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Retransplantation for recurrent hepatitis C
Retransplantation for Recurrent Hepatitis C Rufik M. Ghobriul J Key Points 1. Primary orthotopic livertransplantation(OLT)for hepatitis C is performed with good results. 2. Re-OLT in hepatitis C virus (HCV)-infectedtransplant recipients is performed mostly for indications other than recurrent diseasein the short-term after primaryOLT. 3. Progressive allograft injury and loss caused by recurrent disease predict an increased need for re-OLT for HCV recurrence in thelong term. 4. Outcomes of re-OLTforrecurrenthepatitis C are equivalent to results for other indications of re-OLT. 5. Good outcomesare obtained in selected patients when re-OLT is performed earlyin the courseof recurrent diseasebeforetransplantrecipientsbecomecritically ill.
(Liver Tramp12002;8:S38-S43.)
iver disease caused by hepatitis C virus (HCV) has become the most common indication for orthotopic liver transplantation (OLT).Recurrence ofHCV afier OLT is nearly universal and may lead to progressive liver disease, with graft loss that may require reOLT. Therefore,increasingconcern has developed regarding long-term outcomes, factors that determine the severity of recurrent H C V disease after OLT, and factors that may lead to re-OLT. This review discusses outcomes afterOLT for HCV, causes and outcomes of re-OLT inHCV-infectedpatients, and factorsthat influence results of re-OLT.
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Survival Outcomes After Primary OLT for HCV Most investigatorsdescribe survival outcomesafter OLT for HCV similar to those of other indications for OLT.1 Only patients who undergo OLT for cholestatic liver disease achieve better long-term survival.2 At my 8-year institution, OLTs in 374 patientsduringan
From the Department o f Surgey, Division o f Liver and Pancreas Transplantation, David Geffen School of Medicine at University o f California Los Angeles, Los Angeles, CA. Address reprint requeststo Rafik M. Ghobrial, MD, PhD, DumontUCLA Transplant Center, DavidGefen School o f Medicine at UCLA, I0833 LeConte Ave,77-132CHS, Los Angeles, CA 90095. Telephone: 310-825-2678; FAX 310-267-0392; E-mail:[email protected] Copyright O 2002 by the American Association f . r the Study o f Liver Diseases 1527-6465/02/0810-I015$35.00/0 doi:IO. 1053/j1ts.2002.35861
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period achieved overall patient survival rates of 86%, 82%, and 76% and graft survival rates of 70%, 65%, and 60% at l, 2, and 5 years, respectively.3Comparison to a contemporary cohort of 701 patients who underwent OLT for causes other thanviral infections did not show a difference in patient survival. Multiple other series showed similar results. Casavilla et a14 reported patient survival rates of 80% and 75% at 1 and 5 years inacohortof183patients.Inanotherstudythat included 149 transplant recipients, patient and graft survival were not significantly different from those of HCV-negative patients at 1 and 5 years post-OLT.5 Thus, despite the risk for recurrent HCV after OLT, OLT is performed with goodresults.
Effects of HCV Recurrence AfterOLT Despitegoodshort-term and midterm survival outcomes, H C V recurrence after whole cadaveric OLT, measured by polymerase chain reaction detection of HCV RNA, is nearly universal6 and may lead to progressive allograft injury and failure.1,397,8 However, the reported incidence of histological HCV recurrence varied widely between 14% and 72%. l 5 7 - 9 Such variation may be caused by differences in definitions of chronic hepatitis, lengths of follow-up, and whether protocol biopsies were performed. Nevertheless, approximately 50% of patients may show some degree of abnormal histological characteristics1 year after 0LT.lo Two years after OLT, approximately 25% of patients may show moderate to severe histological hepatitis, shown in a cohort of 124 patients.' At my center, 30% of patients showed evidence of histological recurrence in the first year after OLT.' Sreekumar et a l l 2 reported mean hepatitis activity indices of 2.74, 2.07, and 2.65 and mean fibrosis scores of 1.06, 1.39, and 1.31 at 4 months and 1 and 3 years after whole-organ cadaveric OLT, respectively. In addition, 8% to 31% of patients with post-OLT recurrence developed cirrhosis in 5 to 7 years 192510-14 and ensuinggraftfailurein 10% of patients by postoperative year 5.1,5,7-9911Thus, it is anticipated that with the currentslow, but steady, progression of disease after OLT, increasing numbers of patients will require re-OLT with long-term follow-up.
Liver Transplantation, VoL 8,No 10, Suppl l (October), 2002:pp S38-S43
Retransplantation for Recurrent Hepatitis C
Causes of Graft Loss and Re-OLTin HCVInfected Transplant Recipients
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pendent progression of recurrentdisease predict a need for re-OLT in the long term.
Although histological progression of HCV after OLT predicts a need for re-OLT, only a small subset of Predictors of Re-OLT in HCV-Infected patients appears to develop severeallograft injury Transplant Recipients caused byHCV recurrence that prompts re-OLT in the short-term or midterm.l5,16 In one study that included Much attention currently is directed toward identifica149 patients who underwent OLT for HCV, graft loss tion of factors that influence the rate and severity of hepatitis C recurrence. Determination of such factors occurred in 27 of 149 patients, but only 8 patients would identify patient populations susceptible to deleexperienced graft loss secondary to HCV recurrence.5 terious effects of recurrent HCV and who therefore Recurrent HCV with ensuing graft failure in a series of require antiviral therapy and/or re-OLT. OKT3 treat166 HCV-infected transplant recipients was the cause ment for steroid-resistant infection has been associated of death in 1 1 of 39 patients who died during the convincingly with early and severe HCV recurrence in follow-up period.* Also, sepsis,but not recurrent HCV, allografts.19,20 Cirrhosis was documented in 26.3% of appears to be the most common cause of death in allografts in patients administered OKT3 during their HCV-infected transplant recipients.3 post-OLT course compared with 6% of patients who T o date, numbers of patients undergoing re-OLT were not.20 Similarly, severe or multiple rejection epifor recurrent HCV compared with other causes of resodes were associated with early recurrence.' Greater OLT have been relatively low.In theseries reported by viral replication levels were documented with excessive Sheiner et al,l5 43 of 262 patients (16.4%) underwent steroid use for treatment of rejection episodes.19 Some re-OLT after a successful firstO L T for HCV infection, studies implicated elevated pre-OLT2 or post-OLT. and only 14 of 49 re-OLTs were performed for recurHCV RNA levels12 and infection with HCV genotype rent HCV. From 166 HCV-infected transplant recipil b5 with pooroutcome and increased rateof graft daments reported by Charlton et a l , 2 5 patients required age. However, other reports indicated no difference in re-OLT for recurrent HCV. In our series that included HCV genotype, basal immunosuppression,3 HCV 374 patients with a median follow-up of 23 months, viremia,' or incidence of rejection episodesbetween graft loss requiring re-OLT occurred in 76 patients patients who ultimately developed graft failureand cir(20.4%). Only 13 (3.4%) and 8 patients (2.1%)underrhosis versus those with milder hepatitkg went re-OLTfor recurrent HCV and chronicrejection Several studies analyzed the correlation between (CR), respectively. Thus, graft loss requiring re-OLT in onset of HCV recurrence and progression of disease HCV-infectedtransplant recipients hasbeencaused after OLT. A retrospective analysis byGhobrial eta17 of primarily by graft nonfunction(GNF)andhepatic 5 10 patients who underwent whole-organ cadaveric artery thrombosis shortly after OLT.3>'5 OLT at the University of California at Los Angeles At least two large seriesthat examined overall causes (UCLA) showed that 30% of whole cadaveric organ of re-OLT confirmed that the overwhelming majority recipients showed evidence of histological recurrence of re-OLTs were performed for causes other thanrecurwithin thefirst yearpost-OLT. Stratification of patients rent disease.179'8 In thefirst series by Doyle et al,'7 4.6% into five subgroups based on time to recurrence showed of 341 re-OLTs were performed for recurrent hepatithat early histological recurrence was associated with tis,'7 whereas recurrent disease was the indication in significantly increased risksfor graft failure and patient 3.6% of 356 re-OLTs in the second study.'* In addimortality. Graft failure and patientmortality risk ratios tion, onlya minority of patients(< 5%) developed rapwere 12.59,7.33, 5.55, and 3.53 and 12.4,4.28, 5.55, idly progressive recurrent disease culminating in death and 1.76 (P< .OOl) in patients who experienced recuror need for re-OLT inthe firstyear after OLT.19 rence within thefirst 12, 12 to 24,24 to 36, and longer Together, these data indicate that although recurrent than 36 months, respectively (Fig. 1 ) . Not surprisingly, HCV is associated with a real threat for histological survival estimates showed a stepwise improvement, injury andgraft failure over time, graft loss, death, and with delayed onset of recurrence. Worst patient and need for re-OLT caused by recurrent disease remain graft survival rates were seen in transplant recipients relatively low in the short-term and midtermafter priwho experienced recurrence within the first year after OLT, whereas the best survival was observed in patients mary OLT. However, studies that document time-de-
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Rafk M. Ghobrial
A 15
1
T 0.12
P co.001
12-24
recurrence >36 no
24-36
Months to HCV Recurrence
B , 20
I
P
I
developed cirrhosis were 6.49 5 1.28 ZI 2.43 2 0.77 mg/dL (P= . O l ) in patients without disease progression. Thus, although a significant number of patients may develop allograft hepatitis after OLT, a small group of patients are at risk for the development of allograft injury and/or loss that may require re-OLT. Risk factors include the requirement of OKT3 therapy, excessive use of steroids, histological evidence of recurrence within the first year after OLT, and peak bilirubin level at the timeof initial disease recurrence.
Re-OLT Outcomes in HCV-Infected Transplant Recipients 0-12
12-24
24-36
recurrence >36 no
Months to HCV Recurrence
Figure 1. (A) Patient mortality and (B) graft failure risk ratiosbased on time of histological HCV recurrence. (Reprinted with permission.’)
who experienced recurrence ordid not show recurrence at 36 months.’ The study by Testa et alzl that included 300 liver transplant recipients showed overall histological recurrence in 40.3% of patients. For transplant recipients with disease recurrence within 1 year of OLT, patient and graft survival rates at 5 years were 65.1 % and 56.4%, respectively. Transplant recipients who developed recurrence longer than 1 year post-OLT showed P = .004) andgraft significantly better patient (80.6%; (78.4%; P = .008) survival estimates at 5 years. Also, patients whodeveloped histological recurrence within6 months of OLT had anincreased risk for progressionto cirrhosis compared with patients with disease recurrence after 6 months (risk ratio, 2.3). Analysis of 278 serial allograft biopsies that ranged over 6 years in 34 liver transplant recipientsby Rosen et al8 showed that neither the aspartate aminotransferase to alanine aminotransferase ratio nor the widely used hepatitis activity index showed significant differences at the time of initial allograft disease recurrence between patients who ultimately developed allograft cirrhosis (n = 8) and those with milder allograft hepatitis (n = 26). Nevertheless, thefinding of ballooningand/or degeneration was more frequent in the former group. Peak serum bilirubinlevel in thefirst month after recurrence was the only independent predictor of progression to allograft cirrhosis ( P = .012). Peak total bilirubin levels at time of disease recurrence in patients who
This section outlines results of re-OLT for different causes of graft failure in HCV-infected transplant recipients. In the76 HCV-positive transplantrecipients who underwent re-OLT at UCLA, overall patient survival rate estimates were 63% and 58% at l and 2 years from thedate of the second OLT, respectively.3 O n this study, indication forre-OLT did notaffect patient survival. One-year patient survival rates after the second OLT were 6 1Yo for GNF, 50% for CR, 60%for hepatic artery thrombosis, and 60% for recurrent HCV (P= not significant). However, at re-OLT, 65 of 76 patients (85.3%) were critically ill urgent patients,whereas only 11 of 76 patients (14.7%) were nonurgent patients. Such assignment was based on United Network for Organ Sharing (UNOS) status. When urgent versus nonurgent statuswas considered in patients undergoing re-OLT for CR and recurrent HCV, an 87.5% survival rate at 1 and 2 years was achieved in healthy transplant recipients (n = 8) compared with only 38.4% at 1and 2 years (n = 13; P = .06; Fig. 2) incritically ill patients. Similarly, 33 re-OLTs performed in HCV-infected transplant recipients for multiple indications atBaylor University resulted in overall patient survival rates of 66.3% and 62.7%, whereas overall graft survival rates 100% 80%
60% 40%
20% 0%
Non-urgent
k P 0.06
Urgent
0
10
20
Months
30
40
Figure 2. Survival of patientsundergoingre-OLTfor chronic rejection and HCV according to UNOS status. (Reprinted with permi~sion.~)
RetransplantationHepatitis for Recurrent
were 66.3% and 59.7% at 1 and 2 years, respectively.21 Although numbers were small, no statistically significant differences were observed based on cause of graft failure. Sheiner at all5 reported similar patient survival rates of 64% at 1 and 2 years after re-OLT for recurrent hepatitis C and observed that poor outcomeswere associated with criticallyill transplant recipients. Four deaths causedbysepsis occurred in the initial seven patients who did notundergo re-OLT until theywere severely ill from recurrent disease. Patients who underwent re-OLT when allograft cirrhosis developed, but before the development of renal failure or sepsis, had uneventful post-OLT courses. Thus, most investigators agree that re-OLT early in the course of recurrent disease before deterioration of the patienthas better outcomes. Additionally, irrespective of the cause of graft failure, re-OLT for recurrent disease had an outcome similar to other indications for re-OLT in HCV-infected transplant recipients. Nevertheless, it is clearthat re-OLT in HCV-infected transplant recipients has a worse prognosis than primary OLT. The question therefore arises whether re-OLT outcomes in HCVinfected transplant recipients, particularly for recurrent disease, are inferior to those for re-OLTs performed in non-HCV-infected patients.
Re-OLT Outcomes in HCV-Infected and Non-HCV-Infected Transplant Recipients Initial reports on poor outcomes associated with re-
OLT for recurrent hepatitis C and the suggestion that viral reinfection may negatively influence the prognosis of repeat transplanted livers questioned thewisdom of the procedure.22 However, re-OLT has a worse prognosis than primary O L T for all indications. Evaluation of 299 patients who underwent re-OLT atUCLA for a variety of indications showed 55%, 47%, and 44% survival rates from the date of the second O L T at 1, 5, and 10years, respectively.18 Variables, by bivariate and multivariate analysis, that significantly influenced survival outcome in all 299 patients who underwent reOLT included recipient age (P = .03), time to re-OLT (P = .005), total number of grafts (P = .007), and recipient UNOS status (P= .O 15). Recipient primary diagnosis and cause of re-OLTwere not found to influence survival. In addition, re-OLT for recurrentHCV achieved 1- and 2-year survival rates of 6O%? These studies therefore suggest no difference in re-OLT for recurrent hepatitis C compared with other causes of re-OLT in non-HCV-infected transplant recipients. At least two studies suggested that prognosis afier
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re-OLT for recurrent H C V was inferior to that for re-OLT in non-HCV-infected patients performed for other indi~ations.22,~3 The first report,23,2* which analyzed predictors of mortality after late re-OLT (>6 months after initial OLT), showed that patients who underwent re-OLT for recurrent HCV had poorer survival (57% and43%) compared withthose who underwent re-OLT for other indications (81% and 74%)at 6 months and l year, respectively. Although this difference was not statistically significant(P= .09), it may be clinically relevant becausemost deaths occurred within the first 90 days afterre-OLT. Only one patient died of recurrent HCV 161 days after re-OLT. Independent predictors identified by the study for 90-day mortality included preoperative creatinine levelgreater than 2 mg/dL, recipient age older than 50 years, and use of intraoperative blood products. Thus, the initial high mortality observed with re-OLT for recurrent HCV may reflect the poor preoperative condition of patients and failure to identify predictors of poor prognosis in patients undergoing re-OLT.24 The second study22analyzed UNOS data for 1,539 adults (including357 HCV-positive patients) undergoingre-OLT. Kaplan-Meier analysis showed significantly diminished survival in the HCV-positive group at 1, 3, and 5 years (57%, 55%, and 54%) compared with the HCV-negative group (65%, 63%, and 61%, respectively; P = .0038; relative risk, 1.36). Multivariate logistic regression analysis of the subgroup of HCVpositive patients undergoing re-OLT for graft failure not caused by primary nonfunction identified preoperative serum bilirubin and serum creatinine levelsas significant independent predictors of death after reOLT. In addition, only 7 of 207 patients (3.4%) undergoing re-OLT died of recurrent HCV in their second allografts. Despite inherent limitations of this study caused by incomplete data sets from the UNOS registry, it emphasizes that preoperative condition of the patient, notrecurrent HCV, is the primary determinant for survival after OLT. The initial lack of recognition that HCV recurrence could lead to frank graft failure and delaying re-OLT untilpatients were severely ill and debilitated from recurrent disease may account for the poor early results of re-OLT for recurrent HCV.
Re-OLT and the Organ Shortage The current era of severe organ shortage has highlighted the debate of justice versus utility and implications of organ allocation policies on graft utilization and patient outcomes. Re-OLT for any indication entails massive
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Rafik M. Ghobrial I
for survival is preoperative condition of the patient. health care resource utilization and arguably is an inefTherefore, re-OLT remains an important option in the ficient use of a scarce organ resource. However, re-OLT treatment of recurrent HCV. A favorable response to in HCV-infected transplant recipients cannotbe abanre-OLT is obtained in selected group of patients when doned because of ethical concerns. As shown by this re-OLT is performed early in the course of recurrent review, mostre-OLTsinHCV-infectedtransplant disease, before patients become critically ill. recipients were caused by GNF and other complications of primary OLT. Re-OLT of these patients therefore represents a moral obligation of transplant teams References toward their patients. Much of the debate thereforeis centered on re-OLT 1. Teixeira R, Pastacaldi S, Papatheodoridis GV, Burroughs AK. Recurrent hepatitis C after liver transplantation. J Med Virol forrecurrent disease.25 Althoughthis is currently 2000;61:443-454. required for a small group of patients, the need for 2. Charlton M, Seaberg E, Wiesner R, Everharr J, Zetterman R, re-OLT for HCV recurrence may witness future draLake J, et al. Predictors of patient and graft survival following matic increases. Such debate can be resolved only with liver transplantation for hepatitis C. Hepatology 1998;28:823careful analysis of factors that predict survival after re830. OLT. Whereas some initial studies showed inferior out3. Ghobrial RM, Farmer DG, Baquerizo A, Colquhoun S , Rosen H, Yersiz H, et al. Orthotopic liver transplantation for hepariris comes for re-OLT,16,23 others showed improved results C: Outcome,effect of immunosuppression and causes of retranswhen factors that predict re-OLT outcome were conplantation during an eight year single center experience. Ann sidered.3.15 Preoperative factors thatmayinfluence Surg 1999;6:824-833. post-OLT survival after re-OLT include donor age and 4. Casavilla FA, Rakela J, Kapur S, Irish W, McMichael J, Demetris AJ, et al. Clinical outcome of patients infected with hepatitis C sex and recipient bilirubin level, serum creatininelevel, virus infection on survival after primary liver transplantation UNOS status, and need for mechanical ventilaunder tacrolimus. Liver Transpl Surg 1998;4:448-454. tion.17,18,22,23 Thus, re-OLT for recurrent disease in 5. Gane EJ, Porrmann BC, Naoumov W ,Smith HM, Underhill carefully selected patientswho are not critically ill JA, Donaldson PT, et al. Long-term outcome of hepatitis C would predict a good outcome. Unfortunately, the curinfection after liver transplantation. N Engl J Med 1996;334: 81 5-820. rentorganallocation system that is strongly biased 6. Wright TL, Donegan E, Hsu H H , Ferrell L, Lake JR, Kim M, et toward disease severity may not allow early re-OLT, al. Recurrent and acquired hepatitis C viral infection in liver thereby contributing to poor outcomes after re-OTT.
Summary Primary OLT for HCV-induced liver cirrhosiscurrently is performed with goodresults despite the threat of allograft injury caused by recurrent disease. Requirement of re-OLT in the short- and midtermbecause of recurrent disease remains relatively low compared with other causes of graft failure.GNF and other complications afterOLT account for mostof the indications for re-OLT in HCV-infected transplant recipients in the first few yearsafter OLT. However, theslow but steady progression of recurrent disease and time-dependent allograft injury predict a steadyincrease in numbers of patients who may needre-OLT in the long term. Time to recurrence and peak bilirubin levels at initial recurrence may predict patients who ultimately require reOLT. Results of re-OLT for recurrentdisease in HCVinfected transplant recipientsare equivalent to those for other causes of graft failure.Also, outcomes of re-OLT for recurrentdisease appear to be equivalent to those for otherindicationsfor re-OLT innon-HCV-infected transplant recipients, in whom the primary predictor
transplant recipients. Gastroenterology 1992;103:3 17-322. 7. Ghobrial RM, Steadman R, Gornbein J, Lassman C, Holt CD, Chen P, et al. A ten year experience of liver transplantation for hepatitis C: Analysis of factors determining outcome in over 500 patients. Ann Surg 2001;234:384-394. 8. Rosen H, Grerch DR, OehlkeM, Flora KD, Benner KG, Rabkin JM, Corless CL. Timing andseverity of initial hepatitis C recurrence as predictors of long-term liver allograft injury. Transplantation 1998;65:1178-1182. 9. Samuel D, Feray C. Recurrent hepatitis C after liver transplantation: Clinical and therapeuticissues. J Viral Hepat 2000;7:8792. 10. Feray C, Gigou M, Samuel D, Paradis V, Wilber J, David MF, et al. The course of hepatitis C virus infection after liver transplantation. Hepatology 199420:1137- 1 143. 11. Zhou S, Terrault NA, Ferrell L, Hahn JA, Lau JY,Simmonds P, et al. Severity of liver disease in liver transplantation recipients with hepatitis C virus infection: Relationship to genotype and level of viremia. Hepatology 1996;24: 104 1-1046. 12. Sreekumar S, Gondez-Koch A, Maor-Kendler Y, Batts K, Moreno-Luna L, Poterucha J, etal. Early identification of recipients with progressive histological recurrence of hepatitis C after liver transplantation. Hepatology 2000;32:1125-1130. 13. Prieto M, Berenguer M, Rayon JM, Cordoba J, Arguello L, Carrasco D, et al. High incidence of allograft cirrhosis in hepatitis C virus genotype I b infection following transplantation: Relationship with rejection episodes. Hepatology 1999;9:250256.
Retransplantation f o r Recurrent Hepatitis C
14. Feray C, Caccamo L, Alexander GJ, Ducot B, Gugenheim J, Casanovas T , et al. European collaborative study onfactors influencing outcomeafter liver transplantation forhepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group. Gastroenterology 1999;117:619-625. 15. Sheiner PA, Schluger LK, Emre S , Thung SN, Lau JY, Guy SR., et al. Retransplantation for hepatitis C. Liver Transpl Surg 1997; 3:130-136. 16. Rosen HR, O’Reilly PM, Shackleton CR, McDiarmid S, Holt C, Busuttil RW, Martin P. Graft loss following liver transplantationinpatients with chronic hepatitis C. Transplantation 1996;62:1773-1776. 17. Doyle HR, Morelli F, McMichael J, Doria C, Aldrighetti L, Starzl TE, MarinoIR. Hepatic retransplantation-An analysis of risk factors associated with outcome. Transplantation 1996;61: 1499-1505. 18. Markmann JF, Markowitz JS, Yersiz H , Morrissey M, Farmer DG, Farmer DA, et al. Long-term survival after retransplantation of the liver. Ann Surg 1997;226:408-420. 19. Schluger LK, Sheiner PA, Thung SN, Lau JY, Min A, Wolf DC,
20.
21.
22. 23.
24. 25.
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et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology 1996;23:97 1-976. Rosen HR, Shackleton CR, Higa L, Gralnek IM, Farmer DA, McDiarmid SV, et al. Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation. Am J Gastroenterol 1997;92:1453-1457. Testa G, Crippin JS, Netto GJ, Goldstein RM, Jennings LW, Brkic BS, et al. Liver transplantation for hepatitis C: Recurrence and disease progression in 300 patients. Liver Transpl 2000;6: 553-561. Rosen H , Martin P. Hepatitis C infection in patients undergoing liver retransplantation. Transplantation 1998;66: 16 12- 16. 16 Facciuto M, Heidt D, GuarreraJ,Bodian CA, Miller CM, Emre S, et al. Retransplantation for late liver graft failure: Predictors of mortality. Liver Transpl2000;6: 174-179. Sheiner PA. Hepatitis C after liver transplantation. Semin Liver Dis 2000;20:20 1-209. Rosen HR. Retransplantation for hepatitis C: Implications of different policies. Liver Transpl2000;6(suppl):S4l-S46.
(Liver Tramp12002;8:S38-S43.)
iver disease caused by hepatitis C virus (HCV) has become the most common indication for orthotopic liver transplantation (OLT).Recurrence ofHCV afier OLT is nearly universal and may lead to progressive liver disease, with graft loss that may require reOLT. Therefore,increasingconcern has developed regarding long-term outcomes, factors that determine the severity of recurrent H C V disease after OLT, and factors that may lead to re-OLT. This review discusses outcomes afterOLT for HCV, causes and outcomes of re-OLT inHCV-infectedpatients, and factorsthat influence results of re-OLT.
L
Survival Outcomes After Primary OLT for HCV Most investigatorsdescribe survival outcomesafter OLT for HCV similar to those of other indications for OLT.1 Only patients who undergo OLT for cholestatic liver disease achieve better long-term survival.2 At my 8-year institution, OLTs in 374 patientsduringan
From the Department o f Surgey, Division o f Liver and Pancreas Transplantation, David Geffen School of Medicine at University o f California Los Angeles, Los Angeles, CA. Address reprint requeststo Rafik M. Ghobrial, MD, PhD, DumontUCLA Transplant Center, DavidGefen School o f Medicine at UCLA, I0833 LeConte Ave,77-132CHS, Los Angeles, CA 90095. Telephone: 310-825-2678; FAX 310-267-0392; E-mail:[email protected] Copyright O 2002 by the American Association f . r the Study o f Liver Diseases 1527-6465/02/0810-I015$35.00/0 doi:IO. 1053/j1ts.2002.35861
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period achieved overall patient survival rates of 86%, 82%, and 76% and graft survival rates of 70%, 65%, and 60% at l, 2, and 5 years, respectively.3Comparison to a contemporary cohort of 701 patients who underwent OLT for causes other thanviral infections did not show a difference in patient survival. Multiple other series showed similar results. Casavilla et a14 reported patient survival rates of 80% and 75% at 1 and 5 years inacohortof183patients.Inanotherstudythat included 149 transplant recipients, patient and graft survival were not significantly different from those of HCV-negative patients at 1 and 5 years post-OLT.5 Thus, despite the risk for recurrent HCV after OLT, OLT is performed with goodresults.
Effects of HCV Recurrence AfterOLT Despitegoodshort-term and midterm survival outcomes, H C V recurrence after whole cadaveric OLT, measured by polymerase chain reaction detection of HCV RNA, is nearly universal6 and may lead to progressive allograft injury and failure.1,397,8 However, the reported incidence of histological HCV recurrence varied widely between 14% and 72%. l 5 7 - 9 Such variation may be caused by differences in definitions of chronic hepatitis, lengths of follow-up, and whether protocol biopsies were performed. Nevertheless, approximately 50% of patients may show some degree of abnormal histological characteristics1 year after 0LT.lo Two years after OLT, approximately 25% of patients may show moderate to severe histological hepatitis, shown in a cohort of 124 patients.' At my center, 30% of patients showed evidence of histological recurrence in the first year after OLT.' Sreekumar et a l l 2 reported mean hepatitis activity indices of 2.74, 2.07, and 2.65 and mean fibrosis scores of 1.06, 1.39, and 1.31 at 4 months and 1 and 3 years after whole-organ cadaveric OLT, respectively. In addition, 8% to 31% of patients with post-OLT recurrence developed cirrhosis in 5 to 7 years 192510-14 and ensuinggraftfailurein 10% of patients by postoperative year 5.1,5,7-9911Thus, it is anticipated that with the currentslow, but steady, progression of disease after OLT, increasing numbers of patients will require re-OLT with long-term follow-up.
Liver Transplantation, VoL 8,No 10, Suppl l (October), 2002:pp S38-S43
Retransplantation for Recurrent Hepatitis C
Causes of Graft Loss and Re-OLTin HCVInfected Transplant Recipients
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pendent progression of recurrentdisease predict a need for re-OLT in the long term.
Although histological progression of HCV after OLT predicts a need for re-OLT, only a small subset of Predictors of Re-OLT in HCV-Infected patients appears to develop severeallograft injury Transplant Recipients caused byHCV recurrence that prompts re-OLT in the short-term or midterm.l5,16 In one study that included Much attention currently is directed toward identifica149 patients who underwent OLT for HCV, graft loss tion of factors that influence the rate and severity of hepatitis C recurrence. Determination of such factors occurred in 27 of 149 patients, but only 8 patients would identify patient populations susceptible to deleexperienced graft loss secondary to HCV recurrence.5 terious effects of recurrent HCV and who therefore Recurrent HCV with ensuing graft failure in a series of require antiviral therapy and/or re-OLT. OKT3 treat166 HCV-infected transplant recipients was the cause ment for steroid-resistant infection has been associated of death in 1 1 of 39 patients who died during the convincingly with early and severe HCV recurrence in follow-up period.* Also, sepsis,but not recurrent HCV, allografts.19,20 Cirrhosis was documented in 26.3% of appears to be the most common cause of death in allografts in patients administered OKT3 during their HCV-infected transplant recipients.3 post-OLT course compared with 6% of patients who T o date, numbers of patients undergoing re-OLT were not.20 Similarly, severe or multiple rejection epifor recurrent HCV compared with other causes of resodes were associated with early recurrence.' Greater OLT have been relatively low.In theseries reported by viral replication levels were documented with excessive Sheiner et al,l5 43 of 262 patients (16.4%) underwent steroid use for treatment of rejection episodes.19 Some re-OLT after a successful firstO L T for HCV infection, studies implicated elevated pre-OLT2 or post-OLT. and only 14 of 49 re-OLTs were performed for recurHCV RNA levels12 and infection with HCV genotype rent HCV. From 166 HCV-infected transplant recipil b5 with pooroutcome and increased rateof graft daments reported by Charlton et a l , 2 5 patients required age. However, other reports indicated no difference in re-OLT for recurrent HCV. In our series that included HCV genotype, basal immunosuppression,3 HCV 374 patients with a median follow-up of 23 months, viremia,' or incidence of rejection episodesbetween graft loss requiring re-OLT occurred in 76 patients patients who ultimately developed graft failureand cir(20.4%). Only 13 (3.4%) and 8 patients (2.1%)underrhosis versus those with milder hepatitkg went re-OLTfor recurrent HCV and chronicrejection Several studies analyzed the correlation between (CR), respectively. Thus, graft loss requiring re-OLT in onset of HCV recurrence and progression of disease HCV-infectedtransplant recipients hasbeencaused after OLT. A retrospective analysis byGhobrial eta17 of primarily by graft nonfunction(GNF)andhepatic 5 10 patients who underwent whole-organ cadaveric artery thrombosis shortly after OLT.3>'5 OLT at the University of California at Los Angeles At least two large seriesthat examined overall causes (UCLA) showed that 30% of whole cadaveric organ of re-OLT confirmed that the overwhelming majority recipients showed evidence of histological recurrence of re-OLTs were performed for causes other thanrecurwithin thefirst yearpost-OLT. Stratification of patients rent disease.179'8 In thefirst series by Doyle et al,'7 4.6% into five subgroups based on time to recurrence showed of 341 re-OLTs were performed for recurrent hepatithat early histological recurrence was associated with tis,'7 whereas recurrent disease was the indication in significantly increased risksfor graft failure and patient 3.6% of 356 re-OLTs in the second study.'* In addimortality. Graft failure and patientmortality risk ratios tion, onlya minority of patients(< 5%) developed rapwere 12.59,7.33, 5.55, and 3.53 and 12.4,4.28, 5.55, idly progressive recurrent disease culminating in death and 1.76 (P< .OOl) in patients who experienced recuror need for re-OLT inthe firstyear after OLT.19 rence within thefirst 12, 12 to 24,24 to 36, and longer Together, these data indicate that although recurrent than 36 months, respectively (Fig. 1 ) . Not surprisingly, HCV is associated with a real threat for histological survival estimates showed a stepwise improvement, injury andgraft failure over time, graft loss, death, and with delayed onset of recurrence. Worst patient and need for re-OLT caused by recurrent disease remain graft survival rates were seen in transplant recipients relatively low in the short-term and midtermafter priwho experienced recurrence within the first year after OLT, whereas the best survival was observed in patients mary OLT. However, studies that document time-de-
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Rafk M. Ghobrial
A 15
1
T 0.12
P co.001
12-24
recurrence >36 no
24-36
Months to HCV Recurrence
B , 20
I
P
I
developed cirrhosis were 6.49 5 1.28 ZI 2.43 2 0.77 mg/dL (P= . O l ) in patients without disease progression. Thus, although a significant number of patients may develop allograft hepatitis after OLT, a small group of patients are at risk for the development of allograft injury and/or loss that may require re-OLT. Risk factors include the requirement of OKT3 therapy, excessive use of steroids, histological evidence of recurrence within the first year after OLT, and peak bilirubin level at the timeof initial disease recurrence.
Re-OLT Outcomes in HCV-Infected Transplant Recipients 0-12
12-24
24-36
recurrence >36 no
Months to HCV Recurrence
Figure 1. (A) Patient mortality and (B) graft failure risk ratiosbased on time of histological HCV recurrence. (Reprinted with permission.’)
who experienced recurrence ordid not show recurrence at 36 months.’ The study by Testa et alzl that included 300 liver transplant recipients showed overall histological recurrence in 40.3% of patients. For transplant recipients with disease recurrence within 1 year of OLT, patient and graft survival rates at 5 years were 65.1 % and 56.4%, respectively. Transplant recipients who developed recurrence longer than 1 year post-OLT showed P = .004) andgraft significantly better patient (80.6%; (78.4%; P = .008) survival estimates at 5 years. Also, patients whodeveloped histological recurrence within6 months of OLT had anincreased risk for progressionto cirrhosis compared with patients with disease recurrence after 6 months (risk ratio, 2.3). Analysis of 278 serial allograft biopsies that ranged over 6 years in 34 liver transplant recipientsby Rosen et al8 showed that neither the aspartate aminotransferase to alanine aminotransferase ratio nor the widely used hepatitis activity index showed significant differences at the time of initial allograft disease recurrence between patients who ultimately developed allograft cirrhosis (n = 8) and those with milder allograft hepatitis (n = 26). Nevertheless, thefinding of ballooningand/or degeneration was more frequent in the former group. Peak serum bilirubinlevel in thefirst month after recurrence was the only independent predictor of progression to allograft cirrhosis ( P = .012). Peak total bilirubin levels at time of disease recurrence in patients who
This section outlines results of re-OLT for different causes of graft failure in HCV-infected transplant recipients. In the76 HCV-positive transplantrecipients who underwent re-OLT at UCLA, overall patient survival rate estimates were 63% and 58% at l and 2 years from thedate of the second OLT, respectively.3 O n this study, indication forre-OLT did notaffect patient survival. One-year patient survival rates after the second OLT were 6 1Yo for GNF, 50% for CR, 60%for hepatic artery thrombosis, and 60% for recurrent HCV (P= not significant). However, at re-OLT, 65 of 76 patients (85.3%) were critically ill urgent patients,whereas only 11 of 76 patients (14.7%) were nonurgent patients. Such assignment was based on United Network for Organ Sharing (UNOS) status. When urgent versus nonurgent statuswas considered in patients undergoing re-OLT for CR and recurrent HCV, an 87.5% survival rate at 1 and 2 years was achieved in healthy transplant recipients (n = 8) compared with only 38.4% at 1and 2 years (n = 13; P = .06; Fig. 2) incritically ill patients. Similarly, 33 re-OLTs performed in HCV-infected transplant recipients for multiple indications atBaylor University resulted in overall patient survival rates of 66.3% and 62.7%, whereas overall graft survival rates 100% 80%
60% 40%
20% 0%
Non-urgent
k P 0.06
Urgent
0
10
20
Months
30
40
Figure 2. Survival of patientsundergoingre-OLTfor chronic rejection and HCV according to UNOS status. (Reprinted with permi~sion.~)
RetransplantationHepatitis for Recurrent
were 66.3% and 59.7% at 1 and 2 years, respectively.21 Although numbers were small, no statistically significant differences were observed based on cause of graft failure. Sheiner at all5 reported similar patient survival rates of 64% at 1 and 2 years after re-OLT for recurrent hepatitis C and observed that poor outcomeswere associated with criticallyill transplant recipients. Four deaths causedbysepsis occurred in the initial seven patients who did notundergo re-OLT until theywere severely ill from recurrent disease. Patients who underwent re-OLT when allograft cirrhosis developed, but before the development of renal failure or sepsis, had uneventful post-OLT courses. Thus, most investigators agree that re-OLT early in the course of recurrent disease before deterioration of the patienthas better outcomes. Additionally, irrespective of the cause of graft failure, re-OLT for recurrent disease had an outcome similar to other indications for re-OLT in HCV-infected transplant recipients. Nevertheless, it is clearthat re-OLT in HCV-infected transplant recipients has a worse prognosis than primary OLT. The question therefore arises whether re-OLT outcomes in HCVinfected transplant recipients, particularly for recurrent disease, are inferior to those for re-OLTs performed in non-HCV-infected patients.
Re-OLT Outcomes in HCV-Infected and Non-HCV-Infected Transplant Recipients Initial reports on poor outcomes associated with re-
OLT for recurrent hepatitis C and the suggestion that viral reinfection may negatively influence the prognosis of repeat transplanted livers questioned thewisdom of the procedure.22 However, re-OLT has a worse prognosis than primary O L T for all indications. Evaluation of 299 patients who underwent re-OLT atUCLA for a variety of indications showed 55%, 47%, and 44% survival rates from the date of the second O L T at 1, 5, and 10years, respectively.18 Variables, by bivariate and multivariate analysis, that significantly influenced survival outcome in all 299 patients who underwent reOLT included recipient age (P = .03), time to re-OLT (P = .005), total number of grafts (P = .007), and recipient UNOS status (P= .O 15). Recipient primary diagnosis and cause of re-OLTwere not found to influence survival. In addition, re-OLT for recurrentHCV achieved 1- and 2-year survival rates of 6O%? These studies therefore suggest no difference in re-OLT for recurrent hepatitis C compared with other causes of re-OLT in non-HCV-infected transplant recipients. At least two studies suggested that prognosis afier
C
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re-OLT for recurrent H C V was inferior to that for re-OLT in non-HCV-infected patients performed for other indi~ations.22,~3 The first report,23,2* which analyzed predictors of mortality after late re-OLT (>6 months after initial OLT), showed that patients who underwent re-OLT for recurrent HCV had poorer survival (57% and43%) compared withthose who underwent re-OLT for other indications (81% and 74%)at 6 months and l year, respectively. Although this difference was not statistically significant(P= .09), it may be clinically relevant becausemost deaths occurred within the first 90 days afterre-OLT. Only one patient died of recurrent HCV 161 days after re-OLT. Independent predictors identified by the study for 90-day mortality included preoperative creatinine levelgreater than 2 mg/dL, recipient age older than 50 years, and use of intraoperative blood products. Thus, the initial high mortality observed with re-OLT for recurrent HCV may reflect the poor preoperative condition of patients and failure to identify predictors of poor prognosis in patients undergoing re-OLT.24 The second study22analyzed UNOS data for 1,539 adults (including357 HCV-positive patients) undergoingre-OLT. Kaplan-Meier analysis showed significantly diminished survival in the HCV-positive group at 1, 3, and 5 years (57%, 55%, and 54%) compared with the HCV-negative group (65%, 63%, and 61%, respectively; P = .0038; relative risk, 1.36). Multivariate logistic regression analysis of the subgroup of HCVpositive patients undergoing re-OLT for graft failure not caused by primary nonfunction identified preoperative serum bilirubin and serum creatinine levelsas significant independent predictors of death after reOLT. In addition, only 7 of 207 patients (3.4%) undergoing re-OLT died of recurrent HCV in their second allografts. Despite inherent limitations of this study caused by incomplete data sets from the UNOS registry, it emphasizes that preoperative condition of the patient, notrecurrent HCV, is the primary determinant for survival after OLT. The initial lack of recognition that HCV recurrence could lead to frank graft failure and delaying re-OLT untilpatients were severely ill and debilitated from recurrent disease may account for the poor early results of re-OLT for recurrent HCV.
Re-OLT and the Organ Shortage The current era of severe organ shortage has highlighted the debate of justice versus utility and implications of organ allocation policies on graft utilization and patient outcomes. Re-OLT for any indication entails massive
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Rafik M. Ghobrial I
for survival is preoperative condition of the patient. health care resource utilization and arguably is an inefTherefore, re-OLT remains an important option in the ficient use of a scarce organ resource. However, re-OLT treatment of recurrent HCV. A favorable response to in HCV-infected transplant recipients cannotbe abanre-OLT is obtained in selected group of patients when doned because of ethical concerns. As shown by this re-OLT is performed early in the course of recurrent review, mostre-OLTsinHCV-infectedtransplant disease, before patients become critically ill. recipients were caused by GNF and other complications of primary OLT. Re-OLT of these patients therefore represents a moral obligation of transplant teams References toward their patients. Much of the debate thereforeis centered on re-OLT 1. Teixeira R, Pastacaldi S, Papatheodoridis GV, Burroughs AK. Recurrent hepatitis C after liver transplantation. J Med Virol forrecurrent disease.25 Althoughthis is currently 2000;61:443-454. required for a small group of patients, the need for 2. Charlton M, Seaberg E, Wiesner R, Everharr J, Zetterman R, re-OLT for HCV recurrence may witness future draLake J, et al. Predictors of patient and graft survival following matic increases. Such debate can be resolved only with liver transplantation for hepatitis C. Hepatology 1998;28:823careful analysis of factors that predict survival after re830. OLT. Whereas some initial studies showed inferior out3. Ghobrial RM, Farmer DG, Baquerizo A, Colquhoun S , Rosen H, Yersiz H, et al. Orthotopic liver transplantation for hepariris comes for re-OLT,16,23 others showed improved results C: Outcome,effect of immunosuppression and causes of retranswhen factors that predict re-OLT outcome were conplantation during an eight year single center experience. Ann sidered.3.15 Preoperative factors thatmayinfluence Surg 1999;6:824-833. post-OLT survival after re-OLT include donor age and 4. Casavilla FA, Rakela J, Kapur S, Irish W, McMichael J, Demetris AJ, et al. Clinical outcome of patients infected with hepatitis C sex and recipient bilirubin level, serum creatininelevel, virus infection on survival after primary liver transplantation UNOS status, and need for mechanical ventilaunder tacrolimus. Liver Transpl Surg 1998;4:448-454. tion.17,18,22,23 Thus, re-OLT for recurrent disease in 5. Gane EJ, Porrmann BC, Naoumov W ,Smith HM, Underhill carefully selected patientswho are not critically ill JA, Donaldson PT, et al. Long-term outcome of hepatitis C would predict a good outcome. Unfortunately, the curinfection after liver transplantation. N Engl J Med 1996;334: 81 5-820. rentorganallocation system that is strongly biased 6. Wright TL, Donegan E, Hsu H H , Ferrell L, Lake JR, Kim M, et toward disease severity may not allow early re-OLT, al. Recurrent and acquired hepatitis C viral infection in liver thereby contributing to poor outcomes after re-OTT.
Summary Primary OLT for HCV-induced liver cirrhosiscurrently is performed with goodresults despite the threat of allograft injury caused by recurrent disease. Requirement of re-OLT in the short- and midtermbecause of recurrent disease remains relatively low compared with other causes of graft failure.GNF and other complications afterOLT account for mostof the indications for re-OLT in HCV-infected transplant recipients in the first few yearsafter OLT. However, theslow but steady progression of recurrent disease and time-dependent allograft injury predict a steadyincrease in numbers of patients who may needre-OLT in the long term. Time to recurrence and peak bilirubin levels at initial recurrence may predict patients who ultimately require reOLT. Results of re-OLT for recurrentdisease in HCVinfected transplant recipientsare equivalent to those for other causes of graft failure.Also, outcomes of re-OLT for recurrentdisease appear to be equivalent to those for otherindicationsfor re-OLT innon-HCV-infected transplant recipients, in whom the primary predictor
transplant recipients. Gastroenterology 1992;103:3 17-322. 7. Ghobrial RM, Steadman R, Gornbein J, Lassman C, Holt CD, Chen P, et al. A ten year experience of liver transplantation for hepatitis C: Analysis of factors determining outcome in over 500 patients. Ann Surg 2001;234:384-394. 8. Rosen H, Grerch DR, OehlkeM, Flora KD, Benner KG, Rabkin JM, Corless CL. Timing andseverity of initial hepatitis C recurrence as predictors of long-term liver allograft injury. Transplantation 1998;65:1178-1182. 9. Samuel D, Feray C. Recurrent hepatitis C after liver transplantation: Clinical and therapeuticissues. J Viral Hepat 2000;7:8792. 10. Feray C, Gigou M, Samuel D, Paradis V, Wilber J, David MF, et al. The course of hepatitis C virus infection after liver transplantation. Hepatology 199420:1137- 1 143. 11. Zhou S, Terrault NA, Ferrell L, Hahn JA, Lau JY,Simmonds P, et al. Severity of liver disease in liver transplantation recipients with hepatitis C virus infection: Relationship to genotype and level of viremia. Hepatology 1996;24: 104 1-1046. 12. Sreekumar S, Gondez-Koch A, Maor-Kendler Y, Batts K, Moreno-Luna L, Poterucha J, etal. Early identification of recipients with progressive histological recurrence of hepatitis C after liver transplantation. Hepatology 2000;32:1125-1130. 13. Prieto M, Berenguer M, Rayon JM, Cordoba J, Arguello L, Carrasco D, et al. High incidence of allograft cirrhosis in hepatitis C virus genotype I b infection following transplantation: Relationship with rejection episodes. Hepatology 1999;9:250256.
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14. Feray C, Caccamo L, Alexander GJ, Ducot B, Gugenheim J, Casanovas T , et al. European collaborative study onfactors influencing outcomeafter liver transplantation forhepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group. Gastroenterology 1999;117:619-625. 15. Sheiner PA, Schluger LK, Emre S , Thung SN, Lau JY, Guy SR., et al. Retransplantation for hepatitis C. Liver Transpl Surg 1997; 3:130-136. 16. Rosen HR, O’Reilly PM, Shackleton CR, McDiarmid S, Holt C, Busuttil RW, Martin P. Graft loss following liver transplantationinpatients with chronic hepatitis C. Transplantation 1996;62:1773-1776. 17. Doyle HR, Morelli F, McMichael J, Doria C, Aldrighetti L, Starzl TE, MarinoIR. Hepatic retransplantation-An analysis of risk factors associated with outcome. Transplantation 1996;61: 1499-1505. 18. Markmann JF, Markowitz JS, Yersiz H , Morrissey M, Farmer DG, Farmer DA, et al. Long-term survival after retransplantation of the liver. Ann Surg 1997;226:408-420. 19. Schluger LK, Sheiner PA, Thung SN, Lau JY, Min A, Wolf DC,
20.
21.
22. 23.
24. 25.
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et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology 1996;23:97 1-976. Rosen HR, Shackleton CR, Higa L, Gralnek IM, Farmer DA, McDiarmid SV, et al. Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation. Am J Gastroenterol 1997;92:1453-1457. Testa G, Crippin JS, Netto GJ, Goldstein RM, Jennings LW, Brkic BS, et al. Liver transplantation for hepatitis C: Recurrence and disease progression in 300 patients. Liver Transpl 2000;6: 553-561. Rosen H , Martin P. Hepatitis C infection in patients undergoing liver retransplantation. Transplantation 1998;66: 16 12- 16. 16 Facciuto M, Heidt D, GuarreraJ,Bodian CA, Miller CM, Emre S, et al. Retransplantation for late liver graft failure: Predictors of mortality. Liver Transpl2000;6: 174-179. Sheiner PA. Hepatitis C after liver transplantation. Semin Liver Dis 2000;20:20 1-209. Rosen HR. Retransplantation for hepatitis C: Implications of different policies. Liver Transpl2000;6(suppl):S4l-S46.