Evaluation of the Cost-Effectiveness of Entecavir … 08_021-033.pdf Vol. 14, No. 1 January/February 2008 JMCP Journal of Managed Care Pharmacy 21 Evaluation of the Cost-Effectiveness

www.amcp.org Vol. 14, No. 1 January/February 2008 JMCP Journal of Managed Care Pharmacy 21

Evaluation of the Cost-Effectiveness of Entecavir Versus Lamivudine in Hepatitis BeAg-Positive Chronic Hepatitis B Patients

Yong Yuan, PhD; Uchenna H. Iloeje, MD, MPH; Joel Hay, PhD; and Sammy Saab, MD, MPH

ABSTRACT

BACKGROUND: As new treatment options for chronic hepatitis B virus (HBV) become available, evaluations of cost-effectiveness become important. Entecavir is a deoxyguanine nucleoside analogue approved by the U.S. Food and Drug Administration in March 2005 for HBV infection in adults with evidence of active viral replication and either evidence of persistent eleva-tions in serum aminotransferases (alanine aminotransferase or aspartate aminotransferase) or histologically active disease. Entecavir has demon-strated greater suppression of viral replication compared with lamivudine, but also has a relatively higher drug acquisition cost in the United States.

OBJECTIVE: To estimate the long-term health and economic impact of treating HBV with entecavir versus lamivudine in patients who are positive for hepatitis B e antigen (HBeAg) based on the efficacy and safety results of the Phase 3, double-blind, randomized controlled trial, Benefits of Entecavir for Hepatitis B Liver Disease (BEHoLD).

METHODS: A decision tree model was developed to evaluate the cost-effectiveness of entecavir compared with lamuvidine in suppressing HBV DNA to an undetectable level. Risks for compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC) were derived from the published Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV, 2006) study, a longitudinal (mean follow-up: 11.4 years) cohort study of com-munity residents who were seropositive for the hepatitis B surface antigen; 85% of REVEAL-HBV participants were HBeAg-negative. To estimate future risks of CC, DC, and HCC, the REVEAL-HBV study’s multivariate-adjusted relative risks of CC, DC, and HCC for 5 HBV DNA (viral load level) categories were applied to posttreatment HBV DNA levels obtained from the BEHoLD trial of 709 HBeAg-positive HBV patients treated with entecavir (n = 354) or lamivudine (n = 355). Entecavir and lamivudine were assigned annual costs of $7,365 and $2,604, respectively, based on the wholesale acquisi-tion cost. Life expectancy for DC and HCC was estimated by the declining exponential approximation of life expectancy method. Other model param-eter values, such as utilities and event medical costs, were derived from published sources. The joint uncertainty of projected event time distribution and treatment failure rates beyond the trial period were considered using probabilistic sensitivity analyses (PSA) with 1,000 replicates. The analytic perspective was that of a U.S. third-party payer responsible for all direct health care expenditures.

RESULTS: In the BEHoLD clinical trial (AI463022), subjects were predom-inantly male (75%), Asian (57%), or white (40%) with a mean age of 35 years. Entecavir was superior to lamivudine in the proportion of subjects who achieved undetectable HBV DNA (< 300 copies per mL) by polymerase- chain reaction assay at week 48 (69.1% vs. 39.8%, respectively) (P < 0.001). In the REVEAL-HBV study after statistical adjustment for age, gender, cigarette smoking, and alcohol consumption, rates of CC, DC, and HCC were associated with higher HBV DNA levels (e.g., compared with the reference category [< 300 copies per mL], adjusted hazard ratios for HCC were 1.2, 2.9, 9.5, and 15.2 for serum HBV DNA levels of 300-9,999, 10,000-99,999, 100,000-999,999, and ≥ 1 million copies per mL, respec-tively). In the reference case, for a hypothetical cohort of 1,000 HBV patients aged 35 years, 52 weeks of entecavir treatment compared with lamivudine treatment avoided 71 cases of CC, 8 DC cases, and 42 HCC cases within 10 years, resulting in a 0.728 quality-adjusted life-year (QALY)

gain at an incremental cost of $2,350, with a 3% annual discount. The incremental cost of using entecavir was $3,230 per QALY gained (95% confidence interval [CI], $2,312-$4,528), with 99.3% of PSA-derived estimates below $5,000 per QALY. Results were robust and most sensitive to efficacy, drug cost, and treatment duration.

CONCLUSIONS: Assuming that (1) the efficacy of entecavir after 1 year is sustainable and (2) liver disease risk levels from the REVEAL-HBV study population (a primarily HBeAg-negative group) adequately represent risk for a treated HBeAg-positive patient group, entecavir given for up to 10 years would be highly cost-effective in HBeAg-positive patients.

J Manag Care Pharm. 2008;14(1):21-33

Copyright © 2008, Academy of Managed Care Pharmacy. All rights reserved.

• Chronic hepatitis B virus (HBV) infection is a complexdisease, with 15%-40% of infected persons progressing to severe liverdisease including cirrhosis, liver failure, and liver cancer.ManifestationsofHBVusuallyoccurlateinlife,resultinginsub-stantiallifeyearslostaswellasanegativeeconomicimpactamongindividuals during the most productive decades of life. About 1.25millionHBV-infectedpeople live in theUnited States, andmostofthechronicallyinfectedpersonsintheUnitedStatesareofAsiandescent.

• Currentanalysesofthecost-effectivenessofHBVdrugshavebeenbasedonadiseaseprogressionparadigmfocusedheavilyontheability to achieve hepatitis B e antigen (HBeAg) seroconversion(toHBeAg-negativestatusandHBeantibody)followingtreatmentintervention.However,recentevidencesuggeststhattheincidenceoflivercirrhosisandhepatocellularcarcinoma(HCC),aswellastheriskofprogressiontolivercirrhosisandHCCinHBVpatients,arestronglylinkedtothelevelofcirculatingvirusindependentofHBeAgstatus.Acost-effectivenessanalysisofHBVtherapiesbasedonthisparadigmofdiseaseprogressiontocirrhosisandHCCdoesnotexistintheliterature.

• This study is the first to evaluate the cost-effectiveness ofHBVantiviral therapy based on an ability to suppress viral replica-tion.OurdecisiontreemodelindicatesthatinitiatingtherapyinHBeAg-positiveHBVpatientswithentecavir(bothshort-termandlong-termuse)wouldbeverycost-effectiveat$3,176perquality-adjusted life-year (QALY) gained (95%CI, $2,202-$4,482),with99.3%ofPSA-derivedestimatesbelow$5,000perQALY.

What is already known about this subject

What this study adds

FORMUL ARY MANAGEMENT

Note: Two commentaries and an editorial on the subject of this article appear on pages 61-64, 65-69, and 83-85 of this issue.

22 Journal of Managed Care Pharmacy JMCP January/February 2008 Vol. 14, No. 1 www.amcp.org

ChronichepatitisB(CHB)virusinfectionisdefinedbythepresenceofhepatitisBviralsurfaceantigen(HBsAg)inthebloodfor>6months.BesidesHBsAg,otherantigens

aredetectedintheblood,suchashepatitisBeantigen(HBeAg).However,HBeAgmaybeabsentafterseveraldecadesofinfectionashepatitisBmutants,whichdonotsecreteHBeAg,replacethehepatitisBwildtypes.HBeAg-negativeCHBinfectionisdefinedbynodetectableHBeAg,butevidenceofviralreplicationasindi-catedbythepresenceofviraldeoxynucleicacid(HBVDNA)intheblood.BothHBeAg-positiveandHBeAg-negativeinfectioncanpoten-

tiallyresultinprogressiveliverdiseaseandaffectabout350mil-lionpeopleworldwide,1.25millionofwhomliveintheUnitedStates.1HepatitisBvirus(HBV)patientsareatincreasedriskofdeveloping liver cirrhosis andhepatocellular carcinoma (HCC).Althoughmost patientswill not develop hepatic complicationsfromCHB, 15%-40%will eventually develop serious sequelaeduringtheirlifetime.2

EvenincountriessuchastheUnitedStateswherethepreva-lenceofHBVisrelativelylow(≤1%ofthepopulation),theburdenof illness andhealth care costs associatedwith thedisease aresubstantial. In the United States, health costs associated withHBVwereestimatedat$500millionannually(expressedin1997U.S. dollars).3 Other studies have found that the average costperhospitalization for aHBVpatientwith cirrhosis is $14,063and that the cost of a liver transplant is an estimated $89,076(expressedin1999U.S.dollars).4IndeterminingthevalueofnewmedicinestotreatHBV,drugacquisitioncostsmustbebalancedagainsttheexpectedbenefitsinfuturemorbidity,mortality,andcostsavoidedfromdiseaseprogression.Six drugs are currently approved for treating CHB virus

infection in the United States. Interferons, including alfa-2b,recombinant(Intron-A),andpeginterferonalfa-2a(Pegasys),areassociatedwithseveralsideeffectsandcannotbeusedinpatientswith decompensated liver disease. Additionally,many patientscannot tolerate the adverse events associated with interferons,resulting in treatment discontinuation.5-10 Lamivudine (Epivir)wasthefirstoralantiviralagentapprovedbytheU.S.FoodandDrug Administration (FDA) for HBV in November 1995, andprovidedawell-tolerated,effectiveoptionforpatients.11However,theoccurrenceofdrug-resistantHBVmutantsbecameamajorlimitationwithlamivudinetherapy.12-14

Adefovir dipivoxil (Hepsera) was approved by the FDA forHBVinSeptember2002.15Adefovirisgenerallywelltolerated16,17 andeffectiveagainstlamivudine-resistanthepatitisBstrains.18,19 However, with adefovir therapy, only about 21% of HBeAg-positive patients and 50% of HBeAg-negative patients achieveaviralload<300copiespermLafter1yearoftherapy,makingadefovirthenucleosideanaloguewiththeslowestviralkineticsoftheapprovedagents.Additionally,thelevelofviralresponseafter1yearofadefovirtherapypredictstheriskoffutureresistance,andthe5-yearriskofresistancewithadefovirtherapyis29%.20

Entecavir (Baraclude), a deoxyguanine nucleoside analogue,is a selective inhibitorof the replicationofHBV.Entecavirwasapproved by the FDA in March 200521 and is currently themostpotentantiviralagentforHBVtreatment,suppressingviral replication to <300 copies per mL in approximately 87% oftreatment-naïvepatientsafter96weeksof therapy.Throughout 96 weeks, no patient experienced a virologic breakthrough due to entecavir resistance.22 Telbivudine (Tyzeka) is themostrecentantiviraldrugfortreatingHBV,approvedbytheFDAinOctober 2006.23 Based on registrational studies, telbivudine’s initialantiviraleffectisbetterthanthatoflamivudine;however, its utility is limited by viral resistance that continues eventhrough the secondyearof therapy.24Nohead-to-head clinicaltrials have investigated the safety and efficacy of telbivudineversusentecavir.Ourstudyaimstoevaluatethecost-effectivenessofentecavir

comparedwithlamivudineinchronicHBeAg-positiveinfectionbyusinga statisticalmodel that applied (1) community cohortstudydataonrisksofHBVdiseasesequelaeto(2)randomizedclinicaltrialdataonoutcomesforHBV-treatedpatients.

■■ Methods

Overview of Modeling StructureAdecisiontreemodelwitha fixed10-yearwindowwasdevel-opedtoevaluatethecost-effectivenessofinitiatingtherapywithentecavir in nucleos(t)ide-naïve HBeAg-positive HBV patientscomparedwithastrategyof initiatingtherapywithlamivudineandaddingadefovirtorescuepatientsoncetheydevelopeddrugresistance.ThemodelwasbasedontheabilityofeachstrategytoachieveHBVDNAsuppressiontoanundetectablelevel.Anillus-trativeconceptualmodelframeworkisshowninFigure1.Ahypotheticalcohortof1,000HBVpatientsreceivedeither

lamivudineorentecaviratmodelentry.Becausepatientsmightdevelopviralresistancewithcontinueddruguseorexperienceviral reboundafter treatment cessation, theirHBVDNAvalueswere updated annually to incorporate first-year trial efficacyresults as well as the impacts from subsequent development of viral resistance or viral rebound after treatment cessa-tion. The decision model consisted of 5 disease stages: CHB(HBVwithoutcirrhosisandHCCasentrypoint),compensated cirrhosis, decompensated cirrhosis,HCC, anddeath. Basedonthe pattern and rates of observed liver complications from theRisk Evaluation of Viral Load Elevation and Associated LiverDisease/Cancer-Hepatitis B Virus (REVEAL-HBV) study,25,26 themajorityofpatientsdevelopingHCCwere fromthecirrho-sis health state, but the decisionmodelwasmodified to allowsomeHBV patients to progress to aHCC health state directlywithoutpassingthroughthecompensatedcirrhosishealthstate.However, all patients experiencing decompensated cirrhosis had to progress through the compensated cirrhosis healthstate. The base casemodel assumed treatment for 1 year, and sensitivityanalysesalloweddrugtreatmentforupto10years.Any





patientdevelopingresistancewasrescuedbyastrategyofadding adefovirtothecurrentdrugtherapy.Dataontreatmentefficacywereobtainedfromarandomized,

controlled, double-blind, Phase 3 registrational trial (Benefits

of Entecavir for Hepatitis B Liver Disease [BEHoLD]).27 Usingtheweek-48HBVDNAdatafromthistrial,futurediseasepro-gressionwasprojectedbasedonobservedrates fromtheafore-mentioned REVEAL-HBV study. Progressions to compensated


TABLE 1 Reference Case Model Parameters, Inputs, Data Sources, and Methodology

Entecavir 0.5 mg

Lamivudine 100 mg Source Methodology

Estimated relative risk by serum HBV DNA levels (copies/mL)

<300(undetectable) 1.0forcirrhosis,DC,andHCC REVEAL-HBV25,28,29

Coxproportionalhazardsmodelswereusedwithadjustmentforgender,age,andhabitsofcigarettesmokingandalcoholdrinking.

300-9,999 1.4forcirrhosis(2.7forDC),1.2forHCC REVEAL-HBV25,28,29

10,000-99,999 2.5forcirrhosis(2.7forDC),2.9forHCC REVEAL-HBV25,28,29

100,000-999,999 5.9forcirrhosis(5.9forDC),9.5forHCC REVEAL-HBV25,28,29

≥ 1million9.8forcirrhosis(19.3forDC),

15.2forHCCREVEAL-HBV25,28,29

Proportion of patients with HBV DNA levels (copies/mL)

<300(undetectable) 69.1% 39.8% BEHoLD27

Measuredpostrandomizationatweek48.

300-9,999 24.7% 18.2% BEHoLD27

10,000-99,999 4.4% 11.7% BEHoLD27

100,000-999,999 0.6% 9.3% BEHoLD27

≥ 1million 1.2% 21.0% BEHoLD27

Annual incidence rates with undetectable HBV DNA

CC 0.34% REVEAL-HBV25,26Estimatedbasedon873patientswith undetectableHBVDNAatstudyentry.

DC 0.02% REVEAL-HBV25,26

HCC 0.11% REVEAL-HBV25,26

Annual mortality rate

DC 14.4% Reference33 LifeexpectancyestimatedbasedontheDEALEmethod. HCC 23.3% Reference32

Average time to event from study entry (years)

CC 8 REVEAL-HBV25,26

Estimatedbasedonactualpatient-leveldata. DC 9 REVEAL-HBV25,26

HCC 7 REVEAL-HBV25,26

Annual medical costs

CC $1,130 Reference36 Reimbursedcost(notprovider-submittedcharges)fromU.S.third-partypayers.Publishedcostestimateswereinflatedtoyear2006valuesusingthemedicalcomponentoftheConsumerPriceIndex.

DC $15,095 Reference37

HCC $9,923 Reference37

Utilities

CHB 0.81 Reference34

SurveyofaU.S.sampleof100uninfected individualsusingstandardgamblemethod.

CC 0.82 Reference34

DC 0.36 Reference34

HCC 0.41 Reference34

Study drugs

Dailycost/patient $20.52 $7.61 Reference35 Officiallypublishedfigures.

Actualdaysofuse/patient/year 359 342 BEHoLD27Estimatedbasedonnumberofdaysofdruguserecordedinthetrial.

All costs are expressed in 2006 U.S. dollars.BEHoLD = Benefits of Entecavir for Hepatitis B Liver Disease; CHB = chronic hepatitis B; CC = compensated cirrhosis; DEALE = declining exponential approximation of life expectancy; DC = decompensated cirrhosis; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; REVEAL-HBV = Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus.


cirrhosis, decompensated cirrhosis, and HCC were modeledseparately,andwesubsequentlyestimatedthecostconsequencesand lifeyear impacts fromthemodeledprogression.AllmodelassumptionsanddatainputsusedinthereferencecaseanalysisarepresentedinTable1.This decision tree model structure was chosen instead of

a state transition or patient-level simulation model to capturechronicdiseaseprogressionbecauseof lackofdata access andreliabledetailsforestimatingthediseasestatetransitionratesforHBVDNAlevelsovertime.Thedecisiontreemodelwithafixed-timewindowmadeourmodel as simpleaspossiblewhile stillretainingsufficientstructuretospecifytheassumedrelationshipbetweeninputsandoutcomes.The study perspective was that of a U.S. third-party payer

responsible for all direct health care expenditures. The cost- effectiveness of entecavir compared with lamivudine wasexpressedastheincrementalcostperlife-yeargainedorquality-adjustedlife-years(QALYs)gained.Indirectmedicalcostsandlostproductivitywerenot included in theanalyses.A3%discountratewasapplied tobothcosts and life-yearprojectionsbeyondthemodelbaseyear.Statistical software (SAS,SAS Institute,Cary,NC)wasused

for patient-level data analyses, and an Excel spreadsheet-basedmodelusingVisualBasicforApplications(MicrosoftCorporation,Redmond, WA) was created for all modeling and simulationexecutions.

Efficacy and Safety Data From the BEHoLD Phase 3 Clinical TrialWeobtainedefficacyandsafetydatafromarandomizedPhase3 trial of HBeAg-positive subjects (BEHoLD-AI463022 trial).27 Briefly, this was a randomized, double-blind, double-dummystudyofentecavir0.5mggivenoncedailyfor52weekscompared with lamivudine 100 mg once daily. A total of 709 eligible subjects were randomized (1:1) to receive either entecavir (n=354) or lamivudine (n=355). Subjects who had previouslyreceived anucleoside analogue active againsthepatitisB, inter-feron alfa, or thymosin alfawithin24weeksprior to random-ization were excluded. Any subject with a prior exposure to lamivudine lasting >12 weeks was also excluded. Response to treatment was assessed based on a primary endpoint of histologicimprovementandothersecondaryefficacyendpoints,including our primary study endpoint of interest—serum HBV DNA by polymerase-chain reaction (PCR) assay at theweek-48visit.Entecavirwaswelltolerated,withasafetyprofilecomparable

with that of lamivudine 100 mg. The most frequent adverseevents intheentecavirgroupwereheadache,upperrespiratorytract infection,nasopharyngitis,upperabdominalpain,fatigue,andpyrexia, allofwhichoccurredwithcomparable frequencyinthelamivudinegroup.Asaresult,theriskandcostsofdrug-relatedadverseeventswerenotincludedintheanalysis.

All intent-to-treat patients were considered in this analysis.All patientswithmissingHBVDNAdata at either baseline orweek 48 (n=45) were treated asmissing and excluded in theprimary analyses. An alternative imputation method, usingLastObservationCarriedForwardortreatingnoncompletersasfailures,was also implemented, but it hadminimal impact onourmodelingresults.Thestudyperiodranged fromapatient’srandomization to the end of blinded treatment or week 48,whichevercamefirst.

Data on Disease Progression RiskData on risk of disease progressionbased on the level of viralloadwasderivedfromtheREVEAL-HBVstudy.25,26Thisprospec-tivecohortstudywasconductedaspartofacommunity-basedcancer screening program in Taiwan and designed to evaluatetherelationshipbetweenbaseline(cohortentry)riskfactorsandprogressiontocirrhosisandHCC.Inbrief,of4,115REVEAL-HBVparticipantswhowereHBsAg-

seropositive, free of HCC at cohort entry, and followed until June30, 2004, 3,653participants (88.8%)weredetermined tobe seronegative for anti-hepatitis C virus (HCV) antibody andwerethusincludedintheanalysesofcirrhosisandHCCriskin HBVpatients.Duringameanfollow-uptimeof11.4yearsand41,779person-years,365subjects(10.0%)werenewlydiagnosedwith cirrhosis, 31 of whom (0.8%) were determined to have decompensated cirrhosis events; therewere 164 incident cases of HCC (4.5%). Adjusted relative risks for liver cirrhosis and HCC for each of 5 defined serumHBVDNA levels were esti-matedusingCoxproportionalhazardsmodels,withadjustment for gender, age, and habits of cigarette smoking and alcoholdrinking.25,28

Two stepswere followed to apply theREVEAL-HBV resultstothe709subjects fromtheBEHoLDrandomizedclinical trial to project future events over a 10-year period. First, everyonewithaweek-48posttreatmentHBVDNAlevel<300copiespermL was assigned the baseline event rate for participants withundetectableviralloadsobservedfromtheREVEAL-HBVcohortstudy. The risks of liver events for subjectswithHBVDNA inthehighercategorieswerethenestimatedbasedontheadjustedhazard ratio associated with that viral load category in theREVEAL-HBVstudycohort.Tostratifyallcirrhosisevents intocompensatedanddecompensatedcirrhosissoastoassignrespec-tivemedicalcostsandQALYs,wefurtherdevelopedasubmodelforpredictingdecompensatedcirrhosis,andthensubtractedthispredictednumberfromthetotalcirrhosisestimatetoderivethenumberofcompensatedcirrhosisevents.29

Life Year Gain and Utility EstimatesAge-andgender-specificlifeexpectancyestimatesforHBVandcompensated cirrhosiswerebasedondata fromNationalVitalStatistics Reports.30 Life expectancy for decompensated cirrho-sis orHCCwas estimated based on the declining exponential



approximationoflifemethod:inverseofannualeventmortality.31 Annual mortality was set at 23.3% for HCC32 and 14.4%for decompensated cirrhosis.33 To avoid double-counting lifeyears lost for those patientswithmultiple events,we assumedthat (1) all patients with decompensated cirrhosis had a priorcompensated cirrhosis, and 72% of patients with HCC had a prior compensatedcirrhosis, and (2) ifpatientshadbothHCCand compensated cirrhosis or both decompensated cirrho-sis and compensated cirrhosis, only life expectancy for HCCor decompensated cirrhosis was assigned. These assumptionswerebasedon the finalREVEAL-HBVstudy sample, inwhich all patients with decompensated cirrhosis had prior compen-satedcirrhosis,and72%ofpatientswithHCChadpriorcom-pensatedcirrhosis,butnoonewasobservedtoexperienceboth decompensatedcirrhosisandHCC.All trial patients were assigned a baseline utility of 0.81 at

entry,meaningthat1yearof life inapersonwithHBVwouldbe equivalent to0.81years ofhealthy life, and faced a suddendecline in the utility value—in other words, a tariff—as theydevelopedlivercomplications.34Toadjust for thehealth-relatedqualityoflifeassociatedwithdifferenthealthstates,therelativevalue,orutility,ofeachhealthstatewasratedcomparedwithayear in perfect health.We used the ratings of HBV-associatedhealthstateselicited fromarepresentativesampleof100unin-fected individuals in theUnitedStatesusing a visual analoguescaleandweightedusingthestandardgamblemethod.34Inthisstudy,probabilitywheelswith2-colorpiechartsfortherelativeprobabilitiesofperfecthealthanddeathwereusedaspropsforthestandardgamble,andafeelingthermometerwasusedforthevisualanaloguescale.Asaresult,weassignedanestimatedutilityweight of 0.82 for compensated cirrhosis, 0.36 for decompen-satedcirrhosis,and0.41forHCC(Table1).

Cost EstimatesTwo cost components were considered in the analyses: studydrug costs and medical costs of HBV-related complications. The medical component of the Consumer Price Index (2006Bureauof Labor Statistics data)wasused to adjust all costs to2006values.In the base case analysis, itwas assumed that the duration

of drug treatment was 1 year; we also considered longer-termdrugtreatmentinthesensitivityanalyses.Drugcompliancewasestimatedbasedontheactualusageofstudydrugsrecordedontheclinical trialCaseReportForms.Totalcostsofstudydrugswereestimatedbythewholesaleacquisitioncost(WAC)perdaymultiplied by the mean number of days of drug use (359 for entecavir, 342 for lamivudine) observed in the trial.35 Annualdrug costs were $7,365 for entecavir 0.5 mg and $2,604 for lamivudine100mg.Annual medical costs updated to 2006 U.S. dollars were

$1,130forcompensatedcirrhosis,36$15,095fordecompensatedcirrhosis, and$9,923 forHCC.37 The annualmedical costwas

appliedtoapatient fromthetimeaneventoccurreduntil thatpatientdied.Costsofclinicaltrialoutpatientphysicianvisitsandlaboratory testswere excluded fromcost estimates becauseweassumedthattheywouldbeequivalentinbothgroups.

Modeling AssumptionsIn the REVEAL-HBV cohort, the average times to event fromstudy entry were 8 years for compensated cirrhosis, 9 yearsfor decompensated cirrhosis, and7 years forHCC,with timesranging from1to14years.Toappropriatelydiscount thesub-sequentmedicalcostsandlifeyearslostafteralloftheseeventshadoccurred,inthereferencecaseanalysiswedeterministicallyassignedtheseaverages(at8,9,and10years)tothetrialpatientswho later developed a compensated cirrhosis, decompensatedcirrhosis orHCC event during the follow-upperiod,whilewealsomodeledtimetoeventprobabilisticallylaterinthesensitiv-ityanalyses.DistributionsofsubjectstodifferentHBVDNAlevelsbeyond

the first year after entecavir or lamivudine treatment cessationwere assumed based on HBV DNA data observed at week-24postdosing in those BEHoLD patients with a protocol-defined“response” (defined as HBV DNA <0.7MEq per mL and lossofHBeAgatweek48).Thiswas theonlyandbestdatasourceavailabletoallowustoestimateviralreboundratesforbothente-cavirandlamivudine.Thisassumptionisessentialbecauseviralrebound is an importantphenomenonaccompanyingcessationof therapy, and reboundwill occur in a significant proportionofpatients. For entecavir, 37%had<300 copiespermL,40%hadbetween300and104copiespermL,11%hadbetween104 and105copiespermL,1%hadbetween105and106copiespermL, and 11%had >106 copies permL. For lamivudine, thesepercentageswere 34%, 26%, 12%, 5%, and 23%, respectively.Thenumberofeventswasfirstprojectedbasedontheobservedfirst-yearHBVDNAdataandthenrepeatedforeachyearbasedon rebound-adjusted viral data fromyears 2-10.An average oftheseprojectionswasusedforourfinalestimateofthenumberoflivercirrhosisorHCCevents.

Sensitivity AnalysesToinvestigatetherobustnessofthemodelfindings,weranuni-variatesensitivityanalyses(withachangeof±10%forcontinuousvariablesanduseoftheclosestalternativecategoryforcategoricalvariables)onthefollowingvariables:age,gender,discountrate,efficacy,drugprice,andeventmedicalcosts.Wealsoransensi-tivityanalysesonthe4inputparametersbasedontheiravailablealternativevalues:utility,hepatic flares(definedasanelevationinserumalanineaminotransferase[ALT]toalevel>2timesthepatient’sstablebaselineand>10timestheupperlimitofnormal),lengthoftreatment,andlamivudineresistance.Because utility scores have rarely been measured for HBV

patients,utilitiesforlivercomplicationsusedinourstudyreliedonasinglebutlargesamplesurveyofHBVpatients.Totestthe



impact of varying utility scores for liver complications on ourcost-effectivenessresults,adifferentsetofpublishedutilitytariffvalueswasalsoused38;thesevalueswerenotchosenforreferencecaseanalysesbecausetheirutilityscoreswereprimarilyderivedfromsurveysonhepatitisCpatients.We also considered inclusionof severehepatic flares in the

sensitivityanalyses,assumingthesamemedicalcostsas in thetreatment of decompensated cirrhosis, and a 2% annual eventratethatwasestimatedamonglamivudine-resistantpatientsfromthetrial.Althoughclinicallysignificant,hepaticflareswerenotconsideredintheprimaryanalysisbecausetheir incidenceratewasverylowandthusnoteconomicallyimportant.To evaluate whether entecavir was also cost-effective for

longer-termuse,wemodeledentecavirandlamivudinetreatmentfor3,5,and10years,conservativelyassumingthatthetrialeffi-cacyobservedforentecavirinthefirstyearwouldbesustainedbeyondthetrialperiodwithoutanyincrementalbenefit.Inthelong-term analysis, we assumed that as long as patients weretakinglamivudine,additionalpatientswoulddeveloptreatmentresistance each year. Assumed cumulative lamivudine viralresistanceratesfromyear1toyear5were14%,38%,49%,66%,and69%,39with69%beyond5years.Weassumedthatpatientsdeveloping lamivudine resistance would be treated with theadditionofadefovirtolamivudinetherapytoreflectrecentclini-calpracticeinthemanagementoflamivudine-resistantpatients,whilealsoassumingthatmedicationefficacywouldnotworsen.Annual treatment cost for a once-daily adefovir 10 mg tabletwas$6,975basedonWACin2006dollars.Theadd-onadefovirstrategythereforeincludesbothadefovirandlamivudinecosts.Inaseparatesensitivityanalysis,wealsoassumedthatlamivudine-resistant patients could switch to adefovir monotherapy. Weassumednotreatmentresistanceforentecavirtherapyforthefirst2yearsand0.7%forthethirdyear.Patientsdevelopingentecavirresistanceweretreatedbyaddingadefovirfortheremainingyearsinthesensitivityanalysisbasedonthelong-termtrialdata.To evaluate uncertainty with respect to model parameters,

probabilisticsensitivityanalyses(PSA)with1,000iterationswereconductedforthefollowing2keyparametersforwhichthegreat-est uncertainty existed: (1) viral rebound rates after treatmentcessation, which weremodeled using a beta distribution withvalues for shape parameters alpha (entecavir 44.1; lamivudine37.6)andbeta(entecavir25.9;lamivudine19.4)derivedfromthereportedmeanandstandarddeviationofviralreboundrates,and(2) time to the first event,whichwasmodeledusingagammadistributionwiththesamplemean(survivalyears,compensatedcirrhosis7.6;decompensated cirrhosis8.6;HCC7.1) and stan-darddeviation(compensatedcirrhosis3.95;decompensatedcir-rhosis2.77;HCC3.53)observedfromtheREVEAL-HBVcohort.We did not consider other parameters, such as event costs, inthePSAbecausetheirvariancedatawerenotreported;thus,theunderlyingpropertyof theirprobabilitydistributionscouldnotbedetermined.

■■ Results

Patient characteristics were balanced between the 2 treatmentgroups in the BEHoLD AI463022 study (Table 2). Themajor-ity of treated subjects were predominantly male (75%) andeitherAsian(57%)orwhite(40%),withameanageof35years.Distributionofbaselinehistologyscoreswasbalancedbetweengroups.MeanbaselineKnodellnecroinflammatory scoreswerebalancedbetween the2groups (entecavir7.8, lamivudine7.7).Mean baseline fibrosis scores using the Ishak scoring systemsuggestedmild tomoderate fibrosis forbothgroups (2.3,bothgroups).NoevidenceofdecompensatedHBVdiseasewasappar-entinthesesubjectsbasedonbaselinelaboratorytestsrelatedtoHBVdisease.MeanbaselineserumHBVDNAbyPCRassaywas9.62log10

copies per mL for entecavir and 9.69 log10 copies per mL forlamivudine.AllBEHoLDsubjectshaddetectableserumHBsAg,and all subjectswereHbeAg-positive. Baseline laboratory testsrelated toHBVdiseasecharacteristics (albumin, totalbilirubin,prothrombin time, and international normalized ratio) were


TABLE 2 Baseline Demographics and HBV Characteristics (BMS-AI463022)

CharacteristicETV 0.5 mg

(N = 354)LVD 100 mg

(N = 355)

Age, years

Mean[SD] 35 [13] 35 [13]

Gender, n (%)

Male 274 (77) 261 (74)

Female 80 (23) 94 (26)

Race, n (%)

Asian 204 (58) 202 (57)

White 140 (40) 141 (40)

Other 10 (2) 12 (3)

HBV DNA by PCR, log10 copies per mL

Mean[SD] 9.62 [2.01] 9.69 [1.99]

HBV surface antigen, n (%)

Positive 354 (100) 355 (100)

HBV e antigen, n (%)

Positive 348 (98) 351 (99)

ALT, U per L

Mean[SD] 140.5 [114.33] 146.3 [132.27]

Knodell necroinflammatory score

Mean[SD] 7.8 [2.98] 7.7 [2.99]

Ishak fibrosis score

Mean[SD] 2.3 [1.27] 2.3 [1.29]

Chang TT et al. for the BEHoLD AI463022 Study Group (2006).27

ALT = alanine aminotransferase; ETV = entecavir; HBV = hepatitis B virus; LVD = lamivudine; PCR = polymerase-chain reaction.


comparablebetweengroups.Mean(standarddeviation)baselineALTwas140.5(114.33)UperLand146.3(132.27)UperLforentecavirandlamivudine,respectively.Entecavir was superior to lamivudine for the portion of

subjects who achieved undetectable HBV DNA (<300 copies permL)byPCRassay atweek48.At the endof the48-weektrialperiod,69.1%ofpatientsintheentecavirarmand39.8%ofpatientsinthelamivudinearmreachedthedefinedundetectableHBVDNAlevel(Table1).Ofthe3,653participantsintheREVEAL-HBVcohortstudy,

565(15.5%)wereHbeAg-positive.OftheHBeAg-positivepatients, 92.6% had HBV DNA levels >100,000 copies per mL, and 1.4%hadHBVDNA levels <300 copies permL.Annual inci-denceratesofcompensatedcirrhosis,decompensatedcirrhosis,andHCC for subjectswithundetectable (<300copiespermL)hepatitisBviralloadwere0.34%,0.02%,and0.11%,respectively(Table1).IntheCoxproportionalhazardsmodelsadjustingforsex,age,cigarettesmoking,andalcoholconsumption,hepatitisB viral load was a strong independent predictor of liver cir-rhosisandHCCevents. IncidenceofcirrhosisandHCCeventsincreasedwith the serumHBVDNA level at study entry in adose-responserelationship.Estimated clinical and economic outcomes are reported in

Table 3. Among a hypothetical cohort of 1,000 patients, weprojected71fewercasesofcompensatedcirrhosis,8fewercasesof decompensated cirrhosis, and 42 fewer HCC events in theentecavirarmcomparedwiththelamivudinearm.Theseavoidedeventswouldtranslateintomedicalcostoffsetsofapproximately$2.4millionandagainof817lifeyearsoveraperiodof10years.On a per-person basis, 1 year of entecavir therapy gained

0.728QALYsatanincrementalcostof$2,350,witha3%annual

discount. Compared with lamivudine, entecavir cost an incremental$3,230perQALYgained (95%confidence interval[CI],$2,312-$4,528).Univariatesensitivityanalysesdemonstratedthatourfindings

arerobusttoindividualvariablesandaremostsensitivetoeffi-cacy,drugcosts, and treatmentduration.AssumingalternativeutilityscoresderivedfromahepatitisCpatientsurveystudyof0.99 forHBV,0.80 for compensatedcirrhosis,0.60 fordecom-pensatedcirrhosis,and0.73forHCC,the incrementalcostperQALYgainedwas$2,752,amorefavorableresult.39Asensitivityanalysis showed that inclusion of severe hepatic flares in ourmodeling assumption had very little impact on our economicresultsdue toavery lowevent rateobserved in the trial, eventhoughthisisacostlyandclinicallyimportantevent.Cost-effectivenessacceptabilitycurvesareshowninFigure2.

Thecost-effectivenessresultsarerobust,with98.4%ofsimula-tion-derivedincrementalcost-effectivenessratio(ICER)estimatesbelow$5,000/QALY.Longer-termmodeling, assuming that thetreatment-resistantpatientswoulduseadd-onadefovir,showedthat 3, 5, or 10 years of entecavirwould still be cost-effective,yielding incremental costs per QALY of $9,966, $11,685, and$12,233,respectively,with100%ofPSA-derivedICERestimatesbelow$50,000/QALY.Alternatively,inaseparatesensitivityanal-ysisassumingthatlamivudine-resistantpatientswouldswitchtoadefovirmonotherapy,ICERswerehigher,rangingfrom$11,582(3 years) to $20,662 (10 years), primarily due to the relativelylowercostofadefovirmonotherapy.

■■ Discussion

DespitethedevelopmentofsafeandeffectiveHBVvaccinesthathavebeenavailablesince1982,HBVinfectionremainsaglobalproblem.IntheUnitedStates,HBVinfectionremainsmoreprev-alentincertaingroupssuchasimmigrantsfromendemicareas,menwhohavesexwithmen,injectingdrugusers,andpersonswithmultiplesexpartners.AslongastheseunderlyingsourcesofHBVremain,thesesubgroupswouldmaintainareservoirofthisinfectiousvirus.PatientswithHBVshouldbeactivelycounseledregardinglifestylemodificationsandpreventionoftransmission.These steps are importantbecauseHBVcanbe transmittedbypercutaneous and sexual exposure aswell as by close person-to-person contact, presumably through open cuts and sores. ItshouldbenotedthatcarrierswithhighHBVDNAlevelsaremorelikelytobeinfectious.2

Major health risks and economic impacts associated withHBVinfectionseemtobedrivenprimarilybythedevelopmentof HCC and complications of decompensated cirrhosis. HBVinfection isacomplexdisease thatcanmanifest inavarietyofways.Theheterogeneousnatureofthediseasewithitsslowandvariable progression to distinct endpoints of liver failure, cir-rhosis,HCC,anddeathmeansthatitisoftendiagnosedlateinlife.Currentmanagementoptionsforlivercomplicationsremainlimitedpartlybecauseofapaucityofsensitivemethodsforearly


TABLE 3 Cost-Effectiveness Results for Entecavir Versus Lamivudine

Entecavir 0.5 mg

Lamivudine 100 mg Difference

Number of CHB patients at entry 1,000 1,000

Duration of treatment (year) 1 1

Total discounted drug costs $7,364,799 $2,603,508 $4,761,291

Projected liver complication in 10 years

Compensatedcirrhosis 78 149 71

Decompensatedcirrhosis 8 16 8

Hepatocellularcarcinoma 34 76 42

Total discounted medical costs $2,252,523 $4,663,540 -$2,411,017

Discounted life-year lost 682 1,499 817

Discounted QALY lost 608 1,336 728

Cost per life-year saved $2,877

Cost per QALY saved $3,230

CHB = chronic hepatitis B; QALY = quality-adjusted life-years.


diagnosis, resulting in the diagnosis of HBV formost patientslateinthediseasecourse.Livertransplantationremainstheonly effective therapy for late complications like decompensated cirrhosisandHCC.Therefore,thebenefitsofearlytreatmentforHBVinsuppress-

ingviralloadandreducingconsequentriskofcirrhosisandHCC can be substantial. A consensus seems to have been reached that antiviral therapy, especially if started early, can delay the progression and reduce the severity of liver disease due to HBV.40,41 An evaluation of the cost-effectiveness of such treat-mentswouldbequiteinformativetodecisionmakers.A number of factors can increase the rate of liver disease

progression in patients infected with hepatitis B, including coinfection with HCV.42-44We limited our analysis to patientswithoutHCVcoinfectiontobetterdelineatethenaturalhistoryofhepatitisBalone,thusmakingourresultsgeneralizableonlyto monoinfected patients. Coinfection with human immuno-deficiency virus (HIV) is also an important variable in HBV treatment, but for a reason unrelated to liver disease progres-sion. TheDepartment ofHealth andHuman Services (DHHS)GuidelinesfortheUseofAntiretroviralAgentsinHIV-1InfectedAdults and Adolescents (October 2006) were modified in April2007, toclarify thatentecavir shouldnotbeused for thetreatment ofHBV infectionwithout concomitant treatment forHIVinpatientscoinfectedwithHBVandHIV.45

In the present analysis extrapolated from observed HBVDNA efficacy results, we estimated that in patients initiatinglamivudine therapy, 15% would progress to compensated cir-rhosis within 10 years, 1.6% to decompensated cirrhosis, and 7.6% to HCC. For patients initiating entecavir therapy, 7.8%wouldprogresstocompensatedcirrhosiswithin10years,0.8% to decompensated cirrhosis, and 3.4% to HCC. These estimatesarewellwithintherangeofpublishedfigures.40

Comparedwith lamivudine, the incremental costperQALYgain ranges from $3,230 for 1 year of entecavir treatment to$12,233 for 10 years of entecavir treatment. These estimated cost-effectivenessratiosfallwellwithintherangethatistradition-ally considered acceptable in cost-effectiveness analysesofnewhealthtechnologies.46-48

Althoughtheclinicalbenefitsofreducingviralloadhavebeendemonstrated in recent literature,25,26 to thebestofourknowl-edge, very few economic analyses have been conducted basedontheendpointofantiviraltherapy-inducedsuppressionofviralreplication.HBeAgseroconversion(lossofHBeAgandpresenceofanti-HBeAgantibody)wasuniformlythoughttobeagoodout-comeforpatients,butrecentdatahaveshownthatmanypatientswhohaveundergoneHBeAgseroconversioncontinuetodevelopseverecomplications(includingHCC).49HBeAglossandserocon-versionareimportantclinicalendpoints,buttheriskofdiseaseprogressionevenwhentheseendpointsaremetstilldependsonthedegreeof ongoingviral replication in thehost.Besides theREVEAL-HBVstudy, several studieshavedemonstrated adose

relationshipbetweenhepatitisBviralloadandhepaticcomplica-tions,withhigherhepatitisBviralloadassociatedwithprogres-sive liver disease, including the development of cirrhosis andHCC.25,26,50-52

A key question arises when interpreting our findings: Is itappropriatetoassumethatpatientstreateddowntoanundetect-able viral load (BEHoLDpatientswithHBVDNA<300 copiespermLatstudyendpoint)haverisksofdiseaseprogressionandhepaticcomplicationsthatapproximatetherisksforcommunityresidentswithanundetectableviral load(REVEAL-HBV)?Thishypothesisissupportedbyevidencefromalargemeta-analysisof 26 prospective studies totaling 3,428 study subjects (2,524HBeAg-positiveatbaseline)inwhomthelevelofviralreplicationandthechangeinviralreplicationweresignificantlycorrelatedwithseveraloutcomesincludinghistologicalgrading,andchangeinhistological grading, serological andbiochemical response.53 AnItalianstudypublishedin2004showedthatin656HBeAg-negative CHB subjects treated with lamivudine, patients whodeveloped resistance as determined by viral breakthrough andrebound had a worse outcome in all parameters, includingmortality,whencomparedwiththosewhoseviralloadwaseffec-tively suppressed by lamivudine.54 This study was conductedin patients with e antigen-negative disease in which immune-inducedHBeAg seroconversion is not an option; therefore, thebenefitoftherapyisfromthedirectantiviraleffectofthedrug.Indeed, a decrease in viral load through antiviral therapy hasbeenassociatedwithhistologic improvement,26,27,55-61 increased survival of patients with decompensated liver disease from



hepatitisB,62-70and improvedclinicaloutcome inpatientswithHBVreactivationfollowingchemotherapy.50,52,71-81

Ouranalysesareconservativeinthefollowingaspects.First,longer-termclinical trialdata consistently showedsubstantiallybettersuppressionofviralDNAlevelswithentecaviratweek96forHBeAg-positivetreatment-naïvesubjectsundergoing2yearsof entecavir treatment.22 These resultswere recently publishedin a peer-reviewed journal and thereforewere not included inourcurrentanalysis.Second,wemodeledHBVDNAreductionefficacy only at the end of follow-up, even though viral loadreduction can be observed as soon as the first 6months afterrandomization; thisprocessmayhaveunderestimatedtheben-efitsofentecavirtherapythatsuppressesviralloadtoaverylowlevelinarelativelyshorttimeperiod.Third,duetothelimitationof theobservationperiod in theREVEAL-HBVstudy,wewereabletoprojecteventsonlyupto10years;however,becausetheaverageageoftrialpatientswasonly35years,wecouldexpectmoreeventstobeobservedbeyond10years.Fourth,wedidnotinclude indirectmedical costs, caregiver support cost, and lostproductivityinourstudy;however,webelievethattheseindirectdiseaseburdenscouldbeverysignificantandcostlytoU.S.soci-etyandindividualpatients.

LimitationsFirstandforemostamongstudylimitationswastheapplicationof data on hepatic outcomes from a prospective cohort study(REVEAL-HBV) of community residents, all of whom wereseropositiveforHBsAgbutonly15%ofwhomwereseropositiveforHBeAg,toclinicaltrial(BEHoLD)datafor715patientswithHBeAg-positive CHB. Of the 873 REVEAL-HBV participantswithundetectableviralloadatstudyentrywhoseoutcomeswereusedinourmodeltoindicatebaselinerisksofcirrhosisandHCC,only 0.9% (n=8) were HBeAg-positive. Additionally, only 4%(n=24)oftheREVEAL-HBVstudy’s565HBeAg-positivepartici-pantshadHBVDNA<10,000copiespermL.Thus,thepresentpharmacoeconomicmodel’sassumeddose-responserelationshipbetweenHBVdiseasesequelaeandviralloadforHBeAg-positivepatientswasbasedalmostentirelyoncommunityresidentswhowereHBeAg-negative.Second,reliablelong-termtreatmentreboundratesaftertreat-

ment discontinuation are not yet available for either entecaviror lamivudine. In the BEHoLD results, 6 patients (2%) in theentecavirgroupand63patients(18%)inthelamivudinegroupexperienced virologic rebound during the first year of drugadministration.Amongpatientswithaprotocol-definedresponse,only 37% in the entecavir group and 34% in the lamivudinegrouphadasustainedresponse6monthsafterdiscontinuationof treatment. The optimal duration of entecavir or lamivudineadministrationinHBVpatientsrequiresfurtherstudy.Third, the appropriateness of extrapolation of the BEHoLD

clinical trial results and REVEAL-HBV data to non-Asian

populationsisunknown.TheREVEAL-HBVepidemiologicdatathatprovidedthediseaseprogressionrateswerederivedfromaChinesepatientpopulation.Inherentenvironmentalandgeneticfactors in the cohort may not be seen in other populations.However, REVEAL-HBV is the largest study of HBV-infected persons to examine detailed information on viral factors. Itsresults have been replicated in a second study that was also conductedinChinesepatients.82TherelationshipbetweenviralloadandliverdiseaseoutcomehasbeenfoundinotherstudiesaroundtheworldincludingWestAfrica,China,andJapan,butprimarilyinAsians.42,44

Fourth, potential cost-effectiveness for entecavir comparedwithotherdrugs,suchasadefovirorinterferon,wasnotevalu-atedduetolackofhead-to-headrandomizedtrialdataatthetimeofthisstudy.Futurestudiesshouldexplorethecost-effectivenessofothertreatmentstrategies.Fifth, althoughweaccounted for the actual compliance rate

in theBEHoLDclinical trial,wewould expect the compliance rate inreal-worldpractice tobemuch lower.However, there isno reason to believe that compliance rates between entecavirand lamivudine will differ based on their dosage form (oral), frequency of administration (once daily), and side effect profiles.Sixth,we did not consider those patientswith lamivudine-

resistantviruswhorequirelargerdosesofentecavir.Finally,wedid not evaluate the cost-effectiveness of entecavir in patientscoinfected with HBV and HIV. Patients in our analysis wereassumed to be naïve to antiretroviral treatment and not to becoinfected with HIV, even though ≤10% of all HIV-infectedpersonsarecoinfectedwithHBV.83Aswehavenoted,theDHHSPanel on Antiretroviral Guidelines for Adults and Adolescents no longer recommends entecavir in patients coinfected with HBV and HIV who are not receiving simultaneous HIV drugtreatment;45 entecavir’s package labeling has been changedaccordingly.21

■■ Conclusion

Based on published data for a Chinese population outside theUnited States, our modeling consistently demonstrated that astrategy of initiating therapywith entecavir inHBeAg-positiveHBVpatients(bothshort-termandlong-termuseupto10years)willbecost-effectiveandthereforeeconomicallyattractivetoU.S.health care payers assuming that (1) the efficacy of entecavirafter1year is sustainableand (2) liverdisease risk levels fromtheREVEAL-HBVstudypopulation(aprimarilyHBeAg-negativegroup) adequately represent risk for a treated HBeAg-positivepatientgroup.WhileeradicationofhepatitisBisrarelyachievedusing current treatment options, the availability of entecaviraspartof anearly treatment strategy is economicallyattractive for currentHBV patientswithout coinfectionwith eitherHCVorHIV.



DISCLOSURES

ThisresearchwasfundedbyBristol-MyersSquibb.Twooftheauthors (YongYuanandUchennaH.Iloeje)areemployeesofBristol-MyersSquibb.JoelHayreceivedagrantfromBristol-MyersSquibb.Allauthorscontributedequallytotheconceptanddesign,datacollection,datainterpretation,andwritingandrevisionofthemanuscript.

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YONG YUAN, PhD, is director, Global Epidemiology and Outcomes Research, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Plainsboro, New Jersey; UCHENNA H. ILOEJE, MD, MPH, is group director, Global Epidemiology and Outcomes Research, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Wallinford, Connecticut; JOEL HAY, PhD, is an associate professor, Department of Pharmaceu-tical Economics and Policy, School of Pharmacy, University of Southern California, Los Angeles; SAMMY SAAB, MD, MPH, is an associate professor, Departments of Medicine and Surgery, David Geffen School of Medicine at UCLA, University of California at Los Angeles.

AUTHOR CORRESPONDENCE: Yong Yuan, PhD, Bristol-Myers Squibb Company, P.O. Box 4500, Princeton, NJ 08543-4000. Tel.: 609.897.2688; Fax: 609.897.6319; E-mail: [email protected]

Authors


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