OLT (i.e., MELD 30) argue for poor graft use. In conclusion, we show that approximately 45% of all OLTs are performed for HCV-related liver disease. Survival after re-olt continues to be worse than after primary OLT, but may be improving. HCV is associated with lower survival after re-olt compared with HBV or AIH, but not compared with all other forms of liver disease in our cohort. Our data suggest that a MELD score higher than 25 is associated with poor survival after re-olt. Further studies are required to define a threshold above which survival declines to less than an acceptable level. References 1. Gane EJ, Portmann BC, Naoumov NV, Smith HM, Underhill JA, Donaldson PT, et al. 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