Recent Advances in Management of Chronic Hepatitis B

1
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 of Medicine and
Surgery Director of Baylor Liver Health Chief of
Hepatology Baylor College of Medicine Houston, TX
2
Chronic HCV Infection Ultimate Therapeutic Goals

• HCV as vaccine-preventable disease
• Safe and effective pharmacological cure for acute
  and chronic HCV infections resulting in
• Termination of hepatic and extrahepatic
  disease(s)
• Dissolution of existing hepatic fibrosis
• Reduction in incidence of associated diseases
• Diabetes mellitus
• Non-Hodgkin B cell lymphoma

3
Topic Outline

• Clearance of HCV Lessons from HCV pathogenesis
• Interferon and ribavirin mechanisms of action in
  SVR
• Relevance of prior clinical trials in the study
  of new therapeutic agents
• Selection of patient populations for clinical
  trials of new agents
• New clinical trials
• Design
• Endpoints

4
HCV PathogenesisInfection versus Disease
Infects different cells
Hepatocytes Lymphocytes Other
Tissues Pancreas, Adrenal gland, Bone Marrow
HCV
B cells
T cells
Not cytopathic for hepatocytes
HCV
Immune Response
Minimal Fibrosis
Advanced Fibrosis
5
Natural History of HCV Infection
Biochemical Outcome Histological Outco
me
Acute Hepatitis C
85 15

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

Chronic Infection Anti-HCV HCV RNA
Viremia
75
25
Key Role for liver biopsy to detect
progressive fibrosis
?ALT
?ALT
20
2
Cirrhosis
Cirrhosis
6
Natural History of Hepatitis C CirrhosisAnnual
Rates of HCC, Decompensation and Death

Fattovich G, et al. Gastroenterology.
1997112463.
7
Immunopathogenesis of HCV Infection T Cell
Activation to HCV Antigens
Class II HLA
CD4

• Immune Response
• Vigorous
• Polyclonal
• Multispecific

AntigenPresentingCell

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

Class I HLA
CD8
8
Immunopathogenesis o f HCV Infection Dynamic
Balance of CD4 T-Helper Cells
APC
Treg
HCV Peptide Antigen
MHC Class II
CD4
TGF b, IL-10
TCR/CD3
?
Th0
IL-4
IL-12
Th1
Th2
IFN g
IL-2, TNF a/b, IFN g
IL-4, IL-5, IL-6, IL-10
Greater Immunopathology
Lesser Immunopathology
9
Immune-Mediated Clearance of HCV
HCV-Infected Hepatocyte
Clearance of Infected Hepatocytes
TNF ? IFN ?
Apoptosis
Class I MHC
CD8
TCR
CD8
CTL
10
Immune-Mediated Clearance of HCV
Ineffective Clearance of Infected Hepatocytes
HCV-Infected Hepatocyte
TNF ? IFN ?
Apoptosis
Class I MHC
CD8
TCR
CD8
HCV antagonism promoting viral persistence
CTL
11
HCV Therapy with Interferon Dual Mechanisms of
Biphasic HCV Kinetics
12
HCV InfectionAntiviral Mechanism of Action of
Interferon-a
HCV Replication
IFN Regulated Proteins
IFNa
IFNa
a/?
ISGF-3
Jak STAT IRF9
a/?
IFNa
IFNa
IFNa
IFNa
IFNa
Infected Hepatocyte
IFNa-Treated Hepatocyte
IFNa
HCV
Exogenous IFNa
13
HCV InfectionAntiviral Mechanisms of Action of
Interferon-a
Protein Kinase PKR
2,5OASi
Adenosine Deaminase ADAR1
Protein GTPase Mx
eIF-2a
P-eIF-2a
2,5OASa
Target Nucleocapsids Inhibit RNA Synthesis
RNA Editing
2,5OAA
Inhibit mRNA Translation
RNase L
RNase L
RNA Degradation
14
HCV Infection Interferon-? Effects on NK and Th1
Cells
IL-12
HCV Infection?
NK
Dendritic Cell
IFN?
HCV Antigen
HCV Infected Cells
MHC Class II
TCR/CD3
CD4
IFN?
Th0
IL-4
Th1
Th2
IL-2, TNF a/b, IFN g
IL-4, IL-5, IL-6, IL-10
? Immunopathology Fibrogenesis
? Immunopathology
15
HCV InfectionAntagonism of INFa Effects
5
3
E1 E2
NS2 NS3 NS4 NS5
C
? HCV-Specific CTL
Inhibit NK Functions (CD81)

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

16
HCV InfectionInterferon-? 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

HCV-Infected Hepatocytes
Collagen
Cytokine-Activated Stellate Cell
Fenestratred Endothelial Cells
17
Putative Mechanisms of Action of Ribavirin
?
Immune Modulation
Anti-Fibrotic
18
HCV Infection Ribavirin Antiviral Mechanisms

• RTP Inhibition
• NS5B RNAdRNAp BVDV
• NS5B RNAdRNAp HCV
• RBV Mutagenic for
• Poliovirus
• HGV
• RMP Inhibits IMPDH
• No Effect of RBV on
• NS3 protease
• RNA helicase/NTPase
• 5-IRES

Purine Synthesis
HCV Replication
IFN Regulated Proteins
purine salvage
IMPDH
RMP
ISGF-3
RBV
RBV
RTP
RMP
RDP
HCV-Infected Hepatocyte
19
HCV Infection Interaction of Interferon-? and
Ribavirin
HCV Infection?
IL-12
RBV Inhibition
NK
Dendritic Cell
IFN?
TNF?, IL-1?
HCV Antigen
HCV Infected Cells
MHC Class II
RBV
TCR/CD3
CD4
IFN?
Th0
IL-4
Th1
Th2
IL-2, TNF a/b, IFN g
IL-4, IL-5, IL-6, IL-10
? Immunopathology Fibrogenesis
? Immunopathology Fibrogenesis
20
HCV Therapy with Interferon RegimensSustained
Virological Response (SVR)
Response to Continued Treatment
Initial IFN-Based Treatment

• SVR
• Durable (cure)
• 212/217 (98) HCV RNA (-)
• 5/217 ( 2) HCV RNA ()
• 4/5 liver
• 1/5 PBMC

HCV RNA
LLD
Adapted from Pawlotsky JM, Hepatology vol. 32,
5, 2000
21
HCV Therapy with Interferon RegimensFour
Patterns of Non-Response
Response to Continued Treatment
Initial IFN-Based Treatment
Non-response
HCV RNA
Relapse
Nonresponse Based on EVR
Breakthrough
LLD
Adapted from Pawlotsky JM, Hepatology vol. 32,
5, 2000
22
Chronic HCV InfectionGenotype Distribution in
the U.S.A. (N 6807)
Blatt LM, et al, J. Viral Hepatitis.
2000(3)196-202.
23
HCV Therapeutic TrialsLiver Biopsy
Stratification and as Endpoint

• Assessment
• Grade Inflammation
• Stage Fibrosis (1-4)
• Significant change gt1 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

24
Non-Response to HCV TherapyRelated to
Combination of Viral and Host Factors
100

11
55
30
53
48
59
43
56
80
79
70
60
62
57
SVR ()
47
40
45
44
41
20
2/3
1
Lo
Hi
lt75
gt75
F0/1
F3/4
0
Genotype
Viral Load
Weight (kg)
Fibrosis
Data fromManns MP et al. Lancet.
2001358958. Fried MW et al. N Engl J Med.
2002347975. FDA Antiviral Drug Products
Advisory Committee, 2002.
25
Interferon-Ribavirin for Chronic HCV
InfectionEVR Predicts Probability of SVR
26
Therapy for Chronic HCV InfectionResponse
Predicted by Adherence
27
Interferon-Ribavirin for Chronic HCV
InfectionDifferences in SVR for African
Americans and Caucasians
Conjeevaram HS, et al. Gastroenterology 2006
131 470-7
28
HCV-HIV Co-InfectionAdverse Effect on Survival
29
HCV-HIV Co-Infection Decreased Response to
Interferon-Ribavirin Therapy
Reviewed in Stribling R, et al. Gastro Clin NA
2006 35 463-86.
30
Recurrent HCV Infection Post-OLTAccelerated
Progression and Increased Mortality
Forman LM et al. Gastroenterology 2002 122
889-96
Braun M and Vierling JM. Liver Transpl 2003 9
S79-S89
31
Candidates for Clinical Therapeutic Trials

• Treatment-naïve patients at risk for progression
• Chronic HCV infection with detectable HCV RNA
• Elevated ALT
• Active inflammation by liver biopsy
• Absence of contraindications
• Treatment-experienced patients not achieving SVR
• Relapsers from ETR
• Non-responders discontinued due to absence of EVR
  
• Non-responders with absence of any virological
  response
• Non-responders with breakthrough after EVR
• Special populations
• Children
• Co-infection with HIV or HBV
• Decompensated cirrhosis
• OLT Patients
• Pre-OLT
• Recurrent hepatitis C post-OLT
• Extrahepatic diseases

2002 NIH HCV Consensus Conference, Hepatology
2002
32
Candidates for Clinical Therapeutic
TrialsPriority Ranking

• Treatment-naïve patients at risk for progression
• Chronic HCV infection with detectable HCV RNA
• White, Black, Latino
• Elevated ALT
• Stratified on basis of
• Genotype 1, 2, 3 highest priority due to
  frequency in U.S.A.
• Histopathology
• Grades 1-4
• Stage 0-4
• Treatment-experienced patients not achieving SVR
• Non-responders documented at 12, 24 or 48 wks of
  therapy
• Relapsers with documented ETR
• White, Black, Latino
• Special populations
• Co-infection with HIV gt HBV Treatment-naïve or
  -experienced
• Decompensated cirrhotics
• Orthotopic liver transplantation
• Pre-OLT
• Recurrent hepatitis C post-OLT

33
Candidates for Clinical Therapeutic TrialsStudy
Design

• Treatment-naïve patients at risk for progression
• Proof of short-term monotherapy effect ? Log10
  HCV RNA)
• Assessment of resistance to short-term
  monotherapy
• Randomized, placebo controlled trial for
  superiority, non-inferiority
• PEG-IFN RBV Active Drug
• PEG-IFN RBV Placebo
• Genotypes
• 1 48 wk
• 2 24 wk
• 3 24 wk
• Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
• Compare AEs-SAEs in Placebo vs Active Drug Groups
• Endpoints
• Primary SVR at post-treatment wk 12 and 24
• Secondary
• Normalization of ALT
• Improvement of histological Grade and/or Stage wk
  72

34
Candidates for Clinical Therapeutic TrialsStudy
Design

• Treatment-Experienced patients not achieving SVR
• Proof of short-term monotherapy effect ? Log10
  HCV RNA
• Assessment of resistance to short-term
  monotherapy
• Randomized, placebo controlled trial for
  superiority
• PEG-IFN RBV Active Drug
• PEG-IFN RBV Placebo
• Genotypes 1, 2, 3 treatment for 48 wk
• Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
• Compare AEs-SAEs in Placebo vs Active Drug Groups
• Endpoints
• Primary SVR at post-treatment wk 12 and 24
• Secondary
• Normalization of ALT
• Improvement of histological Grade and/or Stage wk
  72

35
Candidates for Clinical Therapeutic
TrialsSpecial Populations Study Design

• Co-infected HIV Treatment-naïve
• Proof of short-term monotherapy effect in
  HCV-HIV ? Log10 HCV RNA
• Proof of short-term safety, absence drug
  interactions with HAART
• Stable HAART without hepatotoxicity
• CD4 T cells count stable ?200 mm3
• Elevated ALT
• Stratified on basis of
• Genotype 1, 2, 3
• Histopathology
• Grades 1-4
• Stage 0-4
• Randomized, Placebo Controlled Trial of
  superiority
• PEG-IFN RBV Active Drug
• PEG-IFN RBV Placebo
• Treatment for 48 wks
• Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
• Compare AEs-SAEs in Placebo vs Active Drug Groups

• Endpoints
• Primary SVR at post-treatment wk 12 and 24
• Secondary
• Normalization of ALT
• Improvement of histological Grade and/or Stage
  wk 72

36
Candidates for Clinical Therapeutic
TrialsSpecial Populations Study Design

• Decompensated Cirrhotics (Listed for OLT)
• Proof of short-term monotherapy effect ? Log10
  HCV RNA
• Proof of short-term safety in cirrhosis
• Stable therapy for complications of portal
  hypertension
• No hypervascular hepatic lesions on imaging with
  contrast
• CBC Hgb ? 12 g/dL WBC ? 3,000 mm3, ANC ? 1,500
  mm3, Plt ? 70,000
• Elevated ALT
• Stratified on basis of genotype 1, 2, 3
• Randomized, Placebo Controlled Trial of
  superiority
• PEG-IFN RBV Active Drug (half dose PEG-IFN?)
• PEG-IFN Active Drug (RBV substitution)
• PEG-IFN RBV Placebo
• PEG-IFN Placebo
• Treatment for 48 wks
• Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
• Compare AEs-SAEs in Placebo vs Active Drug Groups

• Endpoints
• Primary SVR at post-treatment wk 12 and 24
• Secondary
• Normalization of ALT
• Improvement in MELD (?15)-CTP (?7) scores,
  synthetic function, manifestations
• of decompensation, transplant-free survival
• Absence of HCC on long-term follow-up

37
Candidates for Clinical Therapeutic
TrialsSpecial Populations Study Design

• Recurrent HCV Infection Post-OLT
• Proof of short-term monotherapy effect ? Log10
  HCV RNA
• Proof of short-term safety in immunosuppressed
  OLT recipients
• Assessment of drug interactions with
  immunosuppressive and prophylactic drugs
• CBC Hgb ? 12 g/dL WBC ? 3,000 mm3, ANC ? 1,500
  mm3, Plt ? 70,000
• Elevated ALT
• Biopsy
• Grade and Stage assessment
• Exclusion of ACR or CR
• Genotype 1
• Randomized, Placebo Controlled Trial of
  superiority
• PEG-IFN RBV Active Drug (Low dose PEG-IFN?)
• PEG-IFN Active Drug (RBV substitution)
• PEG-IFN RBV Placebo
• PEG-IFN Placebo
• Treatment for 48 wks
• Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
• Compare AEs-SAEs in Placebo vs Active Drug Groups

• Endpoints
• Primary SVR at post-treatment wk 12 and 24
• Secondary
• Normalization of ALT
• Improvement in histological grade and/or stage

38
Candidates for Clinical Therapeutic
TrialsSpecial Populations Study Design

• Chronic Renal Failure on Dialysis
• Proof of short-term monotherapy effect ? Log10
  HCV RNA
• Proof of short-term safety in dialysis patients
• Assessment of effect of dialysis on drug levels
• CBC Hgb ? 12 g/dL WBC ? 3,000 mm3, ANC ? 1,500
  mm3, Plt ? 70,000
• Elevated ALT
• Biopsy Grade and Stage assessment
• Genotype 1, 2, or 3
• Randomized, Placebo Controlled Trial of
  superiority
• PEG-IFN Active Drug (RBV substitution)
• PEG-IFN Placebo
• Treatment for 48 wks
• Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
• Compare AEs-SAEs in Placebo vs Active Drug Groups

• Endpoints
• Primary SVR at post-treatment wk 12 and 24
• Secondary
• Normalization of ALT
• Improvement in histological grade and/or stage
  at wk 72

39
Chronic HCV InfectionClinical Therapeutic Trials
of Two or More Agents

• Rationale
• Potentially eliminate need for IFN and/or RBV
• Retard or prevent HCV resistance (Model of HAART
  for HIV)
• Possible AE and SAE profile favorable for chronic
  treatment
• Primary endpoints)
• Sustained virological response (post-therapy)
• Sustained virological suppression (chronic
  therapy)
• Secondary endpoints
• Improved histopathology
• Prevention of disease progression
• Reduced incidence of hepatocellular carcinoma
• Improved health-related quality of life

40
Chronic HCV InfectionOld versus New Paradigms of
Treatment

• Concerns regarding selection of patients for HCV
  therapy reminiscent of those regarding the use of
  arsenicals for the treatment of syphilis due to
  the variable efficacy and frequency of AEs and
  SAEs.
• Once penicillin proved to be safe and
  efficacious, therapy offered to all, regardless
  of prior selection criteria.
• When will similar success be achieved in HCV
  infection?