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20  GASTROENTEROLOGY & ENDOSCOPY NEWS JANUARY 2011

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

The Center for the Study of Hepatitis C(CSHC) at NewYork-Presbyterian/Weill Cor-nell Medical Center is engaged in diverseHCV investigations. One of us (Dr. Talal)has undertaken research on viral kinetics,

presenting the first evaluation of pegIFNpharmacokinetics in patients coinfectedwith HCV and HIV, finding that, althoughpharmacokinetic parameters do not differ-entiate sustained virological respondersfrom nonresponders, certain pharmaco-dynamic measurements do and mighttherefore serve as useful predictors oftreatment outcome.2 Another study eluci-dated early ribavirin pharmacokinetics incoinfected patients also receiving pegIFN.3 

Having perfected a fine-needle aspira-tion technique that is less invasive thancore needle biopsy and allows repeatedsampling of the liver with less morbid-ity, the CSHC is now looking at HCV RNA

and telaprevir levels to understand howthe virus declines, both in the liver and inthe blood, in response to treatment witha 3-drug antiviral combination of pegIFN,ribavirin, and telaprevir.4

Another focus of CSHC research hasbeen the role of chemotactic cytokines,known as chemokines, in hepatic inflam-mation by their recruitment of lympho-cytes to the liver parenchyma. Intrahepaticinflammation is a major predictor of

fibrosis progression in CHC and thus isan important element in assessing dis-ease progression and, possibly, treatmentoptions. One author (Dr. Talal) and oth-ers found that CXCR3-associated chemo-

kines play an important role in hepaticnecro-inflammation and fibrosis.5 A sub-sequent study suggested that these samechemokines might be used as noninva-sive markers of liver fibrosis.6 The CSHCcurrently is studying whether this markercan be used in other patient populationsin whom fibrosis is likely to progress.

The CSHC, working with NewYork-Presbyterian/Weill Cornell’s methadonemaintenance treatment program, devel-oped a model therapeutic approach inwhich the same physician who treats thesubstance abuse patient also treats thatpatient in the viral hepatitis clinic, therebymaintaining continuity of care.7 Although

HCV infection affects up to 90% of sub-stance abusers, evaluation and treatmentfollowing referral very frequently is notpursued. Of 125 patients from the Cen-ter’s methadone clinic who were eligi-ble for referral to the CSHC’s hepatitisclinic, 76 (61%) adhered to the referral.Of these, 24 started therapy and 13 (54%)achieved sustained virological response(SVR). The success of this program, whichwas partially funded by the Clinton Global

Initiative,8  offers hope that it could beexpanded to other methadone clinics aswell as other patient populations.

At the recent 2010 meeting of the Ameri-can Association for the Study of Liver Dis-eases (AASLD), several studies involvingNewYork-Presbyterian Hospital researcherselucidated potential new treatment path-ways for CHC. For instance, NewYork-Pres-byterian/Weill Cornell, under the directionof Ira Jacobson, MD, served as a study cen-ter for 2 important international trials. Boththe ADVANCE (study drug: telaprevir) andSPRINT-2 (study drug: boceprevir) Phase IIIclinical trials demonstrated superiority over

current standards of care; publications onboth are planned in 2011. Dr. Jacobson pre-sented the ADVANCE trial results at a ple-nary session and was a coauthor on theSPRINT-2 plenary presentation. Fred Poor-dad, MD, of Cedars-Sinai, Los Angeles, waslead author of the SPRINT-2 trial.

Also at the AASLD, preliminary evidenceof genetic influence on CHC progressionand treatment response has emergedfrom the multicenter IDEAL (IndividualizedDosing Efficacy vs. Flat Dosing to AssessOptimal Pegylated Interferon Therapy)study of 3,070 patients with genotype 1HCV, 1,604 of whom consented to genetictesting. This multi-site study, whichincluded NewYork-Presbyterian/Weill

Cornell, found that the interleukin (IL)28Bpolymorphism previously correlated with

poor treatment response wcantly associated with lower density lipoprotein levels and hof hepatic steatosis.9 AnotheIL28B polymorphism to highebaseline serum alanine amino(ALT) and Metavir A2-3 nematory activity.10  Howeverers found no association betwand either advanced hepatic fIFNα-related neutropenia.12

 Assessing Liver TranspPrognosis

Post-transplant histologic reevident in up to 90% of CHC 5 years, often leading to graft death.13  However, patients wSVR or who are transplanted tectable viral loads on therapyabout a 1 in 5 likelihood of recHowever, by the time CHC-rdisease has progressed to thetransplantation is necessary, maexperience concurrent exaceencephalopathy, infections, andous adverse events (AEs), wilikelihood of SVR and increaseof treatment-related mortality.

A2ALL (the Adult-to-Adult LLiver Transplantation Cohort S

NIH-sponsored 9-center studying donor liver transplants (LD

Advances in Chronic Hepatitis C TreatmenAnd Liver Transplantation: An Update

Robert S. Brown Jr., MD, mphFrank Cardile Professor of Medicine Columbia University College of

Physicians & Surgeons Director, Center for Liver Disease and

TransplantationNewYork-Presbyterian Hospital Medical Director, Transplant Initiative NewYork-Presbyterian Hospital/ 

Columbia University Medical Center New York, New York 

Andrew H. Talal, MD, MPHAssociate Professor of Medicine Weill Cornell Medical College Associate Medical Director, Center for

the Study of Hepatitis C Associate Attending PhysicianNewYork-Presbyterian Hospital/ 

Weill Cornell Medical Center New York, New York 

Chronic hepatitis C (CHC), one of the most common causes of chronic

liver disease and cirrhosis, is a leading reason for liver transplantation in

the United States.1 CHC most often is treated with a combination of pegy-

lated alpha interferon (pegIFN) and ribavirin, but up to 45% of patients

who receive 48 weeks of combination therapy nonetheless relapse after

treatment is discontinued.1 About 70% of patients with hepatitis C have

genotype 1 hepatitis C virus (HCV), which generally is less responsive to

treatment and more likely to relapse.1 

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  GASTROENTEROLOGY & ENDOSCOPY NEWS JANUARY

 Supported and approved by

NewYork-Presbyterian/Columbia UniversityMedical Center (NYP/CU) has participatedfor more than 7 years; Jean C. Emond, MD,of NYP/CU, serves as chair of the execu-tive committee. As part of A2ALL, one ofus (Dr. Brown), with others from the mul-

ticenter trial, examined the use of a low,accelerating dosage regimen of pegIFNand ribavirin to prevent post-transplantrecurrence of HCV infection.17  Seventy-nine patients were selected from 2 groups:candidates for LDLT whose potential donorwas already identified, and candidates fordeceased donor liver transplants who hadbeen granted priority status due to stageT1 or T2 hepatocellular carcinoma. Thesepatients had less severe liver disease thanthose awaiting transplant for complicationsof liver failure, and were thought morelikely to tolerate an antiviral regimen.

The 58 patients in the treatment groupreceived weekly doses of pegIFN-α2b,

0.75 mcg/kg of body weight, and 600 mgper day of ribavirin, with doses escalatedas tolerated. Although 28% of treatedpatients achieved post-transplant viralresponse (pTVR), defined as negative HCVRNA for at least 6 months post-transplant,the treated patients experienced moreAEs and serious AEs as well as infec-tions than the 21 patients in the controlgroup, although mortality rates were simi-lar. Longer treatment duration and lowerModel for End-stage Liver Disease (MELD)scores were associated with pTVR. Due tothe incidence and severity of AEs, the studyauthors declared pegIFN and ribavirin tobe “suboptimal” pretransplant treatments,and suggested that direct-acting antivirals

may promote better outcomes. However,the study results do support the generalconcept of using pretransplant treatmentsfor CHC to increase the likelihood of pTVRand decrease post-transplant AEs.

Improving Transplants forPatients With End-Stage HCV 

The Center for Liver Disease and Trans-plantation (CLDT) at NewYork-Presbyte-rian Hospital has one of the nation’s largestLDLT programs and is the only center inthe country to perform the donor opera-tion via laparoscopy in adult-to-child trans-plants. The CLDT will extend this technique

to selected adult-to-adult LDLT proceduresearly in 2011. This procedure significantlyreduces the donor’s recovery time, pain,scarring, and likelihood of complications.Faster, more comfortable liver donationcould lead to an increase in the number ofliving donors, which in turn may improvethe prognosis for recipients as wait timesare reduced and patients are more likely toreceive optimally healthy donated tissue.18

One very promising area of research

is transplant immunology. Immunosup-pressive agents reduce the likelihood oftransplant rejection but can be particularlydetrimental to patients with CHC, especiallywhen high doses are given in responseto a rejection event.19 Megan Sykes, MD,director of the Columbia Center for Trans-lational Immunology, Columbia Univer-sity College of Physicians & Surgeons, hasbeen experimenting, originally at HarvardMedical and Massachusetts General, with anew nonmyeloablative tolerance-inducingprocedure, using the transplantation of anorgan donor’s bone marrow to encouragethe transplant recipient’s immune systemto accept the donated organ. Following atrial of this procedure, 4 of 5 kidney recip-ients receiving bone marrow transplantsfrom their kidney donors successfully dis-continued the use of immunosuppressivedrugs altogether and retained stable renalfunction so far for more than 3 to 6 yearsfollowing transplantation.20 Animal studies

are now underway at the CLDT to exam-ine the procedure’s utility in human livertransplantation.

Another means by which the supply oflivers for transplantation can be increasedis through hypothermic machine perfu-sion (HMP). HMP is an affirmed approachfor the preservation of kidneys and is animprovement over cold storage (CS), butuntil recently, its use in liver transplanta-tion only had been tested in animals. Inthe first clinical series of its kind, JamesV. Guarrera, MD, and co-authors from theCLDT (including Dr. Brown), report that, of20 adults who received HMP-preservedlivers centrifugally perfused with Vaso-

sol, only 1 recipient experienced earlyallograft dysfunction compared with 5 ina matched control group that receivedCS-preserved livers.21 The HMP livers hadno vascular complications, and only 2 bil-iary complications compared with 4 in thecontrol group. Additionally, patients in theHMP group had significantly lower seruminjury markers and significantly shortermean hospital lengths of stay.

The authors suggest that continuous

centrifugal perfusion—which took place

after the livers had been in CS for sev-

eral hours during transportation from

the donor hospital—brought nutrients

and oxygen into the livers while flush-

ing out cytokines, proteins, and tox-

ins, helping to restore them to a healthystate and undo some of the damage that

occurs during static CS. Future trials will

determine whether patients with chronic

diseases such as CHC show similar

improvements to transplant outcomes

following the substitution of HMP for CS

during stages of liver storage prior to

transplant.

NewYork-Presbyterian Hospital’s multi-disciplinary CLDT program is at the fore-front of the research and development ofeffective treatments for patients with CHCand other liver-related diseases.

References

http://digestive.niddk.nih.gov/ddiseases/pubs/1. chronichepc/. Accessed December 4, 2010.

Talal AH, Ribeiro R, Powers K, Grace M, Cullen2.C, Hussain M, Markatou M, Perelson AS. Phar-macodynamics of PEG-IFN alpha differenti-ate HIV/HCV coinfected sustained virologicalresponders from non-responders. Hepatology.2006;43(5):943-953.

Dahari H, Markatou M, Zeremski M, Haller I,3.Ribeiro RM, Licholai T, Perelson AS, Talal AH.Early ribavirin pharmacokinetics, HCV RNA andalanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with Pegylatedinterferon and ribavirin. J Hepatol. 2007;47:23-30.

http://Clinicaltrials.gov: Study# NCT00892697.4.

Zeremski M, Petrovic LM, Chiriboga L, Dimova5.R, Brown QB, Yee HT, Kinkhabwala M, Jacob-son IM, Markatou M, Talal AH. Intrahepatic levelsof CXCR3-associated chemokines correlate withliver inflammation and fibrosis in chronic hepati-tis C. Hepatology. 2008;48(5):1440-50.

Zeremski M, Dimova R, Brown QB, Jacobson IM,6.Markatou M, Talal AH. Peripheral CXCR3-asso-

ciated chemokines as biomarkers of fibrosis inchronic hepatitis C virus infection. J Infect Dis.2009; 200(1 December):1774–1780.

Martinez AD, Dimova R, Marks KM, Beeder AB,7.Zeremski M, Kreek MJ, Talal AH. Integrated inter-nist–addiction medicine–hepatology model forhepatitis C management for individuals on meth-adone maintenance. J Viral Hep., in press.

http://www.clintonglobalinitiative.org. Accessed8.December 4, 2010.

Clark PJ, Thompson AJ, Zhu M, Zhu Q, Ge D,9.Sulkowski MS, Tillmann HL, Patel K, Naggie S,Muir AJ, Afdhal NH, Jacobson IM, Esteban R,Lawitz E, Poordad F, et al. IL28B genetic polymor-phism has genome wide significant associations

with serum low density lipoprothepatic steatosis in patients witchronic hepatitis C (CHC). Hepatolsuppl): abstract 232.

Thompson AJ, Clark PJ, Zhu M, 10.Sulkowski MS, Muir AJ, TillmanNaggie S, Afdhal NH, Jacobson Poordad F, Lawitz E, et al. Genociation study identifies IL28B pol

be associated with baseline ALTnecro-inflammatory activity in chC patients enrolled in the IDEAL sogy . 2010;52(4 suppl): abstract 189

Thompson AJ, Clark PJ, Fellay J, Mu11.HL, Patel K, Naggie S, Afdhal NHEsteban R, Poordad F, Lawitz E, Mman ML, Galler GW, et al. IL28B gassociated with advanced hepachronic hepatitis C patients enrollestudy. Hepatology . 2010;52(4 supp

Thompson AJ, Clark PJ, Singh A12.J, Sulkowski MS, Muir AJ, TillmanNaggie S, Shianna K, Afdhal NHEsteban R, Poordad F, et al. Comvariants do not associate with IFNtropenia in a genomewide assocchronic hepatitis C patients in thHepatology . 2010;52(4 suppl): abst

Berenguer M. Natural history of re13.tis C. Liver Transpl . 2002;8(10 sup

Everson GT. Treatment of chronic14.patients with decompensated cirrhtroenterol Disord . 2004;4(suppl 1):

Forns X, Garcia-Retortillo M, Serr15.Suarez F, de la Mata M, Garcia-VNavasa M, Rimolo A, Rodes J. Anof patients with decompensated cvent recurrence of hepatitis C afplantation. J Hepatol . 2003;39(3):3

Crippin JS, McCashland T, Terraul16.Charlton MR. A pilot study of the tefficacy of antiviral therapy in heinfected patients awaiting liver tLiver Transpl . 2002;8(4):350-355.

Everson GT, Terrault NA, Lok AS, 17.S, Shiffman ML, Al-Osaimi AM, KulBW, Everhart JE. Interim analysis trial of pre-transplant peginterferovirin (PEG/RBV) to prevent recurrvirus (HCV) infection after liver tranin the adult-to-adult liver transplanstudy. Hepatology . 2009;50(4 supp

http://nyp.org/services/transplanta18.liver-transplant-living-donor.htDecember 4, 2010.

Terrault NA, Berenguer M. Trea19.

C infection in liver transplant reTranspl . 2008;12(8):1192-1204.

Kawai T, Cosimi AB, Spitzer TR, T20.Suthanthiran M, Saidman SL, ShaffDing R, Sharma V, Fishman JA, Dey M, Goes NB, Wong W, Williams WWSykes M, Sachs DH. HLA-mismatcplantation without maintenance imsion. N Engl J Med . 2008;358(4):35

Guarrera JV, Henry SD, Samstein B21.dan R, Kinkhabwala M, Goldstein Renz JF, Lee HT, Brown RS Jr, Emthermic machine preservation intransplantation: the first clinical Transplant . 2010;10(2):372-381.

Figure. Three-dimensional liver reconstructions showing images of living-donor liver sections to be removed for

transplantation.Courtesy of IDEAL, Dept. of Radiology, Weill Cornell Medical College