A Hepatitis C Primer for Non-Treaters

John F. Reinus, M.D.Medical Director of Liver TransplantationMontefiore-Einstein Center for TransplantationProfessor of Clinical MedicineAlbert Einstein College of Medicine

HCV infection: it’s personal

Risk factors for HCV infection

• Parenteralandintranasaldruguse

• Transfusionofinfectedbloodandbloodproducts(before1992)

• Otherneedlesticks:(amateur)tattoo;health-careworkers(surgeons);dialysis

• Analintercourse

Infectionrequiresviralpassagethroughprotectiveanatomicbarriers

Prevalence of hepatitis C: NHANESDenniston MM. Ann Intern Med. 2014;160:293-300

Time course of disease progressionHoofnagle JH. Hepatology. 2002;36:S21-S29.

0

200

400

600

800

1000

0 0.5 1 2 5 10 15 20 25 30 35 40 45 50

ALT

(U/L

)

Years After Exposure

ALT

HCV RNA (>75%)

Anti-HCV (100%)

Fibrosis

HCC

1+2+

3+4+

Cirrhosis

Annual HCV disease progression

• Compensatedcirrhosis,years1-13:0.6%

• Compensatedcirrhosis,year14+:2.3%

• Decompensation:4.0%

• CirrhosistoHCC:4-8%

• Transplantation:4.3%

Davis et al. Liver Transpl, 2003;9:331-338Hornberger et al. J Viral Hepat, 2006;13:377-386

Estimated prevalence of cirrhosisDavis et al. Liver Transpl, 2003;9:331-338

1,200,000

1,000,000

800,000

600,000

400,000

0

200,000

1990 2000 2010 2020 2030

Intheyear2020:• 39%ofHCV-infectedpersons• 1millionAmericanswillhavecirrhosis

AASLD & IDSA treatment guidelineswww.hcvguidelines.org

Hepatitis C virus life cycle

Generic-drug naming conventions

1. Proteaseinhibitors:namesendwith“PREvir,”e.g.simePREvir,paritaPREvir,grazoPREvir

2. Polymeraseinhibitors: namesendwith“BUvir,”e.g.sofosBUvir,dasaBUvir

3. NS5Ainhibitors: namesendwith“ASvir,”e.g.ledipASvir,velpatASvir,daclatASvir

FDA-approved all-oral treatment regimens for hepatitis C

1. Epclusa™:sofosbuvir/velpatasvir

2. Harvoni™:sofosbuvir/ledipasvir

3. Mavyret™:glecaprevir/pibrentasvir

4. Technivie™:paritaprevir/ombitasvir

5. ViekiraPak™:paritaprevir/dasabuvir/ombitasvir

6. Vosevi™:voxilaprevir/sofosbuvir/velpatasvir

7. Zepatier™:grazoprevir/elbasvir

Phase-3 trial: sofosbuvir/ledipasvirAfdhal, et al. NEJM, 2014;370:1889

Factors affecting treatment choice

• Insuranceapproval• Viralgenotype• Renalfunction• Presenceofcirrhosis,decompensation• Treatmenthistory=resistanceprofile• Potentialdrug-druginteractions

AASLD & IDSA treatment guidelineswww.hcvguidelines.org

AASLD & IDSA treatment guidelineswww.hcvguidelines.org

AASLD & IDSA treatment guidelineswww.hcvguidelines.org

Bioavailabilityofdrugsisdependentonfactorsthataltertheirmetabolism andintracellularconcentration through:

• InductionorinhibitionofCYP3A4(metabolizes>50%ofFDA-approveddrugsincludingmanyDAAs)

• Inductionorinhibitionofmembranetransporters[OATP,BCRP(ABCG2),P-gp (ABCB1,MDR1)]responsibleforcellularuptakeandeliminationoforganiccompounds

Thisisamutualeffectofdrugsoneachother:victimsandperpetrators

Drug-drug interactions:

Drug-drug interactions:Viekira Pak™ (steps 1-3)

Component Role Enzymes Transporters

Paritaprevir(ritonavir-boosted)

Victim SubstrateofCYP3A4 Substrateof P-gp,BCRPandOATP1B1

Perpetrator Inhibits multipleenzymes

InhibitsP-gp,BCRPandOATP1B1/3

OmbitasvirVictim SubstrateofCYP3A4 Substrateof P-gp

Perpetrator Inhibits multipleenzymes

DasabuvirVictim SubstrateofCYP3A4

and others Substrateof P-gp

Perpetrator Inhibits UGT1A1 Inhibits BCRP

Hepatitis C drug interactionswww.hep-druginteractions.org

Hepatitis C therapy: conclusions

• Simple• Welltolerated• Multipleoptions• Highlyeffective

Diagnoseandtreatpatientsbeforetheydevelopend-stageliverdiseaseandlivercancer