DigestiveandLiverDisease47(2015)988–993
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Digestive
and
Liver
Disease
j o u r n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d
Correspondence
Direct antiviral agents for treatment-naïve patientswithgenotype1hepatitisC:A statisti-calmodelforcomparingoutcomesbetweenreal worldandclinicaltrials
DearEditor,
Inpharmacotherapy,evidence-basedanalysesfrequentlyaim tocomparetheoutcomesobservedintherealworld(i.e., obser-vationalstudies)withtheeffectivenesssuggestedbyclinicaltrials (e.g.,phaseIIIexperimentalstudies)[1].Thetypicalanalytical strat-egyisretrospective:whenthefinalresultsareavailableforboth theexperimentalandtheobservationalstudies,aseriesof statis-ticaltestsareundertakentodetermineifthelatteragreewiththe effectivenessreportedintheformer[3,4].
InthetreatmentofhepatitisC(particularly,genotype1 infec-tion), clinical trials [2] as well as observational studies in the real world on the newest direct antiviral agents (DAAs), have been performed. Some observational experiences have already beenpublishedasclinicalreports or intheframework of cost-effectivenessstudies[3].
Theanalysispresentedhereinisfocusedonthetreatmentof hepatitisCvirus(HCV)genotype1,treatment-naïvepatientswith
Fig.1. ResultsoftheBayesiananalysis.PanelA(primaryanalysiswithnon-inferioritymarginat−20%).Thegraphillustratesthenumberofsuccessesvs.thecumulative numberofenrolledpatients.AteachvalueofNonthex-axis,theblacklinerepresents100%effectiveness(expressedasabsolutecountofsuccesses)andtheblueline representsexpectedeffectiveness(96.5%).Theredlineindicatestheboundaryforinferiority(accordingtowhichtheprobabilisticareaunderthecurvecorrespondsto inferiorityforobservedeffectivenesswhiletheprobabilisticareaabovethecurveindicatesagreementbetweenobservedandexpectedeffectiveness).Twospecificcasesare shownindetailforvaluesofcumulativeNof100and300(verticaldottedlines).AtcumulativeN=100,0to81successesareassumedtoindicateinferiority(while82–100 successesareassumedtoindicateagreementbetweenobservedandexpectedeffectiveness);likewise,atcumulativeN=300,0–246successesareassumedtoindicate inferiority(while247–300successesareassumedtoindicateagreementineffectiveness).PanelB(analysiswithnon-inferioritymarginat−10%).Thisanalysisemploys amuchnarrowernon-inferioritymargin:consequently,agreementrequiresatleast89successesatN=100.PanelC(analysiswithnon-inferioritymarginat−30%).This analysisisemploysamore“flexible”non-inferioritymargin:agreementissatisfiedifonly75successesareachievedatN=100.
the combination sofosbuvir+ledipasvir [2–4]. In particular, we appliedanoriginalBayesianmodel[5]inwhichthecomparison betweenobservationalandexperimentaloutcomesisiteratively repeated over time as more and more observational patients areenrolled(“continuousmonitoring”[5]).Theobjectiveofthis comparison is todetermine, froma statistical viewpoint,ifthe observationalresults(monitored at differentstages of patients’ enrolment)agreewiththosepreviouslyreportedinexperimental trials.
In comparison with traditional frequentist methods, the Bayesianapproachhasanadvantagebecauseitsstatisticalmodel incorporatesinformationfrompreviouspopulations.Inthisway,a combinedparameterestimationisperformedthatusesnotonlythe datafromthepatientsunderstudy,butalsoinformationfrom pre-viouspopulations.Thisgenerallyleadstomoreconservativeresults thanthoseobtainedbythefrequentistapproach.
In the treatment of genotype 1 infection with sofosbu-vir+ledipasvir, the expected success rate suggested by clinical trialsintreatment-naïvepatients(sustainedvirologicalresponse 12weeksaftertreatmentcompletion)is96–97%[3].Inour pri-maryanalysis,weemployedthevalueof96.5%and,accordingtothe Bayesianmodel[5],wesettheinferiorityboundaryat76.5% there-foreassuminginferiorityforsuccessrateslessthan76.5%(cut-offto
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stopforinferiorityi.e.,failtorejectH0ifPr(H1|Data)<0.05;cut-off tostopforsuperiorityi.e.,rejectH0ifPr(H1|Data)>0.95). Contin-uousmonitoringofenrolledpatientswasforevery4newpatients enrolled; in particular, for each number of enrolled patients, two ranges of absolutesuccesscounts were estimated indicat-ing,respectively,inferiority ofrealpatientsincomparison with expectedeffectivenessoragreementbetweenobservationaland experimentaloutcomes.
The results of our primary analysis (Fig. 1, Panel A; non-inferioritylimitsetat−20%)showhowourtheBayesianmodel managesthiscontinuousmonitoringofoutcomesby distinguish-ing‘agreementwithexpectedresults’ from‘inferiority’.Clearly, this distinction is extremely helpful in practical terms, mainly because situations of poor effectiveness, when present, can be recognisedwithoutdelaywithmethodologicalrigour.One criti-calissueinthisanalysisisthechoiceofthecut-offinthesuccess ratebelowwhichinferiorityis assumed(76.5%inouranalysis). We set this absolute reduction value at −20% mainly because observationalevidence always tendsto beless than in clinical trials. Anyhow,two secondary analyses are presented in Fig.1 (PanelsBandC),wherethenon-inferioritylimitswereset, respec-tively,at−10%and−30%.Sincethisisthemostcriticalparameter of themodel,the resultsoftheanalysis changein responseto changes of this boundary. Thedetailed values of theboundary for any value of cumulative N are reported in Supplementary TableS1.
Anumber ofclinicalfactors(relatedtopatients’ characteris-tics,suchasnon-adherence,druginteractions,co-morbidevents andtoxicity)cancontributetoreducetheeffectivenessinthereal world,andthisislikelytooccuralsoinhepatitisC.Furthermore, hepatitisCcanhaveafurtherpeculiarityrelatedtothehighcostof treatment:whenDAAsaremadeavailabletopatients’freeofcharge throughthenationalhealthsystem,oneexplanationfor ineffective-ness–thatgoesbeyondthetraditionalmedicalscenario–isthata patientcanintentionallyomittotakethedrugstoresellthemon theblackmarket.
Thisstudyhadthepurposeofdescribingthemodelalongwith anexampleofapplication.Furtheranalyseswillbeneededtostudy othercohortsidentifiedonthebasisofothercriteriaincludingtype oftreatment,naïvevs.pre-treatedpatients,presenceofcirrhosis, degreeoffibrosis,orintolerancetointerferon[3].
Conflictofinterest Nonedeclared.
AppendixA. Supplementarydata
Supplementarymaterialrelatedtothisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.dld.2015.06.012 References
[1]RothwellPM. Commentary:External validityof resultsofrandomized tri-als:disentanglingacomplexconcept.InternationalJournalofEpidemiology 2010;39:94–6.
[2]Alqahtani SA, Afdhal N,Zeuzem S,et al. Safety and tolerability of ledi-pasvir/sofosbuvirwithandwithoutribavirininpatients withchronicHCV genotype1infection:analysisofphase3IONtrials.Hepatology2015;62:25–30.
[3]ChhatwalJ,KanwalF,RobertsMS,etal.Cost-effectivenessandbudgetimpactof hepatitisCvirustreatmentwithsofosbuvirandledipasvirintheUnitedStates. AnnalsofInternalMedicine2015;162:397–406.
[4]European.AssociationforthestudyoftheliverEASLrecommendationson treat-mentofhepatitisC2015.JournalofHepatology2015;63:199–236.
[5]JohnsonVE,CookJD.Bayesiandesignofsingle-armphaseIIclinicaltrialswith continuousmonitoring.ClinicalTrials2009;6:217–26.
AndreaMessori∗ HTAUnit,RegionalHealthService,ESTAR-Tuscany Region,Florence,Italy
MauriziaR.Brunetto HepatologyUnit,ReferenceCenteroftheTuscany RegionforChronicLiverDiseaseandCancer, UniversityHospitalofPisa,Pisa,Italy AndreaDeLucaa,b
aInfectiousDiseasesUnit,AziendaOspedaliera
UniversitariaSenese,Siena,Italy
bDepartmentofBiotechnology,UniversityofSiena,
Siena,Italy AnnaLindaZignego DepartmentofInternalMedicine,CenterforSystemic ManifestationsofHepatitisViruses,Universityof Florence,Florence,Italy
∗Correspondingauthorat:HTAUnit,Regional
HealthSystemofTuscany,ViaSanSalvi12,50100 Firenze,Italy.Tel.:+393389513583; fax:+390574701319. E-mailaddress:andrea.mesori.it@gmail.com (A.Messori) http://dx.doi.org/10.1016/j.dld.2015.06.012
Highintensityfocusedultrasoundforthe treat-mentofadvancedlivercancer
DearEditor,
A61-year-oldfemalepatientwithChildClivercirrhosisdueto chronicalcoholicdiseasewasdiagnosedwithhepatocellular carci-noma(HCC)byimagingfindings.Thelesionwassubcapsularand subdiaphragmatic(3.5cm)(Fig.1).
Surgicalresectionor liver transplantation couldnotbe con-sideredastherapeuticoptionsbecauseofthepatient’sdecreased general condition and ongoing alcohol abuse. Treatment with sorafenib was contraindicated due to Child C cirrhosis (MELD score 25). Furthermore, minimally-invasive local ablative tech-niques could not be safely performed because of tumour location.
After tumour board review, treatment approach with high-intensity focused ultrasound (HIFU) was approved. Although transarterialchemoembolizationofHCCsbeforeHIFUmayenhance tumoursusceptibilityfortherapeuticultrasound[1],thiswasnot feasibleduetoimpairedliverfunction.
HIFU-ablation was performed using an ultrasound-guided device(SupplementaryFigs.S-1andS-2).Noperiprocedural com-plications occurred. Imaging 3 days and 12 weeks after HIFU showedacompletelydevascularizedlesionwithoutevidencefor residualtumour(Fig.1).Clinicalcoursewasuneventful.
InadvancedHCCstages,minimally-invasiveablativetechniques oftenallowa satisfactory localtumour control.However, these methodsarebasedonthepercutaneousinsertionofneedle-like devices.Moreover,sizeofablationzoneandboundarytohealthy tissueisnotprecisely predictable.Theiruseisthereforelimited to selectedlocations due to risk of vascular, biliary,cardiac or diaphragmaticinjury.
HIFU may overcome these limitations. It is a non-invasive methodthatcausescoagulationnecrosisinthetargetedlesionby focusedultrasoundenergy.
HIFUcanreachtumoursin everypartoftheliveraslongas thelesioniscompletelyvisualisedwithinthefocaldistanceofthe therapeutictransducer,andaccessiblethroughasafeacousticpath. Completetumournecrosismaybeachievedevenwhenthelesion islocatednearbileducts,theheartormajorhepaticvessels[2].
