Real-World HIV and Liver Disease Cases · A.Retreat with glecaprevir-pibrentasvir 3 tablets daily...

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ACTHIV 2019: A State-of-the-Science Conference for Frontline Health ProfessionalsACTHIV 2019: A State-of-the-Science Conference for Frontline Health Professionals

ACTHIV 2019: A State-of-the-Science Conference for Frontline Health Professionals

Real-WorldHIVandLiverDiseaseCases

OluwaseunFalade-Nwulia,MBBS,MPHAssistantProfessor

DivisionofInfectiousDiseasesJohnsHopkinsUniversity

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FacultyandPlanningCommitteeDisclosuresPleaseconsultyourprogrambookorConferenceApp.

Thiscasediscussionmaycontaindiscussionofoff-labeluses.


LearningObjectivesUponcompletionofthispresentation,learnersshouldbebetterableto:

• Discusssomereal-worldHCVtreatmentissuesrelatedtochoiceofdirect-actingantiviral(DAA)therapyinHIV-HCVcoinfected patients

• IdentifyrelevantdruginteractionswithDAAsandantiretroviraltherapy

• RecognizethepotentialforadverseeventsinselectedpatientsundergoingDAAtherapy

• DiscusstreatmentofhepatitisCinpatientswithongoingsubstanceusedisorders

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HCVLifeCycleandDAATargets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6(12):991-1000.

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SOF

LED

GZR

EBRVEL

Protease NS3/ 4a inhibitors

NS 5A inhibitors

NS 5 B polymerase inhibitors

• Combination Therapies

• Preferred Regimens

–Pibrentasvir (PIB) + Glecaprevir (GLE) –(GT1, 2, 3, 4, 5, 6)

–Elbasvir (EBR) + Grazoprevir (GZR)–(GT1,4)*

Ledipasvir (LDV) + Sofosbuvir (SOF)(FDC, GT1,4,5,6)

RecommendedcombinationsoforalDAAasappliedtodifferentHCVgenotypes

–Velpatesvir (VEL) + Sofosbuvir (SOF)–(GT1, 2,3 ,4, 5, 6)

PIB

GLEVOX

–Velpatesvir (VEL) + Sofosbuvir (SOF) +–Voxilaprevir

–(GT1, 2,3 ,4, 5, 6)

VEL

Hcvguidelines.gov accessed 3/14/2019

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ChoosinganHCVregimen:Basedonvirusandpatientcharacteristics• HCVRNAlevel(<or>6millionIU/mL)(Onlyappliestonon-HIVinfected)• HCVgenotype;ifgenotype1,subtype1aor1b• eGFR (CMP)• Cirrhosis: YesorNo• Ifcirrhosis,CTPscore(albumin,bilirubin,INR),MELDandliverimaging• HBsAb,HBsAg,HBcAb total,HAVtotal• Concurrentmedications

– ART,PPIs,anti-seizuremedications,amiodarone

• PriorHCVtreatment:YesorNo


Mr.BØ 67yearoldAfrican-Americanman

withHIV,wellcontrolledonHAART;hypertension,diabetesandpriorinjectiondruguse.

Ø Oninitialreviewofmedicalrecord:Ø CD4:628,HIVRNA:<20copies/mLØ HCVantibody:reactiveØ HCVRNA5,654,567IU/mlØ HCVgenotype1AØ NopreviousHCVtreatmenthistory

Ø Medications:Ø Darunavir,800mgdailyØ Norvir,100mgdailyØ TDF/FTC,1tabletdailyØ Metoprol XL,50mgdailyØ Lisinopril,20mgdailyØ Metformin,500mgBIDØ Rosuvastatin,10mgdailyØ Omeprazole,20mgdaily

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67yearoldwithwellcontrolledHIV,HCVgenotype1a,HCVRNA5.6millionIU/ml

ØWhatHCVtreatmentregimenwouldyourecommend?

a.Elbasvir/grazoprevirfor12weeksb.Ledipasvir/sofosbuvirfor8weeksc.Glecaprevir/Pibrentasvirfor12weeksd. Ineedmoreinformationtorecommendaregimen


ChoosinganHCVregimen:Basedonvirusandpatientcharacteristics

• HCVRNAlevel(<or>6millionIU/mL)þ• HCVgenotype;ifgenotype1,subtype1aor1bþ

• eGFR (CMP)ý

• Cirrhosis: YesorNoý– Ifcirrhosis,CTPscore(albumin,bilirubin,INR)andliverimaging

• Concurrentmedicationsþ– PPIs,anti-seizuremedications,amiodarone,ART

• PriorHCVtreatment:YesorNoþ

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hcvguidelines.gov accessed 3/14/2019


Genotype1a:RecommendedregimensforpatientswithoutcirrhosisandnopriorHCVtreatment

a Includes genotype 1a resistance-associated substitutions at amino acid positions 28, 30, 31, or 93 known to confer antiviral resistance.


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Genotype1a:Regimensforpatientswithcirrhosis



STAGINGTOASSESSFORPRESENCEORABSENCEOFCIRRHOSIS

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Detectionofcirrhosisisimportant

ØRiskofhepaticdecompensationinpatientswithcirrhosisØ IncreasedriskoflivercancerwithcirrhosisevenafterHCVcureØ ImagingtoassessforhepatocellularcancerØOngoinghepatocellularcancerscreeningevery6months(lifelong)

Ø CirrhosismayimpactHCVtreatmentregimenanddurationØ Esophagogastroduodenoscopy(EGD)requiredtoscreenforvarices


RationaleforNS5ARAStestinginpersonswithgenotype1apriortoElbasvir/Grazoprevir

Zeuzeum S, et al. Ann Intern Med. 2015;163(1):1-13.

99% 100%90%

100%

22%

94%

133135

112112

910

11

29

1617

shift to EBR shift to EBR

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Rationaleforavoiding8weeksofLedipasvir/SofosbuvirinpersonswithHIVcoinfection

Wyles Detal.NEJM2015

ALLY-2 trial: Randomized controlled trial of sofosbuvir and daclatasvir


Rationalefor8weeksofGlecaprevir/Pibrentasvirinnon-cirrhoticpersonswithHIVcoinfection

• 8weeks:137patientswithHIVandnocirrhosis• 12weeks:16patientswithHIVandcirrhosis

Rockstroh J,etal.IAS2017.Abstract918

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Mr.B

Ø 67yearoldmanwithhypertension,diabetes

Ø AcquiredHIV/HCVthroughIDUØ CoronaryarterydiseaseØ Nopreviousevaluationor

treatmentforHCVØ ROS:+Fatigue

Ø SocialhistoryØ Drinks2-3beersdailyØ Noinjectiondruguseinover10years

Ø PE:+forcardiacmurmurØ Labs

Ø CD4628,HIVRNA<20copiesØ HCVRNA:5,654,567IU/mlØ HCVGenotype1aØ ALT48;AST90;plts 125k;INR1.2;Total

bilirubin1.2;Albumin3.3,Hb 13.6;Cr1.8eGFR 49ml/min/1.73mm3


EvaluationofliverdiseasewithserummarkersØ APRI

APRI > 1.0 76% sensitive, 72% specific for cirrhosis

FIB 4 >3.25 97% specificity for cirrhosis

ØFIB-4

http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp

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Transient Elastography


TransientElastography:HCV

2.5 kPa

Affectedbyweight,accessofprobe(2cm),steatosis

Mr B’s Fibroscan score: 12.6KPA

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Evaluationofliverdisease:Cirrhosis

Ø CompensatedØ Asymptomatic

Ø Decompensated-SymptomaticØ ascites,Ø encephalopathy

Child- Turcotte- Pugh score >7 Reports of fatality with use of NS3 protease inhibitors in patients with decompensated cirrhosis• Grazoprevir (GZR) + Elbasvir (EBR)• Glecaprevir/Pibrentasvir• Sofosbuvir/velpatasvir/voxilaprevir


CalculatetheCTPforallcirrhotics

http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp

Mr.B

Criteria Score

Noencephalopathy 1

NoAscites 1

Bilirubin:1.2mg/dl 1

Albumin:3.3g/dl 2

INR: 1.2 1

TotalScore 6

CTPClass A

Compensated Cirrhosis

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CrCl > 30ml/min• Nodosageadjustmentsrequiredfor

anyDAAs

CrCl <30ml/min• Sofosbuvirnotrecommended:

metaboliteGS-331007(half-life27hours)–unknowneffects

Patientswithadvancedkidneydisease



67yearoldwithHIV,genotype1aHCVwithcompensatedcirrhosis,eGFR 49onDRV/RTV,TDF/FTC

A. SendhimforlivertransplantevaluationB. ConsiderswitchinghisantiretroviralregimeninanticipationofHCV

treatment.C. Startelbasvir-grazoprevironetabletdailyfor12weeksD. Startglecaprevir-pibrentasvir3tabletsdailyfor8weeksE. Startledipasvir-sofosbuvironetabletdailyfor12weeks

Which of the following would you do next?

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ARVInteractionScoreCard

ØTreatment regimens for HIV/HCV infected patient identical to those recommended for HIV monoinfected patients

ØSpecial attention to drug interactions with HIV antiretrovirals



LDV/SOFwithTDF

• LDV/SOF+TDFincreasestenofovir plasmaconcentrations– GreatesteffectinpresenceofHIVritonavir-boostedPI’s,whichindependentlyincreasetenofovir levels

– AvoidcombinationofLDVandTDF• CrCl <60mL/min

• RTV-boostedPIs+TDF• ConsiderswitchingTDFtoTAF


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Drugs Elbasvir/Grazoprevir

Glecaprevir/Pibrentasvir

Sofosbuvir/Velpatsvir

Sofosbuvir/Ledipasvir

Daclatasvir +Sofosbuvir

StatinsAtorvastatin Max:20 mg/d statin; Avoid MonitorLovastatin Monitor statin; Avoid

Simvastatin Monitor statin; AvoidRosuvastatin Max:10 mg/d Max: 10mg Max:10 mg/d statin; Avoid

Pravastatin Monitor Reduce dose by 50%

Methadone

Proton pump inhibitors

Take DAA w/ food 4 hrsbefore PPI;

Max: omeprazole 20

mg/dor equivalent

Can be taken together;

Max: omeprazole 20

mg/dor equivalent

OthermajordruginteractionsoforalDAAs


Mr Bcontinued

• Insurancehasledipasvir/sofosbuvironformulary• AntiretroviralregimenwasswitchedtoDTGandTAF/FTC• ConfirmedundetectableHIVRNA,1monthafterARVswitchpriortoHCVtreatmentinitiation

• Tookledipasvir/sofosbuvirfor12weeks• HCVRNA<15IU/mlatendoftreatment• HCVRNA3,013,478IU/ml4weeksafterendoftreatment,HCVgenotype1a

• DeniedsubstanceuseorotherHCVexposure

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Inadditiontoadherencecounselling,whichofthefollowingwouldyoudonext?

A. Retreatwithglecaprevir-pibrentasvir3tabletsdailyfor12weeksB. Retreatwithledipasvir-sofosbuvironetabletdailyfor12weeksC. Retreatwithsofosbuvir-velpatasvirfor16weeksD. Retreatwithsofosbuvir-velpatasvir-voxilaprevirfor12weeks


TreatmentoptionsforNS5Aexperiencedpatients


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SOF/VEL/VOXinDAA-ExperiencedPatients

• 263DAA-experiencedpatientstreatedwithSOF/VEL/VOXfor12wks

• 46%withcirrhosis• 205/248(83%)withNS3orNS5ARAS

– RASsassessedbydeepsequencing(15%assaycutoff)

• HighSVRratesregardlessofpresenceofRAS

SVR12

199205

4243

Bourlière M, et al. N Engl J Med. 2017

SVR 97%

SVR98%

RAS present No RAS

Mr B got cured !


Mr.C

• 23yearoldwhitemalewithHIVinfectionwellcontrolledonDTG+TAF/FTC

• Transitionedfromoxycodonetoheroininteens• 3 previousinpatientrehabstaysforsubstanceusetreatment• Multiplepreviousreferralstooutpatientsubstanceusetreatment• Recentdischargefromsubstanceuserehab• HCVantibodynegative6monthsago

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WhatisyournextsteprelatedtoHCVtesting?

• A.Nothingadditional.Hegottested6monthsprior• B.TestforHCVantibodyandreassurehimthathedoesnothaveHCVifthattestcomesbacknegative

• C.TestforHCVantibodyandHCVRNA


Mr C

• 23yearoldwhoinjectsdrugs• HIVRNAundetectableonDTG+TAF/FTC

• HCVantibodynegative6monthsprior

• Recentdischargefrominpatientrehab3monthsprior

– HCVRNA6,060,000IU/mL– HCVgenotype3– PLT200K– INR1.0;Albumin3.5g/dL;AST52U/L(normal8-37)andALT40U/L(normal8-35).

– Cr0.8– Fibroscan 5.0KPA

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23yearoldwithwellcontrolledHIV,HCVgenotype3infection,nocirrhosis


a.Elbasvir/grazoprevirfor12weeksb.Ledipasvir/sofosbuvirfor8weeksc.Ledipasvirsofosbuvirfor12weeksd.Glecaprevir/Pibrentasvirfor8 weekse.Sofosbuvir/Velpatasvirfor8 weeks


Recommendedregimensforgenotype3patientswithoutcirrhosis

Hcvguidelines.org accessed 3/14/2019

a This is a 3-tablet coformulation. Please refer to the prescribing information.

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Glecaprevir/Pibrentasvirfor8weeksinpersonswithGT3andnocirrhosis(Endurance3RCT)

FosterGetal.EASL2017


SVR1

2(%

)

Overall

160/163 40/43 31/34 33/37 264/277

Cirrhosis No YesTreatment Naïve Treatment ExperiencedNo Yes

Only84%(21/25)withY93HachievedSVR12

3 relapse 3 relapse* 4 relapse1 relapse2 others

SOF/VELinGT3:SVR12byCirrhosisandTreatmentHistory(ASTRAL-3)

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C-EDGECO-STAR:EfficacyofGZR+EBRinPWIDreceivingopioidagonisttherapy(OAT)• Phase3,double-blindRCTinptsonOAT

for>3months– 20%withcirrhosis– 7%HIVcoinfected– 79%hadpositivedrugtoxicologyduringfollowup

52

EBR/GZRn=201

36D1 Wk4 12 282216

Un-blinding

Follow-upfor24weeks

Un-blinding EBR/GZR

8

Follow-upfor24weeksPBO

n=100

91.5 93.5 93.3 91.7

20.0

0

20

40

60

80

100

%SVR

12(9

5%CI)

SVR12 (Full Analysis Set, FAS)

DoreG,etal.AASLD2015,SanFrancisco.#40

All GT1a GT1b GT 4


Mr.C

• 23yearoldCaucasianmale• DiagnosedwithHCVininpatient

rehabheroinandalcohol• PresentedforHCVcare3months

later• HCVgenotype3,nocirrhosis• Referredtooutpatientaddiction

care• Startedonsofosbuvir/velpatasvir1

tabletdailyfor12weeks

Week4followup• Freshtrackmarks• Toxicology:+ve forheroin• Discussedneedforaddictioncare

andreferred• HCVRNAundetectableatweek8,

12andendoftreatment• HCVRNA5monthsafterEOT

60,325IU/ml• HCVgenotype1a

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Whichofthefollowingwouldyoudoatthatvisit?

A. TellthepatienthehaslosthischanceforHCVcureandcontinueHIVmanagement

B. Prescribesofosbuvir/ledipasvironetabletdailyfor12weeksC. Prescribeglecaprevir-pibrentasvir3tabletsdailyfor8weeksD. Linkpatienttoopioidagonisttreatment,syringeserviceprogram,

naloxonewithfollowupforHCVtreatmentdecision


Probability of positive urine toxicology heroin cocaine

Clinic-based

Referral to OTP

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24yearoldpersonwhoinjectsdrugswithHCVgenotype1reinfection,nocirrhosis• Prescribedbuprenorphine/naloxone• AddictioncounselingwithCaseManager• Cameinforweeklyvisits• Weeklyurinetoxicologyandbuprenorphine• UrineconsistentlypositiveforBuprenorphine/norbuprenorphine• Prescribedglecaprevir/pibrentasvir3tabletsdailyfor8weeks• Approvaldeniedbyinsuranceduetolowstageofliverdisease• Applyingforaccesstofreeglecaprevir/pibrentasvirthroughmanufacturerpatientassistanceprogram


Ms Q• 64year-oldfemalewithHIVCD4count350cells/mm3 andHIVRNA<20

copies/mL.

• ARVs:abacavir,dolutegravirandrilpivirine

• HistoryofTDFnephrotoxicity,M184V,andunabletotoleratePIs.

• HCVgenotype1b,HCVRNA5millionIU/ml

• FibroScan score8.8consistentwithF2fibrosis

• AST61,ALT52,INR1.0,Albumin4.0,Cr1.4• HBsAg negative,anti-HBc positive,IgManti-HBc negative,anti-HBsnegative

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Potentialcausesofisolatedanti-HBc

• ResolvedhepatitisBinfectionwithlossofanti-HBs– Anamnesticanti-HBsresponseafterHBVvaccination

• OccultchronicHBVinfectionwithlossofdetectableHBsAg– HBVDNA+

• AcuteHBVInfection– Anti-HBc IgMpositive,HBVDNA+

• Falsepositiveresult


64yearoldwithHCVgenotype1b,nocirrhosis,isolatedhepatitisBcoreab


a.Ledipasvir/sofosbuvirfor8weeksb.Ledipasvirsofosbuvirfor12weeksc.Glecaprevir/Pibrentasvirfor12weeksd.Sofosbuvir/Velpatasvirfor8 weeks

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Genotype1b:NocirrhosisandnopriorHCVtreatment


MsQ

Herinsurancehassofosbuvir/ledipasvirasthepreferredagent

Shereturns4weeksintotherapywithcomplaintoffatigue,irritabilityandmalaise.

Week4Labs:

Totalbilirubinis3.2,ALThasrisento365(from55)andAST250(from40).

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64yearoldonARVsinweek4ofLDV/SOFwithmalaiseandnewLFTelevationsWhichofthefollowingwouldyoudonext?

A. Discontinueledipasvir/sofosbuvirB. CheckHBVDNAC. DiscontinueARVD. SendHCVRNAanddecidewhatnextbasedonresult


HBVReactivationonDAATherapy• UnexpectedALTandASTelevations4-8weeks(mean53days)fromDAAinitiation– 2deathsand1livertransplantationreported– Casereportof29casesofHBVreactivation,13(45%)werechronicHBVcarriers(+HBsAg)

• Meta-analysisof17studies;1621(242chronic;1379resolved)HBVpts• HigherprevalenceinHBsAg +à 24%• VerylowprevalencewithresolvedHBV(anti-HBc+)à 1.4%

• FDAaddedblackboxwarningonriskofHBVreactivationtoalloralDAAs

https://www.fda.gov/Drugs/DrugSafety/ucm522932.htm,Mucke etalLancetGastroenterol hepatol 2018

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Conclusions

– Therearemultipleeffective,safeoptionsforHCVtreatmentandcure

–Genotype,cirrhosisstatus,andtreatmentexperiencemayaffectHCVtreatmentchoice

– SubstanceuseisnotacontraindicationtoHCVtreatment–Whenindoubtlookitup–hcvguidelines.org


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TreatmentofHCV

Thank you!

ACTHIV 2019: A State-of-the-Science Conference for Frontline Health ProfessionalsACTHIV 2019: A State-of-the-Science Conference for Frontline Health Professionals

Real-World HIV and Liver Disease Cases · A.Retreat with glecaprevir-pibrentasvir 3 tablets daily...

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