Chronic%20Viral%20Hepatitis

1
Chronic Viral Hepatitis HBV, HCV and HIV
Edward Gane NZLTU
2
Hepatitis C

• RNA virus discovered in 1989
• Probably around since 1990
• Cause of post-transfusional hepatitis
• No vaccine
• 106 viruses/ml of blood (c.f. 1012 for HBV)
• Less than 1 infectious risk of HBV
• Risk of sexual transmission rare
• Spread by blood to blood contact only
• Blood transfusion pre1992
• Vaginal delivery (6)
• Injecting drug use
• Risk of chronic infection gt85

3
Epidemiology of HCV A Global Health Problem
gt180 Million Infected Worldwide 3-4 Million New
Cases/Year
EUROPE 9 M
CHINA 62 M
MIDDLE EAST 21 M
NORTH SOUTH AMERICA 13 M
SOUTHEAST ASIA 32 M
AFRICA 32 M
AUSTRALIA 200,000
New Zealand 40,000
Weekly Epidemiological Record. N 49, 10 December
1999, WHO
4
Hepatitis C Infection in New Zealand Risk
factors for HCV exposure
Auckland Middlemore Hepatitis Clinics
New referrals 2005
Intravenous drug use 93
5
Hepatitis C infection in IDUChanging Prevalence?
77
0
6

• In patients with untreated post-transfusion
  hepatitis C, the lifetime risk of progression to
  cirrhosis best approximates
• A. 5.
• B. 20.
• C. 80.
• D. 100.

7
Modelling the HCV Epidemic Liver Disease
Progression
Dore,2003
8
Modelling the HCV Epidemic HCV Liver Transplants
in Australasia
ANZLTR, 2006
9
Factors associated with progression to cirrhosis

• Duration of infection gt10years
• Age gt50 at infection
• Alcohol gt 5 drinks/day
• Obesity
• Immunosuppression (transplant)
• HIV infection

10
Cause of Death in HBV and HCV
Amin J, et al. Lancet 2006368938-45
11
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12
Further tests

• HBsAg neg anti-HBs anti-HBcore
• Anti-HCV
• PCR for HCV RNA
• HCV Genotype 3a
• Liver Biopsy cirrhosis

What is the rash?
13
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Extrahepatic Manifestations of HCV Cryoglobulins
IgM(RF) IgG Antigen

• IgM Rheumatoid factor
• Polyclonal (Type III)?monoclonal (Type II)
• Monoclonal RF is highly restricted
• IgG
• IgG is heterologous but specific anti-HCV
• structural proteins (anti-core, anti-E1, E2)
• Antigen
• complexed to anti-HCV
• contains E1, E2, core, RNAwhole virion
• chronic HCV viremia drives the disease?

15
Therapy of EMC?

1. Steroids
2. Cyclophosphamide
3. Lamivudine
4. Standard Interferon 3mU tiw sc
5. Pegylated Interferon plus ribavirin tablets
6. Rituximab

1. Steroids
2. Cyclophosphamide
3. Lamivudine
4. Standard Interferon 3mU tiw sc
5. Pegylated Interferon plus ribavirin tablets
6. Rituximab

16
Treatment of Cryoglobulinaemia (4) Anti-CD20
(Rituximab)

• 4 patients with EMC
• 375mg/m2 IV, weekly for 4 weeks
• purpura resolved in 4/4
• neuropathy resolved in 1/1

Zaja, 2002
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Extrahepatic Manifestations of HCVPorphyria
Cutanea Tarda
19
Pathogenesis of Porphyria Cutanea Tarda
Glycine Succinyl CoA
ALA synthase
ALA
Iron Alcohol

Uroporphyrinogen
Uroporphyrin
Estrogens
URO-D
Iron
URO-D
Coproporphyrinogen
Coproporphyrin
Heme
Biliverdin CO
Heme Oxygenase
20
Non-liver complications of HCV
Found in 40 of people with HCV

• Arthralgias (EMC)
• Skin rash
• Cryoglobulinemic vasculitis
• Porphyria cutanea tarda
• lichen planus
• Raynauds Syndrome
• Sjogrens Syndrome
• Mesangiocapillary GN
• NH Lymphoma
• Thyroid disease
• Diabetes

21
Treatment of Hepatitis CObjectives

• Prevent transplantation and death
• Prevent cirrhosis
• Improve quality of life
• Eradicate HCV infection i.e. cure

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SolutionsImproving Antiviral Treatment
1985? 1992 ? 1996 ? 2003 ? 2004
100
All HCV
75
62
38
50
Sustained Virologic Response
25
12
7
0
Interferon
Interferon
Interferon
Peg-IFN plus
6months
12months
plus Ribavirin
Ribavirin
24
SolutionsImproving Antiviral Treatment
1985 ? 1992 ? 1996 ? 2003 ? 2004
25
Tolerability of Ribavirin

• Accumulates in RBCs
• haemolysis
• gt90 renal clearance
• avoid in renal dysfn

26
Treatment for Chronic Hepatitis C Management of
Side-Effects

• 11 ?anaemia ??Riba dose EPO
• 15 ?neutropenia??IFN G-CSF
• 5 ?thrombocytopenia ??IFN
• Flue syndrome? paracetamol, keep hydrated
• Insomnia ? Imovane
• Thyroid dysfunction ? Thyroxine?
• Depression due to CNS seratonin depletion
  ?pre-emptive SSRIs

27
Treatment for Chronic Hepatitis C Prevention of
IFN-induced Depression

• 36 HCV pts on Pegylated IFN plus Ribavirin
• 12 received prophylactic Citalopram 20mg/day

P lt0.03
Schaefer,2005
28
Contraindication to treatment?

1. Thyrotoxicosis
2. Ascites
3. Uncontrolled hypomania
4. Guttate psoriasis
5. Frequent Angina
6. All of above

29
Treatment for Chronic Hepatitis CSmall molecules
targeting HCV enzymes
Antiviral targets
IFN
Host target
Immunomodulators
Therapeutic vaccine
NS2
NS3
NS4A
NS4B
NS5A
NS5B
NS3
NS5A
NS5B
C
E1
E2
p7
30
Molecular Antivirals against HCVProtease
Inhibitor BILN 2061

• 10 patients with HCV genotype 1
• BILN 2061 200mg bid for 48 hrs vs. placebo

BILN 2061
31
Polymerase inhibitor is the Holy Grail

• Essential enzyme for HCV replication
• More than 70 targets
• Less drug resistance
• Less toxicity

Fingers
Thumb
Palm
32
HCV Polymerase Inhibitor R1626Phase Ib study in
HCV G1 NR (n48)
Treatment
Follow-up
1
Placebo
500 mg bid
0
1500 mg bid
3000 mg bid
-1
4500 mg bid
Mean HCV RNA (Log10) DecreaseFrom Baseline
-2
-3
-4
-5
0
5
10
15
20
25
30
Study Day
8/9 BQL (lt600 IU/mL) and 5/9 PCR negative (lt50
IU/mL) at 4500 mg bid dose
33
Virologic rebound due to emergence of NS3
mutations during VX-950 therapy
VX-950 dosing period
Post-dosing
Long-term follow-up
7
6
5
Long-term follow-up 37 months post-dosing
4
Median log HCV RNA
3
Follow-up 710 days post-dosing
2
EOT 14 days
1
Baseline
Time (days)
156
155
Kieffer. Hepatology 200746631-9
EOD end of dosing
34
How to overcome drug resistanceThe Lessons from
HIV

• Resistance expected for anti-HCV agents
• mutation rate higher than HIV
• replication rate higher than HIV (1012 per day)
• each new virus contains at least 1 mutation
• Resistance will prevent cure
• Cross-resistance to related compounds
• ? Combination therapy is essential

35
Protease inhibitor Telaprevir (VX-950)Phase 1,
14 days, GT 1, naïve
HCV RNA decline (log10 IU/mL)
Therapy (days)
Forestier. Hepatology 200746640-8
36
Protease inhibitor Telaprevir (VX-950)Phase 1,
14 days, GT 1, naïve
1
Baseline
0
-1
PEG-IFN placebo
-2
HCV RNA decline (log10 IU/mL)
-3
VX-950
-4
4.0 log n8
-5
-6
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Therapy (days)
Forestier. Hepatology 200746640-8
37
Protease inhibitor Telaprevir (VX-950)Phase 1,
14 days, GT 1, naïve
1
Baseline
0
-1
PEG-IFN placebo
-2
ongoing phase 2 study safety, sustained
response, shortening treatment duration,
selection of resistance?
HCV RNA decline (log10 IU/mL)
-3
VX-950
-4
-5
VX-950 PEG-IFN
-6
5.5 log n8
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Therapy (days)
Forestier. Hepatology 200746640-8
38
Target Agent Company Phase
NS3 serine protease Celuprivir (BILN2061) Boehringer Phase IIb
NS3 serine protease SCH 503034 Schering Phase IIb
NS3 serine protease ITMN-191 Roche/Intermune Preclinical
NS3 serine protease MK-0608 Merk Preclinical
? Eli-Lilly Preclinical
? Axys/BMS Preclinical
ACH-801 Achillon/Gilead Preclinical
ACH-801 Achillon/Gilead Preclinical
NS3 helicase Telaprevir (VX750) Vertex/JJ Phase IIIFN
NS5b Polymerase Nucleoside Analogue Valopicitabine Novartis/Idenix Phase IIbIFN
NS5b Polymerase Nucleoside Analogue R1626 Roche Phase IIbIFN
NS5b Polymerase Nucleoside Analogue PSI-6130 Roche/Pharmaset Phase I
NS5b Polymerase Nucleoside Analogue A837093 A848837 Abbott Preclinical
NS5b Non-nuc JTK-003 109 Japan Tobacco Phase II
NS5b Non-nuc HCV-796 ViroPharm/Wyeth Phase IIIFN
NS5b Non-nuc DEBIO-025 Debiopharm Phase II
NS5b Non-nuc NIM811 Novartis Phase I
NS5b Non-nuc SCY-635 Scynexis Preclinical
NS5a NNA A-831 Arrow Phase I
39
Risk of Sexual Transmission?

1. lt1
2. 5
3. 10
4. 20
5. 50

40
Life-Style Advice Sexual Transmission
41
Risk of Vertical Transmission?

1. lt1
2. 5
3. 10
4. 20
5. 50

42
Life-Style Advice Mother-to-infant Transmission

• Breast feeding is safe

43
Difficult-to-treat Populations Acute Hepatitis C

• 44 pts with acute Hepatitis C
• All present with acute icteric hepatis
• Received IFN monotherapy for 24 wks

Jaekel, NEJM 20013451452-7
44
Acute Hepatitis CSpontaneous clearance

• 60 pts with acute Hepatitis C
• HCV RNA tested every week

Gerlach. Gastroenterology 200312580-88
45
Management of HIV/HCV Co-infection
46
Prevalence of HCV in HIV
47
Impact of HIV on HCV progressionRate of Cirrhosis
HIV co-infection (N80)
HCV only (N80)
Di Martino, 2001
48
Impact of HCV on Survival in HIV
Gebo et al. JAIDS. 200334165-173.
49
Impact of HCV on Survival in HIV(iii)
Liver-related mortality
New England Medical Center
50
HAART reduced liver-related mortality
Overall Mortality
Liver-related Mortality
Quirshi. NEJM 2004
51
Treatment of HCV/HIV Co-infection Pegylated
Interferon plus Ribavirin
AIDS Pegasys Ribavirin International Co-infection
Trial

• 860 co-infected pts randomised 111 to

IFN-a 2a (3 MIU tiw) plus RIBA (800mg/day)
Follow-up
PEGASYS (180 µg, qw) plus PLAC
SVR
Follow-up
PEGASYS (180µg qw) plus RIBA (800mg/day)
Follow-up
Study Weeks
0
48
24
72
Toriana, NEJM, 2004
52
Treatment of HCV/HIV Co-infection APRICOT Study
Efficacy
40
20
12
n 285
n 286
n 289
Pegasys 180mg/wk Riba 800mg/day
Pegasys 180mg/wk Placebo
IFN-a 3mU tiw Riba 800mg/day
Defined as lt50 IU/mL HCV RNA at week 72 ITT
53
HIV and HCV coinfection Interaction of HCV Rx
with HAART

• AZT-related myelosuppression
• ? ?? Hb with Riba, ? ANC with IFN
• Riba? phosphorylation of AZT, D4T, Zalcitabine
• ? in vivo antiretroviral efficacy ?
• Riba ?phosphorylation of DDI
• ? mitochondrial toxicity (Lactate, steatosis)
• ? Hepatic decompensation in gt10 cirrhotic
• STOP DDI prior to HCV treatment

54
Chronic Hepatitis B
55
Chronic Hepatitis B in Asia-Pacific
WHO and CDC fact sheets www.who.int and
www.cdc.gov
56
Hepatitis B

• Smallest DNA virus
• Difficult to suppress due to lack of polymerase
  proof-reading and high mutation rate (gt1010 day)
• Impossible to eradicate (cccDNA within nucleus)
• 1012-15 viruses/ml blood?gt 100x infectivity of
  HCV
• Spread by most bodily fluids
• High risk of sexual transmission
• High risk of vertical transmission
• Risk of chronic infection related to age
• gt95 in neonates
• lt5 in adults
• Effective vaccine

57
Viral Load predicts Disease ProgressionThe
REVEAL Study

• Risk Evaluation of Viremia Elevation Associated
  Liver Disease
• prospective, multicenter, observational cohort
  study

7 Taiwanese townships Individuals aged 3065
years eligible (n 89,293)
1991-1992 recruitment
Baseline HBsAg (n9800)
Baseline HBV DNA (n 3851)
Follow-up analysis For Cirrhosis/HCC (n 3774)
June 2004 43,993 PYs follow-up
Chen CJ et al. JAMA 2006 295 65-73
58
Higher HBV DNA levels predict long-term risk of
complications (REVEAL)
Progression to Cirrhosis
Progression to Hepatoma
Iloeje UH et al. Gastroenterology 2006 130
67886.
Chen CJ et al. JAMA 2006 295 65-73
59
REVEAL Baseline Factors are associated with
development of HCC (n164)
Baseline Factor Hazard Ratio
Smoker 1.7
Alcohol 2.6
Male gender 3.0
Agegt40 3.6
High ALT 4.1
eAg positive 4.3
HBV DNA gt106 10.7
Cirrhosis 22
Chen CJ et al. JAMA 2006 295 65-73
60
REVEAL Persistently High HBV DNA levels are
associated with increased rate of HCC
Only in those with levels 104 copies/mL at
baseline (n 1376)
Baseline / End of F/U
gt5logs / gt5logs
gt5logs / 4-5logs
gt5logs / lt4logs
lt5logs / gt5logs
lt5logs / 4-5logs
lt5logs / lt4logs
0
5
10
15
20
Adjusted relative risk
Chen CJ, JAMA. 200629565-73
61
Goals of treatment in CHB APASL Consensus
Statement 2005

• The ultimate long-term goal of therapy is to
  prevent progression to cirrhosis, decomp-ensation
  and HCC, and to prolong survival.
• Sustained viral suppression is the key to the
  reduction or prevention of hepatic injury and
  disease progression.
• Therefore, the primary goal of treatment for
  chronic hepatitis B is to permanently suppress
  HBV..

Liaw YF et al. Liver Int 2005
62
Interferon alfa

• Immunomodulatory
• Enhanced MHC class I protein
• Activation of CTL and NK cells
• Antiviral
• 2,5-oligoadenylate synthetase induction leading
  to viral cleavage
• Protein kinase induced
• MxA protein

63
IFN for HBeAg-positive CHB
Meta-analysis of 15 RCTs (837 patients)
IFN 5 to 10 MIU TIW 4 to 6 months
50
37
40
Interferon
33
patients
Untreated
30
17
20
12
8
10
2
0
HBV DNA loss
HBeAg loss
HBsAg loss
Wong, DKH, et al, Ann Intern Med. 1993
64
Long-term benefit of interferon treatment in
HBeAg() CHB

• 103 HBeAg() pts received IFN-a for 6 mths
• compared to 53 untreated HBeAg() CHB pts

(a) Overall Survival
(b) Clinical Complications
IFN response
IFN response
IFN nonresponse
IFN nonresponse
No IFN
No IFN
P0.018
P0.0004
Niederau C. NEJM 19963341422-7
65
Phase III Study in HBeAg-positive CHB

• 814 pts randomised 111 ratio

Lau G, NEJM 2005 3522682-95
66
(i) eAg seroconversion
Lau G, NEJM 2005 3522682-95
67
Lamivudine Site of Action
Extracellular Space
Cytoplasm
Maturation and Release
Nucleus
() Strand DNA Synthesis
(-) Strand DNA Synthesis
68
Virological ResponseLamivudine Phase III Data
Placebo
Serum HBV DNA Median Change
Lamivudine
n192 n404
n171 n359
Lai, NEJM 199833961-8
69
HBeAg seroconversion after 1 year of lamivudine
ULN, upper limit of normal
Lai, NEJM 199833961-8
70
Serologic ResponseLamivudine Phase III Data
Lai, NEJM 199833961-8
71
Benefit of Long-term viral suppression with
Lamivudine

• 651 patients with HBV-cirrhosis
• received Lamivudine for 3-5 years

Placebo (n215)
21
with disease progression
Placebo
Lamivudine (n436)
Plt0.001
9
Lamivudine
Liaw, NEJM 20043511521-31
72
Delayed progression to HCC
with disease progression
If exclude 5 HCC cases in yr 1 ? HR 0.47 P
0.052
Liaw, NEJM 20043511521-31
73
Genotypic Lamivudine Resistance
Lamivudine
Lamivudine
M552
M204V/I
L180M
L528
74
Long-term Lamivudine TherapyVirological
Resistance
75
Delayed Disease progression in Cirrhosis Impact
of resistance
25
Placebo (n215)
21
LAM?YMDD (n209 49)
20
LAM ?Wild Type (n221, 51)
with disease progression
15
10
5
5
LAM?WT
0
0
6
12
18
24
30
36
Time after randomisation (months)
Liaw, NEJM 20043511521-31
76
Nucleoside/Nucleotide Analogues
(a) Purine Analogues
Entecavir
Abacavir
Tenofovir
Adefovir
Cidofovir
(b) Pyrimidine Analogues
LdT
Lamivudine
Emtricitabine
Clevudine
77
Primary Adefovir Therapy in HBV
Change in HBV DNA (log10 copies/mL)
Marcellin. NEJM 2003348808-16
Hadziyannis. NEJM 2003348800-7
78
Long-term Adefovir in HBeAg neg CHB
100
100
90
90
80
80
Patients ()
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
48 wks
96 wks
192 wks
144 wks
N 79 79
70 69
Kaplan Meier estimates
Hadziyannis. NEJM 20053522673-81
79
Long-term Adefovir in HBeAg neg CHB
Week 48
Week 96
Week 144
70
70
50
50
63
63
30
30
53
53
Improved
Improved
34
34
10
10
-10
-10
Worsened
Worsened
-30
-30
Median
Ishak
Fibrosis Score at baseline 2
Median
Ishak
Fibrosis Score at baseline 2
Improvement defined as
1 point reduction
Improvement defined as
1 point reduction
?
?
Worsening defined as
?
1 point increase
Worsening defined as
?
1 point increase
Hadziyannis. NEJM 20053522673-81
80
Adefovir for LAM-resistant HBV
Peters, Gastro 2004
81
Entecavir in HBeAg pos CHB
(3) eAg seroconvert
(2) PCR negative
(1) ALT normal
Entecavir
Lamivudine
Chang. NEJM 20063541001-9
82
Cross Resistance With HBV Drugs
Yang H. et al. Hepatology 200338705A Lai CL et
al Hepatology 200338262A
83
Resistance to Lamivudine, Telbivudine, Adefovir,
Entecavir
84
Lam-Resistance increases Resistance to Adefovir,
Entecavir
(1) Adefovir
(2) Entecavir
85
HBV
HIV
86
Multicenter AIDS cohort study
HIV/HBV co-infection (1) Impact on Natural
History of HBV
Thio, Lancet 2002
87
HIV/HBV co-infection (1) Impact on Natural
History of HBV
HIV co-infection associated with

• ? spontaneous clearance of HBeAg
• ? spontaneous clearance of HBsAg
• ? ALT levels
• ? HBV DNA
• ? progression to cirrhosis
• ? liver-related mortality

88
Lamivudine in HIV/HBV co-infectionEfficacy data
from CAESAR study

• RCT lamivudine vs. placebo

Dore et al J Infect Dis. 1999
89
Lamivudine in HIV/HBV co-infection Incidence of
Lamivudine Resistance
100
90
HIV negative
HIV positive
80
67
60
49
47
38
40
20
20
0
1
2
3
4
Benhamou,1999
90
HIV/HBV co-infection Tenofovir in LAM-naïve HBV
Dore, JID, 2004
91
Management of HBV in HIV co-infection
?HBV DNA, ?ALT
HAART not needed
HAART indicated
92
Immune reconstitution inHBV/HIV co-infection
HAART-naïve, CD4lt200
93
Prevention of HBV Universal Neonatal Vaccination
94
Vaccination in Taiwan Eradication of Chronic HBV
Chang,NEJM 19973361855-9
95
Prevention of HBV-related HepatomaVaccination in
Taiwan
HCC incidence in children (lt14yrs) (100,000
person yrs)
Birth Year
Chang,NEJM 19973361855-9
96
HCC Surveillance in Chronic HBV
InfectionCost-Effectiveness Comparison
Cost/QALYS