Hepatitis B: serious liver infection virus

Hepatitis B is a viral infection that attacks the liver, caused by the Hepatitis B virus (HBV). It spreads through contact with infected blood or body fluids, such as from unprotected sex, shared needles, or mother-to-child during birth. Symptoms include fatigue, jaundice, nausea, and abdominal pain, though some people show no signs. It can lead to chronic liver disease, cirrhosis, or liver cancer. The disease is preventable through vaccination, which provides long-term protection.

1. Options in
Hepatitis B Management
Augusto Jose G. Galang, MD.,
FPCP, FPSG, FPSDE

2. Objectives
•Hepatitis B as a significant public health
problem
•Currently available treatment options for
chronic hepatitis B
–Who to treat? When to start? When to stop?
•Unique features of Clevudine
–Comparison with other antiviral agents

3. What We Should Know
About Hepatitis B

4. Types of Viral Hepatitis
A B C D E G
Source of
virus
Feces Blood, body
fluids
Blood, body
fluids
Blood, body
fluids
Feces Blood
Route of
Transmissio
n
Fecal-
Oral
Childbirth,
needles, sex,
transfusion
Needles,
transfusion
(sex,
childbirth)
Needles,
sex,
transfusion
(requires
HBV co-
infection)
Fecal-OralTransfusion
(requires
HBV, HCV,
or HIV co-
infection)
Chronic
Infection
No Yes Yes Yes No No
(whether it’s
pathogenic
to humans
remains
unclear)
Prevention
Vaccine
Immuno-
globulin
Vaccine
Immuno-
globulin
Blood donor
screening,
risk
management,
education
HBV
Vaccine
Ensure
safe
drinking
water
Blood donor
screening
CDC fact sheets, available at www.cdc.gov

5. Chronic hepatitis B (CHB) is a
major public health problem
Chronic Chronic
InfectionInfection
CirrhosisCirrhosis
Liver FailureLiver Failure
Liver Cancer (HCC)Liver Cancer (HCC)
DeathDeath30%30%
23% in 5 yr23% in 5 yr
Liver Liver
TransplantatioTransplantatio
nn
Acute flareAcute flare
10%–15% in 5 yr10%–15% in 5 yr
5%–10%5%–10%
~15%–40% of people with chronic hepatitis will progress to
cirrhosis and end-stage liver disease
1
Fattovich G, et al. Semin Liver Dis. 2003;23:47-58.
Fattovich G, et al. Gastroenterology. 2004;127:S35-S50. Torresi J & Locarnini S. Gastroenterology. 2000;118:S83-
S103.
Fattovich G, et al. Hepatology. 1995;21:77-82. Perrillo RP, et al. Hepatology. 2001;33:424-432.

6. The Global Impact of Hepatitis B
WHO and CDC fact sheets, available at www.who.int and www.cdc.gov
Almost half of the world’s population lives in an area with high
HBV prevalence
World population
6 billion
2 billion with evidence of
HBV infection
300–400 million with
chronic HBV
15–25% die of
cirrhosis or
liver cancer

7. HBsAg Prevalence
High (≥ 8%)
Intermediate (2% to 8%)
Low (< 2%)
Mast EE, et al. MMWR Recomm Rep. 2006;55:1-33.
Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168.
HBsAg
Positive, %
Taiwan 10.0-13.8
Vietnam 5.7-10.0
China 5.3-12.0
Africa 5.0-19.0
Philippines
5.0-16.0
Thailand 4.6-8.0
Japan 4.4-13.0
Indonesia
4.0
South Korea
2.6-5.1
India 2.4-4.7
Russia 1.4-8.0
US 0.2-0.5
The Philippines is
hyperendemic for Hepatitis B

8. Why Should Filipinos Be
Aware of Hepatitis B?
•As many as one in ten Filipinos have
chronic hepatitis B
•It is considered as the silent Asian
epidemic
•Most do not even know they are infected

9. How is hepatitis B life-threatening?
•One in four carriers of the hepatitis B virus will
eventually die of liver cancer or liver failure
•Hepatitis B is the most common cause of liver
cancer and liver cirrhosis among Filipinos
•Liver cancer is the 4
th
most common cause of
cancer among Filipinos and is the 2
nd
leading
cause of cancer-related deaths in the Philippines

10. Who are at risk for hepatitis B?
•Individuals born in
endemic areas
•Infants born to HBsAg+
mothers
•Those with a family
history of liver disease
such as liver cirrhosis
and liver cancer
•Recipients of blood
products, including
transfusions before 1990s
•Hemodialysis patients
•Healthcare workers
•Sexual partners of HBV
carriers
•People with sexually
transmitted diseases
•Intravenous drug users
•People with multiple
sexual partners

11. Why is hepatitis B often not
diagnosed?
•The danger of hepatitis B lies in its silent
transmission and progression
•Many have no symptoms and feel
perfectly healthy

•Often they have normal blood tests and
are granted a clean bill of health

12. Why is hepatitis B often not
diagnosed?
•The diagnosis cannot be made unless you do a
specific blood test for the hepatitis B surface
antigen (HBsAg)
•Early detection not only benefits the carrier, but
will also prevent the infection from being passed
silently from one child to another and from one
generation to another.

13. •Previously healthy
•Recent onset of
symptoms
•Flu-like symptoms
•Jaundice
•Abdominal pain
•Elevated serum
transaminases (ALT
and AST >1000)
•No symptoms
•Normal laboratory
tests
•Positive hepatitis
serologies
discovered
incidentally
•Symptoms in
advanced stage of
disease
ACUTE HEPATITIS CHRONIC HEPATITIS
How does a patient with
Viral Hepatitis present?
Depends on the age of acquisiton of the infection

14. Diagnosis: Chronic Hepatitis B
•Asymptomatic
•HBsAg reactive > 6 months
•Anti-HBc IgG reactive
•HBeAg or anti-Hbe reactive
•Normal or abnormal serum ALT
•Detectable HBV DNA
•Liver biopsy not required for the diagnosis

15. Objectives
•Hepatitis B as a public health problem
among Filipinos
•Available treatment options for chronic
hepatitis B
–Who to treat? When to start? When to stop?
•Unique features of Clevudine

16. Interferon alfa-2b
Lamivudine
Adefovir
Peginterferon alfa-2a
Telbivudine
Tenofovir
1990 1998 2002 20052006 2008
Entecavir
Evolution of Therapies for
Chronic Hepatitis B Over Time
2007
Clevudine

17. Is Treatment Available?
•There are 7 drugs available in the Philippines
in the form of injections and tablets
•Not 100% effective in eradicating the infection.
Cure or HBsAg loss is rarely achieved
•It can only suppress or control disease activity
and reduce complications to your liver
•Not everyone is a candidate for treatment
•Criteria for initiating antiviral treatment

18. Ultimate goal Cure
Clear
HBsAg
Surrogate
Endpoints
Suppress
virus
HBeAg
serocon-
version
†
Increase
survival
†
HBeAg-positive patients only
Prevent
cirrhosis
Prevent
HCC
Improve
liver
disease
Normalize
ALT
Long termShort term
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936−62.
Lok AS, McMahon BJ. Hepatology. 2007;45:507−39.
Treatment Goals

19. Treatment is not for everyone
•Expensive
•Individualized and tailored to your patients
needs
•Long term commitment
•Need for monitoring to evaluate response
•Should not be stopped abruptly as this
can have adverse effects
•Compliance important because of
emergence of resistance

20. Phase of Infection Progression to
Cirrhosis (%/year)
Immune Tolerant Phase 0.5%
Immune Clearance Phase* 2-6%
Low or Non-replicative Phase 0.9%
Reactivation Phase* 8-10%
* May benefit from antiviral therapy
HSP Guidelines on the Evaluation of the Hepatitis B Surface
Antigen Positive Worker for Employment
Who to Treat?
Identifying those at-risk for complications

21. In the past …
HBeAg POSITIVE
Anti- HBe NEGATIVE
HBeAg NEGATIVE
Anti- HBe POSITIVE
REPLICATIVE NON - REPLICATIVE
ACTIVE INACTIVE
NO TREATMENT
“HEALTHY CARRIER ”

22. Phases of Chronic
Hepatitis B Infection

23. Phase of Infection Progression to
Cirrhosis (%/year)
Immune Tolerant Phase 0.5%
Immune Clearance Phase* 2-6%
Low or Non-replicative Phase 0.9%
Reactivation Phase* 8-10%
* May benefit from antiviral therapy
HSP Guidelines on the Evaluation of the Hepatitis B Surface
Antigen Positive Worker for Employment
Who to Treat?
Identifying those at-risk for complications

24. When to Start Treatment?
•ALT greater than 2x ULN
•HBV DNA greater than 20,000 IU/ml
•Cirrhosis regardless of ALT as long as
HBV DNA detectable
•Prior to immunosuppressive or
chemotherapy and organ transplantation
•Findings of active inflammation and
fibrosis on liver biopsy or Fibroscan

25. When to Stop Treatment?
•Possibility of stopping treatment only when
certain endpoints are achieved
•Consolidation phase
–1 year after HBeAg seroconversion for HBeAg
positive CHB
–1 year after undetectable HBV DNA for HBeAg
negative CHB
•Need for monitoring
–Maintained response on-treatment
–Sustained response off-treatment

26. Objectives
•Hepatitis B as a public health problem
among Filipinos
•Available treatment options for chronic
hepatitis B
–Who to treat? When to start? When to stop?
•Unique features of Clevudine

27. Interferon alfa-2b
Lamivudine
Adefovir
Peginterferon alfa-2a
Telbivudine
Tenofovir
1990 1998 2002 20052006 2008
Entecavir
Evolution of Therapies for
Chronic Hepatitis B Over Time
2007
Clevudine

28. Clevudine (L-FMAU)
• Thymidine analog
• Potent in vitro activity
activity against HBV
and EBV but not HIV
• Long half-life, more
than 40 hours

29. Unique Features of Clevudine
•Reduces cccDNA
•Potent viral suppression
•Potential for a sustained response
–Maintained response while on-treatment
–Sustained response while off-treatment

30. Clevudine: Unique Mechanism of Action
•Acts directly on HBV
DNA polymerase
•Not a chain terminator
•Significantly reduced
cccDNA in woodchucks
Source: Adapted from B.Pai, et al. AAC 40:380-6, 1996
Partially double-Partially double-
stranded DNAstranded DNA
ClevudineClevudine
A(n)A(n)
Infectious Infectious
HBV virionHBV virion
(-)-(-)-DNADNA
mRNAmRNAcccDNAcccDNA
DNA polDNA pol
ReverseReverse
TranscriptaseTranscriptase
Encapsidated Encapsidated
pregenomicpregenomic
mRNAmRNA
X
X
X

31. Role of cccDNA
•Intrahepatic reservoir of the virus
•Template for the synthesis of all viral
transcripts involved in viral protein
production and replication
•Source of relapse when treatment is
stopped

32. By 30 weeks of treatment,
cccDNA levels dropped to
as much as 5.4%
of pretreatment levels
Zhu, Y., et al., J. Virology 2001;75(1):311-22
Reduction in cccDNA
after 30 weeks of Clevudine Therapy in Woodchucks

33. Unique Features of Clevudine
•Reduces cccDNA
•Potent viral suppression
•Sustained response
–Maintained response while on-treatment
–Sustained response while off-treatment
•Antiviral effect is prolonged and lasts even after
treatment is stopped

34. Clevudine showed Potent and Sustained
Antiviral Activity in Chronic Hepatitis B
HBeAg (+) HBeAg (-)
Yoo BC, Lee HS. Hepatology 2007;45:1172-78 Yoo BC, Lee HS. Hepatology 2007;46:1041-48

35. -6
-5
-4
-3
-2
-1
0
0 12 24 36 48
Week
L
o
g
1
0
c
o
p
ie
s
/m
L
Clevudine
Lamivudine
Viral Change (Median) from BaselineViral Change (Median) from Baseline
-3.2
-4.8
(N=24)
(N=25)
Clevudine shows more potent viral
suppression than Lamivudine
P<0.0001
G Lau, et al., Hepatology, Suppl.(4), 2008;48:714A

36. Serum HBV DNA Level below 300 copies/mL
0%
4%
21%
32% 32%
46%
0%
10%
38%
59%
62%
72%
0%
20%
40%
60%
80%
BL Wk12 W24 32W 40W 48W
week
(
%
)
LMV
CLV

37. HBeAg Seroconversion at 48 weeks
17%
8%
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
Clevudine Lamivudine

38. Unique Features of Clevudine
•Reduces cccDNA
•Potent viral suppression
•Sustained response
–Maintained response while on-treatment
–Sustained response while off-treatment
•Antiviral effect is prolonged and lasts even after
treatment is stopped

39. Clevudine showed Potent and Sustained
Antiviral Activity compared to placebo
HBeAg (+) HBeAg (-)
Yoo BC, Lee HS. Hepatology 2007;45:1172-78 Yoo BC, Lee HS. Hepatology 2007;46:1041-48

40. ·
Lamivudine Entecavir
TelbivudineTelbivudine ClevudineClevudine
DeMan RA, et al. Hepatology 2001;34: 578-582
Marcellin P, et al. Hepatology 2004;40:140-148Han S-HvB, et al. Expert Opin. Investig. Drugs 2005;14: 511-519
Tyrrell DLJ, et al., Hepatology 1993;18(4):112A
For most nucleos/tide
analogs,
Maintained response
on-treatment
Relapse off-treatment
Sustained response
off-treatment

41. Relapse is common
when antiviral treatment is stopped
After Treatment
Discontinuation
% Patients with
undetectable virus (<300
copies/ml)
Lamivudine at 24 weeks off
therapy (HBeAg-)
5%
Entecavir at 24 weeks off
therapy (HBeAg-)
3%
Clevudine study 302 at 24
weeks off therapy (HBeAg-)
16%
Shouval D, et al. J. Hep. 2009;50(2):289-95
Yoo BC, Lee HS, et al. Hepatology 2007;46:1041-48

42. Effect of Clevudine on cccDNA
•Acts directly on HBV
DNA polymerase
•Not a chain terminator
•Significantly reduced
cccDNA in woodchucks
Source: Adapted from B.Pai, et al. AAC 40:380-6, 1996
Partially double-Partially double-
stranded DNAstranded DNA
ClevudineClevudine
A(n)A(n)
Infectious Infectious
HBV virionHBV virion
(-)-(-)-DNADNA
mRNAmRNAcccDNAcccDNA
DNA polDNA pol
ReverseReverse
TranscriptaseTranscriptase
Encapsidated Encapsidated
pregenomicpregenomic
mRNAmRNA
X
X
X

43. Study 302(HBeAg-)
Wk 0 Month 24
Study 301(HBeAg+)
Complete Response for HBeAg-Patients :
HBV DNA <4,700 copies/mL
normal ALT
Complete Response for HBeAg+ Patients:
HBV DNA <4,700 copies/mL
Normal ALT
HBeAg seroconversion
Study 303
Clevudine30 mg for 24 weeks
Clevudine10 mg for 24 weeks
Follow- up without treatment for 12 or 24 weeks
Study 304
Long-term follow up of patients with
complete response to Clevudine

44. Patients receiving no treatment for 2 years
HBeAg
positive
(N=26)
HBeAg
negative
(N=37)
Total
(N=63)
HBV DNA <141,500 c/mL 77% 70% 73%
HBV DNA <10,000 c/mL 54% 38% 44%
HBV DNA <4,700 c/mL 46% 27% 35%
Normal ALT 88% 65% 75%
Maintained HBeAg
seroconversion
81% 81%
HBsAg loss 8% 3% 5%
Complete responders to clevudine showed sustained antiviral activity
during follow-up at 2 years

45. Complete responders after
clevudine therapy
5% HBsAg loss after
cessation of therapy
Sustained viral
suppression
Finite Duration of Treatment Possible ?

46. Conclusion
Clevudine shows promising potential
as a
First-line antiviral therapy
for HBeAg(-) as well as
HBeAg (+) chronic hepatitis B

47. Cumulative annual incidence of resistance

48. * Lamivudine-resistant mutations
during 48-week treatment period
Treatment group Mutations
Clevudine None
Lamivudine 9 (31%)

49. Myopathy as an adverse effect of
Clevudine therapy
•Incidence : 0.2% (7/3000)
•Onset after 8 to 13 months or treatment
• Characterized as slowly progressive proximal muscle
weakness, elevated creatine kinase, myonecrosis on
muscle biopsy, typical pattern on EMG
• All recovered after discontinuation of clevudine
•
Seok et al Hepatology 2009

50. Summary: Clevudine
• Potent viral suppression
• Sustained effect without rapid viral rebound after
cessation of therapy
• Reduction in HBsAg titer and HBsAg loss after
cessation of therapy in a subset of patients
•Possibility of finite duration in a subset of patients
• Myopathy and resistance in a few patients

51. Interferon alfa-2b
Lamivudine
Adefovir
Peginterferon alfa-2a
Telbivudine
Tenofovir
1990 1998 2002 20052006 2008
Entecavir
Choosing the right one
2007
Clevudine

52. Thank You

54. Emerging Role
of HBsAg Quantification

55. -3
15−<35 ≥35
High
≤0.5−<15
Low
L
o
g

c
c
c

D
N
A
/
c
e
l
l
-2
-1
0
1
2
P=0.0001
Serum HBsAg levels reflect
levels of Intrahepatic cccDNA
HBsAg (µg/ml)
P=0.004
Werle-Lapostolle et al. Gastro 2004; Volz et al. Gastro 2007
Serum HBsAg
levels as a
non-invasive
indicator of the
number of
infected cells in
the liver

56. Serum HBsAg quantitation can
predict treatment response
Reduction of HBsAg:
good correlation with reduction in log [ccc DNA]
Chan HL et al. Clin Gastroenterol Hepatol 2007;5:1462-8

57. Sustained Viral Suppression of clevudinewas correlated with
greater decrease of serum HBsAgduring follow-up
mean HBV DNAchange from BL(log c/mL)
meanHBsAgchange from BL (log IU/mL)
CLV 304-Follow upCLV 304-Follow up
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
D1W12W24 M3M6M9M12M15M18M21M24
H
B
s
A
g
lo
g

c
h
a
n
g
e
SVR non-SVR
-5
-4
-3
-2
-1
0
D1W12W24 M3M6M9M12M15M18M21M24
H
B
V

D
N
A

lo
g

c
h
a
n
g
e
SVR non-SVR
In the subset achieving an SVR (35%, HBV DNA<4,700 c/mLat the end of F/U),
Clevudineshowed more pronounced HBsAgdecline,
which continued to decline for 24 months post-treatment.

58. Serum HBsAg Quantitation
•Reflects cccDNA in the liver
•Reduction in serum HBsAg titer correlates
with reduction of intrahepatic cccDNA
•Early and steady decline of HBsAg titer
during treatment is a strong predictor of
SVR and HBsAg loss

59. A comparison of 24 and 48 weeks A comparison of 24 and 48 weeks
treatment efficacy between treatment efficacy between
clevudine(n=62) and entecavir (n=59) clevudine(n=62) and entecavir (n=59)
therapy in treatment-naïve patients with therapy in treatment-naïve patients with
chronic hepatitis Bchronic hepatitis B
SR Shin J Hepatol. Suppl.(1), 2009;50:S11

60. HBV DNA reductionHBV DNA reduction
*
Data of 48 weeks are available in 54 patients
0.0
2.0
4.0
6.0
8.0
0 week 24 week 48 week*
CLV
ETV
-5.65 log
10
H
B
V

D
N
A
(

l
o
g
1
0

I
U
/
m
l
)
-5.81 log
10
-5.73 log
10 -5.81 log
10

61. Virologic ResponseVirologic Response
HBV DNA less than 12 IU/mL by real-time PCR
0
20
40
60
80
100
CLV ETV
33/62
(53.2%)
36/59
(61.0%)
10/14
(71.4%)
48 weeks
*
24 weeks
27/40
(67.5%)
p = 0.39 p = 0.25
33%
0
20
40
60
80
100
CLV ETV
68%
36%
71%
*
Data of 48 weeks are available in 54 patients

62. Virologic ResponseVirologic Response
CLV ETV
Primary non-response
1
0 0
Partial response
2
29 23
Virologic breakthrough
3
0 0
1
Less than 2 log10 IU/ml decrease in HBV DNA level from baseline within 24 weeks of therapy
2
Decrease DNA of more than 2 log
10
IU/ml but detectable by real-time PCR at 24 weeks
3
Increase in HBV DNA of more than 1 log
10
IU/ml compared to nadir on therapy

63. Biochemical ResponseBiochemical Response
Normal ALT
0
20
40
60
80
100
CLV ETV
48/62
(77.4%)
41/59
(69.5%)
11/14
(85.7%)
48 weeks
*
24 weeks
p = 0.32 p = 0.25
0
20
40
60
80
100
CLV ETV
70%77%
80% 86%
*
Data of 48 weeks are available in 54 patients

64. HBeAg SeroconversionHBeAg Seroconversion
7/37
(18.9%)
9/39
(23.1%)
2/10
(20.0%)
48 weeks24 weeks
5/23
(21.7%)
p = 0.50
p = 0.43
0
20
40
60
80
100
CLV ETV
19% 23%
0
20
40
60
80
100
CLV ETV
22% 20%

65. Clevudine induces steady decline of HBsAg
unlike entecavir
•Changes of HBV DNA and HBsAg levels in viral responders(HBV DNA < 300 c/mL Changes of HBV DNA and HBsAg levels in viral responders(HBV DNA < 300 c/mL
at M12) during continuous clevudine(n=34) and entecavir(n=49) therapyat M12) during continuous clevudine(n=34) and entecavir(n=49) therapy

66. Summary: Clevudine vs Entecavir
•Similar potent antiviral activity at 24 and 48 weeks
•Efficacy not significantly different
•Primary non-response or virologic breakthrough
within 48 weeks of treatment was not observed in
both groups
•Clevudine showed a reduction in HBsAg unlike
entecavir