ACTHIV 2018: A State-of-the-Science Conference for ... · 28/04/2016 · reduces activation [26]. These results again support early treatment of HIV and HCV. Several pathways for

ACTHIV 2018: A State-of-the-Science Conference for Frontline Health ProfessionalsACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals

Pre-TreatmentEvaluationofHepatitisC

OluwatoyinAdeyemi,MDAssociateProfessorofMedicineDivisionofInfectiousDiseases

CCHHSandRushUniversityMedicalCenter,Chicago


LearningObjectivesUponcompletionofthispresentation,learnersshouldbebetterableto:

• ReviewthestepsthehealthcareteamshouldfollowfromHCVdiagnosistotreatment

• DiscusstheimportanceoffibrosisassessmentinHCVmanagementandhowtoassessfibrosis.

• Describewhenhepatocellularcancer(HCC)screeningisanessentialpartofpost-curecare.

HCVguidelines.org(AASLD/IDSA)


FacultyandPlanningCommitteeDisclosuresPleaseconsultyourprogrambook.

Therewillbenooff-label/investigationalusesdiscussedinthispresentation.

Off-LabelDisclosure


DoyoutreatHCVpatients?• A.yes,ItreatHCVinmyHIV/HCVco-infectedpatients

• B.Yes,ItreatHCVmonoandHIV/HCVco-infectedpatientsinmypractice

• C.IdonottreatHCVandrefertootherspecialists



01234567

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Rateper100

,000

Persons

HepatitisCHIV

16,600deaths

8369deaths

Deaths From Hepatitis C Have Surpassed Deaths From HIV Infection

LyK.Netal.,AnnalsofInt.Med,2012:157(9)

Age-adjusted Mortality Rates of HIV and Hepatitis C: United States, 1999-2010


Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)

0

0.5

1

1.5

2

2.5

3

Repo

rted

cases/10

0,00

0po

pulatio

n

Year

0-19yrs

20-29yrs

30-39yrs

40-49yrs

50-59yrs

>60yrs


ProjectedCasesofHepatocellularCarcinomaandDecompensatedCirrhosisDuetoHCV

Davis GL, et al. Gastroenterology. 2010;138(2):513-521

1950 1960 1970 1980 1990 2000 2010 2020 2030Year

Num

ber o

f cas

es160,000

0

140,000

120,000

100,000

80,000

60,000

40,000

20,000

Decompensated cirrhosis

Hepatocellular cancer

Peak incidence:145,000 cases/year in 2020

Peak incidence:14,000 cases/year in 2019


PathogenesisofHIV/HCVCo-infection

cations in the setting of coinfection, are summarized inFig. 1 and described below.

HIV Disease Progression in the Setting of HCVCo-infection

Although most studies demonstrate increased mortalityamong co-infected individuals, a recent meta-analysis ofover 30 studies with over 100,000 patients found noincrease in mortality in co-infected patients in the pre-HAART era. Post-HAART, co-infection increased risk ofoverall mortality but not of AIDS-defining conditions [22].In contrast, an Italian cohort study found a twofoldincreased AIDS risk among co-infected patients [23]. TheWomen’s Interagency HIV Study (WIHS) found an almosttwofold increased AIDS risk among co-infected womenwithout a CD4 count <200 cells/μL and for ART-naïvewomen [24••]. The Italian cohort showed increases inbacterial and mycotic infections and WIHS found increases

in bacterial pneumonia, HIV encephalopathy, and wastingsyndrome, suggesting the need for earlier and moreaggressive HIV and HCV treatment in co-infected individ-uals [23, 24••].

Recent studies found high levels of T-cell activation inco-infected compared to HIV monoinfected individualseven following HAART [24••, 25, 26]. Chronic immuneactivation may lead to immune dysfunction and cytokineproduction, causing enhanced HIV and HCV replicationand lower T-cell counts [25]. The WIHS study showed thathigh levels of activated CD8 T cells are associated withincident AIDS among HCV-viremic women but not HCV-uninfected women, and CD4 activation predicted AIDS inboth groups [24••, 25]. Suppression of HCV with therapyreduces activation [26]. These results again support earlytreatment of HIV and HCV.

Several pathways for active HCV infection impactingHIV infection have been proposed (Table 1). HCV co-infection may increase immune activation, leading to CD4T-cell apoptosis in HIV-untreated patients and more rapid

Fig. 1 Pathogenesis of HIV/HCV co-infection: Immune activation and dysregulation, effects on HIV and HCV disease progression, andcomplications in multiple organ systems

Curr HIV/AIDS Rep (2011) 8:12–22 13


RiskFactorsAssociatedwithFasterFibrosisProgressioninChronicHCV

Poynard A.AntivirTher.2010;15(3):281-291;Poynard,etal.Lancet.1997;349(9055):825-832.

HCC

DiseaseStateFactorsHost/ViralFactors

• Malegender• Age• Obesity• Diabetes• Metabolicsyndrome• HIV,HBVco-infection• Immunesystemcompromise• Steatosis• Ironoverload• Genotype3

• Heavyalcoholconsumption• Tobaccouse

LifestyleFactors

• Fibrosisstage• Inflammationgrade• PersistentlyelevatedALT

CirrhosisNormalLiver


ExtrahepaticManifestationsofHCV

§ Mixedcryoglobulinemia§ Sjögren (sicca)syndrome§ Lymphoproliferativedisorders

§ Porphyriacutanea tarda§ Neuropathy§ Membranoproliferativeglomerulonephritis

§ Cryoglobulinemic vasculitis

§ Cornealulcers(Mooren ulcers)

§ Thyroiddisease§ Lichenplanus§ Pulmonaryfibrosis§ Type2diabetes§ Systemicvasculitis(polyarteritis nodosa,microscopicpolyangiitis)

§ Arthralgias,myalgias,inflammatorypolyarthritis

§ Autoimmunethrombocytopenia

AdaptedfromAliA,Zein NN.CleveClinJ Med. 2005;72:1005-1008.

Strongly associated Possibly associated


STEP1:SCREENING

-HCVSCREENINGATENTRYINTOCARE(A1)AND….RecommendationforHCVTestingforPersonsWithOngoingRiskFactors

RECOMMENDED RATING

AnnualHCVtestingisrecommendedforpersonswhoinjectdrugsandforHIV-infectedmenwhohaveunprotectedsexwithmen.

PeriodictestingshouldbeofferedtootherpersonswithongoingriskfactorsforHCVexposure.

IIa,C

www.hcvguidelines.orgpril 28, 2016.


Mr HK• 58y/oAAMwellcontrolledHIV+/HCV+.Newtoyourpractice.Hyperlipidemia,DM.HCV- treatmentnaïve.

• Socialhx:hashistoryofrecreationalmarijuanauseandoccasional“otherdrugs”;deniessignificantetoh

• Meds:Darunavir/cobi+Dolutegravir+FTC/TDF,Metformin,atorvastatin,pantoprazoleforheartburn

• PE:normal• Labs:ALT45,AST78,TB1.8,GFR90.Plts 138K• Imaging:ultrasoundshowshyperechoicliverconsistentwithsteatosis• Has“great”privateinsuranceandwantstostartHCVtherapyASAP


Case(cont’d)

• ViraltestingisdoneforpatientandhisHCVRNAis3.2millionIU/ml

• HewantstreatmentforHCVbutwhatothercounselingdoyouneedtodo?


HCVguidelines.orgRecommendations for Counseling Those with Current (Active) HCV Infection

RECOMMENDED RATING

Personswithcurrent(active)HCVinfectionshouldreceiveeducationandinterventionsaimedatreducingprogressionofliverdiseaseandpreventingtransmissionofHCV. IIa,B

1.Abstinencefromalcoholand,whenappropriate,interventionstofacilitatecessationofalcoholconsumptionshouldbeadvisedforallpersonswithHCVinfection. IIa,B

2.Evaluationforotherconditionsthatmayaccelerateliverfibrosis,includingHBVandHIVinfections,isrecommendedforallpersonswithHCVinfection. IIb,B

3.Evaluationforadvancedfibrosisusingliverbiopsy,imaging,and/ornoninvasivemarkersisrecommendedforallpersonswithHCVinfection,tofacilitateanappropriatedecisionregardingHCVtreatmentstrategyandtodeterminetheneedforinitiatingadditionalmeasuresforthemanagementofcirrhosis(eg,hepatocellularcarcinomascreening)(seeWhenandinWhomtoInitiateHCVTherapy).

I,A

4.VaccinationagainsthepatitisAandhepatitisBisrecommendedforallsusceptiblepersonswithHCVinfection. IIa,C

5.Vaccinationagainstpneumococcalinfectionisrecommendedtoallpatientswithcirrhosis(Marrie,2011). IIa,C

6.AllpersonswithHCVinfectionshouldbeprovidededucationonhowtoavoidHCVtransmissiontoothers. I,C


The AASLD/IDSA Recommendations for Patients with Active HCV

• Abstinence from alcohol• Evaluation for other conditions that may lead to fibrosis (e.g. HIV, HBV, NASH)• Evaluation for advanced fibrosis

– APRI, Fib4, imaging• Vaccination against HAV, HBV and pneumococcal infection (in patients with

cirrhosis)• Education on avoidance of transmission

Available at: www.hcvguidelines.org Accessed April 28, 2016.


STEP2:LINKAGETOCAREANDFIBROSISASSESSMENT

RecommendationforLinkagetoCare

RECOMMENDED RATING

AllpersonswithactiveHCVinfectionshouldbelinkedtoaclinicianwhoispreparedtoprovidecomprehensivemanagement. IIa


Whatmoreinformationdoyouneedbeforeyoutreathim?

• A.Confirmgenotypeandstarttreatmentsincehisinsurancecoversthepayment?

• B.Assessfibrosisseveritybeforetreatmentinitiation

• C.OrderbaselineresistancetesttocheckforRAVswithgenotypeorder


HCVRNApositive—Whatdoyouneedtoknow?• HCVGenotype• HepatitisBstatus- BsAg,cAb,sAb• Alcoholuse?• Activesubstanceuse?• Liverfibrosisseverity.• Ifcirrhotic-child’sclass.Compensatedordecompensated?• Priortreatmentexperience• Renalfunction• Medicationlist• Insurancestatus


Stateofhepc.org

Courtesy : NVHRNational Viral Hepatitis Roundtable. nvhr.org


FDAWarning:RiskofHBVReactivationinHCV-PatientsTreatedwithDAAs• 29casesfromNovember2013– Oct2016

• 2deaths,1livertransplant• Reactivationtypically4–8weeksafterHCVtreatmentinitiation• BaselineHBVcharacteristics:

• 9 +HBsAg andHBVDNA• 7 +HBsAg;undetectableHBVDNA.• 3HBsAgandHBVDNAnegative;presumedisolatedcore+• 10HBVtestingnotreported/available• HCVpatientsshouldbescreenedforHBVinfectionbeforestartingDAAtreatmentandshouldbemonitoredforHBVflare-upsorreactivationduringandfollowing treatment

FDA. Drug Safety Communication published –Ann Intern Med 2017; 166 (11):792-798


SuggestionsforchronicHBVManagement/Monitoring

1. +sAganddetectableHBVDNA• HBVtreatmentpriortoHCVtherapy

2. +sAg,undetectableHBVDNA• Closemonitoring(ALT/ASTq2weeks;HBVDNAmonthly)• Duration?

3. Isolatedcore+,HBVDNAnegative• Closemonitoring• Doubledosevaccine?

Slide courtesy of David L Wyles, MD.


Whataboutroutineresistancetesting?


MutationProtease(Linear)

Protease(Macrocyclic)

NS5AInhibitor

NS5BNucleoside

NS5BPalm

NS5BThumb

NS5BFinger Interferon Ribavirin

V36M

T54A

R155K

A156T

D168V

L28V

Y93H

S282T

C136Y

M414T

R422K

M423T

P495S

•HCV DrAG ResisSS. 2012;1.2. http://www.hivforum.org= Resistance mutation

Occurrence of Resistance Mutations


Regimen-SpecificRecommendationsforUseofRASTestinginClinicalPractice

RECOMMENDED RATING

Elbasvir/grazoprevirNS5ARAStestingisrecommended forgenotype1a-infected,treatment-naiveor-experiencedpatientsbeingconsideredforelbasvir/grazoprevir.Ifpresent,weight-basedribavirinshouldbeaddedandtreatmentshouldbeextendedto16weeks,oradifferentrecommendedtherapyused.

I,A

Ledipasvir/sofosbuvirNS5ARAStestingcanbeconsideredforgenotype1a-infected,treatment-experiencedpatientswithoutcirrhosisbeingconsideredforledipasvir/sofosbuvir.If>100-foldresistanceispresent,treatmentshouldinclude12weeksoftherapywithweight-basedribavirin,oradifferentrecommendedtherapy.

I,A

NS5ARAStestingcanbeconsideredforgenotype1a-infected,treatment-experiencedpatientswithcirrhosisbeingconsideredforledipasvir/sofosbuvir.If>100-foldresistanceispresent,treatmentshouldinclude24weeksoftherapywithweight-basedribavirin,oradifferentrecommendedtherapyused.

I,A

Sofosbuvir/velpatasvirNS5ARAStestingisrecommendedforgenotype3-infected,treatment-experiencedpatients(withorwithoutcirrhosis)andtreatment-naivepatientswithcirrhosisbeingconsideredfor12weeksofsofosbuvir/velpatasvir.IfY93Hispresent,weight-basedribavirinshouldbeadded.

I,A

Daclatasvir plussofosbuvirNS5ARAStestingisrecommendedforgenotype3-infected,treatment-experiencedpatientswithoutcirrhosisbeingconsideredfor12weeksofdaclatasvir plussofosbuvir.IfY93Hispresent,weight-basedribavirinshouldbeadded.

I,B

NS5ARAStestingisrecommendedforgenotype3-infected,treatment-naivepatientswithcirrhosisbeingconsideredfor24weeksofdaclatasvir plussofosbuvir.IfY93Hispresent,treatmentshouldincludeweight-basedribavirin,oradifferentrecommendedtherapyused.

I,B


ImportanttoAssessSeverityofLiverDisease

• Liverbiopsy:veryinfrequentlydonesince2014

• Fibroscan:transientelastography

• Fibrotest/Fibrosure:biochemical

• MRelastography• Determiningfibrosislevelisimportantasitmayaffectdurationoftreatmentand

determinestheneedforHCCscreeningpost-cureMR = magnetic resonance; HCC = hepatocellular carcinoma.


ImportanceofAssessingFibrosisinHepatitisCTreatment

• Determinesurgencyoftherapyforsomepayors• Selectspatientsinneedofadditionalscreeningwithcirrhosis

– Varices– Hepatocellularcarcinoma

• Allowsforselectionofpropertreatmentplananddurationoftherapy• Maybeusedbymanypayorsasawaytorestrictaccesstotherapyortoprioritizetherapy


StandardLabTestsSuggestingCirrhosis

• AST:ALTratio>1

• Elevatedtotalbilirubin >2mg/dL

• INR>1.5

• Plateletcount<125,000/μL

Note: If the AST:ALT ratio > 2, then alcohol-related liver injury is likely!


•Clinical Calculators•CTP Calculator•APRI Calculator•BMI Calculator•CrCl Calculator•FIB-4 Calculator•Glasgow Coma Scale•GFR Calculator•MELD Calculator•SAAG Calculator•Substance Use Screening Tools•AUDIT-C Questionnaire•CAGE Questionnaire

https://www.hepatitisc.uw.edu/page/clinical-calculators


Howdoyouassessfibrosisseverityinyourpractice?

• A.Transientelastography (Fibroscan)• B.Serumbiomarkers- fibrotest/fibrosure• C.MRelastography• D.Liverbiopsy• E.Donotroutinelyassessfibrosis




LiverStiffnessMeasurement(LSM)RangesinChronicLiverDisease

METAVIRScore

F0– F1 F2 F3 F4

Liver Fibrosis

Mild Moderate Severe Cirrhosis

LSM 2.5– 7.0kPa à MildorabsentfibrosisislikelyLSM>12.5kPa à Cirrhosisislikely

2.5 7.0 9.5 12.5 12.5 kPa

Castera L, et al. J Hepatol. 2008;48(5):835-847



Fibroscan results


InvasiveandNoninvasiveFibrosisTestsLiverBiopsy SerumMarkers TransientElastography MRE

Methodology Directobservation Measuresdirectandindirectserummarkers*offibrosis

Liverstiffnessbydetectionofultrasound-propagatedshearwaves

LiverstiffnessbyMRIofvibration-propagatedshearwaves

Accuracyfordetectingcirrhosis High Moderate(APRI)tohigh(FibroSURETM,ELF)

High High

Accuracyfordetectingintermediatefibrosis

High Low(APRI)tomoderate(FibroSURETM,ELF)

Moderatetohigh High

Riskofcomplications Riskofpain/bleeding Minimal Minimal Minimal

Contraindications Coagulopathy Minimal Obesity;narrowribspaces Claustrophobia;otherMRIcontraindications

Limitations SamplingerrorObservervariation

False-positiveswithhemolysis,inflammation,Gilbert’ssyndrome

False-positiveswithinflammation,congestion

False-positiveswithinflammation,congestion

Longitudinalmonitoring Unsuitable Indicesmaychangewithdiseaseprogression/therapy

Liverstiffnesschangeswithdiseaseprogression/therapy

Liverstiffnesschangeswithdiseaseprogression/therapy

Cost Highestper-testcost Lowper-testcost Highinitialequipmentcost Veryhighinitialequipmentcost

NguyenD,TalwalkarJA.Hepatology.2011;53:2107-2110.

*Serumteststhatincorporatemarkersoffibrogenesis aregenerallymoreaccurate.APRI=AST-to-plateletratioindex;AST=aspartateaminotransferase;ELF=enhancedliverfibrosis;MRE=magneticresonanceelastography,MRI=magneticresonanceimaging.


IndirectSerumTestsforFibrosisTest TestComponents Sensitivity

(%)*Specificity

(%)*PPV(%)*

NPV(%)*

CirrhosisDiscrimination

FibrosisDiscrimination

AST/ALTratio1 AST,ALT 53 100 100 81 + –

APRI2 AST/plateletcount 77 72 70 79 + +/– (moderate)

FIBROSpect II®3,4 HA,TIMP-1,a2-macroglobulin 72 74 61 82 + +

FibroSURETM5,6

•FibroTesta2-macroglobulin,haptoglobin,ApoA1,GGT,totalbilirubin,ALT 84 95 76 91 + +

HepaScore®7 Age,gender,bilirubin,GGT,HA,g2-macroglobulin 77 70 71 77 + +

ELF8 HA,N-terminalpropeptide oftypeIIIcollagen,TIMP-1 86 62 80 70 + +

1.Sheth SG,etal.AmJGastroenterol.1998;93:44-48;2.LinZHetal.Hepatology.2011;53:726-736;3.ZamanA,etal.AmJMed.2007;120:280.e9-e14;4.www.prometheuslabs.com/Resources/Fibrospect/Fibrospect_II_Product_Detail.pdf;5.Poynard T,etal.CompHepatol.2004;3:8;6.www.labcorp.com/.EdosPortlet/TestMenuLibrary?libName=File+Library&compName=L1080;7.Guéchot J,etal.Clin Chim Acta.2010;411:86-91;8.Guéchot J,etal.Clin Chem LabMed.2012;50:693-699.

ALT=alanineaminotransferase;ApoA1=apolipoprotein A1;GGT=gamma-glutamyl transpeptidase;HA=hyaluronicacid;NPV=negativepredictivevalue;PPV=positivepredictivevalue;TIMP-1=tissueinhibitorofmetalloproteinase.*Sensitivity,specificity,PPV,andNPVvaluesareforsignificantfibrosis,withtheexceptionofAST/ALTratio,wherethevaluesareforcirrhosis.


DetectionofCirrhosis:TransientElastography versusFibroTest &AST-PlateletRatioIndex(APRI)

TransientElastography

FibroTest(FibroSURE) APRI

Cut-off value ≥ 12.5kPa ≥ 0.75 ≥ 1.0

AUROC(95%CI) 0.92(0.86-0.98) 0.78 (0.66-0.89) 0.73 (0.58-0.88)

Sensitivity(%) 76.9 61.5 77

Specificity(%) 86.4 73.8 72.8

PositivePredictiveValue(%) 41.7 22.9 26.3

NegativePredictiveValue(%) 96.7 93.8 96.2

Correctlyclassified(%) 85.3 72.4 68.1

Castera,HIVMed.2014;15:30-39.


ChoosingaRegimen2018

• Youmaynothaveachoice:thechoicemaybemadebythepayors• Decidingfactors

– SVRrates– all>95%,similaramongexistingregimens– Durationoftherapy– 8-12weeksnaïve,longerforcirrhosispatientsandnon-responders– Impairedrenalfunction(GFR,30ml/min);Protease/NS5ainhibitorsmaybeusedsafely– Genotype alsoguidesthechoiceofregimen


Case(cont’d)• Hegetstransientelastography

– 15.4kPa (stage4fibrosis/cirrhosis)– GetsanEGD- novarices– Child’sAcompensatedcirrhosis

• Treatmentisinitiated– SVRachievedwith12weeksoftreatment– Repeatfibroscan postcureis11.0(stage3fibsosis)

• Whatelsedoyouneedtodoforhim?– Cancersurveillance


ScreeningEGDandfollowup

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/variceal-hemorrhage/


CirrhosisandHCCScreening

• CirrhosisisthemostimportantriskfactorfordevelopingHCCinpatientswithchronichepatitis Cinfection.

• Lesscommonly,HCCwilloccurinpatientswhohaveadvancedfibrosisbutwithout cirrhosis.

• TheAASLDpracticeguidelinesrecommendsurveillanceforHCCusingabdominal ultrasoundevery6 months forallHCV-infectedpatientswhohavecirrhosis(oradvancedfibrosis).

• SomeexpertsstillrecommendusingAFPinadditiontoultrasound,butitisstronglyrecommendednottouseAFPasthesolescreeningtool.


HCCScreening


PersistentElevationInALTPostCureofHCV

• ElevatedALTinpatientswithSVR:– 2-8%ofpatientstreatedwithPEGINF– 1%ofpatientstreatedwithoralanti-viraltherapy

• Whatcausesthis?– NAFLD,didtheygainweight?– Anotherco-existentliverdisease– Alcoholconsumption,isASTelevated?– ?re-infection,alwaysneedtoconsiderthis


KeyMessages–Needtoassessfibrosisstagepriortotreatmentinitiation–NeedforcontinuedHCCscreeningpostcurewithadvancedfibrosis(stage3and4).

– Indicationsforbaselineresistancetestingwelllaidout.– ScreeningforandmonitoringforHBVreactivationduringDAARx– ElevatedALTpostcure- ?NASH,?alcohol/meds?Re-infection–CounselingonreinfectionpostCureremainsimportant.–Visithcvguidelines.org OFTEN


Thanksforyourattention

Documents

ACTHIV 2018: A State-of-the-Science Conference for ... · 28/04/2016 · reduces activation [26]. These results again support early treatment of HIV and HCV. Several pathways for