Clinical Experience: Difficulties in Clinical Trial Design for Therapeutic Products to Treat Chronic HCV Infection John M. Vierling, M.D., F.A.C.P. Professor.

Clinical Experience:Clinical Experience:

Difficulties in Clinical Trial Design forDifficulties in Clinical Trial Design for

Therapeutic Products to Treat Therapeutic Products to Treat

Chronic HCV InfectionChronic HCV Infection

John M. Vierling, M.D., F.A.C.P.John M. Vierling, M.D., F.A.C.P.

Professor of Medicine and SurgeryProfessor of Medicine and Surgery

Director of Baylor Liver HealthDirector of Baylor Liver Health

Chief of HepatologyChief of Hepatology

Baylor College of MedicineBaylor College of Medicine

Houston, TXHouston, TX

Chronic HCV InfectionChronic HCV Infection Ultimate Therapeutic GoalsUltimate Therapeutic Goals

HCV as vaccine-preventable diseaseHCV as vaccine-preventable disease

Safe and effective pharmacological cure for acute and chronic HCV infections resulting in:Safe and effective pharmacological cure for acute and chronic HCV infections resulting in:

Termination of hepatic and extrahepatic disease(s)Termination of hepatic and extrahepatic disease(s)

Dissolution of existing hepatic fibrosisDissolution of existing hepatic fibrosis

Reduction in incidence of associated diseases:Reduction in incidence of associated diseases:

Diabetes mellitusDiabetes mellitus

Non-Hodgkin B cell lymphomaNon-Hodgkin B cell lymphoma

Topic OutlineTopic Outline

Clearance of HCV: Lessons from HCV pathogenesisClearance of HCV: Lessons from HCV pathogenesis

Interferon and ribavirin mechanisms of action in SVRInterferon and ribavirin mechanisms of action in SVR

Relevance of prior clinical trials in the study of new therapeutic agentsRelevance of prior clinical trials in the study of new therapeutic agents

Selection of patient populations for clinical trials of new agentsSelection of patient populations for clinical trials of new agents

New clinical trialsNew clinical trials

DesignDesign

EndpointsEndpoints

HCV PathogenesisHCV PathogenesisInfection versus DiseaseInfection versus Disease

HCVHCV

HepatocytesHepatocytes

LymphocytesLymphocytes

Other Tissues:Other Tissues:Pancreas, Adrenal gland, Bone MarrowPancreas, Adrenal gland, Bone Marrow

HCVHCV

Not cytopathic Not cytopathic for hepatocytesfor hepatocytes

B cells T cells

Immune ResponseImmune Response

Infects different cells

Minimal Minimal FibrosisFibrosis

AdvancedAdvancedFibrosisFibrosis

Natural History of HCV InfectionNatural History of HCV Infection

AcuteHepatitis C

AcuteHepatitis C

Spontaneous Resolution• Anti-HCV+• RIBA+• HCV RNA-

Spontaneous Resolution• Anti-HCV+• RIBA+• HCV RNA-

CirrhosisCirrhosis CirrhosisCirrhosis

ALTALT ALTALT

Chronic InfectionAnti-HCV+HCV RNA+

Chronic InfectionAnti-HCV+HCV RNA+

BiochemicalBiochemicalOutcomeOutcome

HistologicalHistologicalOutcomeOutcome

85%85% 15%15%

75%75% 25%25%

20%20% 2%2%

Key Role for liver biopsyto detect progressivefibrosis

Viremia

Fattovich G, et al. Gastroenterology. 1997;112:463.

%%

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

CompensatedCompensated

DecompensatedDecompensated

0

10

20

30

40

50

0 1 2 3 4 5 6 7 8 910

YearsYears

HCCHCC

Decompensation*Decompensation*

%%

YearsYears

*60% ascites; *60% ascites; 25% variceal bleeding25% variceal bleeding

Natural History of Hepatitis C CirrhosisNatural History of Hepatitis C CirrhosisAnnual Rates of HCC, Decompensation and DeathAnnual Rates of HCC, Decompensation and Death

Class IIClass IIHLAHLA

Immunopathogenesis of HCV InfectionImmunopathogenesis of HCV InfectionT Cell Activation to HCV AntigensT Cell Activation to HCV Antigens

Immune ResponseImmune Response VigorousVigorous PolyclonalPolyclonal Multispecific Multispecific

Class IClass IHLAHLA

CD8

CD4

HCVHCV Core 21-40Core 21-40 NS3 1253-1272NS3 1253-1272 NS3 1767-1286NS3 1767-1286 NS4 1909-1229NS4 1909-1229

AntigenPresentingCell

Immunopathogenesis o f HCV InfectionImmunopathogenesis o f HCV Infection Dynamic Balance of CD4 T-Helper Cells Dynamic Balance of CD4 T-Helper Cells

IL-12IL-12

TGF TGF , IL-10, IL-10??

GreaterGreaterImmunopathologyImmunopathology

LesserLesserImmunopathologyImmunopathology

TregTreg

Th1Th1 Th2Th2

IL-2, TNF IL-2, TNF //, IFN , IFN IL-4, IL-5,IL-4, IL-5,IL-6, IL-10IL-6, IL-10

IFN IFN

IL-4IL-4

APCAPC

MHC Class IIMHC Class IIHCV Peptide AntigenHCV Peptide Antigen

CD4CD4

Th0Th0

TCR/CD3TCR/CD3

Immune-Mediated Clearance of HCVImmune-Mediated Clearance of HCV

CD8CD8 TCRTCR

Class I MHCClass I MHC

HCV-InfectedHepatocyte

TNF TNF IFN IFN

ClearanceClearanceof Infectedof InfectedHepatocytesHepatocytes

ApoptosisApoptosis

CTLCD8

Immune-Mediated Clearance of HCVImmune-Mediated Clearance of HCV

CD8CD8 TCRTCR

Class I MHCClass I MHC


TNF TNF IFN IFN

IneffectiveIneffectiveClearanceClearanceof Infectedof InfectedHepatocytesHepatocytes

ApoptosisApoptosis

CTLCD8

HCV antagonismHCV antagonismpromoting viralpromoting viralpersistence persistence

HCV Therapy with InterferonHCV Therapy with Interferon Dual Mechanisms of Biphasic HCV KineticsDual Mechanisms of Biphasic HCV Kinetics

–3

–2.5

–2

–1.5

–1

–0.5

0

Daily IFNDaily IFNDaily IFNDaily IFN

0 7 14DaysDays

Mea

n L

og

Mea

n L

og

1010 H

CV

RN

A H

CV

RN

A

Inhibition of HCV Replication

Immunological Clearance HCV Infected Cells

HCV InfectionAntiviral Mechanism of Action of Interferon-α

InfectedHepatocyteHCV

IFNα

IFNα-TreatedHepatocyte

IFNα

IFNα

IFNα

IFNαIFNα

IFNα

α/

HCV Replication

IFNα

JakSTATIRF9

IFN Regulated Proteins

ISGF-3

Exogenous IFNα

α/

HCV InfectionAntiviral Mechanisms of Action of Interferon-α

Protein Kinase PKR

eIF-2α P-eIF-2α

Inhibit mRNATranslation

2’,5’OASi

2’,5’OASa

2’,5’OAA

RNase L RNase L

AdenosineDeaminase

ADAR1

RNAEditing

RNA Degradation

Protein GTPase Mx

TargetNucleocapsids

+Inhibit RNASynthesis

HCV InfectionHCV InfectionInterferon-Interferon- Effects on NK and Th1 Cells Effects on NK and Th1 Cells

IL-12IL-12

ImmunopathologyImmunopathologyFibrogenesisFibrogenesis

ImmunopathologyImmunopathology

Th1Th1 Th2Th2


IFNIFN IL-4IL-4

DendriticDendriticCellCell

MHC Class IIMHC Class IIHCV HCV AntigenAntigen

CD4CD4

Th0Th0

TCR/CD3TCR/CD3

HCVHCVInfectedInfected

CellsCells

NKNKIFNIFN

HCV Infection?HCV Infection?

HCV InfectionHCV InfectionAntagonism of INFAntagonism of INFαα Effects Effects

E1 E2E1 E2 NS2NS2 NS3NS3 NS4NS4 NS5NS55’5’

CC3’3’

HCV-SpecificCTL

InhibitNK

Functions(CD81)

Antagonize PKR Functions• Antiproliferation• Phosphorylation-eIF-2α• Maintenance of cellular proteins• Apoptosis

HCV InfectionHCV InfectionInterferon-Interferon- Inhibition of Hepatic Fibrosis Inhibition of Hepatic Fibrosis

Antifibrotic Mechanisms mRNA Expression:

TGF- Procollagen type I Procollagen III Procollagen IV

Serum Levels: Procollagen type III peptide Hyaluronate TIMP-1

mRNA Expression: Collagenase MMP

Collagen

Cytokine-ActivatedStellate Cell

FenestratredEndothelial Cells

HCV-InfectedHepatocytes

Putative Mechanisms of Action of RibavirinPutative Mechanisms of Action of Ribavirin

Antiviral

ImmuneModulation Anti-Fibrotic

?

HCV Infection Ribavirin Antiviral Mechanisms


HCV Replication

IFN Regulated Proteins

ISGF-3

RBV

RTPRDPRMP

RBV

RTP Inhibition: NS5B RNAdRNAp BVDV NS5B RNAdRNAp HCVRBV Mutagenic for: Poliovirus HGVRMP Inhibits IMPDHNo Effect of RBV on: NS3 protease RNA helicase/NTPase 5’-IRES

PurineSynthesis

RMP

IMPDH purinesalvage

HCV InfectionHCV InfectionInteraction of Interferon-Interaction of Interferon- and Ribavirin and Ribavirin

IL-12IL-12



Th1Th1 Th2Th2


IFNIFN IL-4IL-4

MHC Class IIMHC Class IIHCV HCV AntigenAntigen

CD4CD4

Th0Th0

TCR/CD3TCR/CD3

HCVHCVInfectedInfected

CellsCells

NKNKIFNIFN

RBVRBV

RBV InhibitionRBV InhibitionTNFTNF, IL-1, IL-1

DendriticDendriticCellCell

HCV Infection?HCV Infection?

HCV Therapy with Interferon RegimensSustained Virological Response (SVR)

RResponse esponse to Continuedto Continued

TreatmentTreatment

Adapted from Pawlotsky JM, Hepatology vol. 32, #5, 2000

HC

V R

NA

InitialIFN-BasedTreatment

SVR Durable (“cure”)

212/217 (98%) HCV RNA (-) 5/217 ( 2%) HCV RNA (+)

4/5 liver 1/5 PBMC

LLD

Post-TreatmentPost-TreatmentObservationObservation

HCV Therapy with Interferon RegimensFour Patterns of Non-Response

““Breakthrough”Breakthrough”

RelapseRelapse

““Non-response”Non-response”

RResponse esponse to Continuedto Continued

TreatmentTreatment

Adapted from Pawlotsky JM, Hepatology vol. 32, #5, 2000

HC

V R

NA

InitialIFN-BasedTreatment

““Nonresponse”Nonresponse”Based on EVRBased on EVR

LLD

Post-TreatmentPost-TreatmentObservationObservation

Chronic HCV InfectionChronic HCV InfectionGenotype Distribution in the U.S.A. Genotype Distribution in the U.S.A.

(N = 6807) (N = 6807)

Blatt LM, et al, J. Viral Hepatitis. 2000;(3):196-202.

44

3a3a

2b2b

2a2a

1b1b

1a1a

1a

1b

2b2a

3a

4 3b3b

3b

HCV Therapeutic TrialsHCV Therapeutic TrialsLiver Biopsy Stratification and as EndpointLiver Biopsy Stratification and as Endpoint

Assessment: Grade: Inflammation Stage: Fibrosis (1-4) Significant change >1 or 2?Caveats: Adequate specimens required:

8-10 portal tracts 16 gauge needle Aspiration biopsy better than “gun”

Optimal timing of before and after comparison (6-18 months):

T1/2 inflammatory infiltrates Conversion from fibrogenesis to

collagenase activity

Non-Response to HCV TherapyNon-Response to HCV TherapyRelated to Combination of Viral and Host FactorsRelated to Combination of Viral and Host Factors

0

20

40

60

80

100

Genotype Viral Load Weight (kg) Fibrosis

SV

R (

%)

Data from:Manns MP et al. Lancet. 2001;358:958.Fried MW et al. N Engl J Med. 2002;347:975.FDA Antiviral Drug Products Advisory Committee, 2002.

79

45

70

47

62

41

57

44

2/3 1 Lo Hi <75 >75 F0/1 F3/4

11 55 30 53 48 59 43 56

Non-response (ITT)%

91

72

60

4843

0

20

40

60

80

100

HCV RNA HCV RNA Week 4Week 4 Negative Negative >>2 log 2 log <2 log <2 log >>2 log 2 log <2 log <2 log Week 12Week 12 Negative Negative Negative Negative Negative Negative >>2 log 2 log >>2 log 2 log Week 24Week 24 Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative

Pat

ien

ts w

ith

aP

atie

nts

wit

h a

Vir

olo

gic

Res

po

nse

(%

)V

iro

log

ic R

esp

on

se (

%)

Ferenci P et al. J Hepatol 2005; 43: 425-33.

Interferon-Ribavirin for Chronic HCV InfectionEVR Predicts Probability of SVR

Therapy for Chronic HCV InfectionTherapy for Chronic HCV InfectionResponse Predicted by AdherenceResponse Predicted by Adherence

424248485151

6363

3434 3434

00

2020

4040

6060

8080

100100PEGPEG-2b 1.5 -2b 1.5 g/kgg/kg + Ribavirin 800 mg+ Ribavirin 800 mg

PEG PEG -2b 1.5 -2b 1.5 g/kgg/kg+ Weight-Based Ribavirin+ Weight-Based Ribavirin

SV

R (

%)

SV

R (

%)

McHutchison JG et al. Gastroenterology. 2002;123:1061.

OverallOverallAdherentAdherentNonadherentNonadherent

Effect of Effect of 80-80-80 Adherence on SVR80-80-80 Adherence on SVR

PP=0.034=0.034 PP=0.011=0.011PP=0.046=0.046 PP=0.008=0.008

Interferon-Ribavirin for Chronic HCV InfectionInterferon-Ribavirin for Chronic HCV InfectionDifferences in SVR for African Americans and CaucasiansDifferences in SVR for African Americans and Caucasians

10

4246

40

2822

6574

70

52

0

10

20

30

40

50

60

70

80

90

100

4 12 24 48 SVR

% U

nd

etec

tab

le H

CV

RN

A (

<50

IU

.mL

)

African Americans

Caucasian Americans

p 0.0014 <0.0001 <0.0001 <0.0001 <0.0001

Conjeevaram HS, et al. Gastroenterology 2006; 131: 470-7

HCV-HIV Co-InfectionHCV-HIV Co-InfectionAdverse Effect on SurvivalAdverse Effect on Survival

0 500 1000 1500 2000

0.00

0.25

0.50

0.75

1.00

HCV+HCV+

HCV–HCV–

Kap

lan-

Mei

er

Kap

lan-

Mei

er

Sur

viva

l Est

imat

esS

urvi

val E

stim

ates

Analysis Time (Days)Analysis Time (Days)

Sulkowski MS, et al. 8th CROI, Feb. 4-8, 2001, Chicago, Ill; abstract 34.

ES

LD-R

elat

ed D

eath

s (%

)E

SLD

-Rel

ated

Dea

ths

(%) 19911991

19961996

19981998

50

40

30

20

10

0

11111414

5050

Bica I, et al. Clin Infect Dis. 2001;32:492.

CD4 Counts: 50-250/mmCD4 Counts: 50-250/mm33

CD4 Counts: 55% withCD4 Counts: 55% with>200/mm>200/mm33 6 mos prior to 6 mos prior to deathdeath

1417

29

38

73

44

62

53

12

39

25

15

0

10

20

30

40

50

60

70

80

90

100S

ust

ain

ed V

iro

log

ical

Res

po

nse

(%

)

Genotypes 1, 4

Genotypes 2, 3

Discontinuation

ACTG 5071 RIBAVIC APRICOT Barcelona

Reviewed in: Stribling R, et al. Gastro Clin NA 2006; 35: 463-86.

HCV-HIV Co-InfectionDecreased Response to Interferon-Ribavirin Therapy

Recurrent HCV Infection Post-OLTAccelerated Progression and Increased Mortality

2%HCV-

99%HCV+

2-5% SevereCholestatic

Hepatitis

30-50% Minimal

Liver Injury

40-60%Hepatitis

10-30%Cirrhosis

5 yrs

42%Decompensated

1 yr

Risk Factor(s)? HCV Replication Th2 Response

Risk Factors Host-Donor HCV Replication Immunosuppression

ACR Pulse steroids OKT3

??% Delayed

Liver Injury

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5

Follow-Up (Years)Pe

rcen

tage

of P

atie

nts

Surv

ivin

g

Non-HCV n=6,597

HCV n=4,439

p< 0.0001

Forman LM et al. Gastroenterology 2002; 122: 889-96Forman LM et al. Gastroenterology 2002; 122: 889-96Braun M and Vierling JM. Liver Transpl 2003; 9: S79-S89Braun M and Vierling JM. Liver Transpl 2003; 9: S79-S89

Candidates for Clinical Therapeutic TrialsCandidates for Clinical Therapeutic Trials

Treatment-naïve patients at risk for progression*Treatment-naïve patients at risk for progression* Chronic HCV infection with detectable HCV RNAChronic HCV infection with detectable HCV RNA Elevated ALTElevated ALT Active inflammation by liver biopsyActive inflammation by liver biopsy Absence of contraindicationsAbsence of contraindications

Treatment-experienced patients not achieving SVR:Treatment-experienced patients not achieving SVR: Relapsers from ETRRelapsers from ETR Non-responders discontinued due to absence of EVR Non-responders discontinued due to absence of EVR Non-responders with absence of any virological responseNon-responders with absence of any virological response Non-responders with breakthrough after EVRNon-responders with breakthrough after EVR

Special populations:Special populations: Children Children Co-infection with HIV or HBVCo-infection with HIV or HBV Decompensated cirrhosisDecompensated cirrhosis OLT PatientsOLT Patients

Pre-OLTPre-OLT Recurrent hepatitis C post-OLT Recurrent hepatitis C post-OLT

Extrahepatic diseasesExtrahepatic diseases

*2002 NIH HCV Consensus Conference, Hepatology 2002

Candidates for Clinical Therapeutic TrialsCandidates for Clinical Therapeutic TrialsPriority RankingPriority Ranking

Treatment-naïve patients at risk for progressionTreatment-naïve patients at risk for progression Chronic HCV infection with detectable HCV RNAChronic HCV infection with detectable HCV RNA White, Black, LatinoWhite, Black, Latino Elevated ALTElevated ALT Stratified on basis of Stratified on basis of

Genotype: 1, 2, 3 highest priority due to frequency in U.S.A.Genotype: 1, 2, 3 highest priority due to frequency in U.S.A. Histopathology Histopathology

Grades 1-4Grades 1-4 Stage 0-4Stage 0-4

Treatment-experienced patients not achieving SVRTreatment-experienced patients not achieving SVR Non-responders documented at 12, 24 or 48 wks of therapyNon-responders documented at 12, 24 or 48 wks of therapy Relapsers with documented ETRRelapsers with documented ETR White, Black, LatinoWhite, Black, Latino

Special populationsSpecial populations Co-infection with HIV > HBV: Treatment-naïve or -experiencedCo-infection with HIV > HBV: Treatment-naïve or -experienced Decompensated cirrhoticsDecompensated cirrhotics Orthotopic liver transplantationOrthotopic liver transplantation

Pre-OLTPre-OLT Recurrent hepatitis C post-OLT Recurrent hepatitis C post-OLT

Chronic renal failureChronic renal failure

Candidates for Clinical Therapeutic TrialsCandidates for Clinical Therapeutic TrialsStudy DesignStudy Design

Treatment-naïve patients at risk for progressionTreatment-naïve patients at risk for progression Proof of short-term monotherapy effect: Proof of short-term monotherapy effect: Log Log1010 HCV RNA) HCV RNA) Assessment of resistance to short-term monotherapyAssessment of resistance to short-term monotherapy Randomized, placebo controlled trial for superiority, non-inferiorityRandomized, placebo controlled trial for superiority, non-inferiority

PEG-IFN + RBV + Active DrugPEG-IFN + RBV + Active Drug PEG-IFN + RBV + PlaceboPEG-IFN + RBV + Placebo Genotypes: Genotypes:

1: 48 wk 1: 48 wk 2: 24 wk2: 24 wk 3: 24 wk 3: 24 wk

Assess HCV RNA at wks 4, 12, 24, 48, 60, 72Assess HCV RNA at wks 4, 12, 24, 48, 60, 72 Compare AEs-SAEs in Placebo vs Active Drug GroupsCompare AEs-SAEs in Placebo vs Active Drug Groups

EndpointsEndpoints Primary: SVR at post-treatment wk 12 and 24Primary: SVR at post-treatment wk 12 and 24 Secondary: Secondary:

Normalization of ALT Normalization of ALT Improvement of histological Grade and/or Stage wk 72Improvement of histological Grade and/or Stage wk 72

Candidates for Clinical Therapeutic TrialsCandidates for Clinical Therapeutic TrialsStudy DesignStudy Design

Treatment-Experienced patients not achieving SVRTreatment-Experienced patients not achieving SVR Proof of short-term monotherapy effect: Proof of short-term monotherapy effect: Log10 HCV RNA Log10 HCV RNA Assessment of resistance to short-term monotherapyAssessment of resistance to short-term monotherapy Randomized, placebo controlled trial for superiorityRandomized, placebo controlled trial for superiority

PEG-IFN + RBV + Active DrugPEG-IFN + RBV + Active Drug PEG-IFN + RBV + PlaceboPEG-IFN + RBV + Placebo

Genotypes: 1, 2, 3 treatment for 48 wk Genotypes: 1, 2, 3 treatment for 48 wk Assess HCV RNA at wks 4, 12, 24, 48, 60, 72Assess HCV RNA at wks 4, 12, 24, 48, 60, 72 Compare AEs-SAEs in Placebo vs Active Drug GroupsCompare AEs-SAEs in Placebo vs Active Drug Groups



Candidates for Clinical Therapeutic TrialsCandidates for Clinical Therapeutic TrialsSpecial Populations Study DesignSpecial Populations Study Design

Co-infected HIV: Treatment-naïveCo-infected HIV: Treatment-naïve Proof of short-term monotherapy effect in HCV-HIV: Proof of short-term monotherapy effect in HCV-HIV: Log10 HCV RNA Log10 HCV RNA Proof of short-term safety, absence drug interactions with HAARTProof of short-term safety, absence drug interactions with HAART Stable HAART without hepatotoxicityStable HAART without hepatotoxicity CD4 T cells count stable: CD4 T cells count stable: 200 mm200 mm33

Elevated ALTElevated ALT Stratified on basis of Stratified on basis of

Genotype: 1, 2, 3 Genotype: 1, 2, 3 Histopathology Histopathology

Grades 1-4Grades 1-4 Stage 0-4Stage 0-4

Randomized, Placebo Controlled Trial of superiorityRandomized, Placebo Controlled Trial of superiority PEG-IFN + RBV + Active DrugPEG-IFN + RBV + Active Drug PEG-IFN + RBV + PlaceboPEG-IFN + RBV + Placebo

Treatment for 48 wksTreatment for 48 wks Assess HCV RNA at wks 4, 12, 24, 48, 60, 72Assess HCV RNA at wks 4, 12, 24, 48, 60, 72 Compare AEs-SAEs in Placebo vs Active Drug GroupsCompare AEs-SAEs in Placebo vs Active Drug Groups




Decompensated Cirrhotics (Listed for OLT)Decompensated Cirrhotics (Listed for OLT) Proof of short-term monotherapy effect: Proof of short-term monotherapy effect: Log10 HCV RNA Log10 HCV RNA Proof of short-term safety in cirrhosisProof of short-term safety in cirrhosis Stable therapy for complications of portal hypertensionStable therapy for complications of portal hypertension No hypervascular hepatic lesions on imaging with contrastNo hypervascular hepatic lesions on imaging with contrast CBC: Hgb CBC: Hgb 12 g/dL; WBC 12 g/dL; WBC 3,000 mm 3,000 mm33, ANC , ANC 1,500 mm 1,500 mm33, Plt , Plt 70,000 70,000 Elevated ALTElevated ALT Stratified on basis of genotype: 1, 2, 3 Stratified on basis of genotype: 1, 2, 3 Randomized, Placebo Controlled Trial of superiorityRandomized, Placebo Controlled Trial of superiority

PEG-IFN PEG-IFN ++ RBV + Active Drug (half dose PEG-IFN?) RBV + Active Drug (half dose PEG-IFN?) PEG-IFN + Active Drug (RBV substitution)PEG-IFN + Active Drug (RBV substitution) PEG-IFN PEG-IFN ++ RBV + Placebo RBV + Placebo PEG-IFN + PlaceboPEG-IFN + Placebo



Normalization of ALT Normalization of ALT Improvement in MELD (Improvement in MELD (15)-CTP (15)-CTP (7) scores, synthetic function, manifestations7) scores, synthetic function, manifestations of decompensation, transplant-free survivalof decompensation, transplant-free survival Absence of HCC on long-term follow-upAbsence of HCC on long-term follow-up


Recurrent HCV Infection Post-OLTRecurrent HCV Infection Post-OLT Proof of short-term monotherapy effect: Proof of short-term monotherapy effect: Log10 HCV RNA Log10 HCV RNA Proof of short-term safety in immunosuppressed OLT recipientsProof of short-term safety in immunosuppressed OLT recipients Assessment of drug interactions with immunosuppressive and prophylactic drugsAssessment of drug interactions with immunosuppressive and prophylactic drugs CBC: Hgb CBC: Hgb 12 g/dL; WBC 12 g/dL; WBC 3,000 mm 3,000 mm33, ANC , ANC 1,500 mm 1,500 mm33, Plt , Plt 70,000 70,000 Elevated ALTElevated ALT Biopsy: Biopsy:

Grade and Stage assessment Grade and Stage assessment Exclusion of ACR or CRExclusion of ACR or CR

Genotype 1 Genotype 1 Randomized, Placebo Controlled Trial of superiorityRandomized, Placebo Controlled Trial of superiority

PEG-IFN PEG-IFN ++ RBV + Active Drug (Low dose PEG-IFN?) RBV + Active Drug (Low dose PEG-IFN?) PEG-IFN + Active Drug (RBV substitution)PEG-IFN + Active Drug (RBV substitution) PEG-IFN PEG-IFN ++ RBV + Placebo RBV + Placebo PEG-IFN + PlaceboPEG-IFN + Placebo



Normalization of ALT Normalization of ALT Improvement in histological grade and/or stageImprovement in histological grade and/or stage


Chronic Renal Failure on Dialysis:Chronic Renal Failure on Dialysis: Proof of short-term monotherapy effect: Proof of short-term monotherapy effect: Log10 HCV RNA Log10 HCV RNA Proof of short-term safety in dialysis patientsProof of short-term safety in dialysis patients Assessment of effect of dialysis on drug levelsAssessment of effect of dialysis on drug levels CBC: Hgb CBC: Hgb 12 g/dL; WBC 12 g/dL; WBC 3,000 mm 3,000 mm33, ANC , ANC 1,500 mm 1,500 mm33, Plt , Plt 70,000 70,000 Elevated ALTElevated ALT Biopsy: Grade and Stage assessmentBiopsy: Grade and Stage assessment Genotype 1, 2, or 3 Genotype 1, 2, or 3 Randomized, Placebo Controlled Trial of superiorityRandomized, Placebo Controlled Trial of superiority

PEG-IFN PEG-IFN ++ Active Drug (RBV substitution) Active Drug (RBV substitution) PEG-IFN PEG-IFN ++ Placebo Placebo



Normalization of ALT Normalization of ALT Improvement in histological grade and/or stage at wk 72Improvement in histological grade and/or stage at wk 72


Clinical Therapeutic Trials of Two or More AgentsClinical Therapeutic Trials of Two or More Agents

Rationale:Rationale: Potentially eliminate need for IFN and/or RBVPotentially eliminate need for IFN and/or RBV Retard or prevent HCV resistance (Model of HAART for HIV)Retard or prevent HCV resistance (Model of HAART for HIV) Possible AE and SAE profile favorable for chronic treatmentPossible AE and SAE profile favorable for chronic treatment

Primary endpoints)Primary endpoints) Sustained virological response (post-therapy)Sustained virological response (post-therapy) Sustained virological suppression (chronic therapy)Sustained virological suppression (chronic therapy)

Secondary endpointsSecondary endpoints Improved histopathologyImproved histopathology Prevention of disease progressionPrevention of disease progression Reduced incidence of hepatocellular carcinomaReduced incidence of hepatocellular carcinoma Improved health-related quality of lifeImproved health-related quality of life


Old versus New Paradigms of TreatmentOld versus New Paradigms of Treatment

Concerns regarding selection of patients for HCV Concerns regarding selection of patients for HCV therapy reminiscent of those regarding the use of therapy reminiscent of those regarding the use of arsenicals for the treatment of syphilis due to the arsenicals for the treatment of syphilis due to the variable efficacy and frequency of AEs and SAEs.variable efficacy and frequency of AEs and SAEs.

Once penicillin proved to be safe and efficacious, Once penicillin proved to be safe and efficacious, therapy offered to all, regardless of prior selection therapy offered to all, regardless of prior selection criteria.criteria.

When will similar success be achieved in HCV When will similar success be achieved in HCV infection?infection?

Clinical Experience: Difficulties in Clinical Trial Design for Therapeutic Products to Treat Chronic HCV Infection John M. Vierling, M.D., F.A.C.P. Professor.

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