12/9/16

1

10ImportantLiverCareQuestionsand10BrilliantAnswers

MarionPetersMDUCSF

12-2016

10ImportantLiverCareQuestionsand10BrilliantAnswers

MarionPetersMDUCSF

12-2016

×

Cirrhosis

1.ArethereanycirrhoticpatientsthatwecanstopscreeningforHCCaftertheyarecuredofHCV?

HCCandHIV• IncreasingprevalenceofHCCwithlongerlifespanofHIV

– Viralhepatitis,ETOHandNAFLD• Diagnose cirrhosis- Biopsy,Fibroscan,APRI,FIB-4• Screening forearlydiagnosisofHCCcritical(<30%)

– allcirrhotics andinHBVnoncirrhotics q6mos– Selectnoncirrhotics F3,HIVuc,older,?MS

• HIVpatientsworseoutcome?biology?screening• Screeningallowsaccesstotherapiesincludinglocoregional therapyandlivertransplant

• Treatingviralhepatitis-decreasescirrhosisandHCC– Fibroscan appearstounderestimatefibrosisstagepostSVR– HCCcanoccurafterSVR??higherpostDAA– Don’tdischargeyourSVRsfromyourpractice!!!!!!!

12/9/16

2

PredictorsofHCCpostHCVSVR- IFN

OR(CI) P value

DM 1.80(1.2-2.9) 0.005

Hispanicvs Cauc 2.3(1.1-4.8) 0.03

CirrhosisatSVR 6.69 (4.3-10.4) <0.0001

Alcohol 1.68(1.08-2.60) 0.02

Age55-64y 2.04(1.3-3.2) 0.002

Age>65 4.51(2.0-10.4) 0.004

33,005VApatients;10,827SVR 100newHCCcasesIncidencerateofnoSVR 1.32%peryearSVRtoIFNbasedRx 0.33%peryear

El-Serag Hepatology 2016

NASHquestions

2.HowshouldwediagnoseNAFLD&NASHinourpatients(imagingandwhentobiopsy)3.Whoshouldwetreat?4.Withwhat?

Diagnosis of Non-Alcoholic Fatty Liver Disease

Usually with clinical evidence of metabolic syndrome

Other causes of CLD excluded

Abdominal imaging with steatosis (+/- elevated liver

enzymes)+

+

Steatosis detection - Imaging• Ultrasound

– 60–94% sensitivity and 84–95% specificity need >30% fat• Controlled Attenuation Parameter (CAP) with fibroscan

– AOC 0.90-0.95 depending on amount steatosis– >300 severe (>66%) >?220 moderate

• CT scan– Accurate but not sensitive for mild/moderate steatosis

• MRI and MR spectroscopy– Can detect small quantity of fat– Not in routine use, time consuming

Ultrasound Med. Biol. 36, 1825–1835 (2010)Liver Int. 32, 902–910 (2012)Radiology 250, 95–102 (2009)

12/9/16

3

NAFLD:WhentoConsideraLiverBiopsy?• Cannot exclude other types of liver disease

(autoimmune hepatitis, drug-induced liver disease)

• Atypical phenotype: NAFLD in absence of obesity or metabolic syndrome

• Evidence of iron overload • Confirm clinical suspicion of cirrhosis

– Platelet count, imaging, NAFLD fibrosis score

• NASH diagnosis prior to pharmacotherapy• Support major therapeutic decision - bariatric

surgery, clinical trials?

USHIVcohortandsteatosis

• 339HIVsubjectsLondonUK• Hepaticsteatosis in71(21%)correlatedwith

– AbnormalfastingglucoseOR5.5(5.4,18.3)p<.001

– ARTNRTI(ddI,d4T,ddC,ZDV)OR20.34(1.4,361.1)p=0.04

– StatintherapyOR3.31(1.8,6.2)p<0.001

• ObesityandmetabolicsyndromeseeninHIV

Mok etalAbstractHIVDrugtherapyGlasgow2016

NASH: Current Standard of Therapy• First line:

– Lifestyle modification - weight loss 5-10% through diet and exercise is effective, but high probability of failure

– Drug therapy of Metabolic syndrome complications -dyslipidemia, hypertension, diabetes

• Second line: Pharmacotherapy for NASH– vitamin E for confirmed NASH non DM– Obeticholic acid– Ineffective or uncertain benefit in NASH: Metformin,

UCDA, omega-3 fatty acids, pentoxyfilline

• Clinical Trials– GFT505, LOXL2

Nat. Rev. Gastroenterol. Hepatol. 10, 676–685 (2013)

Pioglitzazone, Vitamin E, or Placebo for NAS score Improvement in NASH*

05

101520253035404550

Vit E Placebo Pioglitazone

% Improved

P = 0.001 P = 0.04

*Decrease in NAS by ≥ 2 ptswith ≥1 point decrease in ballooning.

43% 34%

19%

Sanyal et al, NEJM 2010

N=84 83 802yearstudyNoDMorF4

NAS:fat,inflammation,ballooningPio weightgain

Noeffectonfibrosis

12/9/16

4

Pioglitazone in NASH

• Side effect profile may limit use– CV events, CHF, weight gain 3-5kg in 70% pts, bladder

cancer?, bone fractures in post menopausal women

• Longterm safety and efficacy in NASH unknownAliment Pharmacol Ther. 2012

Obeticholic acid (OCA) = potent activator of farnesoid X nuclear receptor inNASH

Pruritus23%Inc LDLtotalcholDecHDL

Neuschwander-Tetri et al. Lancet 2015

N=28372w

Cenicriviroc:KeyEfficacyandSafetyFindings

Outcome at Yr 1, n (%) Cenicriviroc (n = 145)

Placebo(n = 144)

P Value

ImprovementinNASby≥2points*andnofibrosisworsening† 23(16) 27(19) .519

CompleteNASHresolutionandnofibrosisworsening 11(8) 8(6) .494

Improvementinfibrosisstageof≥1andnoNASHworsening 29(20) 15(10) .023

Grade3/4AE 38(26)‡ 37(26) NRSeriousAE 16(11)‡ 10(7) NR§ Causingd/c 1(< 1)‡ 2(1) NR

Death 0 0 --

Slide credit: clinicaloptions.comSanyal AJ, et al. AASLD 2016. Abstract LB1.

*With ≥ 1 point reduction in lobular inflammation or hepatocellular ballooning. †Primary endpoint. ‡Cenicriviroc safety population, n = 144.• Cenicrivirocmayhavepotentialroleasantifibrotic

• NAFLD is most common cause of CLD- 75-100M individuals in the U.S

• NASH will soon be the leading cause of cirrhosis, HCC, and need for LT

• #1 cause of death in NAFLD is CAD• Aggressive management of cardiovascular risk factors is

essential• Steatosis is diagnosed by imaging, though diagnosis of

NASH requires biopsy • Common in HIV patients not just NRTI use

– Associated with metabolic syndrome

NAFLDSummary

12/9/16

5

Transplantquestions

5.WhenshouldHIV/HCV+patientswhoarelivertransplantcandidatesbetreatedforHCV?Beforetransplantorafter?

SpectrumofCirrhosisAmongPatientsontheWaitingList

§Compensatedcirrhosis§Child-PughA§MELD<10§HCCasindicationforLT

§Decompensatedcirrhosis§Child-PughC§Severe/refractoryportalhypertensivecomplications§Moderate-severeliversyntheticdysfunction

§Decompensatedcirrhosis§Child-PughB§Mild-moderateportalHT§Mild-moderatealteredliversyntheticfunction

§ ManyDAAoptions§ HigherchanceofSVR§ Highchanceofclinicalbenefits

§ Curebeforedeathlikely

§ FewerDAAoptions§ ModestreductioninSVR§ RiskofdyingbeforeorwithSVR

§ Modestclinicalbenefitsinshort-term

§ FewerDAAoptions§ SlightreductioninSVR§ Curebeforedeathlikely

§ Moderatechanceofclinicalbenefits

SOF-VEL± RBVforG1-6PatientswithChild-PughBCirrhosis

SVR12§ ASTRAL-4§ HCVGT1-6patientswith

CPTB cirrhosis

Week 0 12 24

SOF/VELSVR12

36

SOF/VEL+RBVSVR12

SOF/VEL

n=75

n=75

n=75

Overall GT 1 GT 3 GT 2, 4, 6

83 88

50

10094 96 85 10086 92

50

86

0

20

40

60

80

100

Patie

nts

(%)

CharltonM,NEnglJMed.2015;373:2618-28

N=908790

GT1 GT3 GT2,4,6

Relapse 5 1 3 6 1 4

VBT 1 1

Death/LTFU 3 2 3 1 1 1

RBVshouldbeincludedintreatmentofallpatientswithdecompensatedcirrhosis,especiallyG3

ClinicalandBiochemicalResponsesinDAATreatedPatientsonWaitingList

(CPTA-C)

36%

28%

36%

CirrhosisN=53

21%ChildB25%ChildC

72%ChildA

Completeresponse:Tbili<2,PT<1.2,albumin<3.5+noascitesorHEPartialresponse:changeinCPclassNoresponse

Frenchmulticentercohortstudy

CoillyA,AASLD2015,Abstract95Meanfollow-up:68wks(12-95)

RateofCompleteResponse

12/9/16

6

SVRisAssociatedwithClinicalandBiochemicalImprovements

§ CPTClassimprovedin40%(72/180)CPTBpatients§ CPTClassimprovedin76%(51/67)CPTCpatients

§ 64%(43/67)improvedtoCPTB;12%(8/67)improvedtoCPTA

§ 247patientswithdecompensatedcirrhosiswhoachievedSVR12§ CPTscorechangefrombaselineto24Weekspost-CureinCPTB/Cpatients

GaneE,APASL2016 BelliL,JHepatol2016;65:524–531

§ 103patientslistedfordecompensatedHCVin11centers§ TreatedwithSOF/RBV,SOF/LDV,SOF/DCV,medianf/u52wks§ 34deactivatedforimprovement" 19formallydelisted

Variable %DelistingBaselineMELD<1616–20>20

25/51(49%)7/38(18%)2/13(15%)

MELDpre-treatmentpredictslikelihoodofbeingdelisted

CumulativeIncidenceofDelisting

ClinicalOutcomeinWait-ListedPatientswithCP-B/CCirrhosisAchievingSVR

LTDelisted

DeathDropout

0%24wks10%48wks19%60wks

SafetyofDAATherapyinPatientswithDecompensatedCirrhosis

§ Overall, DAAs appear to be safe with relatively low discontinuation rates

§ Ribavirin-associated anemia is common and more problematic to manage

§ Other AEs consistent with clinical sequelae of advanced liver disease: difficult to determine if DAAs increases risk as most studies are uncontrolled§ In few controlled studies, AEs predicted by severity of

liver disease and not treatment per se§ Lactic acidosis occurred in 5/35 (14%) patients during

therapy, while no event of lactic acidosis was observed prior to therapy

WelkerTJHepatol2016

SaxenaV,Hepatology,2015

ToTreatorNotToTreatpreLT?No!§ LowerSVRrates- mayenduptoDAAresistanceà moredifficulttotreatpost-LT

§ Fewtreatmentoptionifdevelopsrenaldysfunction

§ LikelihoodofendingupinMELDpurgatoryisgreater

Yes!§ MajoritywillhaveimprovementinMELD,CPTandsymptomsofdecompensation

§ Modestchanceofavoidinglivertransplant

§ ReduceslikelihoodofdyingbeforeLT

§ Iftransplanted,preventsHCVpost-LT

12/9/16

7

SummaryUCSFApproachwithHCVPatients

§Compensatedcirrhosis§Child-PughA§MELD<10

§Decompensatedcirrhosis§Child-PughC§MELD>20?25?§Significantrenaldysfunction

§ TreatallunlessHCC(concernofinabilitytogettoLTwithexceptionstatus)

§ Don’ttreatunlessLTisnotanoptionandexpectedtosurvivalatleast6months

§Decompensatedcirrhosis(MELD<20)§Child-PughB§LesssevereportalHT

§ Treatmostpatients§ Considerage,severityofPHTcomplications,severityofnecroinflammation

HCCandHCV:ToTreatorNotToTreat?

Yes!§ High chance of cure

with 12 weeks therapy§ Keep liver function

stable for locoregionaltherapy

§ Prevent worsening decompensation

§ Eliminates the risk of HCV post-LT àsimplifies management

No!§ Easy to treatment post-

LT (what’s the rush)§ May have negative

impact on HCC- Bad tumor biology

§ Needs all options for LT available including anti-HCV+ donors

RiskofHCCRecurrenceafterInitialSuccessfulTreatmentinDAA-TreatedPatients

Author,Country

NwithHCC

NtreatedwithDAAandTiming

SeverityofCirrhosis/HCC

HCCTreatmentGiven

HCCRecurrenceRate

Conti,Italy 59 59(100%)Median1yearpost-HCCtreatment

CP-A/B56withinMilan

Resection,RFA,TACE,alcoholinjection

29%24weekspost-DAAtherapy

Reig,Spain 58 58(100%)Median11.2 mo.post-HCCtreatment

CP-A/BAllwithinMilan

Resection,ablation,TACE

28%Median3.5 mos afterDAAtherapy

Pol,France 79CIRVIRCohort

13(16%) CP-A96%withinMilan

Resection,ablationorboth

1.73(noDAA)vs1.11(DAA)per100p-yrsMediantimetorecur16.5months

WhetherDAAcurativetherapyincreasesriskofHCCrecurrenceremainsacontroversialissue

JHEP2016Reig;ANRS;Kozbial;Conti.KobayashiJMedVirol 2016

Transplantquestions

6.WhatshouldourHIV/HCV+patientswhoareRENALtransplantcandidatesbetreated?Beforeorafterrenaltransplant?

12/9/16

8

ManagementofHCVinKTRecipients§ HCV-infectedKTrecipientshavehigherriskof

§ Overallandliver-relatedmortality§ RecurrentHCV-associatedrenaldisease

§ PriorstrategyforpreventionofcomplicationswasHCVeradicationpre-KT§ IFNmonotherapywastreatmentofchoice§ Notallpatientseligibleandresponseratesmodest

§ Changedwith§ DAAregimens§ HCVpositivedonors

Severe Renal Impairment CrCl <30 mL/min or End-Stage Renal disease on dialysis

HCVtreatmentbeforekidneytransplant• genotype1a,or1b,or4,dailyFDCelbasvir (50mg)/grazoprevir (100mg)for12weeks ClassIIa,LevelB

• genotype1bdailyFDCparitaprevir (150mg)/ritonavir(100mg)/ombitasvir (25mg)plustwice-dailydoseddasabuvir (250mg)for12wRating:ClassIIb,LevelB

• HCVgenotype2,3,5,or6infectionPEG-IFNanddose-adjustedribavirin**(200mgdaily)Rating:ClassIIb,LevelB– ribavirinshouldberestrictedtothosewithabaselinehemoglobinconcentrationabove10g/dL.

AASLDIDSAguidelines2016

Treatment: pre-KTvsPost-KT§ Even when treatment in dialysis patients is feasible, post-

KT may be preferred§ Maintain ability to receive HCV+ donor kidneys à

reduce wait-time by years and waitlist mortality§ Pre-KT treatment may be preferred in patients with

advanced liver fibrosis§ Decrease liver disease progression/need for combined

liver/kidney transplant§ Reduce risk of peri-transplant and early post-transplant

liver-related complications§ KT recipients in whom treatment should be prioritized:

§ Recurrent HCV-associated GN and graft dysfunction§ Progressive or advanced liver fibrosis

HBVquestions

7.CanTAFbeusedinHBV/HIVcoinfectedpatients?ArethereanyHBV/HIVpts inwhomyouwouldNOTuseTAFforHBVcontrol?

• Tenofovir (disoproxil fumarate oralafenamide)shouldbeusedinallHBVHIVcoinfectedsubjects

• TAFifrenalorbonedisease,older– NodataaboutFanconi’s recurrenceorresolution

12/9/16

9

HBVquestions

8.WhyareHBVcoinfected patientsatriskforreactivationduring/afterHCVtreatment?

HBVReactivationinPtsReceivingDAAs:PostmarketingCasesReportedtoFDA

• CasereportsofHBVreactivationinptsreceivingDAAs– Reactivation:increaseinHBVDNAorseroconversiontoHBsAgpositive

• 29confirmedcasesin~3yrs(November2013toOctober2016)– PtsfromJapan(n=19ASV),US(n=5),other(n=5)– Mostcasesoccurredwithin4-8wksofinitiation– 2deaths,1transplant,6hospitalizations,10DAAdiscontinuations

Slide credit: clinicaloptions.comBersoff-Matcha SJ, et al. AASLD 2016. Abstract LB17.

HBV Reactivation (N = 29)

Not reported, uninterpretable, or undetectable HBV DNA w/o HBsAg statusDetectable HBV DNAHBsAg+, undetectable HBV DNAHBsAg-, undetectable HBV DNA

HBV at Baseline

31%(n = 9)

38%(n = 11)

21%(n = 6) 10%

(n = 3)

HBVReactivationRiskinHBV/HCVCoinfected Pts ReceivingHCVDAAs

• Case reports of HBV reactivation in pts treated with SMV + SOF ± RBV,[1,2] DCV + ASV,[3,4] and LDV/SOF[5]

• Observational study of Chinese pts treated with DAAs (N = 327 screened)[6]

– 3/10 HBsAg+ pts experienced hepatitis due to HBV reactivation– Of 124 HBsAg-/HBcAb+ pts, none experienced hepatitis due to

HBV reactivation• Analysis of open-label phase IIIb trial[7]

– No evidence of HBV reactivation in HBsAg-/HBcAb+ pts receiving LDV/SOF (n = 103)

• Led FDA to require boxed warning for certain DAAs regarding the risk of HBV reactivation and need for HBV screening/monitoring [8]

1.CollinsJM,etal.Clin InfectDis.2015;61:1304-1306;2.Ende AR,etal.JMedCaseRep.2015;9:164;3.HayashiK,etal.Clin JGastroenterol.2016;9:252-256;4.TakayamaH,etal.HepatolRes.2016;46:489-491;5.DeMonteA,etal.JClinVirol.2016;78:27-30;6.WangC,etal.Clin Gastroenterol Hepatol.2016;[Epub aheadofprint];7.Sulkowski MS,etal.Clin InfectDis.2016;[Epub aheadofprint];8.FDA.DrugSafetyCommunication–http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm523690.html

HBVReactivationduringDAARxforHCV

• CaseswerenotreceivingHBVantiviraltreatment• In8cases,whentransaminasesstartedtorise,DAAhepatotoxicitywasinitialdiagnosis- DAAdiscontinued.Aspatientsdeterioratedorfailedtoimprove,HBVreactivationwasconsideredamongthelikelydiagnosis

• 12caseseventuallyreceivedHBVantiviraltreatment• TreatmentforHBVwasdelayedinatleastfiveofthe12cases,andonepatientdied.

• WithHBVtreatment,mostpatientshadimprovementinHBVDNA,andothersignsandsymptoms

FDA.gov 10-26-2016

12/9/16

10

HBVquestions

8.WhyareHBVcoinfected patientsatriskforreactivationduring/afterHCVtreatment?• Clearanceofonevirusmayallowfor

– increasedactivationofothervirus(seenwithHCVHBVandHBVHDVcoinfections- onepredominates)

– AlteredimmunecontrolofHCC?HCVspecificTcellswereremovedpartofHCCcontrol?

• Pathogenesisstudiesrequired

HBVquestions

9.Shouldweprophylax anyofourHBVpatientsagainstreactivationduringHCVtreatmentincludingHIV/HCVandHCVmonoinfectedpatients?• Isitsufficienttohaveanti-HBc+/HBsAg negpatientsonlamivudine/FTCaspartofARTwhenundergoingHCVtreatment?

• OrwouldTDF/TAFbasedARTbepreferabletosuppressHBV?

HBVTestingandMonitoringDuringHCVDAATherapy:AASLD/IDSAGuidance

• TestallptsinitiatingHCVtherapyforHBsAg,anti-HBc,andanti-HBs– NoHBVmarkers:VACCINATE(thisisnotnew)– HBVmarkerspresent:

HBV DNA detectable

HBsAg negative;anti-HBc positive

(± anti-HBs)

HBV DNA meets criteria for treatment in

AASLD HBVguidelines

“Insufficient data to provide

recommendations”

HBV DNA low or undetectable

Treat with HBV drug

Monitor for reactivation; treat if

HBV DNA level meets AASLD HBV guideline

treatmentcriteria

Slide credit: clinicaloptions.comAASLD/IDSA. HCV guidance. September 2016.Graphic created by Ira M. Jacobson, MD.

HBsAg positive

HBVquestions

9.Shouldweprophylax anyofourHBVpatientsagainstreactivationduringHCVtreatmentincludingHIV/HCVandHCVmonoinfectedpatients? YESIsitsufficienttohaveanti-HBc+/HBsAg negpatientsonlamivudine/FTCaspartofARTwhenundergoingHCVtreatment? maybeOrwouldTDF/TAFbasedARTbepreferabletosuppressHBV?YES

12/9/16

11

HBVquestions

10.CanwecureHBV?Averybriefoverviewofthesterilizingcure/functionalcureargumentandthecurrentdrugpipeline

HBVControl

• Inflammatory:normalizeserumALT,biopsy

• Virologic: decreaseHBVDNA

• Immune:seroconversion

– HBeAg toanti-HBe

– HBsAg toanti-HBs

• HBVasof2016not“cured” butcontrolled

Types of HBV cureFunctionalCure- clinicalresolutionSustained,offdrug:• Noinflammation:ALTandliverbiopsy• HBsAg loss• Anti-HBsgain

Completecure- virological cure• Allofaboveplus• LossofcccDNA inliver

IsChronicinactivestateenough• Noinflammation:normalALTandliverbiopsy• HBVDNAloworu/d• HBsAg positive

Strategies to Eradicate HBVVirologic approaches

• Entryinhibitors• BlockcccDNA• Transcriptioninhibitors• RNAinterference• HBVcapsidinhibitor• polymeraseinhibitors• Secretioninhibitors

Hostimmuneapproaches

• Interferons• TLR-7• PD-1/PDL-1• IL-7• Therapeuticvaccines

– Immune complex vaccines– Nasal HBV (NASVAC)

vaccines– DNA vaccines– T cell vaccines– Adenovirus based vaccines

(TG1050)– Yeast based vaccines

12/9/16

12

Gonzalez 2015 Antimicrobe

• siRNA HBsAg

ViralLifeCycle- “latentorrecovered”HBV:functionalcure

ER

cccDNA

Nucleus

HBsAg negAnti-HBsAnti-HBc

Immunesystemconsidersthis“recovered”BUTcccDNA remains:templateforviralreplication