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NAs Induced Immune Response and Antiviral Therapy in Chronic Hepatitis B
Gui-Qiang WangDepartment of Infectious Diseases
Center for Liver DiseasesPeking University First Hospital
HBV immunityliver
Other organs
Persistance of Infection
Virus Host immunity Control of infection
Impaired immunityDCs, CTL, cytokinesPD-1 in active T cells regulatory T lymphocytes
Host
immunityViral
replication
cccDNAHigh viral load
Mutation Replication out of liver
Chronic hepatitis B is hard to treat
CD8 and CD4 response: Acute hepatitis B vs. Chronic hepatitis B
Acute Chronic50
40
30
20
10
0
60
45
30
15
0
Ferrari C et al. J Immunol. 1990; Penna A et al. J Exp. Med. 1991; Bertoletti A et al. Proc. Natl.Acad. Sci. USA,1991; Rehermann B et al. J Exp. Med. 1995; Jung C et al. Virology 1999;Maini et al. J Exp. Med. 2000
Specific lysis %
Goals of CHB therapy: Sustained immune control
HBsAg clearance
Reduction of HCC and
cirrhosis, and improve
survival rate
Permanent suppression
of HBV DNA replication
ALT normalization
Sustained immune control
Antiviral therapy
After the end of therapy
HBeAg (+) patients:
sustained HBeAg seroconversion
HBeAg (-) patients:
permanent HBV suppression
lower quantitation of HBsAg
Perrillo et al. Hepatology 2006; 17. EASL guidelines 2009;van Zonneveld et al. Hepatology 2004; 19. Marcellin et al. APASL 2010
Treatment Options
AntiviralsAntiviralsMaintained remission
LamivudineLamivudineAdefovirAdefovirEntecavirEntecavirTelbivudineTelbivudineTenofovirTenofovir
Immuno-modulatorsImmuno-modulatorsAiming for sustained remission
IFNIFNαα Peg IFNPeg IFNNx cytokinesNx cytokinesVaccine therapyVaccine therapy
Treatment combinationsTreatment combinations
CD8CD8++
HBVHBV
Immune response
during NAs treatment
Lamivudine
Boni C, et al. J Hepatol, 2003, 39: 595-605.
CTL responses to individual HBV peptides containing the HLA-A2 binding motif
Boni C, et al. HEPATOLOGY 2001;33:963-971
Boni C, et al. J Hepatol, 2003, 39: 595-605.
P<0.002
Treatment initiation
40
30
20
10
0 -24-0 2-12 16-24 28-36 40-52 52-56
weeks
Lamivudine induced the restoration of anti-viral T cell responses is transient
Treatment termination
HBV specific CTL response for Sustained HBeAg seroconversion after LAM treatment
Lee CK, et al. Korea J Hepatol 2005; 11:34-42
Entecavir
Zhang J, et al. PLoS ONE 2010 Nov 30; 5(11): e13869.
Entecavir yields transient decrease of Treg cells and ratios of Treg cells to Th17 cells
Zhang J, et al. PLoS ONE 2010 Nov 30; 5(11): e13869.
During treatment of entecavir in HBeAg-positive patients, Treg cells and Treg/Th17 ratios decreased and bottomed out at 3 months and then increased, exhibiting a reverse ‘‘V’’-type change. These transient changes of Treg cells and Treg/Th 17 ratios correlate with suppression of HBV DNA.
Treg/TH17 ratios and HBV DNA levels
0 1 3 6 9 12
months
0.0
0.6
1.2
1.8
2.4
3.0
r=1.00
8 6 4 2 0
HBV DNA, log10 IU/mLT
reg
/Th
17 r
atio
s
* *§
*§
Frequency of Treg cells
months0 1 3 6 9 12
P=0.002 P=0.042 P=0.016
0
2
4
6
8
10
12
%F
ox
P3+
CD
4+ T
cel
ls
Adefovir Dipivoxil
.Jeroen N. et,al. Virology 361 (2007) 141–148
Adefovir induces transient decrease in expression of Treg cells in chronic hepatitis B patients
Jeroen N. et,al. Virology 361 (2007) 141–148
Comparison of CD4 T-cell reactivity to HBcAg in patients receiving ADV or the placebo
Cooksley H, et al. Antimicrobial agents & chemotherapy, 2008, 312–320
ADV N=13 PLB N=6
HBcAg-specific T-cell proliferation according to virological response
Cooksley H, et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2008, 312–320
Group1: HBeAg seroconversion Group2: non-responderGroup3: placebo
Telbivudine preserves Th1 cytokine production and down regulates PD-L1
in a mouse model of viral hepatitis
Telbivudine(ug/ml)
Lamivudine (ug/ml)
0 10 50 100 25 5050
*
*
*
Telbivudine enhances the production of TNF-α in MHV-3-infected macrophages compared to lamivudine
0
50
100
150
200
250
300
350
TN
F-α
(p
g/m
l)
Q.Ning et al. J Viral Hepat., 2010, 17 (Suppl. 1), 24–33.
Vitro study
Effects of antiviral therapy with telbivudine on peripheral iNKT cells in HBeAg-positive chronic hepatitis B patients
Shi TD, et al. Clin Exp Med. 2012 Jun;12(2):105-13.
0.4
0.3
0.2
0.1
0.0
0.4
0.3
0.2
0.1
0.0
*P<0.05 (vs. healthy controls) P<0.05 (vs. baseline)
Baseline 12 weeks 24 weeks 52 weeks Baseline 12 weeks 24 weeks 52 weeks
0.3
0.2
0.1
0.0
0.3
0.2
0.1
0.0
P<0.05P<0.05
P<0.05P<0.05CHB cellsCHB cells
Shi TD, et al. Clin Exp Med. 2012 Jun;12(2):105-13.
This study included 29 HBeAg-positive and HBsAg-positive CHB patients. Telbivudine was orally administered at a dose of 600 mg per day, and heparinized venous blood was taken at four study visits: baseline and treatment weeks 12, 24 and 52 to detect the frequencies, function and PD-1 expression of peripheral iNKT cells.
This study included 29 HBeAg-positive and HBsAg-positive CHB patients. Telbivudine was orally administered at a dose of 600 mg per day, and heparinized venous blood was taken at four study visits: baseline and treatment weeks 12, 24 and 52 to detect the frequencies, function and PD-1 expression of peripheral iNKT cells.
iNK
T c
ells
freq
uenc
y (%
)
IFN
+iN
KT
cel
ls fr
eque
ncy
(%)
Healthy controls
Baseline 12 weeks 24 weeks 52 weeks Baseline 12 weeks 24 weeks 52 weeks
Telbivudine continuously increased frequencies of IFN-γ iNKT cells in chronic hepatitis B patients
Baseline 12 weeks 24 weeks 52 weeksBaseline 12 weeks 24 weeks 52 weeks
* P<0.05(vs. healthy controls) P<0.05(vs. baseline)
50
40
30
20
10
0
CHB patients
.Shi TD, et al. Clin Exp Med. 2012 Jun;12(2):105-13.
Continually decreased PD-1 expression of iNKT cells in CHB patients was found during telbivudine treatment
PD
-1+ iN
K c
ells
(%
)
Healthy controls
This study included 29 HBeAg-positive and HBsAg-positive CHB patients. Telbivudine was orally administered at a dose of 600 mg per day, and heparinized venous blood was taken at four study visits: baseline and treatment weeks 12, 24 and 52 to detect the frequencies, function and PD-1 expression of peripheral iNKT cells.
This study included 29 HBeAg-positive and HBsAg-positive CHB patients. Telbivudine was orally administered at a dose of 600 mg per day, and heparinized venous blood was taken at four study visits: baseline and treatment weeks 12, 24 and 52 to detect the frequencies, function and PD-1 expression of peripheral iNKT cells.
The frequencies of PD-1+ CD4+ and CD8+ T cells during treatment with LDT
29 HBeAg positive CHB treated with LDT for 52 weeks, 19 patients achieved virological response with HBV DNA less than 60IU/ml.
Unpublished data
Conclusion
CHB is characterized by an impaired immune response to HBV.
The host immune response is crucial to control HBV infection, Neither IFN nor NAs will not work without host immune response
The immune modulatory effects of telbivudine have been broadly investigated because its higher HBeAg seroconversion rates, and shown promising data
We need further study on immunological profiles with NAs based treatment to elucidate the whole story
