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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
HCV-InfectedHepatocyte
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
IL-2, TNF IL-2, TNF //, IFN , IFN IL-4, IL-5,IL-4, IL-5,IL-6, IL-10IL-6, IL-10
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-InfectedHepatocyte
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
ImmunopathologyImmunopathologyFibrogenesisFibrogenesis
ImmunopathologyImmunopathologyFibrogenesisFibrogenesis
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
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
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 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
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 TrialsSpecial Populations Study DesignSpecial Populations Study Design
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
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
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 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
Candidates for Clinical Therapeutic TrialsCandidates for Clinical Therapeutic TrialsSpecial Populations Study DesignSpecial Populations Study Design
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
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
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 in histological grade and/or stageImprovement in histological grade and/or stage
Candidates for Clinical Therapeutic TrialsCandidates for Clinical Therapeutic TrialsSpecial Populations Study DesignSpecial Populations Study Design
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
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
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 in histological grade and/or stage at wk 72Improvement in histological grade and/or stage at wk 72
Chronic HCV InfectionChronic HCV Infection
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
Chronic HCV InfectionChronic HCV Infection
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?