15 price important liver care - · pdf file10 important liver care questions and 10 brilliant...

12/8/17

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10ImportantLiverCareQuestionsand10BrilliantAnswers

JenniferPrice,MD,PhDUCSFHepatologyDecember8,2017

10ImportantLiverCareQuestionsand10BrilliantAnswers

JenniferPrice,MD,PhDUCSFHepatologyDecember8,2017

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Disclosures

• Grantsupport:Gilead,Merck• Advisoryboard:Intercept• Ownershipinterest:Bristol-MyersSquibb,JohnsonandJohnson,Merck,Abbvie

Outline

• Complicationsofcirrhosis– Surveillanceforhepatocellularcarcinoma(HCC)– RiskofHCCwithDAA’s– Surveillanceforesophagealvarices

• TimingofHCVtreatmentintransplantcandidates• HepatitisBvirus

– IsolatedHBcAb+– Newtreatments

• Nonalcoholicfattyliverdisease(NAFLD)– Diagnosisandmanagement

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Acute hepatitis C

Chronic infection

Chronic hepatitis

Cirrhosis

Time(yr)

55 - 85%

70%

20%

10 20 30

Decompensation

Hepatocellular Carcinoma

1-4%/yr

4-5%/yr

NaturalHistoryofChronicLiverDisease(HCVexample)

HCCSurveillance:U/S+/- AFPevery6months

• Risingincidenceoverpast20years– Estimated39,230casesand27,170deathsin2016– AgingHCV+population,increasingNAFLD– Incidenceexpectedtoriseuntil2030

• Highriskgroups:– Cirrhosis– ChronicHBV– F3fibrosis

• Observationalstudiesincirrhosis:screeningassociatedwithimprovedsurvival,detectionofearly-stageHCC

Heimbach J,AASLDPracticeGuidelines,2017.

HCCSurveillance:ChronicHBV1.HowshouldweapproachHCCscreeninginpatientswithHIV/HBV?

HCCSurveillance:ChronicHBV

Bruix J,AASLDPracticeGuidelines,2011.

Surveillancerecommended

HBVPopulationGroup Thresholdincidenceforefficacyofsurveillance

IncidenceofHCC

Cirrhosis 0.2-1.5%/yr 3-8%/yr

Familyh/oHCC 0.2%/yr Incidencehigherthanwithoutfamilyhistory

Asianmale>40years 0.2%/yr 0.4-0.6%/yr

Asianfemale>50years 0.2%/yr 0.3-0.6%/yr

African/NorthAmericanBlacks 0.2%/yr Occursatearlierage

Benefituncertain

Males<40,Females<50 0.2%/yr <0.2%/yr

1.HowshouldweapproachHCCscreeninginpatientswithHIV/HBV?

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HBVPopulationGroup

Cirrhosis

Familyh/oHCC

Asianmale>40years

Asianfemale>50years

African/NorthAmericanBlacks

Benefituncertain

Males<40,Females<50


WhataboutCaucasianpts?




HBVPopulationGroup

Cirrhosis

Familyh/oHCC

Asianmale>40years

Asianfemale>50years


Benefituncertain

Males<40,Females<50


WhataboutCaucasianpts?─ IfnocirrhosisandchronicinactiveHBV(long-termnormalALT,lowHBVDNA)“theincidenceofHCCisprobablytoolowtomakesurveillanceworthwhile”

─ However…“additionalriskfactorshavetobetakenintoaccountincludingolderage,persistenceofviralreplication,co-infectionwithHCVorHIV,orpresenceofotherliverdisease”

─ …“CaucasianptswithactiveHBVarelikelyatriskforHCCandshouldbescreened”




HBVPopulationGroup

Cirrhosis

Familyh/oHCC

Asianmale>40years

Asianfemale>50years


Benefituncertain

Males<40,Females<50


WhataboutCaucasianpts?─ IfnocirrhosisandchronicinactiveHBV(long-termnormalALT,lowHBVDNA)“theincidenceofHCCisprobablytoolowtomakesurveillanceworthwhile”

─ However…“additionalriskfactorshavetobetakenintoaccountincludingolderage,persistenceofviralreplication,co-infectionwithHCVorHIV,orpresenceofotherliverdisease”

─ …“CaucasianptswithactiveHBVarelikelyatriskforHCCandshouldbescreened”

HCCSurveillance:ChronicHBV2.HowshouldweapproachHCCscreeninginnon-cirrhoticptswithisolatedHBcAb+:• IsolatedHBcAb+:

• IsolatedHBcAb+associatedwithincreasedHCCriskinJapaneseptswithnon-HBV,non-HCVcirrhosis1

• HighprevalenceofHBcAb+inKoreanptswithnon-HBV,non-HCVHCC2

• HBcAb+notassociatedwithHCCinU.S.HCVcohort3

• SystematicreviewsuggestedincreasedriskofHCC4─ Mostlycase/control,fewadjustmentsforconfounders,only1inUS

• Insufficientevidencetosupportsurveillanceinthisgroup

1IkedaK,JViralHepat,2009.2LeeSB,LiverInt,2016.3LokAS,Hepatology,2011.4LeeSB,LiverInt,2016.

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HCCSurveillance:ChronicHBV2.HowshouldweapproachHCCscreeninginnon-cirrhoticptswithHBsAgloss(spontaneousorduetotx)?

1SungJJY,AlimentPharmacol Therp,2008.2HungCH,JViralHepat,2017.3KimGA,JHepatol,2015.4EASL-EORTCGuidelines,2012.

• HBsAgloss• HBVtxreduces(butdoesnoteliminate)riskofHCC1

• HCCstilloccursinptswholoseHBsAgspontaneouslyorwithtx2,3

• FactorspredictingHCC:age≥50atseroclearance,cirrhosis,lowalbumin,malesex3

• Continuesurveillanceinptsatriskduetobaselinefactors4

HCCSurveillance:HCV3.ShouldwescreeninHCV+ptswithF3fibrosis?

HCCSurveillance:HCV

Lok AS,Gastroenterology,2009.

3.ShouldwescreeninHCV+ptswithF3fibrosis?• HCV+ptswithF3fibrosishaveelevatedHCCrisk

HCCSurveillance:HCV

Lok AS,Gastroenterology,2009.

3.ShouldwescreeninHCV+ptswithF3fibrosis?• HCV+ptswithF3fibrosishaveelevatedHCCrisk• HCCguidelinesareconflicting

– RecommendedforF3fibrosisinHCVbyEASL(2012)– BenefituncertaininAASLDguidelines(2010)

• Post-SVRTreatmentguidelinesareconsistentandrecommendsurveillanceinptswithF3fibrosis

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HCCSurveillance:HCV

AASLD/IDSAHCVGuidelines,2017.

3.ShouldwescreeninHCV+ptswithF3fibrosis?

HCCSurveillance:HCV

EASLHCVGuidelines,2017.

3.ShouldwescreeninHCV+ptswithF3fibrosis?

HCCSurveillance:HCV3.ShouldwescreeninHCV+ptswithF3fibrosis?

Yes!• EssentialtoadequatelystagefibrosispriortoHCVtx

– Nearly50%ofptswithF3fibrosisonpre-treatmentFibroscan(≥9.5kPa)willhavepost-SVRFibroscan<9.5kPa

– Fibroscanandothernon-invasivefibrosissurrogateshavenotbeenvalidatedinpost-SVRpts

– Limitedevidencecomparingpost-SVRbiopsywithFibroscanshowsyouwillunderestimatefibrosisstageifyourelyonpost-SVRresults

• 5UCSFptswith≥F3fibrosisonpost-SVRbiopsy:3(60%)hadpost-SVRFibroscan<9.5;1ofthesedevelopedHCCpost-SVR

HCCRiskwithHCVDAA’s4.DoDAA’sincreasetheriskofHCC?

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HCCRiskwithHCVDAA’s4.DoDAA’sincreasetheriskofHCC?IncidentHCCrisk

HCCRiskwithHCVDAA’s4.DoDAA’sincreasetheriskofHCC?IncidentHCCrisk• HighdenovoHCCoccurrencerateswithin12monthsofDAAcessationreportedin3earlystudies


• Subsequentlargerstudiesshowednoincreasedrisk


• Subsequentlargerstudiesshowednoincreasedrisk

HR0.28(95%CI0.22-0.36)• LargeVAstudyof22,500

pts(39%withcirrhosis):SVRafterDAAsreduced

riskofHCC

Kanwal F,Gastroenterology,2017.

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HCCRiskwithHCVDAA’s4.DoDAA’sincreasetheriskofHCC?IncidentHCCrisk

Llovet JM,NatRevGastroHepatol,2016.

SVR(DAA-basedtx)1.5-4%peryear

• We are now treating older pts with more advanced liver disease (higher risk for HCC)

DAAsarenotassociatedwithincreasedINCIDENTHCC

HCCRiskwithHCVDAA’s4.DoDAA’sincreasetheriskofHCC?Recurrencerisk

HCCRiskwithHCVDAA’s4.DoDAA’sincreasetheriskofHCC?Recurrencerisk• SomedatasuggestspossibilityofearlyrecurrenceofHCCwithDAAtherapy


• Severalstudiesshownoincreasedrisk

ANRSStudyGroup,JHepatology,2016.

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ANRSStudyGroup,JHepatology,2016.

• Severalstudiesshownoincreasedrisk

• ForptswithHCCandcompleteresponsewithresectionorlocoregionaltx,thereisinsufficientevidencetojustifywithholdingDAA’s

EsophagealVaricesScreening5.WhoshouldbescreenedforvariceswithEGDandhowoftenshouldthisberepeatedafterinitialEGD?

EsophagealVaricesScreening• Seenin45-50%ofpatientswithcirrhosis

– 40%inCPTA,60%inCPTB,80%inCPTC

• Activebleedisassociatedwith20-30%mortality• Primaryprophylaxis:non-selectivebetablockersorbandligation

Smallvarices LargevaricesNovarices

8%/year 8%/yearD’AmicoG.PortalHypertensioninthe21St Century,2004

EsophagealVaricesScreening• Seenin45-50%ofpatientswithcirrhosis

– 40%inCPTA,60%inCPTB,80%inCPTC

• Activebleedisassociatedwith20-30%mortality• Primaryprophylaxis:non-selectivebetablockersorbandligation

Smallvarices LargevaricesNovarices

8%/year 8%/yearD’AmicoG.PortalHypertensioninthe21St Century,2004

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Diagnosis of Cirrhosis

Endoscopy

No Varices

Follow-up EGD in 2-3 years*

Small Varices

Follow-up EGD in 1-2 years*

Medium/Large Varices

•Step-wise increase until maximally tolerated dose•Continue beta-blocker (life-long)

No Contraindications

ContraindicationsorBeta-blocker intolerance

Beta-blocker therapy

Endoscopic Variceal Band Ligation

*EGD every year in decompensated cirrhosis

EsophagealVaricesScreening EsophagealVaricesScreening5.WhoshouldbescreenedforvariceswithEGDandhowoftenshouldthisberepeatedafterinitialEGD?• Allpatientswithcirrhosis(traditionalcriteria)• Ptswithclinicallysignificantportalhypertension(HVPG≥10mmHg)areatriskofbleeding

• Patientswithcompensated cirrhosis,FibroscanLS<20kPa andplatelets>150,000mm3 haveverylowprobability(<5%)ofhavinghigh-riskvaricesandEGDcanbesafelyavoided(akaBaveno VIcriteria)

Garcia-Tsao G,AASLDGuidelines,2016.MauriceJB,JHepatol,2016.

TimingofHCCTreatmentinTransplantCandidates

6.HowdoyouapproachHCVtreatmentinliverorkidneytransplantcandidates?


6.HowdoyouapproachHCVtreatmentinliverorkidneytransplantcandidates?• Invastmajorityofpts:waituntilaftertransplant

─ AbilitytoreceiveaHCV+kidneysignificantlyreduceswaitlisttime

─ HCVcanbesafelytreatedpost-transplant

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─ HCVcanbesafelytreatedpost-transplant• Insomeptswithcirrhosis,treatmentisconsideredtodecreaseneedforcombinedliver/kidney




─ HCVcanbesafelytreatedpost-transplant• Insomeptswithcirrhosis,treatmentisconsideredtodecreaseneedforcombinedliver/kidney

• DonottreatHCVarecandidatesforkidneytransplantuntilaftertheyareevaluatedbytransplantnephrologyandhepatology


6.HowdoyouapproachHCVtreatmentinliver orkidneytransplantcandidates?


6.HowdoyouapproachHCVtreatmentinliver orkidneytransplantcandidates?• Trickierandtransplantregion-specific

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6.HowdoyouapproachHCVtreatmentinliver orkidneytransplantcandidates?• Trickierandtransplantregion-specific• PtswithHCC:oftenwaituntilaftertransplant

– LowerSVRratesinptswithHCC– 25%waitlistdrop-offforHCCptsinourregion;allowsforexpandeddonorpool

– Willconsidertxtopreventdecompensation,allowingforlocoregionaltherapywhilewaiting


6.HowdoyouapproachHCVtreatmentinliver orkidneytransplantcandidates?• Trickierandtransplantregion-specific• PtswithHCC:oftenwaituntilaftertransplant

– LowerSVRratesinptswithHCC– 25%waitlistdrop-offforHCCptsinourregion;allowsforexpandeddonorpool

– Willconsidertxtopreventdecompensation,allowingforlocoregionaltherapywhilewaiting

• Ptswithdecompensatedcirrhosis

§Compensatedcirrhosis§Child-PughA§MELD<10

§Decompensatedcirrhosis§Child-PughC§MELDcut-off???§Significantrenaldysfunction

§ TreatallunlessHCC(concernofinabilitytogettoLTwithexceptionstatus)

§ Don’ttreatunlessLTisnotanoptionandexpectedtosurvivalatleast6months

§Decompensatedcirrhosis§Child-PughB§LesssevereportalHTN

§ Treatmostpatients§ Considerage,severityofPHTcomplications,severityofnecroinflammation


TransplantCandidates

HBV7.HowdoyouapproachisolatedHBcAb+patients?

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HBV7.HowdoyouapproachisolatedHBcAb+patients?• Potentialscenarios:

a) “Windowphase”ofacuteHBVrecovery─ CheckHBsAb 1-3months



b) OccultHBV─ Ratesvarydependingonstudy─ CheckHBVDNA(IreserveforHIV+,ESRDonHD,cirrhosis,

immunocompromised)




immunocompromised)c) PriorexposurewithlossofHBsAb

─ Mostcommonscenario;ifriskfactorsforpriorexposure,novaccinationneededunlessHIV+orimmunocompromised




immunocompromised)c) PriorexposurewithlossofHBsAb

─ Mostcommonscenario;ifriskfactorsforpriorexposure,novaccinationneededunlessHIV+orimmunocompromised

d) Falsepositive─ Highersuspicionifnoriskfactorsforexposure- givefullseries

vaccineifindicatedandunsureofexposurehistory

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362ptswithisolatedHBcAb+

(Paris)

11falsepositive(3%)

1“Windowphase”(0.3%)

10HBVDNA+(3%)

341HBVDNA-(94%)

RepeatHBcAb

HBc IgM

HBVDNA


Launay O,JViralHep,2011.

362ptswithisolatedHBcAb+

(Paris)

11falsepositive(3%)

1“Windowphase”(0.3%)

10HBVDNA+(3%)

341HBVDNA-(94%)

RepeatHBcAb

HBc IgM

HBVDNA


Launay O,JViralHep,2011.

Riskofreactivationwithimmunosuppression,HCV

DAAtreatment

HBV8.Istenofoviralafenamide(TAF)effectiveinHBV?

HBV8.Istenofoviralafenamide(TAF)effectiveinHBV?

• TenofovirprodrugwithgreaterplasmastabilitythanTDF

• Enhancesdeliveryofactivedrugtohepatocytes

• TAFnon-inferiortoTDFatwks48and96

• Smallandsimilar%ofptswithHBVDNA≥69IU/mL

• Virologicbreakthroughinfrequent• NoresistancetoTAFdetected

through96wks

AgarwalK,EASL2017,FRI-153.Brunetto MR,EASL2017,PS-042.ChenHLY,AASLD2017,Abstract26.

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HBV:Whatisonthehorizon?Mechanism Drug

Entryinhibitors Myrcludex

Polymeraseinhibitors TAF,CMX-157,AGX-1009,Besifovir,Lagociclovir

Capsid blockers GLS-4,NVR3-778

Releaseinhibitors Rep-2139,Rep-2165

cccDNA cleavage(geneediting)

CRISPR/Cas9,TALENS, ZFNs

Transcriptioninhibitors(RNAinterference)

ARC-520,ARC-521

Innateimmunity GS-9620,Birinapant

Adaptiveimmunity Therapeuticvaccines(GS-4774), EngineeredTcells

SorianoV,ExpertOpin Investig Drugs,2017.

Viruslifecycle(antivirals)

Hostimmuneresponse(immunomodulators)

NAFLD/NASH

~30%

~3-10%

~0.3-2%

NAFLD/NASH

HIV+similartoHIV-

LikelyhigherinHIV+(42%NASH,22%≥F2)

IsithigherinHIV?

~30%

~3-10%

~0.3-2%

NAFLD/NASH9.HowdoyoumakethediagnosisofNAFLD,andwhenshouldwebiopsypatientswithsuspectedNAFLD/NASH?

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NAFLD/NASH9.HowdoyoumakethediagnosisofNAFLD,andwhenshouldwebiopsypatientswithsuspectedNAFLD/NASH?• SuspectNAFLDif:

– Metabolicsyndrome,historyofd-druguse– Abnormalliverenzymes(notnecessaryforNAFLD)inabsenceofotherchronicliverdiseaseorheavyEtOH use

– UltrasoundsuggestsNAFLD

NAFLD/NASH9.HowdoyoumakethediagnosisofNAFLD,andwhenshouldwebiopsypatientswithsuspectedNAFLD/NASH?• SuspectNAFLDif:

– Metabolicsyndrome,historyofd-druguse– Abnormalliverenzymes(notnecessaryforNAFLD)inabsenceofotherchronicliverdiseaseorheavyEtOH use

– UltrasoundsuggestsNAFLD• Itremainsundiagnosedinthemajorityofpts

– Fibroscanwithcontrolledattenuationparameter(CAP)canbeusedtoscreen

• Notrecommendedyetinprimarycareclinics

– MRimaging(MRS,MRI-PDFF)isnon-invasivegoldstandard

NAFLD

SimpleSteatosis NASH

Nonprogressive Progressive

BorderlineNASH

SimpleSteatosis(n=8)NASH(n=109)

Survival

1.00

0.75

0.50

0.25

00 10 20 30

Years

SöderbergC,Hepatology,2010.Slidecredit:clinicaloptions.com

NAFLD/NASH:WhyBiopsy?

BiopsyisneededtodifferentiatesimplesteatosisvsNASH

NAFLD/NASH:ApproachtoBiopsyElevatedliverenzymesorevidenceofhepaticsteatosisonimaging

Trialof3-6mosofdietandexerciseforweightloss

Reassessevery6-12mosLiverbiopsy

Considerbiopsyifundergoingcholecystectomyorbariatricsurgery

Presenceof:• Diabetes• Metabolicsyndrome• Olderage

Baselineworkup:• CBC,platelets,ALT,AST,ALP,GGT,INR,totalbili,albumin• Ruleoutothercausesofchronicliverdisease(eg,viral

hepatitis,autoimmune)• Fastingglucoseandlipidlevels,A1C

Unsuccessful

NoYes

• HighAST:ALT• HighAST:platelet• Decreasedalbuminorplts

Noureddin M,Clin Liver Dis, 2012.. Slide credit: clinicaloptions.com

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NAFLD/NASH:ApproachtoBiopsyElevatedliverenzymesorevidenceofhepaticsteatosisonimaging

Trialof3-6mosofdietandexerciseforweightloss

Reassessevery6-12mosLiverbiopsy

Considerbiopsyifundergoingcholecystectomyorbariatricsurgery

Presenceof:• Diabetes• Metabolicsyndrome• Olderage

Baselineworkup:• CBC,platelets,ALT,AST,ALP,GGT,INR,totalbili,albumin• Ruleoutothercausesofchronicliverdisease(eg,viral

hepatitis,autoimmune)• Fastingglucoseandlipidlevels,A1C

Unsuccessful

NoYes

• HighAST:ALT• HighAST:platelet• Decreasedalbuminorplts

Noureddin M,Clin Liver Dis, 2012.. Slide credit: clinicaloptions.com

HIV

HIVandNASHPrevalenceNASH

Fibrosis

Median(IQR)or%

HIV-monoinfected

(n=18)Uninfected

(n=17)Age 53(46,57) 54(44,59)Male 28% 24%Hispanic 22% 6%Race:AfricanAmerican 39% 59%

White 33% 24%Other 28% 18%

BMI(kg/m2) 29.7(25.5,33.6) 34.4(30.1,38.3)Waistcircumference(cm) 101(95,114) 116(105,122)Fastingglucose≥126 22% 29%ALT 26.5(16,42) 18(13,23)AST 25.5(17,32) 20(17,25)LiverstiffnesskPa 4.3(3.9,6.7) 4.4(3.5,5.6)CAPdB/m 306(261,324) 286(248,347)

p=0.03

p=0.03

Price JC, unpublished data.

NAFLD/NASH10.HowdoyoutreatNAFLD/NASH?


Treat• NASH• NASHwithfibrosis• Advancedfibrosis• NASH-relatedcirrhosis

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Treat• NASH• NASHwithfibrosis• Advancedfibrosis• NASH-relatedcirrhosis

DoNotTreat• Ptswithoutbiopsy-confirmedNASH

• Simplesteatosis─ FocusonCVDrisk

factormodification

NAFLD/NASH10.HowdoyoutreatNAFLD/NASH?• Weightloss:goal≥10%weightloss

─ ImprovesNASHandfibrosis



• Treatdiabetes,hypertension,dyslipidemia



• Treatdiabetes,hypertension,dyslipidemia• VitaminEforconfirmedNASH;800IU/day

─ ImprovedNASHinPIVENStrial─ Increasedriskofbleeding,prostatecancerinoldermen,andpossiblyhemorrhagicstroke

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• Treatdiabetes,hypertension,dyslipidemia• VitaminEforconfirmedNASH;800IU/day

─ ImprovedNASHinPIVENStrial─ Increasedriskofbleeding,prostatecancerinoldermen,andpossiblyhemorrhagicstroke

• Pioglitazone─ ImprovedNASHandfibrosisinPIVENStrial─ Associatedwithweightgain,bonefractures,?long-termsafety

NAFLD/NASH:EmergingTreatments,PhaseIII

Slide credit: clinicaloptions.com1ClinicalTrials.gov.NCT02704403.2ClinicalTrials.gov.NCT02548351.3ClinicalTrials.gov.NCT03053050.4ClinicalTrials.gov.NCT03053063.5ClinicalTrials.gov.NCT03028740.

NAFLD/NASH:EmergingTreatments,PhaseIII

Slide credit: clinicaloptions.com1ClinicalTrials.gov.NCT02704403.2ClinicalTrials.gov.NCT02548351.3ClinicalTrials.gov.NCT03053050.4ClinicalTrials.gov.NCT03053063.5ClinicalTrials.gov.NCT03028740.

StudiesinHIV:Aramchol,Tesamorelin

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