- Email: [email protected]
Treatment of posttransplantation recurrence of hepatitis C with interferon and ribavirin: Lessons on tolerability and efficacy
Treatment of Posttransplantation Recurrence of Hepatitis C With Interferon and Ribavirin: Lessons on Tolerability and Efficacy Kozbikode K Nuruyunun Menon, *JohnJ Poterucbu, * Omer M. El-Amin, * LuwrenceJ Burgart, Wulter K Kremers, * Cbudes B. Rosen, * Russell H. Wiesner,* und Micbuel Churlton"
'
Recurrenceof hepatitis C virus (HCV) infection after for allograft failure leading to death or graft loss in orthotopic liver transplantation is a major cause of graft approximately 10% of transplant recipients bythe fifth failure. The aim ofour study was to determine the safety, postoperative efficacy, and tolerability of combination therapy with Unfortunately, the plethora of robust data in the interferon and ribavirin in the treatment of recurrent hepnontransplantation setting is not available in transplant atitis after liver transplantation. Twenty-six patients (18 men) with histologically established HCV recurrence after recipients. Although the number and size of studies are liver transplantation for cirrhosis secondary to chronic small, studies that reported the efficacy of nonpegylated HCV infection were treated with a combination ofinterinterferon alfa have ribavirin combination therapy in feron alfa-2b (3 million units threetimesweekly) and ribavirin (800 to 1,000 mg/d). Dosage modifications were the treatment of posttransplantation HCV infection suggest that theoverall efficacy of these agents is broadly accordingto a standard protocol incorporatinglaboratory similar to that in the nontransplantation setting, with values and clinical side effects. Fifty percent of patients completed 1 year or more of therapy. On an intention-toend-of-treatment virologicalresponseratesvarying treat basis, nine patients (35%) showed an end-of-treatbetween 15% and 50%.15-20 Reversal of fibrosing choment virological response. Six of these nine patients comlestatic posttransplantation HCV infection, although and pleted greaterthan 6 additional months of follow-up, appears to be unusual.22 all have had sustained virological responses. A histologicalreported,21,20 We designed a protocol to determine the efficacy response (decrease in histological activity index2 2 ) was and 67% of nonreseen in 75% of virological responders and tolerability of posttransplantation interferon and sponders. Adverse events requiring dose modification or ribavirin therapy initiated on histological documentacessation of therapy occurred in 66% of patients. Adjution of recurrence of HCV infection. vant therapies used to support hemoglobin levels included erythropoietinand red blood cell transfusions. There were no independent pretreatment predictors of a virological Methods response, perhaps because ofthe small sample size. Combination therapy with interferon and ribavirin may be Study Population beneficial in patients withrecurrent HCV after liver transAll patientswhounderwenttransplantationforend-stage plantation. The majority ofpatients require dose modifiliver disease secondary t o H C V infection were eligible for cations because of side effects. Histological response is common in virologicalnonresponders. (Liver Tramp2 combination antiviral therapy with interferon and ribavirin. 2002;8:623-629.) All patients had H C V RNA by polymerase chain reaction (PCR) before transplantation. Recurrent H C V was diagnosed during routine (annual) scheduled evaluations iforabnormal liver test results were noted between scheduled evaluations.
nd-stage liver disease secondary to hepatitis C virus WCV) infection is the most common indication for liver transplantation intheUnited States and Europe.'P2 In contrast to other causes ofdecompensated From the *Liver Transplant Center and fDepartmento f Pathology, Mayo Clinic and Foundztion, Rochester, MN. liver disease, such as alcohol, cholestatic liver diseases, Supported in part by a grantfiom the Carhon-Nelson Foundation. and cryptogenic cirrhosis, posttransplantation HCV Presented in part at the annual meeting of the International Liver recurrence, defined by detection of HCV RNA, is Transplant Sociev, Berlin, Germany,July 11-13, 2001. nearly universal.3-7In the nontransplantation setting, it Address reprint requests to Michael Charlton, MD, Mayo Clinic, is estimated that the mean time from infection to the IO, 200 First St Sy Rochester, M N TransplantCenter,Charlton development of cirrhosis is approximately 30 year~.~>5 -55902.Telephone: 507-266-7054; Fax: 507-266-2810; E-mail: charlton. [email protected] Among liver transplant recipients, the course of HCVCopyright O 2002 by the American Association for the Study of induced liver injury is accelerated. Recurrence of HCV Liver Diseases is apparent histologically in approximately 50% of 1527-6465/02/0807-0009$35.00/0 doi:IO.1053/jlt2002.33968 HCV-infected transplant recipients and is responsible
E
Liver Transplantation, Vol8, No 7 (/.h), 2002: pp 623-623
623
624
Narayanan Menon et a1
Recurrent hepatitis C was defined by the presence of all the alternate days. After cytomegalovirus infection, azathioprine following criteria: H C V R N A detectable by P C R in serum, and MMF therapy were reduced or withdrawn. abnormaltransaminase levels (anydegree), andabnormal Virological Methods liver histological characteristics consistent with recurrent hepatitis C. Viral RNA was extracted from aliquots of 100 p L of sera bya Other causes of graft dysfunction, including rejection, guanidine thiocyanate lysis protocol using reagents supplied viralinfections(such as cytomegalovirus), and vascular or intheAmplicorHepatitis C Testkit(RocheDiagnostic, biliary complications, were excluded by Doppler ultrasound Branchburg,NJ) as previouslydescribed.5Modifications examination of the allograft, cholangiograms, and cultures, as included the addition of 2 p L of Pellet Paint (Novagen, appropriate in all cases. pellets after Madison, W I ) to facilitate recoveryof nucleic acid Patients who met the following criteria were ineligible for isopropanol precipitation and the addition of 40 U of recomantiviral therapy: history of ischemic heart disease, hemoglobinant RNasin (Promega, Madison, W I ) in a final 25-pL bin level less than 8.5 g/dL, total white blood cell count of volume with RNase-free water to stabilize recovered the RNA before reverse-transcriptase PCR. H C V viremia was assessed 1.O X lO7/L or less, absolute neutrophil count of 0.5 X l O9/L by reverse-transcriptase PCR, as previously described.20 or less, platelet count of 25 X lO9/L or less, presenceof Genotypes were assigned using nucleotide primers specific ongoing rejection, or concurrent pretransplantation evidence fora401-bptargetsequencewithintheNS5region as of autoimmunehepatitis. described by Simmonds etal.23 Specimens were subjected to Treatment D N A sequencing and gel electrophoresis on an AB1 Prism 377 Genetic Analyzer (ABI, Foster City, CA). D N A sequence Interferon therapy was started at a dose of 3 million units information was compared with published HCV-type referthree times weekly subcutaneously, and ribavirin, at 800 mg ence sequences using the FASTA algorithm (Wisconsin (<70 kg) to1,OOO mg (170 kg)orallydaily.Doseswere Genetics Computer Group, Madison,W). modified according the following criteria. HCV RNA quantitation was performed using a branchedInterferon dose was reduced to 1.5 millionunitsfora chain D N A assay. HCV RNA, expressed in viral equivalents hemoglobin level less than 10 g/dL, total white blood cell per milliliter (vEq/mL), was quantitated in serum by signal count less than 1.5 X lO’/L, absolute neutrophil count less amplification using branched DNA in a sandwich hybridizathan 0.75 X lO9/L, or platelet count less than 50 X lO9/L. tion assay (Quantiplex Version 2.0; Chiron, Emeryville, CA). Interferon therapy was discontinued for a hemoglobin The lower limit of sensitivity of thisassay is 0.2 X lo6 vEq/mL. level less than 8.5 g/dL, total white blood cell count less than
l .O X 109/L, absolute neutrophil count less than 0.5 X 109/L, Histological Examination or platelet count less than 25 X lO9/L. Liver biopsies were performed before treatment and subseRibavirin dose was reduced to 400 to 600 mg/d if the quently at the completion of treatment if possible. All biopsy hemoglobin level decreased toless than 10 g/dL, and ribavirin specimens were read by a single pathologist (L.J.B.) who was therapy was discontinued if the hemoglobin level decreased to blindedtobiochemicalandvirological responses ofthe less than 8.5 g/dL. Adjuvant therapies included the use of patient. Histological recurrence of H C V was based on finderythropoietin injections and packed red blood cell transfusions. ings of portal and/or periportal inflammation with mononuA biochemical response was defined by normalization of clear cells. Disease severitywas determined using the modified liver enzyme levels. An end-of-treatment virological response was defined by the absence HCV of RNA in serum at the endhistological activity indexof Kn0de11.~* of completion of therapy (defined by the completion of at Statistical Analysis least l year of treatment or at the point of cessation of treatBaseline characteristics and measures of tolerability and effiment because of persistent side effects) measured by qualitacacy of treatment between responders and nonresponders are the tive PCR. A sustained virological response was defined by described as proportions or medians and range and were comabsence of H C V R N Ain serum6 months after completion of pared using two-sided Fisher’s exact and Wilcoxon’s tests. therapy, measured by qualitative PCR. Correlations were assessed using Spearman’s correlation coefImmunosuppression therapy consisted of cyclosporine or ficient. The primary outcome of the is study end-of-treatment tacrolimus, prednisone, and azathioprine until 1994,at which virological response. Secondary outcomes are tolerability of 1997, time a tacrolimus-based regimen was introduced. In treatment, defined by completion of 48 weeks of antiviral mycophenolate mofetil (MMF) was introduced as part of a therapy, and biochemical response, defined by normalization randomized clinical trial comparing azathioprine and MMF. of biochemistry test result. Since the beginning of 1999, typical primary immunosuppression has been tacrolimus, prednisone, and MMF. Prednisone dose was tapered and stopped between 3 and 6 months posttransplantation. Patients who developed biopsy-proven acute cellular rejection were treated with three intravenous boluses of methylprednisolone (1,000 mg) administered on
Results Patient demographics are listed in Table 1. The median time to treatment after liver transplantation was 58.4
625
Posttransplantation Treatment of HCV
Tabie 1. Patient Demographics
I
Responders Range Normal Age (yr) Men Hemoglobin (g/dL) Creatinine (mg/dL) (66-312) Serum AST (U/L) Serum ALT (U/L) Serum AP (U/L) Serum bilirubin (mg/dL) Viral load (mEq/mL) HA1 Fibrosis score Weeks to treatment Weeks of treatment
118
(n = 9) 46.4 6 12.5 1.2
0.6-0.9 12-31 10-45 90-234 0.1-1.1
Nonresponders (n = 17)
P
47.9 (40.3-72) 12 (70.6) 11.9 (10-16) 1.1 (0.8-1.9) 114 (21-324) 180 (30-638) 465 (133-1 112) 1.4 (0.8-12.4) 25.8 (0.22-120) 4 (309) 1 (0-6) 55.3 (8.7-242.6) 40.6(6.3-57.4)
NS NS NS
(36.2-67.9) (66.7) (1 1-14.8) (0.9-3.7)
143 (5 1-446) 261 (75-688) 1.2 (0.9-3.2) 1.8(0.2-44) 5 (4-9) 2 (1-6) 66.7(13.7-284.4) 50.3 (13.1-77.9)
NS NS NS NS NS NS NS NS NS NS
NOTE. Values expressed as median (range)or number (percent). Genotypes were known in 18 of 26 patients. Of these, 4 of 13 patients (31%) with genotype 1 and I of 5 patients (20%) with non-l genotypes had sustained virological responses. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; AP, alkaline phosphatase; HAI, histological activity index; NS, not significant.
weeks (range, 8.7 to 284.4 weeks). HCV genotypes were availablefor 18 of 26 patients. Of the 18 patients in whom HCV genotypeswere known, 13 patients (72%)were infected with genotype 1; 3 patients, genotype 2; 1 patient, genotype 3; and 1patient, genotype 4.
treatment but went on to have an end-of-treatment responsewere treated for 37.3, 27.3, 15.1, and 13.1 weeks.
Biochemical Response O n an intention-to-treat basis, a biochemical response was seen in 42% (1 1of 26 patients) of patients. This included biochemical responsesin 56% of end-of-treatment responders and 35% of virologicalnonresponders (P= .42). Four patients (44%) with an end-of-treatment virological response did not show a biochemical response. In one patient, enzyme levels normalized soon after stopping treatment, whereas in the second patient, enzyme levels normalized spontaneously 2 years after stopping treatment. A third patient continues to have mildly abnormal liver enzyme levelswith no evidence of histological or virological recurrence of hepatitis C. The fourth patient developed an autoimmunetype hepatitis resulting in elevated liver enzyme levels that gradually normalized after stopping treatment.
Virological Response O n an intention-to-treat basis, nine patients (35%) showed an end-of-treatment virological response (Fig. 1). Eight of eight end-of-treatment virological responders who completed at least 6 months of posttreatment follow-up also have shown a sustained response, measured by qualitative PCR. Follow-up is pending in the remaining patient. Among the 18 patients for whom genotype was known, 4 of 13 patients (3l %) with genotype 1 andl of 5 patients (20%) with non-l genotypes had virological responses. Of the 8 patients for whom genotype was unknown, 4 patients (50%) had virological responses. The four patients who did not complete 1 year of
I Figure 1. Outcomes afterinitiation of combination treatment. (IFN, interferon; RIBA, ribavarin; Rx, medication; m, month.)
Initiated on IFNlRlBA n=26 Cessation of R x due to Side Effects n=13 (50%) I
n=13
I
PCR negative at 12m
n=4 (62%)
(31%)
PCR postive at 12m n=9 (69%)
626
Narayanan Menon et a1
Histological Response Paired liver biopsy specimens (before and after treatment) wereavailable in 12 patients (4 responders, 8 nonresponders). The median pretreatment necroinflammatory score was 5 (range, 3 to 9),which improved to 3 (range, 0 to 11) after treatment. A decrease in necroinflammatory score posttreatment wasseen in 75% of both responders (3 patients) and nonresponders (6 patients). A decrease in necroinflammatory score of 2 or greater was seen in 75% (3 patients) of responders and 67% ( 5 patients) of nonresponders. Among patients who showed a virological responseto therapy, fibrosis score improved by 1 in 1 patient (25%) and remained the same in 3 patients (75%).Among nonresponders, fibrosisscoreworsened by 1 in 2 patients (25%) and remained the same in 6 patients (75%).
Tolerability/Adverse Events Sixty-five percent of patients completed 6 months and 50% completed at least 1 year oftherapy. Four patients continued treatmentbeyond 1 year (62,78,79, and 86 weeks). Greater pretreatment hemoglobin levelwas found to correlate with longer duration of therapy (Spearman's correlation coefficient, 0.5; P < .Ol), and patients with a hemoglobin level greaterthan l .5 l g/dL had a significantly greater likelihood of completing at least 6 months of therapy (87% U 36%). Adverse events were seen in 69% (18 patients; Table 2), with 66% (17 patients) requiring dose modification or cessation of treatment. An additional patient had elevations in hisliverenzymelevels that normalized after stopping therapy. Anemia and leukopenia were the most common adverse events, occurring in 46% and 15%, respectively. Thirteen of 25 patients (52%) had a decrease in hemoglobin level of 2 g/dLor greater at the end of 1 month of therapy. Of these 13 patients,
Table 2. Adverse Effects of Combination TherapyWith Interferon andRibavirin Event
Adverse Anemia (Hb < 10 g/dL) Leukopenia ( W C < 1.5 X 109/L) Fever/chills Fatigue Rash Diarrhea Depression hepatitis Autoimmune
Number (percent) 12 (46) 4 (15) 2 (8) 2 (8) 1 (4) 1 (4)
1 (4) 1 (4)
Abbreviations: Hb, hemoglobin; W C , white blood cell.
only 3 patients (23%) were ableto complete 12 months of therapy. Ten of 12 patients (83%) with a hemoglobin level decrease less than 2 g/dL were ableto complete 12 months of therapy (P= .005 U those with hemoglobin level decrease L 2 g/dL). The occurrence of adverse events resulted in cessation of treatment in 50% (n = 13) of patients. Indications for cessation of therapy were anemia (n = 5), anemia with concomitant neutropenia (n = 4 ) , rash (n = I), autoimmune hepatitis (n = l), diarrhea (n = l), and increasing bilirubin level (n = 1). Three patients died during follow-up. Two patients died of liver failuresecondary to recurrence ofhepatitis C, whereas the thirdpatient died soon afterretransplantation. In all three patients, treatment with interferon and ribavirin failed. Adjuvant therapies were usedto maintain hemoglobin levels during treatment. These included packed red blood cell transfusions in six patients (23%) and erythropoietin injections in four patients (15%). Antidepressant therapy also was used in one patient (4%).
Discussion Treatment of hepatitis C with interferon and ribavirin in the nontransplantation population has resulted in sustained response rates of30% to 50% and may be of benefit in preventing progression of liver fibrosis. However, data regarding end-of-treatment virologic responserates and,in particular, sustained response rates are sparsein the transplant population. The numbers of patients studied are small, and available data suggest that response rates are lowerthan those seen in the nontransplantation population. We report a 35% end-of-treatment response ratein 26 patients with recurrent hepatitis C after liver transplantation when using a treatment-on-recurrence strategy. More importantly, all patients with an end-oftreatment virologic response went on to have a sustained response, with negative HCV RNA levels at the end of at least 6 months after stopping treatment. The low relapse rate seen in our patients is in contrast to that reported in the nontransplantation population.25,26A longer duration of follow-up is necessaryto determine the ultimate durability of virological responses among our transplant recipients. Other studies of combination therapy with interferon and ribavirin in thetreatment of posttransplantation HCV infection have reported greater or equal end-of-treatment virological and histological response ratesto those seen in our current study.'9 Although there are case reports of biochemicaland partial virological responsesin cho-
Posttransplantation Treatment of HCV
lestatic transplant recipient~,~l>~7 initiation of combination therapy in patients who were cholestatic at treatment initiation was unsuccessful in our study. Few studies have reported sustained response rates. Bizollon et a l l 6 reported on 21 patients treated with interferon and ribavirin for a period of 6 months, followed by maintenance ribavirin therapy for an additional 6 months. Serum HCV RNA was negative in 10 patients (48%) at the endof 6 months of therapy, with a sustained response seenin 5 patients during follow-up (24%). A study from North America showed an endof-treatment response rate of 12%,20 whereas the largest report to date found a relapse rate of approximately 50Y0.l~Conversely, none of our patients who experienced an end-of-treatment responseexperienced a relapse after stopping treatment. Longer follow-up will be necessary to determine whether this remains true in the long term. The frequency of side effects necessitating cessation of treatment in our study was greater than thatgenerally reported in the nontransplantation setting (> 10%).25,26 This difference appearsto be substantially caused bythe high prevalenceof anemia and renalinsufficiency among liver transplant recipients. Hemolysis may be exacerbated in the presence of calcineurin inhibitorinduced nephrotoxicity and subsequently decreased endogenous erythropoietin production. A low threshold for ribavirin dosage reduction must be considered in this patient population. In a previous study, ribavirin monotherapy in HCV-infected liver transplant recipients required dose reduction or cessation in a proportion similar to that seen in our patients.28Sixty-six percent of our patients required dose reductions, and 50% had to stop treatment because of persistent side effects. Adverse events resulting from interferon included rejection, cytopenia, infection, and constitutional symptoms such as headaches and myalgias. The major reported sideeffect of ribavirin was anemia, treated primarily by dose reduction. Overall, dose reduction and/or cessation of therapy have been reported to be required in 40% to 50% of patients administered interferon and ribavirin in the posttransplantation setting. A large prospective study, in which erythropoietin therapy was initiated early in the course of antiviral therapy, showed efficacy in preventing dose reductions and cessation ofribavirin therapy? Anemia secondary to ribavirin therapy in our study was treated with acombination of red blood cell transfusion and erythropoietin in six (23%) and four (15%) patients, respectively. However, all four patients administered erythropoietin subsequently discontinued treatment because of anemia. A similar experience
627
was reported by De Vera et a l , 3 O who administered erythropoietin to 28% of patientson combination therapy. Of the handful of studies describing the outcome of treating HCV with interferon in liver transplant recipients, two studies suggested that interferon treatment may be associated with an increasedrisk for rejecti0n.3l.3~Acute vanishing bile duct syndrome also has been described after interferon therapy for recurrent HCV.33 Interferon monotherapy was not associated with an increased risk for rejection in three other studie~.~*,3*,35 None of the larger more recent studies of combination therapy with interferon and ribavirin reported an increased risk for frequency or severity of reje~tion.'~>~O>3~-39 episodes No of rejection were noted among our patients on combination therapy. One patient developed markedly abnormal transaminases (210 times the upper limit of normal) during therapy, along with hyperbilirubinemia. A liver biopsy in this patient showed marked lymphocytic and plasma cell infiltrate in the portal tract, suggestive of autoimmune hepatitis, with no cholangitis, endotheliitis, or eosinophilia. Interferon and ribavirin therapy were discontinued, with subsequent normalization of liver test results. Another patient had mildly elevated liver test results that returned to normal after completing treatment. We were not able to identifjr pretreatment predictors of response to therapy. However, the end-of-treatment response rate in patients who completed 6 months or more of therapy was double that inpatients who did not complete 6 months of therapy (41% v 22%; P = .42). This finding suggests that continuationof treatment for the longest possibleperiod, especially in thesetting of a biochemical response, might help achieve a sustained response. The observation that a greater pretreatment hemoglobin level and greater stability of hemoglobin levels on therapy were associatedwith greater tolerability of treatment (average pretreatment hemoglobin, 13.2 g/dL for patients who tolerated > 6 months v 11.65 g/dL for those who underwent therapy for < 6 months) suggests that measures to maintain hemoglobin levels should be considered early in the course of treatment. Only 2 1% of patients who underwent less than 6 months of treatment had virological end-oftreatment responses. Additional studies with much larger numbers of patients are neededto clearly identify host and/or viral characteristics predictive of responsiveness and tolerability to antiviral therapy. In summary, we have shown that approximatelyone third of patients with recurrent hepatitis C after liver transplantation show an end-of-treatment response to combination therapy with interferon and ribavirin. A sustained response may be seen in the majority of those
628
Narayanan Menon et a/
infection after liver transplantation. Hepatology 1997;25:203210. 14. 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. 15. Bellati G, Alberti AB, Belli LS, VaiC, Airoldi A, Rondinara GF, et al. Therapy of chronic hepatitis C after liver transplantation: Multicenter Italianexperience[abstract]. J Hepatol 1999; 30(suppl):S51A. 16. Bizollon T, Palazzo U, Ducerf C, Chevallier M, Elliott M, Baulieux J, et al. Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitisC after liver transplanReferences tation. Hepatology 1997;26:500-504. 1.Belle SH, BeringerKC, Detre KM, Terasaki PI, Cecka JM. 17. LavezzoB,Rizzetto M, SmedileA, Ottobrelli A,GhisettiV, Recent findings concerning liver transplantation in the United Franchello A, et al. Combination therapy of interferon alfa 2b States. In: ClinicalTransplants 1996. Los Angeles: UCLA Tissue and ribavirin for recurrent hepatitis C after liver transplantation. Typing Laboratory; 1997:15-30. J Hepatol 1999;30:67-72. 2. Feray C, CaccamoL,Alexander GJ, Ducot B, Gugenheim J, 18. Shah1 AO, McGuire B, Crippin JS, Conjeevaram HS, TeperCasanovas T, et al. European collaborativestudy on factors influman L, Gish R, et al. Interferon-alfa 2b and ribavirin combinaencing outcome after livertransplantation for hepatitis C. Eurotion therapy in liver transplant recipients with recurrent hepatitis pean Concerted Actionon Viral Hepatitis (EUROHEP) Group. C [abstract]. Hepatology 2000;32:217A. Gastroenterology 1999;117:619-625. 19. Mazzaferro V, Regalia E, Pulvirenti A, Tagger A, Andreola S, 3. Wright TL, Donegan E,Hsu HH, Ferrell L, LakeJR, Kim M, et Pasquali M, et al. Prophylaxis againstHCV recurrence after liver al. Recurrent and acquired hepatitis C viral infection in liver transplantation: Effect of interferon and ribavirincombination. transplant recipients. Gastroenterology 1992;103:317-322. Transplant Proc 1997;29:519-521. 4. Tong MJ, el-Farra NS, Reikes AR, CORL. Clinical outcomes 20. Kapur A, Rodriguez MJ, SchecterP, Tzakis A, Schiff ER. Interafter transfusion-associated hepatitisC. N Engl J Med 1995;332: feron alfa and ribavirinin established post liver transplant recur1463- 1466. rent hepatitisC infection [abstract]. Gastroenterology1998;114: 5. KiyosawaK,Sodeyama T, Tanaka E, Gib0 Y,YoshizawaK, 1268A. Nakano Y, et al. Interrelationship of blood transfusion, non-A, 21. Muramatsu S, KuY, Fukumoto T, Iwasaki T, Tominaga M, non-B hepatitisand hepatocellular carcinoma: Analysis by detecKusunoki N, et al. Successful rescue of severe recurrent hepatitis tion of antibody to hepatitis C virus. Hepatology 1990;12:671Cwithinterferonandribavirin in a livertransplantpatient. 675. Transplantation 2000;69:1956-1958. 6. Charlton M, Seaberg E, Wiesner R, Everhart J, Zetterman R, 22. Gopal DV, Rabkin JM, Berk BS, Corless CL,Chou S, Olyaei A, Lake J, et al. Predictors of patient and graft survival following et al. Treatment of progressive hepatitis C recurrence after liver liver transplantation for hepatitis C. Hepatology 1998;28:823transplantation with combination interferon plus ribavirin. Liver 830. Transpl200 1;7:181- 190. 7. Gane EJ, Portmann BC, Naoumov NV, Smith HM, Underhill 23. Simmonds P, Alberti A, Alter HJ, Bonino F, Bradley DW, BreC JA, Donaldson PT, et al.Long-termoutcomeofhepatitis chot C, et al. A proposed system thefor nomenclature ofhepatitis infection after liver transplantation. N Engl J Med 1996;334: C viral genotypes. Hepatology 1994; 19: 132 1-1 324. 8 15-820. 24. Knodell RG, Ishak KG, BlackWC, Chen TS,Craig R, Kaplow8. Vargas HE, Laskus T, Wang LF, RadkowskiM, Poutous A, Lee itz N, et al. Formulation and application of a numerical scoring R, et al. The influence of hepatitis C virus genotypes on the system for assessing histological activity in asymptomatic chronic outcome of livertransplantation. Liver Transpl Surg 1998;4:22active hepatitis. Hepatology1981;1:431-435. 27. 25. DavisGL,Esteban-MurR,RustgiV,Hoefs J, GordonSC, 9. Feray C, Samuel D, Thiers V, GigouM, Pichon F, Bismuth A,et Trepo C, et al. Interferon alfa-2b alone or in combination with al. Reinfection of liver graft by hepatitis C virus after liver transribavirin for the treatment of relapse of chronic hepatitis C. plantation. J Clin Invest 1992;89:1361-1365. International Hepatitis Interventional Therapy Group. N Engl 10. AscherNL,Lake JR, Emond J, Roberts J. LivertransplantaJ Med 1998;19:1493-1499. tion forhepatitis C virus-relatedcirrhosis.Hepatology 1994; 26. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee 20(suppl):S24-S27. W M , Rustgi VK, et al. Interferon alfa-2b alone or in combina11. Rosen HR, O’Reilly PM, Shackleton CR, McDiarmid S, Holt tion with ribavirin as initial treatment for chronic hepatitis C. C, Busuttil RW, Martin P. Graft loss following liver transplanHepatitis Interventional Therapy Group. N Engl J Med 1998; tation in patients with chronic hepatitis C. Transplantation 19:1485-1492. 1996;62:1773-1776. 27. Telegdy L, Gorog D, Horanyi M, Schaff Z. Severe relapse of 12. Rosen HR, Gretch DR, Oehlke M, Flora KD, BennerKG, hepatitis C following liver transplantation. Successfultreatment Rabkin JM, Corless CL. Timing and severity of initial hepatitis with a combination of interferon-alpha and ribavirin.Orv Hetil C recurrence as predictors of long-term liver allograft injury. 1999;140:1891-1893. Transplantation 1998;65:1178-1182. 13. Boker KH, Dalley G, BahrMJ,Maschek H, Tillmann HL, 28. Gane EJ, Lo SK, Riordan SM, Portmann BC, Lau JY, Naoumov Traunvein C, et al.Long-termoutcomeofhepatitis C virus NV, Williams R. A randomized study comparing ribavirin and
who show an end-of-treatment response. However, dose modification and/or cessation oftherapy were necessary in the majority of patients. Studies with larger numbers of patients are necessary to identifi independent predictors of a response in the posttransplantation population. Trials incorporating newer interferon preparations, such as pegylated interferon, and prophylactic treatment strategies are awaited.
Posttransplantation Treatment of HCV
29.
30.
31.
32.
33.
34.
interferon alfa monotherapy for hepatitis C recurrence after liver transplantation. Hepatology 1998;27: 1403-1407. WassermanR,Brau N, Hassanein T, BiniE,Sulkowski M, 35. Dieterich D. Onceweekly epoetin alfa increases hemoglobin and decreases ribavirin dose reductions among HCV-infected patients who develop anemia on ribaviridinterferon alfa 2b therapy [abstract]. Hepatology 2000;32:833A. 36. de Vera ME, Smallwood GA, Rosado K, Davis L, Martinez E, Sharma S, et al. Interferon-alpha and ribavirin forthe treatment of recurrent hepatitis C after liver transplantation. Transplantation 200 1;71:678-686. 37. Feray C, Samuel D, Gigou M, Paradis V, DavidMF, Lemonnier C, et al. An open trial of interferon alfa recombinant for hepatitis C after liver transplantation: Antiviral effects and risk of rejection. Hepatology 1995;22: 1084-1089. Vargas V, Charco R, Castells L, Esteban R, Margarit C. Alpha38. C in livertransplantpatients. interferonforacutehepatitis Transplant Proc 1995;27:1222-1223. Dousset B, Conti F, Houssin D, Calmus Y. Acute vanishing bile duct syndrome after interferon therapy for recurrent HCV infec39. tion in liver-transplant recipients [letter]. N Engl J Med 1994; 330:1160-1161. Wright TL, Combs C, Kim M, Ferrell L, BacchettiP, Ascher N,
629
et al. Interferon-alpha therapy for hepatitis C virus infection after liver transplantation. Hepatology 1994;20:773-779. Sheiner PA, Boros P, Klion FM, Thung SN, Schluger LK, Lau JY, et al. The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation. Hepatology 1998;28:831-838. Mazzaferro V, Regalia E, Pulvirenti A, Tagger A, Andreola S, Pasquali M, et al. Prophylaxis againstHCV recurrence after liver transplantation: Effect of interferon and ribavirin combination. Transplant Proc 1997;29:519-521. Samuel D, Bizollon T, Feray C, Lemonnier C, Cohard M, Bismuth H, Trepo C. Combination of interferon alfa 2-B plus ribavirin for recurrentHCV infection after liver transplantation: A randomized controlledstudy [abstract]. Hepatology 2000;32: 542A. Gotz G, Schon MR, Haefker A, Neuhaus R, Berg T, Hopf U, Neuhaus P. Treatment of recurrent hepatitis C virus infection after liver transplantation with interferon and ribavirin. Transplant Proc 1998;30:2104-2106. Willner IR, Chavin KD, Rogers J, Baliga P, Reuben A. Combination interferon-ribavirin is ineffective and poorly tolerated by liver transplant recipients with genotype 1 recurrent hepatitis C [abstract]. Hepatology 2000;32:290A.
'
Recurrenceof hepatitis C virus (HCV) infection after for allograft failure leading to death or graft loss in orthotopic liver transplantation is a major cause of graft approximately 10% of transplant recipients bythe fifth failure. The aim ofour study was to determine the safety, postoperative efficacy, and tolerability of combination therapy with Unfortunately, the plethora of robust data in the interferon and ribavirin in the treatment of recurrent hepnontransplantation setting is not available in transplant atitis after liver transplantation. Twenty-six patients (18 men) with histologically established HCV recurrence after recipients. Although the number and size of studies are liver transplantation for cirrhosis secondary to chronic small, studies that reported the efficacy of nonpegylated HCV infection were treated with a combination ofinterinterferon alfa have ribavirin combination therapy in feron alfa-2b (3 million units threetimesweekly) and ribavirin (800 to 1,000 mg/d). Dosage modifications were the treatment of posttransplantation HCV infection suggest that theoverall efficacy of these agents is broadly accordingto a standard protocol incorporatinglaboratory similar to that in the nontransplantation setting, with values and clinical side effects. Fifty percent of patients completed 1 year or more of therapy. On an intention-toend-of-treatment virologicalresponseratesvarying treat basis, nine patients (35%) showed an end-of-treatbetween 15% and 50%.15-20 Reversal of fibrosing choment virological response. Six of these nine patients comlestatic posttransplantation HCV infection, although and pleted greaterthan 6 additional months of follow-up, appears to be unusual.22 all have had sustained virological responses. A histologicalreported,21,20 We designed a protocol to determine the efficacy response (decrease in histological activity index2 2 ) was and 67% of nonreseen in 75% of virological responders and tolerability of posttransplantation interferon and sponders. Adverse events requiring dose modification or ribavirin therapy initiated on histological documentacessation of therapy occurred in 66% of patients. Adjution of recurrence of HCV infection. vant therapies used to support hemoglobin levels included erythropoietinand red blood cell transfusions. There were no independent pretreatment predictors of a virological Methods response, perhaps because ofthe small sample size. Combination therapy with interferon and ribavirin may be Study Population beneficial in patients withrecurrent HCV after liver transAll patientswhounderwenttransplantationforend-stage plantation. The majority ofpatients require dose modifiliver disease secondary t o H C V infection were eligible for cations because of side effects. Histological response is common in virologicalnonresponders. (Liver Tramp2 combination antiviral therapy with interferon and ribavirin. 2002;8:623-629.) All patients had H C V RNA by polymerase chain reaction (PCR) before transplantation. Recurrent H C V was diagnosed during routine (annual) scheduled evaluations iforabnormal liver test results were noted between scheduled evaluations.
nd-stage liver disease secondary to hepatitis C virus WCV) infection is the most common indication for liver transplantation intheUnited States and Europe.'P2 In contrast to other causes ofdecompensated From the *Liver Transplant Center and fDepartmento f Pathology, Mayo Clinic and Foundztion, Rochester, MN. liver disease, such as alcohol, cholestatic liver diseases, Supported in part by a grantfiom the Carhon-Nelson Foundation. and cryptogenic cirrhosis, posttransplantation HCV Presented in part at the annual meeting of the International Liver recurrence, defined by detection of HCV RNA, is Transplant Sociev, Berlin, Germany,July 11-13, 2001. nearly universal.3-7In the nontransplantation setting, it Address reprint requests to Michael Charlton, MD, Mayo Clinic, is estimated that the mean time from infection to the IO, 200 First St Sy Rochester, M N TransplantCenter,Charlton development of cirrhosis is approximately 30 year~.~>5 -55902.Telephone: 507-266-7054; Fax: 507-266-2810; E-mail: charlton. [email protected] Among liver transplant recipients, the course of HCVCopyright O 2002 by the American Association for the Study of induced liver injury is accelerated. Recurrence of HCV Liver Diseases is apparent histologically in approximately 50% of 1527-6465/02/0807-0009$35.00/0 doi:IO.1053/jlt2002.33968 HCV-infected transplant recipients and is responsible
E
Liver Transplantation, Vol8, No 7 (/.h), 2002: pp 623-623
623
624
Narayanan Menon et a1
Recurrent hepatitis C was defined by the presence of all the alternate days. After cytomegalovirus infection, azathioprine following criteria: H C V R N A detectable by P C R in serum, and MMF therapy were reduced or withdrawn. abnormaltransaminase levels (anydegree), andabnormal Virological Methods liver histological characteristics consistent with recurrent hepatitis C. Viral RNA was extracted from aliquots of 100 p L of sera bya Other causes of graft dysfunction, including rejection, guanidine thiocyanate lysis protocol using reagents supplied viralinfections(such as cytomegalovirus), and vascular or intheAmplicorHepatitis C Testkit(RocheDiagnostic, biliary complications, were excluded by Doppler ultrasound Branchburg,NJ) as previouslydescribed.5Modifications examination of the allograft, cholangiograms, and cultures, as included the addition of 2 p L of Pellet Paint (Novagen, appropriate in all cases. pellets after Madison, W I ) to facilitate recoveryof nucleic acid Patients who met the following criteria were ineligible for isopropanol precipitation and the addition of 40 U of recomantiviral therapy: history of ischemic heart disease, hemoglobinant RNasin (Promega, Madison, W I ) in a final 25-pL bin level less than 8.5 g/dL, total white blood cell count of volume with RNase-free water to stabilize recovered the RNA before reverse-transcriptase PCR. H C V viremia was assessed 1.O X lO7/L or less, absolute neutrophil count of 0.5 X l O9/L by reverse-transcriptase PCR, as previously described.20 or less, platelet count of 25 X lO9/L or less, presenceof Genotypes were assigned using nucleotide primers specific ongoing rejection, or concurrent pretransplantation evidence fora401-bptargetsequencewithintheNS5region as of autoimmunehepatitis. described by Simmonds etal.23 Specimens were subjected to Treatment D N A sequencing and gel electrophoresis on an AB1 Prism 377 Genetic Analyzer (ABI, Foster City, CA). D N A sequence Interferon therapy was started at a dose of 3 million units information was compared with published HCV-type referthree times weekly subcutaneously, and ribavirin, at 800 mg ence sequences using the FASTA algorithm (Wisconsin (<70 kg) to1,OOO mg (170 kg)orallydaily.Doseswere Genetics Computer Group, Madison,W). modified according the following criteria. HCV RNA quantitation was performed using a branchedInterferon dose was reduced to 1.5 millionunitsfora chain D N A assay. HCV RNA, expressed in viral equivalents hemoglobin level less than 10 g/dL, total white blood cell per milliliter (vEq/mL), was quantitated in serum by signal count less than 1.5 X lO’/L, absolute neutrophil count less amplification using branched DNA in a sandwich hybridizathan 0.75 X lO9/L, or platelet count less than 50 X lO9/L. tion assay (Quantiplex Version 2.0; Chiron, Emeryville, CA). Interferon therapy was discontinued for a hemoglobin The lower limit of sensitivity of thisassay is 0.2 X lo6 vEq/mL. level less than 8.5 g/dL, total white blood cell count less than
l .O X 109/L, absolute neutrophil count less than 0.5 X 109/L, Histological Examination or platelet count less than 25 X lO9/L. Liver biopsies were performed before treatment and subseRibavirin dose was reduced to 400 to 600 mg/d if the quently at the completion of treatment if possible. All biopsy hemoglobin level decreased toless than 10 g/dL, and ribavirin specimens were read by a single pathologist (L.J.B.) who was therapy was discontinued if the hemoglobin level decreased to blindedtobiochemicalandvirological responses ofthe less than 8.5 g/dL. Adjuvant therapies included the use of patient. Histological recurrence of H C V was based on finderythropoietin injections and packed red blood cell transfusions. ings of portal and/or periportal inflammation with mononuA biochemical response was defined by normalization of clear cells. Disease severitywas determined using the modified liver enzyme levels. An end-of-treatment virological response was defined by the absence HCV of RNA in serum at the endhistological activity indexof Kn0de11.~* of completion of therapy (defined by the completion of at Statistical Analysis least l year of treatment or at the point of cessation of treatBaseline characteristics and measures of tolerability and effiment because of persistent side effects) measured by qualitacacy of treatment between responders and nonresponders are the tive PCR. A sustained virological response was defined by described as proportions or medians and range and were comabsence of H C V R N Ain serum6 months after completion of pared using two-sided Fisher’s exact and Wilcoxon’s tests. therapy, measured by qualitative PCR. Correlations were assessed using Spearman’s correlation coefImmunosuppression therapy consisted of cyclosporine or ficient. The primary outcome of the is study end-of-treatment tacrolimus, prednisone, and azathioprine until 1994,at which virological response. Secondary outcomes are tolerability of 1997, time a tacrolimus-based regimen was introduced. In treatment, defined by completion of 48 weeks of antiviral mycophenolate mofetil (MMF) was introduced as part of a therapy, and biochemical response, defined by normalization randomized clinical trial comparing azathioprine and MMF. of biochemistry test result. Since the beginning of 1999, typical primary immunosuppression has been tacrolimus, prednisone, and MMF. Prednisone dose was tapered and stopped between 3 and 6 months posttransplantation. Patients who developed biopsy-proven acute cellular rejection were treated with three intravenous boluses of methylprednisolone (1,000 mg) administered on
Results Patient demographics are listed in Table 1. The median time to treatment after liver transplantation was 58.4
625
Posttransplantation Treatment of HCV
Tabie 1. Patient Demographics
I
Responders Range Normal Age (yr) Men Hemoglobin (g/dL) Creatinine (mg/dL) (66-312) Serum AST (U/L) Serum ALT (U/L) Serum AP (U/L) Serum bilirubin (mg/dL) Viral load (mEq/mL) HA1 Fibrosis score Weeks to treatment Weeks of treatment
118
(n = 9) 46.4 6 12.5 1.2
0.6-0.9 12-31 10-45 90-234 0.1-1.1
Nonresponders (n = 17)
P
47.9 (40.3-72) 12 (70.6) 11.9 (10-16) 1.1 (0.8-1.9) 114 (21-324) 180 (30-638) 465 (133-1 112) 1.4 (0.8-12.4) 25.8 (0.22-120) 4 (309) 1 (0-6) 55.3 (8.7-242.6) 40.6(6.3-57.4)
NS NS NS
(36.2-67.9) (66.7) (1 1-14.8) (0.9-3.7)
143 (5 1-446) 261 (75-688) 1.2 (0.9-3.2) 1.8(0.2-44) 5 (4-9) 2 (1-6) 66.7(13.7-284.4) 50.3 (13.1-77.9)
NS NS NS NS NS NS NS NS NS NS
NOTE. Values expressed as median (range)or number (percent). Genotypes were known in 18 of 26 patients. Of these, 4 of 13 patients (31%) with genotype 1 and I of 5 patients (20%) with non-l genotypes had sustained virological responses. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; AP, alkaline phosphatase; HAI, histological activity index; NS, not significant.
weeks (range, 8.7 to 284.4 weeks). HCV genotypes were availablefor 18 of 26 patients. Of the 18 patients in whom HCV genotypeswere known, 13 patients (72%)were infected with genotype 1; 3 patients, genotype 2; 1 patient, genotype 3; and 1patient, genotype 4.
treatment but went on to have an end-of-treatment responsewere treated for 37.3, 27.3, 15.1, and 13.1 weeks.
Biochemical Response O n an intention-to-treat basis, a biochemical response was seen in 42% (1 1of 26 patients) of patients. This included biochemical responsesin 56% of end-of-treatment responders and 35% of virologicalnonresponders (P= .42). Four patients (44%) with an end-of-treatment virological response did not show a biochemical response. In one patient, enzyme levels normalized soon after stopping treatment, whereas in the second patient, enzyme levels normalized spontaneously 2 years after stopping treatment. A third patient continues to have mildly abnormal liver enzyme levelswith no evidence of histological or virological recurrence of hepatitis C. The fourth patient developed an autoimmunetype hepatitis resulting in elevated liver enzyme levels that gradually normalized after stopping treatment.
Virological Response O n an intention-to-treat basis, nine patients (35%) showed an end-of-treatment virological response (Fig. 1). Eight of eight end-of-treatment virological responders who completed at least 6 months of posttreatment follow-up also have shown a sustained response, measured by qualitative PCR. Follow-up is pending in the remaining patient. Among the 18 patients for whom genotype was known, 4 of 13 patients (3l %) with genotype 1 andl of 5 patients (20%) with non-l genotypes had virological responses. Of the 8 patients for whom genotype was unknown, 4 patients (50%) had virological responses. The four patients who did not complete 1 year of
I Figure 1. Outcomes afterinitiation of combination treatment. (IFN, interferon; RIBA, ribavarin; Rx, medication; m, month.)
Initiated on IFNlRlBA n=26 Cessation of R x due to Side Effects n=13 (50%) I
n=13
I
PCR negative at 12m
n=4 (62%)
(31%)
PCR postive at 12m n=9 (69%)
626
Narayanan Menon et a1
Histological Response Paired liver biopsy specimens (before and after treatment) wereavailable in 12 patients (4 responders, 8 nonresponders). The median pretreatment necroinflammatory score was 5 (range, 3 to 9),which improved to 3 (range, 0 to 11) after treatment. A decrease in necroinflammatory score posttreatment wasseen in 75% of both responders (3 patients) and nonresponders (6 patients). A decrease in necroinflammatory score of 2 or greater was seen in 75% (3 patients) of responders and 67% ( 5 patients) of nonresponders. Among patients who showed a virological responseto therapy, fibrosis score improved by 1 in 1 patient (25%) and remained the same in 3 patients (75%).Among nonresponders, fibrosisscoreworsened by 1 in 2 patients (25%) and remained the same in 6 patients (75%).
Tolerability/Adverse Events Sixty-five percent of patients completed 6 months and 50% completed at least 1 year oftherapy. Four patients continued treatmentbeyond 1 year (62,78,79, and 86 weeks). Greater pretreatment hemoglobin levelwas found to correlate with longer duration of therapy (Spearman's correlation coefficient, 0.5; P < .Ol), and patients with a hemoglobin level greaterthan l .5 l g/dL had a significantly greater likelihood of completing at least 6 months of therapy (87% U 36%). Adverse events were seen in 69% (18 patients; Table 2), with 66% (17 patients) requiring dose modification or cessation of treatment. An additional patient had elevations in hisliverenzymelevels that normalized after stopping therapy. Anemia and leukopenia were the most common adverse events, occurring in 46% and 15%, respectively. Thirteen of 25 patients (52%) had a decrease in hemoglobin level of 2 g/dLor greater at the end of 1 month of therapy. Of these 13 patients,
Table 2. Adverse Effects of Combination TherapyWith Interferon andRibavirin Event
Adverse Anemia (Hb < 10 g/dL) Leukopenia ( W C < 1.5 X 109/L) Fever/chills Fatigue Rash Diarrhea Depression hepatitis Autoimmune
Number (percent) 12 (46) 4 (15) 2 (8) 2 (8) 1 (4) 1 (4)
1 (4) 1 (4)
Abbreviations: Hb, hemoglobin; W C , white blood cell.
only 3 patients (23%) were ableto complete 12 months of therapy. Ten of 12 patients (83%) with a hemoglobin level decrease less than 2 g/dL were ableto complete 12 months of therapy (P= .005 U those with hemoglobin level decrease L 2 g/dL). The occurrence of adverse events resulted in cessation of treatment in 50% (n = 13) of patients. Indications for cessation of therapy were anemia (n = 5), anemia with concomitant neutropenia (n = 4 ) , rash (n = I), autoimmune hepatitis (n = l), diarrhea (n = l), and increasing bilirubin level (n = 1). Three patients died during follow-up. Two patients died of liver failuresecondary to recurrence ofhepatitis C, whereas the thirdpatient died soon afterretransplantation. In all three patients, treatment with interferon and ribavirin failed. Adjuvant therapies were usedto maintain hemoglobin levels during treatment. These included packed red blood cell transfusions in six patients (23%) and erythropoietin injections in four patients (15%). Antidepressant therapy also was used in one patient (4%).
Discussion Treatment of hepatitis C with interferon and ribavirin in the nontransplantation population has resulted in sustained response rates of30% to 50% and may be of benefit in preventing progression of liver fibrosis. However, data regarding end-of-treatment virologic responserates and,in particular, sustained response rates are sparsein the transplant population. The numbers of patients studied are small, and available data suggest that response rates are lowerthan those seen in the nontransplantation population. We report a 35% end-of-treatment response ratein 26 patients with recurrent hepatitis C after liver transplantation when using a treatment-on-recurrence strategy. More importantly, all patients with an end-oftreatment virologic response went on to have a sustained response, with negative HCV RNA levels at the end of at least 6 months after stopping treatment. The low relapse rate seen in our patients is in contrast to that reported in the nontransplantation population.25,26A longer duration of follow-up is necessaryto determine the ultimate durability of virological responses among our transplant recipients. Other studies of combination therapy with interferon and ribavirin in thetreatment of posttransplantation HCV infection have reported greater or equal end-of-treatment virological and histological response ratesto those seen in our current study.'9 Although there are case reports of biochemicaland partial virological responsesin cho-
Posttransplantation Treatment of HCV
lestatic transplant recipient~,~l>~7 initiation of combination therapy in patients who were cholestatic at treatment initiation was unsuccessful in our study. Few studies have reported sustained response rates. Bizollon et a l l 6 reported on 21 patients treated with interferon and ribavirin for a period of 6 months, followed by maintenance ribavirin therapy for an additional 6 months. Serum HCV RNA was negative in 10 patients (48%) at the endof 6 months of therapy, with a sustained response seenin 5 patients during follow-up (24%). A study from North America showed an endof-treatment response rate of 12%,20 whereas the largest report to date found a relapse rate of approximately 50Y0.l~Conversely, none of our patients who experienced an end-of-treatment responseexperienced a relapse after stopping treatment. Longer follow-up will be necessary to determine whether this remains true in the long term. The frequency of side effects necessitating cessation of treatment in our study was greater than thatgenerally reported in the nontransplantation setting (> 10%).25,26 This difference appearsto be substantially caused bythe high prevalenceof anemia and renalinsufficiency among liver transplant recipients. Hemolysis may be exacerbated in the presence of calcineurin inhibitorinduced nephrotoxicity and subsequently decreased endogenous erythropoietin production. A low threshold for ribavirin dosage reduction must be considered in this patient population. In a previous study, ribavirin monotherapy in HCV-infected liver transplant recipients required dose reduction or cessation in a proportion similar to that seen in our patients.28Sixty-six percent of our patients required dose reductions, and 50% had to stop treatment because of persistent side effects. Adverse events resulting from interferon included rejection, cytopenia, infection, and constitutional symptoms such as headaches and myalgias. The major reported sideeffect of ribavirin was anemia, treated primarily by dose reduction. Overall, dose reduction and/or cessation of therapy have been reported to be required in 40% to 50% of patients administered interferon and ribavirin in the posttransplantation setting. A large prospective study, in which erythropoietin therapy was initiated early in the course of antiviral therapy, showed efficacy in preventing dose reductions and cessation ofribavirin therapy? Anemia secondary to ribavirin therapy in our study was treated with acombination of red blood cell transfusion and erythropoietin in six (23%) and four (15%) patients, respectively. However, all four patients administered erythropoietin subsequently discontinued treatment because of anemia. A similar experience
627
was reported by De Vera et a l , 3 O who administered erythropoietin to 28% of patientson combination therapy. Of the handful of studies describing the outcome of treating HCV with interferon in liver transplant recipients, two studies suggested that interferon treatment may be associated with an increasedrisk for rejecti0n.3l.3~Acute vanishing bile duct syndrome also has been described after interferon therapy for recurrent HCV.33 Interferon monotherapy was not associated with an increased risk for rejection in three other studie~.~*,3*,35 None of the larger more recent studies of combination therapy with interferon and ribavirin reported an increased risk for frequency or severity of reje~tion.'~>~O>3~-39 episodes No of rejection were noted among our patients on combination therapy. One patient developed markedly abnormal transaminases (210 times the upper limit of normal) during therapy, along with hyperbilirubinemia. A liver biopsy in this patient showed marked lymphocytic and plasma cell infiltrate in the portal tract, suggestive of autoimmune hepatitis, with no cholangitis, endotheliitis, or eosinophilia. Interferon and ribavirin therapy were discontinued, with subsequent normalization of liver test results. Another patient had mildly elevated liver test results that returned to normal after completing treatment. We were not able to identifjr pretreatment predictors of response to therapy. However, the end-of-treatment response rate in patients who completed 6 months or more of therapy was double that inpatients who did not complete 6 months of therapy (41% v 22%; P = .42). This finding suggests that continuationof treatment for the longest possibleperiod, especially in thesetting of a biochemical response, might help achieve a sustained response. The observation that a greater pretreatment hemoglobin level and greater stability of hemoglobin levels on therapy were associatedwith greater tolerability of treatment (average pretreatment hemoglobin, 13.2 g/dL for patients who tolerated > 6 months v 11.65 g/dL for those who underwent therapy for < 6 months) suggests that measures to maintain hemoglobin levels should be considered early in the course of treatment. Only 2 1% of patients who underwent less than 6 months of treatment had virological end-oftreatment responses. Additional studies with much larger numbers of patients are neededto clearly identify host and/or viral characteristics predictive of responsiveness and tolerability to antiviral therapy. In summary, we have shown that approximatelyone third of patients with recurrent hepatitis C after liver transplantation show an end-of-treatment response to combination therapy with interferon and ribavirin. A sustained response may be seen in the majority of those
628
Narayanan Menon et a/
infection after liver transplantation. Hepatology 1997;25:203210. 14. 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. 15. Bellati G, Alberti AB, Belli LS, VaiC, Airoldi A, Rondinara GF, et al. Therapy of chronic hepatitis C after liver transplantation: Multicenter Italianexperience[abstract]. J Hepatol 1999; 30(suppl):S51A. 16. Bizollon T, Palazzo U, Ducerf C, Chevallier M, Elliott M, Baulieux J, et al. Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitisC after liver transplanReferences tation. Hepatology 1997;26:500-504. 1.Belle SH, BeringerKC, Detre KM, Terasaki PI, Cecka JM. 17. LavezzoB,Rizzetto M, SmedileA, Ottobrelli A,GhisettiV, Recent findings concerning liver transplantation in the United Franchello A, et al. Combination therapy of interferon alfa 2b States. In: ClinicalTransplants 1996. Los Angeles: UCLA Tissue and ribavirin for recurrent hepatitis C after liver transplantation. Typing Laboratory; 1997:15-30. J Hepatol 1999;30:67-72. 2. Feray C, CaccamoL,Alexander GJ, Ducot B, Gugenheim J, 18. Shah1 AO, McGuire B, Crippin JS, Conjeevaram HS, TeperCasanovas T, et al. European collaborativestudy on factors influman L, Gish R, et al. Interferon-alfa 2b and ribavirin combinaencing outcome after livertransplantation for hepatitis C. Eurotion therapy in liver transplant recipients with recurrent hepatitis pean Concerted Actionon Viral Hepatitis (EUROHEP) Group. C [abstract]. Hepatology 2000;32:217A. Gastroenterology 1999;117:619-625. 19. Mazzaferro V, Regalia E, Pulvirenti A, Tagger A, Andreola S, 3. Wright TL, Donegan E,Hsu HH, Ferrell L, LakeJR, Kim M, et Pasquali M, et al. Prophylaxis againstHCV recurrence after liver al. Recurrent and acquired hepatitis C viral infection in liver transplantation: Effect of interferon and ribavirincombination. transplant recipients. Gastroenterology 1992;103:317-322. Transplant Proc 1997;29:519-521. 4. Tong MJ, el-Farra NS, Reikes AR, CORL. Clinical outcomes 20. Kapur A, Rodriguez MJ, SchecterP, Tzakis A, Schiff ER. Interafter transfusion-associated hepatitisC. N Engl J Med 1995;332: feron alfa and ribavirinin established post liver transplant recur1463- 1466. rent hepatitisC infection [abstract]. Gastroenterology1998;114: 5. KiyosawaK,Sodeyama T, Tanaka E, Gib0 Y,YoshizawaK, 1268A. Nakano Y, et al. Interrelationship of blood transfusion, non-A, 21. Muramatsu S, KuY, Fukumoto T, Iwasaki T, Tominaga M, non-B hepatitisand hepatocellular carcinoma: Analysis by detecKusunoki N, et al. Successful rescue of severe recurrent hepatitis tion of antibody to hepatitis C virus. Hepatology 1990;12:671Cwithinterferonandribavirin in a livertransplantpatient. 675. Transplantation 2000;69:1956-1958. 6. Charlton M, Seaberg E, Wiesner R, Everhart J, Zetterman R, 22. Gopal DV, Rabkin JM, Berk BS, Corless CL,Chou S, Olyaei A, Lake J, et al. Predictors of patient and graft survival following et al. Treatment of progressive hepatitis C recurrence after liver liver transplantation for hepatitis C. Hepatology 1998;28:823transplantation with combination interferon plus ribavirin. Liver 830. Transpl200 1;7:181- 190. 7. Gane EJ, Portmann BC, Naoumov NV, Smith HM, Underhill 23. Simmonds P, Alberti A, Alter HJ, Bonino F, Bradley DW, BreC JA, Donaldson PT, et al.Long-termoutcomeofhepatitis chot C, et al. A proposed system thefor nomenclature ofhepatitis infection after liver transplantation. N Engl J Med 1996;334: C viral genotypes. Hepatology 1994; 19: 132 1-1 324. 8 15-820. 24. Knodell RG, Ishak KG, BlackWC, Chen TS,Craig R, Kaplow8. Vargas HE, Laskus T, Wang LF, RadkowskiM, Poutous A, Lee itz N, et al. Formulation and application of a numerical scoring R, et al. The influence of hepatitis C virus genotypes on the system for assessing histological activity in asymptomatic chronic outcome of livertransplantation. Liver Transpl Surg 1998;4:22active hepatitis. Hepatology1981;1:431-435. 27. 25. DavisGL,Esteban-MurR,RustgiV,Hoefs J, GordonSC, 9. Feray C, Samuel D, Thiers V, GigouM, Pichon F, Bismuth A,et Trepo C, et al. Interferon alfa-2b alone or in combination with al. Reinfection of liver graft by hepatitis C virus after liver transribavirin for the treatment of relapse of chronic hepatitis C. plantation. J Clin Invest 1992;89:1361-1365. International Hepatitis Interventional Therapy Group. N Engl 10. AscherNL,Lake JR, Emond J, Roberts J. LivertransplantaJ Med 1998;19:1493-1499. tion forhepatitis C virus-relatedcirrhosis.Hepatology 1994; 26. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee 20(suppl):S24-S27. W M , Rustgi VK, et al. Interferon alfa-2b alone or in combina11. Rosen HR, O’Reilly PM, Shackleton CR, McDiarmid S, Holt tion with ribavirin as initial treatment for chronic hepatitis C. C, Busuttil RW, Martin P. Graft loss following liver transplanHepatitis Interventional Therapy Group. N Engl J Med 1998; tation in patients with chronic hepatitis C. Transplantation 19:1485-1492. 1996;62:1773-1776. 27. Telegdy L, Gorog D, Horanyi M, Schaff Z. Severe relapse of 12. Rosen HR, Gretch DR, Oehlke M, Flora KD, BennerKG, hepatitis C following liver transplantation. Successfultreatment Rabkin JM, Corless CL. Timing and severity of initial hepatitis with a combination of interferon-alpha and ribavirin.Orv Hetil C recurrence as predictors of long-term liver allograft injury. 1999;140:1891-1893. Transplantation 1998;65:1178-1182. 13. Boker KH, Dalley G, BahrMJ,Maschek H, Tillmann HL, 28. Gane EJ, Lo SK, Riordan SM, Portmann BC, Lau JY, Naoumov Traunvein C, et al.Long-termoutcomeofhepatitis C virus NV, Williams R. A randomized study comparing ribavirin and
who show an end-of-treatment response. However, dose modification and/or cessation oftherapy were necessary in the majority of patients. Studies with larger numbers of patients are necessary to identifi independent predictors of a response in the posttransplantation population. Trials incorporating newer interferon preparations, such as pegylated interferon, and prophylactic treatment strategies are awaited.
Posttransplantation Treatment of HCV
29.
30.
31.
32.
33.
34.
interferon alfa monotherapy for hepatitis C recurrence after liver transplantation. Hepatology 1998;27: 1403-1407. WassermanR,Brau N, Hassanein T, BiniE,Sulkowski M, 35. Dieterich D. Onceweekly epoetin alfa increases hemoglobin and decreases ribavirin dose reductions among HCV-infected patients who develop anemia on ribaviridinterferon alfa 2b therapy [abstract]. Hepatology 2000;32:833A. 36. de Vera ME, Smallwood GA, Rosado K, Davis L, Martinez E, Sharma S, et al. Interferon-alpha and ribavirin forthe treatment of recurrent hepatitis C after liver transplantation. Transplantation 200 1;71:678-686. 37. Feray C, Samuel D, Gigou M, Paradis V, DavidMF, Lemonnier C, et al. An open trial of interferon alfa recombinant for hepatitis C after liver transplantation: Antiviral effects and risk of rejection. Hepatology 1995;22: 1084-1089. Vargas V, Charco R, Castells L, Esteban R, Margarit C. Alpha38. C in livertransplantpatients. interferonforacutehepatitis Transplant Proc 1995;27:1222-1223. Dousset B, Conti F, Houssin D, Calmus Y. Acute vanishing bile duct syndrome after interferon therapy for recurrent HCV infec39. tion in liver-transplant recipients [letter]. N Engl J Med 1994; 330:1160-1161. Wright TL, Combs C, Kim M, Ferrell L, BacchettiP, Ascher N,
629
et al. Interferon-alpha therapy for hepatitis C virus infection after liver transplantation. Hepatology 1994;20:773-779. Sheiner PA, Boros P, Klion FM, Thung SN, Schluger LK, Lau JY, et al. The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation. Hepatology 1998;28:831-838. Mazzaferro V, Regalia E, Pulvirenti A, Tagger A, Andreola S, Pasquali M, et al. Prophylaxis againstHCV recurrence after liver transplantation: Effect of interferon and ribavirin combination. Transplant Proc 1997;29:519-521. Samuel D, Bizollon T, Feray C, Lemonnier C, Cohard M, Bismuth H, Trepo C. Combination of interferon alfa 2-B plus ribavirin for recurrentHCV infection after liver transplantation: A randomized controlledstudy [abstract]. Hepatology 2000;32: 542A. Gotz G, Schon MR, Haefker A, Neuhaus R, Berg T, Hopf U, Neuhaus P. Treatment of recurrent hepatitis C virus infection after liver transplantation with interferon and ribavirin. Transplant Proc 1998;30:2104-2106. Willner IR, Chavin KD, Rogers J, Baliga P, Reuben A. Combination interferon-ribavirin is ineffective and poorly tolerated by liver transplant recipients with genotype 1 recurrent hepatitis C [abstract]. Hepatology 2000;32:290A.