Transcript Clinical Care Options Hepatitis Annual Update 2009

Clinical Care Options Hepatitis
Annual Update 2009
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Clinical Care Options Hepatitis Annual Update 2009
clinicaloptions.com/hepatitis
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Program Faculty
Program Directors
Program Faculty
 Marion G. Peters, MD,
FRACP
Raymond T. Chung, MD
 David L. Thomas, MD, MPH
Geoffrey M. Dusheiko, MD,
FCP(SA), FRCP
Anna S. F. Lok, MD
Timothy Morgan, MD
Jean-Michel Pawlotsky, MD,
PhD
HBV Infection: Deciding Who and
When to Treat
Anna S. F. Lok, MD
Professor of Internal Medicine and
Director of Clinical Hepatology
University of Michigan, Ann Arbor
Ann Arbor, Michigan
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NIH Guidelines: Indications for HBV
Treatment
Patients for Whom Therapy Is Indicated
Patients who have
 Acute liver failure
 Cirrhosis and clinical complications
 Cirrhosis or advanced fibrosis and HBV DNA in serum
 Patients who will be receiving cancer chemotherapy or immunosuppressive
therapy
Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.
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NIH Guidelines: Indications for HBV
Treatment (cont)
Patients for Whom Therapy May Be Indicated
Patients with active liver disease who do not have advanced fibrosis or cirrhosis,
ie, patients with HBeAg-positive or HBeAg-negative chronic hepatitis B
Patients for Whom Immediate Therapy Is Not Routinely Indicated
Patients in the immune-tolerant phase (HBeAg positive, high levels of serum HBV
DNA but normal ALT or little activity on liver biopsy)
Patients in the inactive carrier phase (HBeAg negative, low or undetectable levels
of serum HBV DNA, and persistently normal ALT)
Patients who have latent HBV infection (HBV DNA without HBsAg)
Adapted from Sorrell MF, et al. Ann Intern Med. 2009;150:104-110.
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Interferon Alfa Vs Nucleos(t)ide Analogue
Treatment
Treatment
Interferon alfa
Nucleos(t)ide
Analogues
Route
Subcutaneous injection
Oral
Duration of treatment
Finite duration ~ 12 mos
Long duration, yrs to
lifelong
Antiviral activity
Modest, additional
immunomodulatory
effects
Stronger antiviral activity
HBsAg loss
1% to 3% after 1 yr
Rare, 0% to 1% after 1 yr
None
0% to 25% after 1 yr,
varying by agent
Frequent
Rare
18,000
~ 2500-9000
Resistant mutants
Adverse effects
Cost/yr (in US dollars)
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LAM Genotypic Resistance in Patients
Receiving PegIFN + LAM vs LAM Alone
Peginterferon alfa +
Lamivudine
Lamivudine Alone
N
Lamivudine
Resistant, n (%)
N
Lamivudine
Resistant, n (%)
Janssen, 2005*
130
14 (11)‡
NA
NA
Chan, 2005*
48
10 (21)§
48
19 (40)
Lau, 2005*
256
9 (4)
254
69 (27)
Marcellin, 2004†
173
1 (1)
179
32 (18)
*HBeAg-positive patients.
†HBeAg-negative patients.
‡7 had previous lamivudine therapy with lamivudine resistance mutation at entry.
§Peginterferon x 32 weeks.
Janssen HL, et al. Lancet. 2005;365:123-129. Chan HL, et al. Ann Intern Med. 2005;142:240-250. Lau GK,
et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.
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LAM + ADV vs LAM Responses at
Week 104
Lamivudine + Placebo,
n/N (%)
Lamivudine + Adefovir,
n/N (%)
ALT normalization
19/56 (34)
15/35 (43)
HBV DNA negative
(polymerase chain
reaction)
8/56 (14)
14/53 (26)
HBeAg seroconversion
11/54 (20)
7/52 (13)
Lamivudine resistance
mutation
15/35 (43)
6/41 (15)
Sung JJ, et al. J Hepatol. 2008;48:728-735.
Benefits and Risks of Hepatitis B
Therapy
Geoffrey M. Dusheiko, MD,
FCP(SA), FRCP
Professor of Medicine
Royal Free Hospital and School of
Medicine
London, United Kingdom
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Evolution of Chronic HBV Therapy Over
Time
Peginterferon alfa-2a
Entecavir
Lamivudine
1990
Interferon alfa-2b
1998
2002
Adefovir
2005
Tenofovir
2006
Telbivudine
2008
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Factors Associated With Choosing
Interferon as Initial Therapy
 Favorable predictors of response
• Genotype A or B > C or D
• Low HBV DNA (baseline and on treatment)
• High ALT (baseline)
 Specific patient demographics
• Younger people
 Young
woman wanting future pregnancy
 Patient preference
 No coinfection with HIV
 Concomitant HCV infection
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Factors Associated With Choosing
Nucleos(t)ides as Initial Therapy
 Favorable predictors of response
• High ALT
• Low HBV DNA (baseline and on treatment)
 Specific patient demographics
• Older people
 Patient preference
 Concomitant HIV infection
 No HCV coinfection
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Cumulative Rates of Resistance With Oral
Agents in Nucleos(t)ide-naive Patients
Not head-to-head trials; different patient populations and trial designs
Lamivudine
Adefovir
Entecavir
Telbivudine
Tenofovir
100
Patients (%)
80
70
67
60
40
49
38
20
0
29
24
0 0.2
1
3
4
0
17
0.5
2
18
11
0
1.2
1.2
3
4
1.2
5
1.2
6
Year
EASL clinical practice guidelines. J Hepatol. 2009;50:227-242. Tenney DJ, et al. EASL; 2009; Copenhagen,
Denmark. Abstract 20.
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Cross-Resistance Data for Nucleos(t)ide
Analogues
L180M +
M204V/I ± I169T
N236T
±V173L ±
M250V
L180M+M20
4V/I ±
T184G ±
S202I/G
Wild
type
M204
I
L180M
+
M204V
LAM
S
R
R
I
S
R
R
LdT
S
R
R
S
S
R
R
ETV
S
I
I
S
S
R
R
ADV
S
S
S
R
R
S
S
TDF
S
S
S
S
I
S
S
A181T/
V
EASL clinical practice guidelines. J Hepatol. 2009;50:227-242.
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Recommended Resistance Management
Strategies
Drug Resistance
Lamivudine resistance
Adefovir resistance
Management Strategy
Add adefovir or tenofovir
Switch to tenofovir/emtricitabine*
If N236T substitution:
add lamivudine, entecavir, or switch to tenofovir/emtricitabine*
If A181T/V substitution:
add entecavir or switch to tenofovir/emtricitabine*
Telbivudine resistance
Same as for lamivudine
Entecavir resistance
Switch to or add adefovir or tenofovir
Tenofovir resistance
(not yet described)
?
*Not approved by the US Food and Drug Administration.
Lok AS, McMahon BJ. Hepatology. 2007;45:507-539. Ghany MG, Doo EC. Hepatology. 2009;
49:S174-S184.
Update on HCV Investigational
Agents
Jean-Michel Pawlotsky, MD, PhD
Professor, Department of Virology
Henri Mondor Hospital
University of Paris 12
Créteil, France
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Schematic Representation of the HCV
Lifecycle
Transport
and release
Receptor binding
and endocytosis
Fusion and
uncoating
(+) RNA
ER lumen
LD
LD
Virion
assembly
LD
Membranous
web
ER lumen
Translation and
polyprotein processing
RNA
replication
Reprinted by permission from Macmillan Publishers Ltd: NATURE Lindenbach BD, Rice CM. Unravelling
hepatitis C virus replication from genome to function. 36:933-938, copyright 2005. www.nature.com
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Selected HCV Drugs in Clinical
Development
Type of Drug
Drug
Interferons





Ribavirin prodrug
 Taribavirin
Other drugs
 Nitazoxanide
 Silibinin
Albinterferon alfa-2b
Controlled-release interferon alfa-2b
Interferon alfa-2bXL
ITCA638
Peginterferon-lambda (PEG-rIL-29)
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Selected HCV Drugs in Clinical
Development
HCV Inhibitors
Entry inhibitors
NS3/4A protease inhibitors
Nucleos(t)ide analogues
Nonnucleoside RdRp inhibitor
NS5A inhibitors
Cyclophilin inhibitors
HCV assembly/release inhibitors
*Development recently halted.
Drug
 PRO206*
 Telaprevir (VX-950)
 Boceprevir (SCH 503034)
 TMC435
 R7227 (ITMN-191)
 MK-7009
 BI201335
 SCH 900518
 R7128
 IDX184
 GS-9190
 ANA598
 BI207127
 VCH-916
 Filibuvir (PF-00868554)
 BMS-790052
 DEBIO-025
 SCY-635
 NIM811
 Celgosivir
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Sustained Virologic Response Rates in the
PROVE 1, PROVE 2, and PROVE 3 Trials
Study
PROVE
1[1]
PROVE
2[2]
PROVE
3[3]
Patient
Population
Treatment naive,
genotype 1
Treatment naive,
genotype 1
Peginterferon and
ribavirin treatment
failure, genotype 1
Treatment Arm*
N
SVR,† n
(%)
PR48‡
75
31 (41)
T12PR24§
79
48 (61)
.02
T12PR48||
79
53 (67)
.002
T12PR12¶
17
6 (35)
ND
PR48‡
82
38 (46)
T12PR24§
81
56 (69)
.004
T12PR12¶
82
49 (60)
.12
T12P12#
78
28 (36)
.20
PR48‡
114
16 (14)
T12PR24§
115
59 (51)
< .001
T24PR48**
113
59 (52)
< .001
T24P24‡‡
111
26 (23)
.035
P Value vs
PR48
1. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 2. Hézode C, et al. N Engl J Med.
2009;360:1839-1850. 3. Manns M, et al. EASL 2009. Abstract 1044.
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SVR Rates in the SPRINT-1 Trial in TreatmentNaive Patients Infected With Genotype 1 HCV
N
SVR, n (%)
P Value vs Control
Control*
104
39 (38)
--
P/R/B 28 wks†
107
58 (54)
.013
P/R 4 wks -> P/R/B 24 wks‡
103
58 (56)
.0005
P/R/B 48 wks§
103
69 (67)
< .0001
P/R 4 wks -> P/R/B 44 wks||
103
77 (75)
< .0001
P/low-dose R/B 48 wks¶
59
21 (36)
NR
Treatment Arm
*Control: peginterferon alfa-2b 1.5 g/kg/wk + weight-based ribavirin (800-1400 mg/day) for 48 wks.
†P/R/B 28 wks = boceprevir 800 mg 3 times daily + peginterferon alfa-2b + weight-based ribavirin for
28 wks (no lead-in phase).
‡P/R 4 wks -> P/R/B 24 wks: peginterferon alfa-2b + weight-based ribavirin for 4 wks (lead-in phase),
then boceprevir + peginterferon alfa-2b + weight-based ribavirin for 24 wks.
§P/R/B 48 wks: boceprevir + peginterferon alfa-2b + weight-based ribavirin for 48 weeks (no lead-in
phase).
||P/R 4 wks -> P/R/B 44 wks: peginterferon alfa-2b + weight-based ribavirin for 4 wks (lead-in phase),
then boceprevir + peginterferon alfa-2b + weight-based ribavirin for 44 wks.
¶P/low-dose R/B 48 wks: boceprevir + peginterferon alfa-2b + low weight-based dose ribavirin
(400-1000 mg/day) for 48wks.
Kwo P, et al. EASL 2009. Abstract 4.
Mechanisms of Response and
Nonresponse to HCV Treatment
Raymond T. Chung, MD
Associate Professor of Medicine
Department of Medicine
Harvard Medical School
Director of Hepatology
Medical Director, Liver Transplant Program
Massachusetts General Hospital
Boston, Massachusetts
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Recognition of HCV RNA by RIG-I & TLR3 &
Activation of Type I Interferon Transcription
Endosome
Cytoplasm
RIG-1
5'-ppp
TLR3
IKK-
TBK1
IRF-3
Interferon b
Nucleus
Reprinted from Journal of Hepatology, Vol 50, Andrew W. Tai and Raymond T. Chung, Treatment failure in
hepatitis C: Mechanisms of non-response, 412-420, Copyright (2009), with permission from Elsevier.
http://www.sciencedirect.com/science/journal/01688278
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Classification of Interferon Response and
Nonresponse
HCV RNA (log10 IU/mL)
8
PegIFN/RBV
7
Null response/nonresponse
6
5
2 log10 decline
4
Slow virologic response
3
2
1
Limit of detection
RVR
SVR
0
0 4 8 12 18 24 30 36 42 48 54 60 66 72 78
Weeks
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Proposed Mechanisms of Suppression of Innate
and Adaptive Immune Responses by HCV
Structural and Nonstructural Proteins
Protein
Innate Immunity
Adaptive Immunity
Core
 SOCS3 induction leads to inhibition of STAT1
phosphorylation[1]
 Direct binding to STAT1 leads to proteasomal
degradation and inhibition of STAT1
phosphorylation[2,3]
 PP2A upregulation leads to STAT1
hypomethylation and binding by PIAS1[4]
 Inhibition of T cell proliferation by
binding to gC1q receptor[9]
E2
 Binding and inhibition of PKR[5]
 No known role
NS3-4A
 Cleavage of the adaptor proteins Cardif and
TRIF[4,6,7]
 No known role
NS5A
 Binding and inhibition of PKR[8]
 No known role
NS5B
 No known role
 Error prone RNA polymerase leads to
high viral mutation rates and escape
from adaptive immune responses[10]
1. Bode JG, et al. FASEB J. 2003;17:488-490. 2. Lin W, et al. Gastroenterology. 2005;128:1034-1041. 3. Lin
W, et al. J Virol. 2006;80:9226-9235. 4. Duong FH, et al. Gastroenterology. 2004;126:263-277. 5. Taylor DR,
et al. Science. 1999;285:107-110. 6. Meylan E, et al. Nature. 2005;437:1167-1172. 7. Li K, et al. Proc Natl
Acad Sci U S A. 2005;102:2992-2997. 8. Gale MJ Jr, et al. Virology. 1997;230:217-227. 9. Kittlesen DJ, et al.
J Clin Invest. 2000;106:1239-1249. 10. Timm J, et al. J Exp Med. 2004;200:1593-1604.
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Possible Approaches to Overcoming
Interferon Resistance
Approach
Proposed Mechanism(s)
NS3-4A protease inhibitors
Inhibition of Cardif and TRIF cleavage by NS3-4A
and restoration of interferon β activation[1-3]
S-adenosyl-L-methionine
and betaine
Restoration of STAT1 methylation and rescue from
PIAS1 inhibition[4]
High-dose ribavirin
Interferon sensitization by increasing ISG
expression and decreasing expression of inhibitors
of interferon signaling[5]
Reversal of insulin
resistance
Decreasing SOCS3 expression[6]
Targeting host cofactors of
HCV life cycle
1. Meylan E, et al. Nature. 2005;437:1167-1172. 2. Li XD, et al. Proc Natl Acad Sci U S A. 2005;102:1771717722. 3. Li K, et al. Proc Natl Acad Sci U S A. 2005;102:2992-2997. 4. Duong FH, et al. Hepatology.
2006;43:796-806. 5. Feld JJ, et al. Hepatology. 2007;46:1548-1563. 6. Walsh MJ, et al. Gut. 2006;55:529-535.
Update in the Diagnosis and
Management of Decompensated
Cirrhosis
Timothy Morgan, MD
Professor, Medicine
School of Medicine
University of California (Irvine)
Orange, California
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Categories of Conditions Causing Hepatic
Encephalopathy
Type
Description (Cause)
A
Acute liver failure
B
Portosystemic bypass (shunt)
C
Cirrhosis
Mullen KD. Aliment Pharmacol Ther. 2007;25(suppl 1):11-16.
Haussinger D, et al. Gut. 2008;57:1156-1165.
Category
Episodic
Persistent
Minimal
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West Haven Criteria of Severity of Hepatic
Encephalopathy
Grade
Description
Minimal
Normal standard clinical exam;
abnormal responses to detailed psychometric tests
1
Euphoria or anxiety; shortened attention span;
mild lack of awareness
2
Lethargy or apathy; mild distortion of place or time; mild personality
changes; impaired performance on addition/subtraction
3
Confusion, disorientation, or somnolence to semistupor
but responsive to verbal stimuli
4
Coma
Atterbury CE, et al. Am J Dig Dis. 1978;23:398-406.
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Clinical Hepatic Encephalopathy Staging
Scale
Item
1. Does the patient know which month it is (eg, January, February)?
2. Does the patient know the day of the week (eg, Monday, Tuesday)?
3. Can the patient count backward from 10 to 1 without making mistakes or
stopping?
4. If asked to do so, does the patient raise arms?
5. Does the patient understand what you are saying? (Based on answers to
questions 1-4)
6. Is the patient awake and alert?
7. Is the patient fast asleep and difficult to awake/arouse?
8. Can the patient talk?
9. Can the patient speak correctly? (ie, can you understand what they say, and
do they speak without stammering)
*Clinical hepatic encephalopathy staging scale score is the sum of scores for all 9 questions.
Range is from 0 (no hepatic encephalopathy) to 9.
Ortiz M, et al. Aliment Pharmacol Ther. 2007;26:859-867.
Score*
0
1
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
Yes
Yes
No
No
No
Yes
No
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Algorithm for Screening Cirrhotic Patients
for Esophageal Varices*
Cirrhosis
No
Continued observation;
do not perform EGD
Yes
EGD
No varices
Repeat EGD
in 3 yrs
Small varices
Red
markings on
varices or
Child B/C?
No
*No previous
esophageal
variceal bleeding
Repeat EGD in 2 yrs
Moderate or large varices
Yes
NSBB adjusted to the maximal
tolerated doses to heart rates of
55-60 beats/min
Intolerant of NSBB
or patient prefers
EVL
EVL every 2-4 wks until obliterated;
repeat at 1-3 mos followed
by 6-12 mos
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Algorithm for the Management of Acute
Variceal Hemorrhage
Acute Variceal Hemorrhage
Intravenous:
octreotide 50 µg bolus
followed by 50 µg/hr
for 3-5 days
Endoscopy within 12 hrs with
banding of moderate/large
varices
EGD and EVL every 2 wks
until varices are obliterated
EGD (and EVL) after 1-3 mos
and again every 6-12 mos
Antibiotics for 7 days
Oral:
Norfloxacin 400 mg BID
Ciprofloxacin 500 mg BID
or
Intravenous:
Ceftriaxone 1 g/24 hrs
Ciprofloxacin 400 mg/12 hrs
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Algorithm for Secondary Prophylaxis of
Variceal Hemorrhage
Secondary Prophylaxis of Variceal Hemorrhage
NSBB + EVL
Rebleeding from
varices or portal
hypertension?
Yes
TIPS or
distal splenorenal shunt
No
Continue NSBB + EVL
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AASLD Recommended Treatment for
Uncomplicated Ascites
Uncomplicated ascites
2 g/day sodium diet
+
Furosemide 40 mg orally daily (maximum 160 mg orally daily)
+
Spironolactone 100 mg orally daily
(maximum 400 mg orally daily)
Runyon BA, AASLD Practice Guidelines Committee. Hepatology. 2009;49:2087-2107.
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Recommended Treatment for Refractory
Ascites
Refractory ascites
Treatment:
LVP with intravenous albumin for each 6-8 g/L of ascites removed
TIPS if:
Frequent LVP required,
bilirubin < 3 mg/dL,
CTP < 11-12,
no hepatic encephalopathy
Runyon BA, AASLD Practice Guidelines Committee. Hepatology. 2009;49:2087-2107.
Moore KP, et al. Gut. 2006;55(Suppl 6):vi1-vi12.
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Diagnostic Criteria for Hepatorenal
Syndrome
 Cirrhosis with ascites
 Serum creatinine > 1.5 mg/dL
 No improvement of serum creatinine (decrease to < 1.5 mg/dL)
after at least 2 days with diuretic withdrawal and volume
expansion with albumin (1 g/kg body weight per day, maximum
of 100 g/day)
 Absence of shock
 No current or recent treatment with nephrotoxic drugs
 Absence of parenchymal kidney disease as indicated by
proteinuria > 500 mg/day, microhematuria (< 50 red blood cells
per high-power field) and/or abnormal renal ultrasonography
Salerno F, et al. Gut .2007;56:1310-1318.
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Recommended Treatment for Hepatorenal
Syndrome
Hepatorenal syndrome
Diagnosis:
Creatinine > 1.5 mg/dL after intravenous albumin 1 g/kg/day for 2 days,
no shock or nephrotoxic drugs, no intrinsic renal disease
Treatment of HRS-1:
Midodrine 5 mg orally 3 TID (15 mg TID maximum)
Octreotide subcutaneously 100 µg TID (200 µg TID maximum)
Albumin intravenously 20-50 g/day
Salerno F, et al. Gut .2007;56:1310-1318.
Angeli P, et al. J Hepatol. 2008;48(suppl 1):S93-S103.
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Modified Child-Turcotte-Pugh Score
Factor
1 Point
2 Points
3 Points
Albumin, g/dL
> 3.5
3.5-2.8
< 2.8
Bilirubin, mg/dL
< 2.0
2.0-3.0
> 3.0
International normalized ratio
< 1.7
1.7-2.3
> 2.3
Ascites
Absent
Hepatic encephalopathy
Absent
 Child-Turcotte-Pugh Class
– A = 5-6 points
– B = 7-9 points
– C = 10-15 points
Pugh RN, et al. Br J Surg. 1973;60:646-649.
Easily controlled Large or resistant
Mild (1.0-2.0)
Chronic
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Prophylaxis of Spontaneous Bacterial
Peritonitis
Spontaneous Bacterial Peritonitis
Previous
SBP
No previous SBP
Ascites protein < 1.5 g/dL and 1 of the
following: CTP ≥ 9 and bilirubin
≥ 3 mg/dL, or creatinine ≥ 1.2 mg/dL,
sodium < 130 mEq/L, or
BUN ≥ 25 mg/dL
No
No antibiotics
Terg R, et al. J Hepatol. 2008;48:774-779.
Fernández J, et al. Gastroenterology. 2007;133:818-824.
Yes
Oral norfloxacin 400 mg QD or
oral ciprofloxacin 500 mg QD
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AASLD Recommendations for HCC
Monitoring Patient Populations
Patients for Whom HCC Surveillance Is Recommended
Hepatitis B carriers
 Asian males 40 yrs of age and older or Asian females 50 yrs of age and older
 Cirrhosis
 Family history of hepatocellular carcinoma
 Africans 20 yrs of age and older
 Noncirrhotic patients with HBeAg, high HBV DNA, elevated alanine aminotransferase, and/or
inflammation on liver biopsy
Hepatitis C, with bridging fibrosis or cirrhosis
Alcoholic cirrhosis
Genetic hemochromatosis with cirrhosis
Primary biliary cirrhosis (with histological cirrhosis)
Consider screening patients with the following conditions if they have cirrhosis
 Alpha-1 antitrypsin deficiency
 Nonalcoholic steatohepatitis
 Autoimmune hepatitis
Bruix J, et al. Hepatology. 2005;42:1208-1236.
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