Curing Hepatitis C:

Individualized Approach and

New Therapies

Lorenzo Rossaro, MD

Gastroenterology and Hepatology

University of California Davis Medical Center

Reprinted from Cohen J. Science. 1999;285:26.

HCV Infection:HCV Infection:Worldwide PrevalenceWorldwide Prevalence

c/o Liver Cancer (HCC)

HCV History: Outcome FactorsHCV History: Outcome FactorsA cu te H epa tit is

D ea th

D eco m p en sa tio n (6 % )

D ea th

H ep a to m a (4 % )

C irrh o s is (2 -3 0 % , 2 0 y r s)

C h ro n ic H epa tit is (8 5 % ) Male, Age,

3.6%

POSITIVE

ETOH HBV

HIV

Interferon + RibavirinTransplant

NEGATIVE

HCV Screening: HCV Screening: Who is at risk (%)Who is at risk (%) Blood product for clotting problems

produced 1987 (i.e.hemophilia) ~90

Injected illegal drugs (IVDU) 80 Long-term kidney dialysis 10Blood transfusion or solid organ

transplant July, 1992 6Born from HCV+ mother 5Tattoos, cocaine, body piercing ?

HCV: diagnosis and stagingHCV: diagnosis and stagingProposed Algorithm

1 Screening: (ALT) and HCV Antibody

2 Confirmation: HCV-RNA (not RIBA)

3 Predict success: HCV-Genotype

4 Refer to Liver Clinic and/or Request

Liver Biopsy (if appropriate)

Hepatitis C Genotype in U.S.:Hepatitis C Genotype in U.S.: Predict Response to TreatmentPredict Response to Treatment

36%

34%8%

9%8% 5%

1a 1b 2a 2b 3 4 BEST RESPONSE

Type 2

INTERMEDIATE RESPONSE

Type 3 and 4

LOWEST RESPONSE

Type 1

HCV: Severity of Liver DiseaseHCV: Severity of Liver DiseaseSymptoms and Liver “Function”

Tests: usually in late stagesALT levels: often normalUltrasound Examination: not

sensitive for fibrosis/staging Liver Biopsy: gold standardConsider fibrosis markers or

elastography

FibrospectFibrospectLow values (<20) indicative of

mild diseaseHigh values (>80) indicative of

advanced diseaseBetween 20 and 80: can be

anything

Assessing the Severity of Liver Assessing the Severity of Liver DiseaseDisease

LIVER BIOPSY The most accurate method of

determining disease severity and activity Disease severity = Fibrosis (stage: 1-4) Indicator of prognosis Helpful in guiding treatment options

Liver Biopsy by Stage

Cirrhosis

Mild Fibrosis

Treatment Response by Genotype and Duration of Therapy

0

20

40

60

80

100

IFN IFN+RBV PEG+RBV

HCV-1,4 = 48-72 wksHCV-2,3 = 24-48 wks

1987-1997

2002-2011

1998-2001

Hepatitis CHepatitis CThe Goals of TreatmentThe Goals of Treatment

1. Virus eradication = negative HCV-RNA six months after the end of treatment = CURE

2. Decrease progression of disease:1. from hepatitis to cirrhosis (or reverse ?)2. risk of cancer (Hepato Cellular

Carcinoma)3. need for liver transplant or retransplant

HCV: Who should be treated ?HCV: Who should be treated ?

Whoever is affected in some way by the chronic disease

AND

fully understands the risks and benefits of therapy

Side effects of InterferonsSide effects of InterferonsFLU-like symptoms (®Tylenol)Behavioral changes:

–Depression, IrritabilityMyelosuppression:

–Neutropenia–Thrombocytopenia

Skin, GI, Thyroid, Hair loss

Ribavirin:Ribavirin:Risk of TreatmentRisk of Treatment

Hemolytic anemia–Reversible–May require dose reduction or

erythropoietin in selected patientsPregnancy Risks

–Contrtraception required

SustainedResponder

Null Responder

RelapserRelapser

Partial Responder

HCV RNAnegative

Time (weeks)

HCV RNA

12 (EVR)

24 48 (EOT)

72 (SVR)

Patient Profiles During HCV Therapy

Adapted from:Davis GL, et al. Hepatology. 2003;38:645-652.Fried MW, et al. N Engl J Med. 2002;347:975-982. Sanchez-Tapias JM. Gastroenterology 2006;131:451-460

4(RVR)

RVR = HCV RNA (-) at week 4EVR = ≥2log10 drop in HCV RNA or HCV RNA (-) at week 12EOT = HCV RNA (-) at week 48 (genotype 1)SVR = HCV RNA (-) 24 weeks post treatment cessation

C

P

C = Complete EVR; P = Partial EVR

SVR with 48 wks PEG+RIBASVR with 48 wks PEG+RIBAand Patterns of Virological Responseand Patterns of Virological Response

(R=Rapid 4w, E=Early 12w, N=none, c=complete, p=partial)(R=Rapid 4w, E=Early 12w, N=none, c=complete, p=partial)

16%

42%

22%

20%

RVR

cEVRpEVR

NVRRVR 87%

cEVR 68%

pEVR 27%

NR 5%0%

10%20%30%40%50%60%70%80%90%

100%

SVRMarcellin P. AASLD 2007

272234-Day 1-9-On-Treatment Response (Shiffman)-v1 - 186/1/2008 8:15 PM

Slow To Respond PatientsExtending TherapySlow To Respond PatientsExtending Therapy

33

16

5246 44

69

0

20

40

60

80

Berg Sanchez Ferenci

48 weeks

72 weeks

Berg T et al. Gastroenterology. 2006;130:1086-1097; Sanchez-Tapias JM et al. Gastroenterology. 2006;131:451-460;Ferenci P et al. EASL. 2007.

RVN dose = 800 mg/d 800 mg/d 1000-1200 mg/d

Patients HCV RNA (-) after week 12

SV

R (

%)

Factors Associated with CureFactors Associated with Cure Viral

– Non-1 Genotype (2,3)– Lower Viral Load– Rapid/Early response

Disease related– No fibrosis/cirrhosis– Higher ALT– Lack of steatosis

Ribavirin dosage (~15 mg/kg)

Adherence– More than 80% of

intended treatment for > 80% of intended duration

Host Factors– Lower body weight– Younger age– Female gender– Race (non-AA, non-

Latino)

January 15, 2009

We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously

The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001).

January 15, 2009

New Studies for Hepatitis C at UC-Davis Fully enrolled*

Drug Patient Population Phase Sponsor

Protease * PEG+RBV

Naïve genotype 1

And Non Respond.3 Schering

Protease *

PEG+RBVNaïve geno 1 3 Vertex

Polymerase

PEG+RBVNaïve geno 1 2b

Roche/

Pharmassett

Protease

PEG+RBVNaïve geno 1 2b

Roche/

Intermune

New IM+RBV

No PEGRelapsers 2b Sciclone

Cyclophillin + * PEG

Non Responders 1 Novartis

NEW drugs for Hepatitis CNEW drugs for Hepatitis C

Will not be approved until 2011-2012 ?Improved efficacy with TRIPLE Rx (~70%)Ribavirin and IFN still platform 3-5 yrsAdded side effects: neutropenia,

lymphopenia, skin toxicitiesBreakthrough and resistance concernsHow many will pass phase 2 and 3 ?

Education for Health ChoicesEducation for Health ChoicesMoving Mountains

– Train Providers for “Hands on” management of liver disease

Leslie Benson (916) 717-5722

HCV UniversityHCV Universityhttp://www.hcvu.orgHCV University is a project of OASIS, a

not-for-profit community-based clinic located in Oakland, CA (Diana Sylvestre)

SummarySummary Hepatitis C is a serious disease Ask about risk factors and HCV Ab Confirm HCV-RNA and Genotype Consider treatment to cure and to halt

progression to cirrhosis and cancer Standard therapy: Pegylated

Interferons and Ribavirin Refer for Clinical Trials with New Rx

GI and Hepatology Clinical GI and Hepatology Clinical Research GroupResearch Group

Thank youThank you Thomas Amankonah Chris Bowlus Juan Carlos Garcia Valentina Medici Thomas Prindiville Lorenzo Rossaro Natalie Torok Shiro Urayama Mark Zern

Laura Lester (Supervisor) Annika Bryant Sandeep Dhaliwal Nicole Ekedahl Mia Minoletti Emanuel Obanor Nina Parks Elizabeth Pickett Monica Ruiz Ann Sanchez Yihey Yuk

How to refer for GI and Hep studiesHow to refer for GI and Hep studies

Laura Lester, NPPhone (916) 734-8696 Fax (916) 734-8666E-mail: laura.lester@ucdmc.ucdavis.edu

Nina Willis, MAPhone (916) 734-8942 Fax (916) 734-8850E-mail: nina.willis@ucdmc.ucdavis.edu