treating hbv infection: sustained remission with immune control joseph sung md, phd department of...
TRANSCRIPT
Treating HBV Infection: Sustained Remission with
Immune control
Joseph Sung MD , PhDDepartment of Medicine and Therapeutics
Institute of Digestive DiseasesThe Chinese University of Hong Kong
Treatment Goals in CHB
Sustained remission
=
Maintained remission
=
Low viraemia
+
Low viraemia
+
ALT normalisation ALT normalisation
Immune control,
no antiviral drugs
Long term viral suppression
antiviral drugs
Ganem, D. et al. N Engl J Med 2004;350:1118-1129
Why is HBV so difficult to clear?
1. Clearanceof circulating
virus
2. Inhibit newvirus
production
3. Preventionof infectinguninfected
hepatocytes
4. Preventionof reinfecting
infectedhepatocytes
5. Eliminationof cccDNAfrom infectedcells
6. Elimination of extrahepatic reservior
Immune Response to HBV Infection
DCmaturation
NK CellActivation
Innate Response
Type 1 IFN production
B cellBlocking viral spreadwith Ab production
CTLDirect recognitionof infected cells
Th1
Th2T helper cellsExpansion of
Immune response
YY
Y
Y
Adaptive Response
Ganem, D. et al. N Engl J Med 2004;350:1118-1129
Cellular Immune Responses is important to HBV Clearance
1. HBsAg particles and virions recognized by APC2. Processed antigen recognized by CD4+ and CD8+ cells3. Virus specific CD8+ cells (with help from CD4+) recognize MHC class I chain on infected hepatocytes4. Direct lysis of infected hepatocytes or relatease of IFNand TNFa
HBsAg Seroconversion: The ‘Ultimate’ Goal of Therapy in CHB
• HBsAg seroconversion1
– Represents an identical state to that achieved in patients who effectively control HBV following acute infection
– Reliable marker for the resolution of CHB, both HBeAg-positive and HBeAg-negative
• Constitutes the outcome closest to a ‘cure’ of CHB in clinical practice
– Stringent criterion, rarely achieved with current treatments within a short time frame
1. Ganem and Prince. NEJM 2004
Fattovich G et al. Am J Gastroenterol 1998
HBsAg Seroconversion: A Potent Marker of Sustained Remission
Retrospective study of 309 patients over mean follow-up of 5.7 years S
urv
ival
Pro
bab
ility
(%
)
WITH HBsAg seroconversion
WITHOUT HBsAg seroconversion
Proportion of patients surviving
Months
100
80
60
40
20
48 72 96 120 144 16824
P<0.001
Treatment Endpoint for HBeAg-positive
• During CHB infection, presence of HBeAg is associated with active and progressive liver disease
• HBeAg loss/seroconversion is the strongest indicator of lasting remission in HBeAg-positive CHB
Lok and McMahon. Hepatology 2004
84
Niederau NEJM 1996
Proportion of patients surviving Proportion free of hepatic complications
Months Months
1.0
0.8
0.6
0.4
0.2
24 36 48 60 72 8412 24 36 48 60 7212
IFN-treated WITH HBeAg loss
1.0
0.8
0.6
0.4
0.2
IFN-treated WITHOUT HBeAg loss
P=0.004* P=0.018*
*According to the proportional hazards model
HBeAg Loss Following IFN Treatment Results in Increased Survival
From CHB to Liver Cirrhosis:
Cirrhosis
Number %/year
1. Liaw YF et al. Hepatology 1988; 2. Liaw YF et al. 2005;3. Hsu et al. Hepatology 2002; 4. Chen et al. Gastroenterology 2002
HBeAg (+)1 509 3 35 2.4
(+) (+)2 134 6.8 3.5
(+) (-)2 74 6.8 1.5
HBeAg seroconversion3 269 8.6 21 0.9
HBsAg seroclearance4 189 5.3 0
Status
NumberF/U
(year)
van Zonneveld. Hepatology 2004
Time from start of therapy (years)
4 6 8 10 12 142
1.0
0.8
0.6
0.4
0.2
0
HBeAg response *
No HBeAg response
Pro
port
ion
of p
atie
nts
w
ith H
BsA
g lo
ss
* Response defined as HBeAg loss within12 months of treatment
50%
HBsAg Response After HBeAg Clearance in HBeAg-positive CHB
Long-term outcome following IFN treatment
NucleosideNucleosideanaloguesanalogues
TTHHTTSS
Immunostimulants
ImmunosuppressivesImmunosuppressivesNKCTL
+++ -
-
- Lamivudine
Prednisone
Levamisole, Thymosin
Treatment Options for Chronic HBV
AdevofirEntecavirLdT
InterferonInterferon
+
+
+-
pIFN
Approach to Sustained Remission Immune control
100%
0%
Direct viral suppressionImmuno-modulation
HB
V D
NA
Sustained phaseAssay limit
Suppress viral replication Clear infected hepatocyteInduction phase
NA
APC
CTL
NK
Lymphocyte
Th
B cell
PIFNIFN
About 14.5 years to deplete replication template with single NA
Mea
n H
BV
DN
A (
log
10 c
op
ies/
mL
)
* log10 reduction from baseline
HBV DNA Reduction On-treatment
HBeAg Seroconversion 24 Weeks Post-treatment
PEGASYS LAM
32%
P<0.01
2
4
6
8
10
12
0 6 12 18 24 30 36 42 48
-4.5*
PEGASYS
-5.8*
LAM
19%
0
10
20
30
40
50
Fried et al EASL 2005
PEGASYS vs LAM in HBeAg PositiveDespite a More Profound Viral Reduction with LAM, Sustained
HBeAg Response at Week 72 was Higher with PEGASYS
-4.1*
-4.2*
Mea
n H
BV
DN
A (
log
10 c
op
ies/
mL
)
2
3
4
5
6
7
8
0 12 24 36 48
PEGASYS
LAM
HBV DNA Reduction On-treatment
Sustained Responses 24 Weeks Post-treatment
Lai et al APASL 2004 and Roche data on file
0
20
40
60
80
PEGASYS vs LAM in HBeAg NegativeDespite a More Rapid Viral Reduction with LAM, Sustained
Response at Week 72 was Higher with PEGASYS
PEGASYS LAM
59%
44%43%
29%
ALT normalisationHBV DNA <20,000 cp/mL
P<0.01
* log10 reduction from baseline
Antiviral Potency and HBeAg Seroconversion
0
5
10
15
20
25
30
35
0 1 2 3 4 5 6 7 8
HBV DNA change from baseline 1 year post treatment (log10)
HB
eA
g s
ero
co
nve
rsio
n
(%)
Adefovir(antiviral)
Lamivudine*(antiviral)
Entecavir(antiviral)
Pegasys* (antiviral + immun.)
* Study WV16240
Pegasys*+Lamivudine (antiviral + immun.)
Interferon (antiviral + immun.)
Favorable Outcome of HBV Treatment
Hoofnagle et al. Ann Intern Med 1981; Fattovich et al. Hepatology 1986; Di Bisceglie et al. Gastroenterology 1987; Niederau et al. NEJM 1996; Chu et al. Gastroenterology 2002; van Zonneveld et al. Hepatology 2004
HBeAg seroconversion
HBsAg loss/seroconversionPrevention of HCC Improved survival
HBeAg loss
Normal ALT, Reduced HBV DNA
Developments in Therapeutic Approaches: Treatment Strategies
1st choice therapy
Finite therapy course with highest chance of sustained response (remission)eg peginterferon alfa-2a or IFN
Survival
Sustainedresponse
yes
no*2nd choice therapy
Maintenance therapyeg nucleoside/tide analogues
*or IFN contraindicated / not tolerated