B型肝炎治療新知
新竹馬偕醫院
肝膽胃腸科張瀚文
The HBV Genome
preS1
 Relaxed circular partially
preS2
(-)
double-stranded DNA
(+)
S
 Approximately 3,219 bps
 Four overlapping open
reading frames
Core
DR1
DR2
Pre-core
X
Adapted from Lee WM. N. Engl. J. Med. 1997; 337:1733–45
POL
The Life Cycle of HBV in the
Hepatocyte
Infectious
HBV virion
Subviral
Particles
HBsAg
Hepatocyte
HBeAg
ER/Golgi
Viral POL converts
pgRNA to
partially dsDNA
Partially
dsDNA
HBeAg
Encapsidated
pre-genomicRNA
cccDNA
mRNA
HBsAg
HBcAg
Pre-core/Core
Nucleus
Adapted from Lai CL and Yuen MF. J. Med. Virol. 2000; 61:367–73
HBV
Infection
15-20% HBsAg carrier in
adult
Infants
Inapparent Disease
Recovery
(<10%)
30-40%
Chronic
Infection (>90%)
60-70%
Chronic Hepatitis
2%/year
0.8%/year
Healthy Carrier
Cirrhosis
0.1%/year
3-10%/year
HCC
哪些B型肝炎容易變成肝硬化肝癌
Stage of chronic hepatitis B
Immune Immune Remission Reactivation Recover
Tolerance Clearance
stage
stage
HBsAg
+
+
+
+
--
HBeAg
+
+
--
--
--
HBV
DNA
+++
++
+-
++
--
GOT/
GPT
N
N
N
Stage
HBeAg Positive
of
chronic
hepatitis
HBeAg Negative
hepatitis
B
hepatitis
Immune Immune Remission Reactivation Recover
Tolerance Clearance
stage
stage
HBsAg
+
+
+
+
-
HBeAg
+
+
-
-
-
HBV
DNA
+++
++
+-
++
-
GOT/
GPT
N
N
N
B型肝炎如何致病？
HBV主要的致病機轉並不是直接殺死肝細胞，它是藉
由人體的免疫機轉而導致肝細胞壞死的。人體免疫系
統內的T cell，平常不會攻擊體內的正常細胞，當體內
的正常細胞遭受到病菌感染時，它就會將已受感染的
細胞殺死，目的是為了要除去入侵的病菌。
B型肝炎病毒導致肝炎就是經由這樣的途徑。T cell要
將HBV「驅除出境」，然而HBV是在肝細胞內，所以在T
cell欲除去HBV同時，肝細胞也跟著陪葬了。
Who should be tested for HBV infection
Who should be tested for HBV infection
Recommendations for Infected Persons Regarding
Prevention of Transmission of HBV to Others
Evaluation of Patients with Chronic HBV Infection
Suggested follow-up for patients not considered
for treatment
Definition of Response to Antiviral Therapy of
Chronic Hepatitis B
Definition of Terms Relating to Antiviral Resistance to
Nucleoside Analogue(NA) Treatment
Genotypes of HBV and Geographic Distribution
Genotype
Geographic Distribution
A
Africa, India, Northern Europe, United States
B
Asia, United States
C
Asia, United States
D
India, Middle East, Southern Europe, United States
E
West and South Africa
F
Central and South America
G
Europe, United States
H
Central and South America, California in United States
Int J Med Sci. 2005; 2(1): 36–40.
治療慢性B型肝炎的目標
 Stop HBV replication, ideally permanently
 Improve hepatitis: normalise ALT, HBeAg
seroconversion, improve symptoms
 Arrest/reverse hepatic fibrosis: Improve
long-term prognosis



Stop progressive liver damage  cirrhosis
Prevent HBV-related hepatocellular
carcinoma
Prolong life, or at least improve life quality
慢性B型肝炎治療之endpoints
Biochemical:
Normalisation of ALT
Virological:
 Decrease HBV DNA to <105 copies/mL
 Loss of HBeAg
Histological:
Decrease HAI score by >2 points and to
below score of 7
Complete:
 Biochemical and virological response plus
loss of HBsAg
治療慢性B型肝炎的藥物
抗病毒 (Antiviral)
Interferon
Lamivudine (3TC)
*Adefovir dipivoxil
*Entecavir
Telbivudine (L-dT)
Emtricitabine (FTC)
*Tenofovir
*Remofovir
*LB80380
*Clevudine (L-FMAU)
*L-Fd4C
*DAPD
免疫調節
(Immunomodulation)
Interferon ( PEG-IFN )
Thymosin-1
Steroid withdrawal,
IL-12
Therapeutic vaccines
無效或有毒 (Toxic or ineffective)
Acyclovir, ganciclovir, levamisole,
IL-2, ribavirin, AZT, ddI, ARA-AMP,
fialuridine, foscarnet, lobucavir,
famciclovir
*Effective for YMDD mutants
Endpoints defining efficacy of treatment
 Termination of HBV replication
 Loss of HBeAg, seroconversion to Anti-HBe
 Loss of HBV DNA by hybridization assay
 Cessation of chronic liver injury
 Normalization of aminotransferases
 Decreased symptomatology, if any
 Disease-free state
 Seroconversion to HBsAg–negative and Anti-HBs–
positive status
 Absence of HBV DNA from serum and liver tissue by
PCR
Stage of chronic hepatitis B
?
Immune Immune Remission Reactivation Recover
Tolerance Clearance
stage
stage
HBsAg
+
+
+
+
-
HBeAg
+
+
-
-
-
HBV
DNA
+++
++
+-
++
-
GOT/
GPT
N
N
N
TREATMENT OF CHRONIC
HEPATITIS B
Interferon
FDA approved
Since 1991
Action of the interferons
干擾素治療慢性B型肝炎的好處

Short treatment course (4-6 months)

40% HBeAg seroconversion (less in Asians)

Best predictors:


ALT> 5 ULN

HBV DNA <200 pg/mL

Short duration infection
Alters outcome of chronic liver disease
- Wang, NEJM, 1996
干擾素治療慢性B型肝炎的缺點
Few cases are optimal
 Most are neonatally acquired, low ALT
 Minimally effective with HBeAg (-) variants
Poorly tolerated
 Frequent unpleasant side effects
 Occasional dangerous side effects
 Hazardous for decompensated cirrhosis
Poorly accepted
 Need for injections
 Expensive
TREATMENT OF CHRONIC
HEPATITIS B
Lamivudin
(Zeffix)干安能
FDA approved Since 1998
NH2
NH2
N
N
O
O
O
P
O
P
O
P
O
O
O
(-)O
P
(-)O
O
P
O
P
N
O
O
S
(-)O
(-)O
O
O
N
(-)O
O
(-)O
(-)O
(-)O
O
OH
Deoxycytidine Triphosphate (dCTP)
Lamivudine Triphosphate (3TCTP)
Antiviral mechanism of lamivudine
Lamivudine
Infectious
HBV virion
DNA
Partially pol
doublestranded DNA
cccDNA
Infectious
HBV virion
HBsAg
envelopes
RT
(-)DNA
A(n)
mRNA
Encapsidated
pregenomic
mRNA
Lai et al., J Med Virol 2000
Lamivudine, IFN- 與安慰劑副作用的比較
Adverse event
Malaise and fatigue
Headache
Viral respiratory infection
Nausea and vomiting
Muscle pain
Temperature disturbance
Arthralgia
Depression
Feeding problems
Hair loss
Decreased white cells
Placebo
n=200
Lamivudine
n=416
IFN-
n=70
28
21
19
17
9
9
5
5
3
3
1
26
22
19
16
8
7
6
4
3
3
1
70
47
37
34
40
43
23
13
33
23
26
Integrated data from NUCB3009, NUCA3010, NUCB3010 and NUCAB3011
治療前血清ALT值與e抗原陰轉的關係
HBeAg seroconversion
Placebo
70
(%) ALT < 2X ULN
ALT 2–5X ULN
Lamivudine
ALT >5X ULN
50
30
10
0
0
8 16 24 32 40
52 0 8
16 24 32 40
52 0 8
16 24 32 40
Duration of lamivudine therapy (weeks)
52
TREATMENT OF CHRONIC HEPATITIS
B
Adefovir Dipivoxil
(干適能)
FDA approved Since 2002
Adefovir Dipivoxil
Lamivudine Naive
Adefovir in HBeAg positive CHB
(Beyond 48 weeks)
75
80
67
70
60
46
50
44
41
Week 24
Week 48
40
30
20
Week 72
26
14
23
23
14
13
8
10
0
HBV DNA
ALT
< 400 copies/mL normalization
HBeAg
loss
HBeAg
seroconversion
Marcellin, et al. AASLD 2002
TREATMENT OF CHRONIC HEPATITIS B
Entecavir
(Baraclude貝樂克)
FDA approved Since 2005
HBV DNA suppression after 2 years
treatment
HBeAg
seroconversion
Long-term ETV therapy
Chang TT Hepatology 2010
Long term ETV therapy achieved histologic improvement
Chang TT Hepatology 2010
Lont-term ETV therapy induce reversal of advanced
fibrosis or cirrhosis
Schiff ER Clin Gastrol and Hepatol 2011
TREATMENT OF CHRONIC HEPATITIS
B
Pegylated-Interferon alpha 2a
Pegasys
FDA approved Since 2004
Pegas
Pegylated interferon (PEG IFN) alpha 2-a
in HBeAg negative chronic hepatitis B
(from Marcellin et al. NEJM 2004).
Pegylated interferon (PEG IFN) alpha 2-a
in HBeAg positive chronic hepatitis B
(from Cooksley et al. Journal of Viral Hepatitis 2003).
HBeAg Seroconversion rate
May Last After Drug is Stopped
Treatment
Follow up
TREATMENT OF CHRONIC HEPATITIS B
Telbivudine (Tyzeka)
Idenix Pharmaceuticals, Inc.
FDA approved 2006
Telbivudine (LdT) vs. Lamivudine in
Lamivudine-Experienced Patients: Week 24
E Gane, R Safadi, Q Xie, et al. 57th AASLD. 2006. Abstract 1007.
Telbivudine vs Lamivudine in Chronic Hepatitis B
HBeAg+
1 year:
LDT
PCR-negative (%)
60
LAM
40
HBeAg loss (%)
26
23
HBeAg seroconversion (%)
22
21
Resistance
3
8
Primary treatment failure (%)
5
PCR-negative (%)
eAg seroconversion (%)
P
< .01
HBeAgLDT
88
LAM
71
2
7
13
0
3
69
41
84
67
33
24
< .01
P
< .01
< .01
1.5 year:
< .05
Comparison of neucletide analogues
Lamivudin Adefovir
Resistance
E seroconversion*
Durability
~70%/5yr ~29%/5yr
Telbivudi
n
<1%/3yr
~22%/2yr
~17%
~12%
~22%
~22%
50~80%
~90%
~80%
~80%
low
low
-
3.5-4.5
5.2-7.0
5.2-6.5
Flare after
Moderate
withdrawal
Viral suppression* 4.5-5.5
DNA negative*
Entecavir
32%-78% 21%-51% 69%-91% 60%-88%
Long term data
>5yr
>5yr
3 yr
2yr
Adverse effect
rare
rare
rare
rare
* 1 year data