' Ardo Abdiueli Aden, '

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1 ORIGINAL ARTICLES Slowlv Tapering Off Steroids Protects the Graft Against Hepatiti's C Kecurrence After Liver Transplantahon ' Ardo Abdiueli Aden, ' St$uno Brillunti, * Murco fivurelli, ' Nicolu De Ruvo, Vuleriu Cumaggi, * Antonid D Errico,' Giuliano Furlini,' Roberto Bellusci, * Enrico Rodu, * und Antonino Cuvulldri' Chronic hepatitis C represents a major clinical problem after liver transplantation, but factors influencing the recurrent disease have not been well characterized. We analyzed the clinical records of all the patients transplanted for hepatitis C virus (HW-related liver disease in our Center between 1991 and Eighty consecutive HCV-positive (+) patients (60 men, ages 28 to 64) survived more than 1 month after transplantation and were followed for a median of 45 months. Diagnosis of recurrent chronic hepatitis C was made in 38 patients (47.5%), of whom 22 had moderate/severe chronic hepatitis. Decompensated cirrhosis occurred in six patients (7.5%). No difference in patient survival was found between patients with and without hepatitis C recurrence. No association was found between recurrent hepatitis C and presumed risk factors. The method of tapering off corticosteroids was significantly associated with both hepatitis C recurrence and the severity of hepatitis. In patients receiving a higher daily prednisone dose, 12 months after transplantation, the proportion of recurrent hepatitis C was 35.7% versus 66.6% (P =.02; odds ratio [OR], 3.6; 95% confidence interval (CI): 1.25 to 10.36), and among patients receiving a higher daily prednisone dose, 6 months after transplantation, the proportion of moderate/severe chronic hepatitis C was 40% versus 89% (P =.03; OR: 0.08, 95% CI: to 0.84). Finally, prednisone dose at month six was significantly associated with disease-free survival of the liver graft. In conclusion, our results seem to indicate that in HCV-infected liver transplant recipients, a long-term treatment with corticosteroids, slowly tapered off over time, may prevent the more aggressive forms of recurrent liver disease. (Liver Tramp1 2002;8: ) From the *Department of Internal Medicine and Gastroenterology, the?department of Surgery and Transplantations, the $Department of Oncology & Hematology, and the $Department of Clinical and Experimental Medicine, Universiv of Bologna, Itah. Address reprint requests to Stefdno Brillanti, MD, the Department of InternalMedicine and Gastroenterology, via Massarenti 9,40138 Bologna, Itah. Telephone: (39) ; Fm: (39) ; sbrillanti@compuser.com Copyright by the American Association fir the Study of Liver Diseases /02/ $35.00/0 doi:io. 1053~lts D ecompensated cirrhosis caused by hepatitis C virus (HCV) infection is the leading indication for orthotopic liver transplantation (OLT) in Western countries. Hepatitis C infection usually returns after transplantation, and many patients will have histologic changes of hepatitis and sometimes cirrhosis. Early reports seemed to indicate that only a minority of transplanted patients had severe a recurrence of chronic hepatitis C. Unfortunately, recent works and the experience in many transplant centers reveal a more aggressive progression of the recurrent disease in the last ~ears.3.~ If this situation persists, hepatitis C in the liver graft may rapidly become a major clinical and social problem, hampering the great benefits resulting from liver transplant. The aim of our study was to evaluate the clinical records of all patients who underwent transplantation in our single center during the last decade to outline the features of recurrent hepatitis C and, possibly, to identi!+ the risk factors eventually associated with the more severe forms of this disease. Patients and Methods Patient Population 884 Liver Transplantation, Vol8, No l0 (October), 2002: pp Between January, 1991 and December, 1997, 251 adult patients underwent OLT at the Department of Surgery and Transplantation, University of Bologna, ofwhom 97 received liver graft for end-stage liver disease secondary to HCV infection. Of these patients, 12 with a concomitant hepatitis B virus (HBV) infection, one with de novo HBV infection after OLT, and four who died within 30 days after surgery were excluded from the analysis. Therefore, our study population included 80 consecutive patients (60 men and 20 women, ages ranging from 28 to 64 years), who underwent transplatation for HCV-related liver disease, who survived more than 1 month after OLT, with well-established HCV infection (anti-hcv and HCV-RNA positivity by polymerase chain reaction) before and after after liver transplant, Clinical and laboratory data were availablefor thecompleteseriesof patients at the time of transplantation and subsequently.

2 Hepatitis and Steroid C Recurrence 885 Operation and Immunosuppression least one liver biopsy, in the period after the first month post-olt in 63 of the 80 patients. Subsequent liver biopsies OLT wasperformedin standard technique. All patients were performed if clinically indicated (median number of received whole livers. For induction of immunosuppression, a biopsies, two; range, 1 to 7). HCV infection was diagnosed by standard intravenous 1 -g dose of methylprednisolone intraboth demonstration of anti-hcv antibody (second generaoperatively at reperfusion was administered in all patients. tion HCVEIA; Abbott Laboratories, Chicago, IL) and HCV- Subsequent immunosuppressive regimen was based on cyclo- RNA determination by standardized polymerase chain reacsporin in 65 patients (initial dosage of 15 mg/kg/d, then 5 to tion technique (Amplicor HCV; Roche, Basel, Switzerland). 10 mg/kg/d in the first post-olt year; mean cyclosporin HCV genotyping was performed using second generation trough level of 250 ng/ml in the first post-olt year, then InnoLipa HCV test (Innogenetics NV, Belgium). All patients between 100 and 200 ng/ml) and prednisone, whereas positive for hepatitis B surface antigen were excluded from the tacrolimus (initial dosage of mg/kg/d, then 0.10 present study. mg/kg/d in the first post-olt year; mean tacrolimus trough level of 15 ng/ml in the first post-olt year, then between 8 Outcomes of the Study and Statistical Analysis and 12 ng/ml), and prednisone were used in 15 patients. The principal outcomes of the study were long-term patient Because different of immunosuppressive strategies and liver graft survival, the recurrence of histologically conadopted by the 2 surgical teams in our center, in 37 patients firmed hepatitis C, and the evaluation of the histologic activazathioprine was added, at adoseof 1 to 2mg/kg/d, as ity grade in the first biopsy in which hepatitis C recurrence additional immunosuppressive drug to the maintenance reg- was diagnosed. Recurrent hepatitis C was defined as the presimen, usually in patients receiving cyclosporin, and provided ence of histologic changes compatible with hepatitis C recurabsence of leuko-thrombocytopenia, and was suspended by rence in a patient without evidence of liver graft rejection or month six after transplantation. In 44 patients, prednisone other potential factors of liver injury, and with circulating oral dosage was varied in a slow tapering fashion, to reach 25 HCV-RNA, as detected by polymerase chain reaction. All mg/d by the end of the first post-olt month, 20 mg/d by the biopsies obtained from the study population were retrospecend of month 3, 10 mg/d by the end of month 6, 5 mg/d by tively re-evaluated in a coded blind fashion by a single expert the end of month 12, and then 2.5 mg/d fromonth 12 to 24 pathologist for this study. The Knodell s histology activity or indefinitely; whereas in 36 patients the oral prednisone index was used to asess the extent of inflammation and the dose was changed to 25 mg/d by thend of the first post-olt month, then 12.5 mg/d by the end of month 3,5 mg/d by the end of month 6,2.5 mg/d by the end of month 12, and then 2.5 mg/d was stopped between month 12 and month 24. Rejection episodes were detected by close monitoring of clinical and biochemical parameters and confirmed by liver stage of fibrosis, when recurrent hepatitis C was the clinical and histologic diagnosis. For the purpose of recurrent disease severity classification, a histologic activity index of eight or lower was considered as mild chronic hepatitis in comparison with a score of nine or higher that was considered as moderate/severe chronic hepatitis. biopsyineachsuspectedcase. In patientswithhistologic Factors included in the statistical analysis as potential preconfirmation of acute rejection, a schedule of three boluses of dictors of outcome are those reported in Table 1. Cumulative intravenously methylprednisolone, 1 g/d, weregiven,fol- patient, liver graft, and disease-free survivals were assessed by lowed by rapid steroid tapering to reach the prednisone dose administered before rejection. In any patient, the diagnosis of Kaplan-Meyer analysis. Survival differences between subgroups were examined by log rank test. Factors influencing recurrent hepatitis C or of acute rejection was not a reason to survival were analyzed by Cox regression method. Factors change the selected way of tapering off steroids. influencing the severity of post-olt hepatitis C were analyzed by Mann-Whitney Utest or X-square test. Patients were Postoperative Follow-Up, Laboratory, and dividedinthosewith and withoutrecurrenthepatitis C. Pathologic Evaluations Patients were followed with scheduled clinical and laboratory Those with recurrent hepatitis C were divided according to severity of histologic changes. investigations for a median of45 months (range, 1.5 to months). According to our clinical protocol, recurrent hepa- Results titis C was suspected if alanine aminotransferase (ALT) values increased above l.5 times the upper limit of normal in two or Clinical Outcome more occasions. In all of such cases, within 3 months of the During the follow-up period of up to 106 months, first ALT increase, a liver biopsy was performed to assess the clinical and histologic diagnosis of chronic hepatitis C degree of histologic changes and to distinguish between recurrent hepatitis C and other possible types of graft injury (ie, was made in 38 of the HCV infected patients (47.5%), rejection, ischemia, cytomegalovirus [CMV infection). Sim- after a median interval of 13.6 months from transplanilarly, acute rejection was detected by histologic evaluation tation (range, l. 1 to 75.7 months). Because of tempowhen the close clinical and laboratory follow-up indicated this possible occurrence. This strategy led to the performance at rary liver enzyme increase, liver biopsies also were performed in additional 25 patients after a median interval

3 886 Brillanti et al Table 1, Characteristics of Patients With and Without Recurrence of Chronic Hepatitis C Patients Without Patients With Recurrent Chronic Recurrent Chronic Hepatitis C (n = Hepatitis 42) C (n = 38) P Gender (M/F) 29/9 31/11 Patient (28-64) age (yr)* 53.6 (33-63) 53.9 Donor age (yr) 41.5 (12-73) 39 (17-72) (IU/L) 1-224) ALT (3 * 90 (24-353) 61 95) 2.56 ( ) Bilirubin 3.23 (mg/dl)* Year of OLT Initial immunosuppression 18 Cyc/Tacr, Predn, h a 19 Cyc/Tacr, Predn Acute rejection 27 No Yes 19 Steroid boluses >l Past HBV infection (**) Anti-HBc (+) Anti-HBc (-) 15 HCV genotype Type 24 on- Type Abbreviation: h a, azathioprine. *Data present at time of transplantation. **Anti-HBc status not available in all patients. of 6.8 months from transplantation (range, 1.1 to 75.7 caused by recurrent hepatitis C occurred in six patients months), but histolgy was not consistent with recurrent (7.5%), and three of these subjects underwent a second hepatitis C. In these 63 patients, a median number of liver transplantation. Thirty patients experienced mild two liver biopsies were performed to assess liver condi- to moderate acute rejection episodes that were treated tion. The remaining 17 patients did not show any clin- with steroid boluses. ical or laboratory evidence that could raise the suspect of recurrent HCV-related liver disease, despite virologic evidence of persistent HCV infection (only two patients lost HCV-RNA during follow-up). Because no other liver disease was clinically suspected, these 17 patients did not undergo liver biopsy after the first month post-olt. In patients with recurrent hepatitis C, histologic evaluation of the first diagnostic liver biopsy showed a total Knodell s score of four to eight in 18 patients, of nine to 11 in 13 patients, and of 12 to 14 in seven patients. The score for the fibrosis component was three in eight patients, two in two patients, and one in the remaining 28 patients. No statistical difference in patient survival was found between patients with and without recurrence of chronic hepatitis C. Decompensated liver cirrhosis Predictive Factors of Recurrence Results of the analysis of the association between the recurrence of hepatitis C and several potential risk factors are shown in Table 1. At univariate statistical analysis, no factor was significantly associated with chronic hepatitis C recurrence. As previously stated with respect to immunosuppression, the way of tapering off corticosteroids was not the same in our population, and in almost half of the patients (n = 36) daily prednisone was more rapidly decreased to less than 7.5 mg by the end of the sixth month and to less than 5 mg by the end of the twelfth month after liver transplantation. When we analyzed the association between corticosteroid treatment and recurrence of chronic hepatitis C, no significant differences were found in terms of cumulative prednisone

4 Hepatitis Steroids and C Recurrence 887 dosage and of duration of prednisone treatment between patients with and without hepatitis C recurrence. On the contrary, the median daily prednisone dose, at 12 months after transplantation, was significantly lower in patients who did experience recurrent hepatitis C, in comparison with those who did 4.5 not: (0.5 to 30) versus 5.0 (3 to 32.5) mg, (P =.03). Using receiver operating characteristic curve, the optimum cut-off point for the daily prednisone dose at month 12 after OLT was selected as 4.9 mg, with a sensitivity of 61 (YO and a specificity of 60% in identifying patients with and without hepatitis C recurrence. Among patients receiving a daily prednisone dose of 4.9 mg or higher, the proportion of recurrent hepatitis C was 35.7% versus 66.6% among those receiving a lower daily prednisone dose (P =.02; odds ratio [OR], 3.6; 95% CI, 1.25 to 10.36). The diagnosis of recurrent hepatitis C was not a reason to change the selected way of tapering off steroids. Predictive Factors of Severe Outcome Among the 38 patients with recurrent hepatitis C, 16 patients had a histologic activity index of eight or lower (considered as mild chronic hepatitis), in comparison with the remaining 22 patients whose histology activity index (HAI) score was nine or higher (considered as moderate/severe chronic hepatitis). The median daily prednisone dose, at 6 months after transplantation, was significantly lower in patients with moderate/severe chronic hepatitis than in those who had milder histologic changes: 6.3 (0 to 19.5) versus 9.6 (4.4 to 46.6) mg (P =.OS). Again, using the receiver operating characteristic curve, the optimum cut-off point for daily the prednisone dose at month six after OLT was selected as 7.7 mg, with a sensitivity of 71% and a specificity of 73%. Among the 20 patients receiving a daily prednisone dose of 7.7 mg or higher, the proportion of moderate/severe chronic hepatitis C was 40% versus 89% in the 18 subjects receiving a lower daily prednisone dose (P =.03; OR, 0.08; 95% CI, to 0.84). Prednisone dose at month six was significantly associated with the disease-free survival of the liver graft, when disease is considered as moderate/severe chronic hepatitis (Fig. 1). The significance of this association was confirmed by Cox regression method. Finally, five out of six patients who experienced posttransplant decompensated cirrhosis were in the group of subjects who rapidly tapered off the drug. As stated above, the diagnosis of recurrent hepatitis C was not a reason to change the selected way of tapering off steroids in any patient. t P Fast tapering off.---- Slow tapering off 0 04 i Days post OLT Figure 1. Estimated disease-free survival after liver transplantation in patients with recurrent hepatitis C, according to fast or slow way of tapering off steroids (disease = moderate or severe chronic hepatitis, P =.02 by log rank test). Discussion Recurrent hepatitis C after liver transplantation represents a major clinical problem. We studied a homogeneous population of 80 consecutive HCV-positive patients, transplanted at single a center over a period of seven years (l 991 to 1997), and subsequently followed up to 106 months (median: 45 months). As reported in other previous series,5 we found a recurrence rate of chronic hepatitis C in about half of the transplant recipients (47.5%). The survival analysis indicated a similar outcome after OLT in patients with and without recurrent chronic hepatitis C. This indicates that even a long-term follow-up period does not reveal an excess mortality because of the recurrent viral disease. It is likely that the full effect of recurrent hepatitis C will become apparent only with observations longer than a decade. Persistence of HCV infection after transplantation was confirmed in all recipients, but persistent increase in aspartate aminotransferase values, ALT values (or both) was not seen in 52% of them. Routine liver biopsies were not performed in the 17 patients with continuously normal aspartate aminotransferase and ALT values, but it is unlikely that these subjects developed a moderate severe or chronic hepatitis C,6,7 even if it is possible that some of them had mild histologic changes. The possibility of identifying risk factors able to select those patients who develop chronic hepatitis C would be of great clinical significance, allowing to target specific antiviral treatment to patients with a high likelihood of progressive disease.8~9 We analyzed several factors potentially affecting the recurrence of HCV-

5 888 Brillanti et a1 related liver disease, but were not able to identify virus Acknowledgment or host-related variables significantly associated with The authors thank Emilio De Raffaele, MD, for his great help hepatitis C recurrence. in collecting serum samples from transplanted patients over Over 80% of our patients received steroids for at several years. least 1 year after transplantation, and the total cumulative dosage was quite similar among patients. 60% In of patients with recurrent chronic hepatitis C, significant increase in ALT values started before withdrawal of steroids, whereas in 40% of them, clinical evidence of recurrent hepatitis C started after steroid withdrawal. References 1. 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 1994;20: Interestingly, chronic hepatitis C recurred more fre- 2. Gane EJ, Portmann BC, Naoumov W, Smith HM, Underhill quently in patients who were assigned to a rapid JA, Donaldson PT, et al. Long-term outcome of hepatitis C decrease in steroids than in those whose steroid tapering was slow. In addition, the histologic lesions were more infection after liver transplantation. N Engl J Med 1996;334: severe in patients receiving a lower daily maintenance 3. Prieto M, Berenguer M, Rayon JM, Cordoba J, Arguelo L, Carrasco D, et al. High incidence of allograft cirrhosis in hepatitis C dose of prednisone, and five of the six patients who virus genotype 1 b infection following transplantation: Relationship experienced posttransplant decompensated cirrhosis with rejection episodes. Hepatology 1999;29: were in the group of subjects who rapidly off tapered the 4. Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, Rayon M, drug. We have not definite explanations for the apparent et al. HCV-related fibrosis progression following liver transplantation: Increase in recent years. J Hepatol2000;32: protective role of slow steroid withdrawal against recur- 5. Boker KH, Dalley G, Bahr MJ, Maschek H, Tillmann HL, Trautwein C, et al. Long-term outcome of hepatitis C virus infecrent hepatitis C. In patients infected with HCV, cortition after liver transplantation. Hepatology 1997;25: costeroids are known to reduce the biochemical and 6. Zhou S, Terrault NA, Ferrell L, Hahn JA, Lau JY, Simmonds P, histologic expression of liver disease activity. 1 This is et al. Severity of liver disease in liver transplantation recipients possibly caused by a reduction in the immune-mediated with hepatitis C virus infection: Relationship to genotype and damage of liver infected cells. Unfortunately, HCV level of viremia. Hepatology 1996;24: viremia levels normally increase during steroid treat- 7. Shuhart MC, Bronner MP, Gretch DR, Thomassen LV, Wartelle CF, Tateyama H, et al. Histological and clinical outcome ment, and a rapid decrease in steroid immunosuppresafter liver transplantation for hepatitis C. Hepatology 1997;26: sion could expose large a amount of HCV-infected cells to a partially restored immune aggression. This may 8. Charlton M, Seaberg E, Wiesner R, Everhart J, Zetterman R, Lake explain the higher incidence and severity of hepatitis C J, et al. Predictors of patient and graft survival following liver transrecurrence in patients with a faster steroid withdrawal. plantation for hepatitis C. Hepatology 1998;28: Feray C, Caccamo L, Alexander GJ, Ducot B, Gugenheim J, Indirect confirmation of our findings also comes from Casanovas T, et al. European collaborative study on factors influthe lack of any advantage in preventing hepatitis C encing outcome after liver transplantation for hepatitis C. Eurorecurrence observed in recent trials of patients in whom pean Concerted Action on Viral Hepatitis (EUROHEP) Group. steroids were very rapidly tapered off or were not totally Gastroenterology 1999;117: included in the immunosuppressive regimen of liver 10. Fong TL, Valinluck B, Govindarajan S, Charboneau F, Adkins graft recipients. RH, Redeker AG. Short-term prednisone therapy affects aminol2 transferase activity and hepatitis C virus RNA levels in chronic In conclusion, our results seem to indicate that in hepatitis C. Gastroenterology 1994; 107: HCV-infected liver transplant recipients, a long-term 11. Magrin S, Craxi A, Fabian0 C, Simonetti RG, Fiorentino G, treatment with corticosteroids, slowly tapered off over time, may prevent the more aggressive forms of recur- Marino L, et al. Hepatitis C viremia in chronic liver disease: Relationship to interferon-alpha or corticosteroid treatment. rent HCV-related liver disease. Because hepatitis C Hepatology 1994; 19: Nelson DR, Soldevila-Pico C, Reed A, Abdelmalek MF, Hemrecurrence seems to be more aggressive in recent years, ming AW, Van der Werf WJ, et al. Anti-interleukin-2 receptor we suggest a careful evaluation of the role of corticostetherapy in combination with mycophenolate mofetil is associroids, despite the side effects commonly associated with ated with more severe hepatitis C recurrence after liver transplanthese drugs. tation. Liver Transpl200 ;7: