The interaction of recipient gender and hepatitis C infection on patient and allograft survival after orthotopic liver transplantation

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AASLD ABSTRACTS

HEPATOLOGYO c t o b e r 2 0 0 1

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DURABILITY OF SUSTAINED VIROLOGIC RESPONSE IN PATIENTS W I T H CHRONIC HEPATITIS C AFTER TREATMENT W I T H INTERFERON o~-2B ALONE OR IN COMBINATION W I T H RIBAVIRIN. John G McHutchison, Scripps Clinic, LaJoUa, CA; Gary L Davis, University of Florida College of Medicine, Gainesvflle, FL; Rafael Esteban-Mur, Hospital Valle Hebron, Barcelona Spain; Thierry Poynard, Hospitalier Pitie-Salpetriere, Paris France; Mei-Hsiu Ling, Jean-Jacques Garaud, Janice Albrecht For The International Hepatitis Interventional Therapy Group, Schering Plough Research Institute, Kenilworth, NJ

IMPACT OF PEGYLATED INTERFERON ALFA-2B A N D RIBAVIRIN ON PROGRESSION OF LIVER FIBROSIS IN PATIENTS W I T H CHRONIC HEPATITIS C. Thierry Poynard, Hepatologie Groupe Hospitalier Pitie Salpetriere, Paris France; J o h n McHutchison, Scripps Clinic a n d Research F o u n d a tion, Division of Gastroenterology/Hepatology, La Jolla, CA; Michael Manns, Division of Gastroenterology- a n d Hepatology, Medical School of Hannover, H a n n o v e r Germany; Christian Trepo, : Service d'H~pato-Gastroent~rologie, H6tel Dieu, Lyon France; Karen Lindsay, Division of Gastrointestinal a n d Liver Disease, University of Southern California, Los Angeles, CA; Zachary Goodman, Department of Hepatic a n d Gastrointestinal Pathology, A r m e d Forces Institute of Pathology, Washington, DC; Mei-Shu Ling, Janice K Albrecht, Schering Plough Research Institute, Kennilworth, NJ

Background: Patients w h o achieved a sustained virologic response in the large scale international trials comparing interferon alfa-2b alone to interferon alfa-2b plus ribavirin (Rebetron, Schering Corp) have n o w been followed for 4 years to assess the durability of their response (Davis et al, NEJM 1998;339: 1493, M c H n t c h i s o n et al NEJM 1998; 339:1485;' P o y n a r d et al, Lancet 1998; 352:1426). Methods: In these four protocols all patients with chronic hepatitis C, naive or relapsed, were treated with interferon alfa-2b plus ribavirin (I/R) or interferon alfa-2b alone (I) for either 24 or 48 weeks. At the end of the 6 - m o n t h post treatment follow-up 455 patients treated with I/R a n d 103 treated with treated with I were sustained virologic responders (SR). 395 of these SR (71%) have participated in long-term follow-up; 322 treated with I/R (112 naive 24 weeks/151 naive 48 w e e k s / 5 9 relapse 24 weeks) a n d 73 treated with I (4 naive 24 weeks/61 naive 48 w e e k s / 8 relapse 24 weeks). Serum HCV-RNA has been measured by PCR annually (NGI; LLQ 100 copies/ml). These patients are also assessed yearly for disease progression by physical examination a n d hematological a n d biochemical testing. Sustained Response: Relapse has occurred in 7 I/R patients (3 naive 24 w e e k s / 2 naive 48 weeks/2 relapse 24 weeks) a n d 3 I patients. A m o n g naive patients treated with I/R the relapses occurred in the first two years, 2 at 1 year a n d the other 3 at 2 years; no patient has relapsed b e y o n d the 2-year follow-up. For relapse patients treated with I/R, one occurred at 1 year a n d the other at 2 y e a r s of follow-up. Two patients w h o relapsed, 1 I/P 24 a n d 1 I/R 48 were HCV RNA positive in the liver at the end of the initial 6 m o n t h follow-up. The corresponding actuarial likelihood (Kaplan-Meier) of maintaining response after 4 years in patients w h o initially achieved SR is: I/R 24 naive 97% + 1.6%, I/R 48 naive 99% + 1% a n d I/R 24 relapse 96% + 2.9%. Disease Progression: One patient (treated with UP relapse) with pre-existing cirrhosis developed hepatocellular carcinoma. No evidence of hepatic decompensation as d o c u m e n t e d b y physical examination, laboratory evaluation or serious adverse event reporting has been observed in a n y other patients in this follow u p study. Conclusion: Late relapse is rare in chronic hepatitis C patients w h o remain HCV RNA negative 6 m o n t h s after the end of interferon-based therapy.

Background: The extent of liver fibrosis is an important prognostic factor in patients infected with hepatitis C virus. The effect of PEG interferon alone or its combination with ribavirin on hepatic fibrosis has n o t been established. Methods: W e pooled individual data from 3010 naive patients with pre- a n d post-treatment biopsies from 4 randomized trials. Tell different regimen combining standard interferon, pegylated interferon a n d ribavirin were compared. The histological impact of each regimen was estimated by the percentage of patients with at least one grade i m p r o v e m e n t in the necrosis a n d inflammation (METAVIR score), the percentage of patients with at least one stage worsening ill fibrosis METAVIR score a n d by the fibrosis progression rate per year. Reshits: Necrosis a n d inflammation i m p r o v e m e n t ranged from 39% in patients treated b y interferon 24 weeks to 73°/0 ill patients receiving the optimized PEG 1.5 a n d ribavirin c o m b i n a t i o n (p<0.001). Fibrosis worsening ranges from 23°/0 in patients treated with interferon for 24 weeks to 8°/0in patients receiving the optimized PEG 1.5 a n d ribavirin combination ( p < 0 . 0 0 1 ) . All regimens significantly reduced the fibrosis progression rates in comparison to rates before treatment. The reversal of cirrhosis was observed in 75 patients (49 0/0) of 153 patients with baseline cirrhosis. Six factors were independently associated with the absence of significant fibrosis after treatment: baseline fibrosis stage (odds ratio O R = 0 . 1 2 ; P < 0 . 0 0 0 1 ) , sustained viral response ( O R = 0 . 3 6 P<0.0001), age y o u n g e r than 40 years ( O R = 0.51; P < 0 . 0 0 1 ) , b o d y mass index lower than 27 kg/m2 ( O R = 0 . 6 5 P < 0 . 0 0 1 ) , no or minimal baseline activity ( O R = 0 . 7 0 p = 0 . 0 2 ) a n d viral load lower than 3.5 millions copies per ml ( O R = 0 . 7 9 p = 0 . 0 3 ) . Conclusion: PEG-interferon and ribavirin combination significantly reduces the rate of fibrosis progression in patients with hepatitis C.

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THE INTERACTION OF RECIPIENT GENDER A N D HEPATITIS C INFECTION O N PATIENT A N D ALLOGRAFT SURVIVAL AFTER ORTHOTOPIC LIVER TRANSPLANTATION. Lisa M Forman, James D Lewis,Jesse A Berlin, University of Pennsylvania, Philadelphia, PA; Michael R Lucey, University of Wisconsin, Madison, WI BACKGROUND:HepatitisC (HCV)infectionis the most commonindicationfor orthotopicliver transplantation(OLT).We havedemonstratedpreviouslythat HCVinfectionis associatedwith a 23%increased mortalityrate and a 30% increasedallograftfailurerate in the first fiveyears.It has been reported that transplantoutcomesare worsein HCV-positiverecipientstransplantedin the secondhalfofthe 1990s.The objectiveof the presentstudywas to identifyfactors,suchas demographicsofdonoror recipient,or yearof transplantationwhichmightmodifythe effectof HCVinfectionon survival.METHODS:Usingdata from the UnitedNetworkfor OrganSharing,we performeda retrospectivecohortstudy of 11,036patientswho underwent11,791livertransplantsbetween I992 and 1998.HCVstatuswas determinedusing results of HCVserologicaltesting.Patientswereexcludedif theyhad missingor equivocalserology.Coxproportional-hazardsanalysiswasused to examinethe potentialinteraction(effectmodification)betweenHCVstatus and recipient/donorsex, raceand age,and year of tral~splatuation.RESULTS:A statisticalinteractionwas identifiedbetweenHCVstatusandsex (P<0.001)for patientand allograftsm'vival.Femalerecipientswith HCVrefectionhave56%and 51%lowerratesofpatientand aUograftsurvivalinthe firstfiveyearscompared to femalerecipientswithoutHCV(hazardratios 1.56and 1.51,respectively),whereasthe associationwas weakerwhencomparingtransplantoutcomesin maleswithHCVto maleswithoutHCV(hazardratios1.06 and 1.18).The decrementin outcomesfor femaleswithHCVpersistedwhensexwasanalyzedas a function of donor and recipientmatching/mismatching.To examinewhether the interactionwas reflectingthe excellent survivalof the cholestaacHCV-negativegroup (primaryscleroslngeholangitisPSC, primary biliarycirrhosisPBC)who are predominantlyfemale,this cholestaticgroupwas excludedand the remaining cohortre-allalyzed.Femalerecipientswith HCVinfectioncontinuedto demonstrateworsepatientand allograitsurvivalwith hazardratiosof 1.38and 1.37,respectively,when comparedto the non-cholestatic HCV-negativeaUograftrecipients.No significantinteractionswere foundbe~veenHCVstatus and age or race of recipient,age or race of donor, or year of transplantationfor patientand allograftsurvival.CONCLUSIONS:The effectofHCVon survivalis modifiedbyrecipientsex.Thisassociationis not accountedfor by donorsex, or a predominanceof PBCin the controlHCV-negativeallograftrecipient.Yearof OLTdid not afftectoutcomesin HCV-infectedrecipients.

POST-TRANSPLANT ERADICATION OF HEPATITIS C BY PRE-TRANSPLANT TREATMENT IN LIVING D O N O R LIVER TRANSPLANT RECIPIENTS. Arthur Halprin, James F Trotter, Gregory T Everson, Michael Wachs, Thomas Bak, Marcelo Kugelmas, Igal Kam, University of Colorado Health Sciences Center, Denver, CO

Patient Survival Hazard Ratio (95% Cl) 1.23 (1.12-t.35)* 1.56 (1.35-t~81)* 1.06 (0.95--1.19) 1.12 (0.97-1.29) 1.54 (I.26-1.89)* 0.98 (0.81-1.19) 1.58 (1.28-1.96)'

Nlograft Survival Hazard Ratio (95% CI) 1.30 (1.2t-1.39)" 1.51 (1.34-1.70)" 1.18 (1.08-1.29)" 1.24 (1.11-1.39)* 1.46 (I .23-1.72)* 1.09 (0.96-1.26) 1.56 (I .32-I .85)*

HCV+ Female Male DM-->RM DM-->RF DF-.~RM DF--~RF Excluding Cholestatics Female 1.38 (1.18-1.62)* 1.37 (1.21-1.56)* Male 0.96 (0.85-t .08) 1.14 (1.03-1,25)* The hazard ratio is for survival of HCV-positive compared to HCV-negative recipients. DM denotes donor male, RM denotes recipient male, DF denotes donor female, and RF denotes recipient female. *P<0.05

Introduction: At our center, patients with hepatitis C (HCV) represent over 50 % of patients u n d e r g o i n g living d o n o r liver transplantation (LDLT). Since 1999, we have started treating patients listed for transplantation with a lowaccelerating dose regimen (LADR) of interferon-alpha a n d ribavirin. Under this protocol, 17 % of patients achieved a sustained virologic remission rate (Hepatology 200;32308A). LDLT offers a unique o p p o r t u n i t y to treat HCVinfected patients prior to transplantation. LDLT is a scheduled surgery a n d allows the potential of treatment of the recipient prior to transplantation. W e have treated a n d cleared HCV in a n u m b e r of LDLT recipients resulting in clearance of HCV after transplantation. Methods: Twenty four patients infected with HCV received LDLT between 8/97 a n d 4/2001. Six LDLT recipients entered the LADR protocol prior to transplant. Age range 45 - 64 years, male/ female 4/2. LADR protocol was initiated with 1.5 mU tiw interferon and ribavirin 600 mg po qd. After 2 weeks, the interferon dose was increased to 3 mU tiw as tolerated a n d ribavirin was increased every 2 weeks b y 200 m g per day to a m a x i m u m dose of 1 - 1.2 g qd. Sustained virologic response is defined as HCV-RNA negative 6 m o n t h s after transplant. Results: Of the 24 LDLT recipients, 12 received no therapy for HCV a n d remained HCV-RNA positive before a n d after transplant. Two received interferon m o n o t h e r a p y a n d were n o n responders with positive HCV-RNA before a n d after transplant. F o u r received standard interferordribavirin combination therapy, 3 were non-responders a n d the 4th was HCV-RNA negative at the time of transplant achieving a sustainted virologic response after transplant. Six LDLT recipients were treated with the LADR protocol. Three patients were non-responders a n d remained HCV-RNA positive before a n d after transplant. Three h a d complete virological response after transplant. Of these 3, 2 were u n d e r g o i n g therapy at the time of transplant, 1 completed 52 weeks of treatment a n d remained a complete responder for an additional 39 weeks at w h i c h time she was transplanted. All 3 have remained free of virus 6 m o n t h s or more after transplant. Conclusions: 1) All patients with HCV a n d cirrhosis should be considered for anti-viral therapy. 2) Because LDLT is a scheduled surgery, selected LDLT recipients m a y u n d e r g o treatment for HCV to achieve viral eradication prior to transplantation. 3) This a p p r o a c h m a y reduce post-transplant reinfection with HCV as well as posttransplant graft loss a n d death from recurrent HCV.