Hepatitis B
State of the Art
Joanna Ready, M.D.
SGNA
September, 2013
Magnitude of HBV Infection(s)
• World wide: 2 billion persons infected
— 350 million cases of chronic HBV
— 15-40% progress to cirrhosis/HCC
• US: 1.25 million persons with chronic
HBV
— In Asian Americans: 7-16% carrier rate
HBV is a life long, dynamic disease
• Changes over time
• Risk of end stage liver disease and cancer
increases with ongoing inflammation and viremia
in adults
• Fibrosis can be reversible
• Drugs can decrease fibrosis progression
• HBV can be controlled but not cured
• Reactivation can occur even in those who have
lost HBsAg
Slide 3
Who should be tested for HBV?
•
•
•
•
•
Blood and organs donors
Hemodialysis patients
Pregnant women
Infants of HBsAg + mothers
Behavioural contacts:
— Household and sexual contacts
— HIV+, MSM, IDU
• Individuals from countries where prevalence is
≥2%
• Patients receiving immunosuppressive therapy
• Abnormal ALT of unknown cause
CDC 2008
Slide 4
Geographic Distribution of
Chronic HBV Infection
Country
HBsAg+ (%)
China
5.3-122
South Korea
2.6-5.12
India
2.4-4.72
Taiwan
10-13.82
Vietnam
5.7-102
Japan
4.4-133
Africa
5-192
Russia
1.4-82
US/Europe
0.3-122
HBsAg
8:
2–8:
<2:
Prevalence (%)1
High
Intermediate
Low
1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158.
3. WHO/WPRO data.
Slide 5
Geographic Distribution of HBV Genotypes
Greenland:
A, B, D
Ae, Bj, C,
D, F
B, A/Bj
Ae
B,C,A,D
D
C
G
G
A D
D
FF1&, H
H
H
F2
E
Bj
Ba B
B3
Aa
BC D
Slide 6
Why is Genotype Important?
• Risk of cirrhosis
— B/C: highest risk of cirrhosis (B<C)
— D: also high risk
• Risk of Heptocellular carcinoma
— B/C: highest risk of HCC
— B: HCC at younger age; absence of cirrhosis
• Response to treatment
— A: most responsive to IFN
Slide 7
How to test for HBV?
• HBsAg
• Anti-HBs
• Anti-HBc
Slide 8
What to do with results?
HBsAg
HBsAb
HBcAb
• +
-
+
refer to care
• -
+
+
past infection
• -
-
-
vaccinate
• -
+
-
vaccinated
Slide 9
Hepatitis B Vaccine
• Vaccine licensed in 1982
— Plasma-derived  recombinant vaccine
— 3-dose series, high efficacy, no boosters, safe
• Since licensing, adolescents and adults at high risk
recommended to receive vaccine
• Comprehensive strategy to eliminate HBV transmission
implemented in 1991
— 1991: universal infant vaccination recommended
— 1995: expansion to include vaccination of all
adolescents ages 11-12 yrs
— 1998: vaccination of all persons age 0-18 yrs not
previously vaccinated
Slide 10
Achievements With HBV Vaccination
• Decline in acute HBV in past decade by 67%
— Reflects effects of routine infant and childhood
vaccination
• Vaccination rates high in this population but
decline to ~ 60% in adolescents
— Slowest rate of decline in adults
• Some adult subgroups showing increase in
incidence (men ≥ 19 yrs, women ≥ 40 yrs)
• Decline in risk of serious complications of chronic HBV
— Reduced rates of childhood HCC in countries of
high endemnicity
Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.
Slide 11
The phases of chronic hepatitis B
Immune
tolerance
Immune
clearance
HBeAg+ve
<
Immune
control
Immune
escape
HBeAg–ve
><
>
HBV-DNA
ALT
HBeAg +ve
chronic hepatitis
Inactive (carrier)
state*
*Previously considered to be ‘healthy carriers’
HBeAg –ve active
chronic hepatitis
Slide 12
HBV Control
the goal
• Inflammatory: normalize serum ALT, biopsy
• Virologic: decrease HBV DNA
• Immune: seroconversion
— HBeAg to HBeAb
— HBsAg to HBsAb
• HBV never “cured” but controlled
Slide 13
Who should be considered for treatment?
Immune
tolerance
Immune
clearance
HBeAg+ve
<
Immune
control
><
Immune
escape
HBeAg–ve
>
HBV-DNA
ALT
treat
treat
HBeAg +ve
chronic hepatitis
Inactive (carrier)
state
HBeAg –ve/+ve active
chronic hepatitis
Slide 14
Overview of Algorithm Used to Determine
Need for Treatment of HBV
HBeAg Positive
HBV DNA >20,000 IU/mL
HBeAg Negative
HBV DNA >2,000 IU/mL
ALT Level
Elevated ALT
Normal ALT
Monitor ALT
Q3mos for 1y
Treat
Consider Liver
Biopsy If >40yrs
Significant fibrosis or
inflammation
Lok AS et al Hepatology, 2009
Slide 15
Approved HBV treatments 2013
• Interferon alfa-2b – 1991
• Lamivudine – 1998
• Adefovir – 2002
• Entecavir – 2005
• Peginterferon alfa-2a – 2005
• Telbivudine – 2006
• Tenofovir - 2008
For HIV:
— Emtricitabine
— Tenofovir + emtricitabine (single pill co-formulation)
Slide 16
Therapeutic endpoints over time
Improved
Improved
Anti-HBs+ survival
histology
Loss of
Anti-HBe+
HBsAg
Loss of
HBeAg
Loss of
HBV DNA
TIME
Slide 17
Treatment Goals in CHB: Remission
Differences between the two strategies
On-therapy
Off-therapy sustained
maintained response
response
=
Low viremia
=
Low viremia
ALT normalization
ALT normalization
Continued need for
Immune control,
antiviral drugs
no antiviral drugs
Slide 18
HBV Nucs: Nonresponse, Suboptimal
Response, and Virologic Breakthrough
Change in HBV DNA
(log10 IU/mL)
1.0
Antiviral Drug
Primary
nonresponse
0
Virologic
breakthrough
-1.0
Suboptimal
response
-2.0
-3.0
Nadir
-4.0
0
6
1 log
12
18
Months
Lok AS, et al. Hepatology. 2007;45:507-539.
Slide 19
HBeAg Seroconversion Rates Over
Time in HBeAg-Positive Patients
HBeAg Seroconversion (%)
Not head-to-head trials; different patient populations and trial designs
100
Extended Treatment With Nucleos(t)ide Analogues* vs
Limited Duration (1 Yr) Peginterferon Treatment
80
Entecavir
Tenofovir
Peginterferon
60
39
40
20
31
21
22 22-27
26 29-32
35
26
0
1.0 Yr
1.5-2.0 Yrs
3.0-4.0 Yrs
*With sustained undetectable HBV DNA.
Chang TT, et al. J Viral Hepat. 2009;16:784-789. Chang TT, et al. AASLD 2006. Abstract 109. Lau GK, et al. N Engl J Med.
2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology.
2008;135;459-467. Heathcote J, et al. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483.
Janssen HL, et al. Lancet. 2005;365;123-129.
Slide 20
HBsAg Loss Over Time in HBeAgPositive Patients
Not head-to-head trials; different patient populations and trial designs
HBsAg Loss (%)
100
Extended Treatment With Nucleos(t)ide Analogues*
vs 1 Yr Peginterferon Treatment
80
Entecavir
Tenofovir
Peginterferon
60
40
20
2
3
5
5
6
0
1.0 Yr
8
6
1.5-2.0 Yrs
8
NA
3.0-4.0 Yrs
*With sustained undetectable HBV DNA.
Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al.
Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008.
Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129.
Slide 21
Undetectable HBV DNA Over Time in
HBeAg-Negative Patients
Not head-to-head trials; different patient populations and trial designs
Undetectable HBV DNA (%)
Extended Treatment With Nucleos(t)ide Analogues vs
1 Yr Peginterferon Treatment
100
90
96
93
80
100*
91
87
Entecavir
Tenofovir
Peginterferon
63
60
40
20
15
NA
0
*Single center study.
16
1 Yr
2 Yrs
3 Yrs
Lok AS, et al. Hepatology. 2009;50:661-662. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. AASLD 2009.
Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136:2169-2179. Baqai S, et al. AASLD 2009. Abstract 476. Lai CL,
et al. Hong Kong International Liver Congress 2006.
Slide 22
HBsAg Loss Over Time in
HBeAg-Negative Patients
Not head-to-head trials; different patient populations and trial designs
100
Extended Treatment With Nucleos(t)ide Analogues*
Vs 1 Yr Peginterferon Treatment
Patients (%)
80
Entecavir
Tenofovir
Peginterferon
60
40
20
0
<1 0
4
1.0 Yr
<1 0
9
7
1.5-2.0 Yrs
NA 0
3.0-4.0 Yrs
*With sustained undetectable HBV DNA.
Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455.
Marcellin P, et al. AASLD 2008. Abstract 146. Shouval D, et al. J Hepatol. 2009;50:289-295.
Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract 683.
Slide 23
Duration of nucleoside analogue
treatment in Chronic HBV
• HBeAg-positive: until HBeAg seroconversion to anti-HBe
and consolidation 6-12 mos (80% durable)
• HBeAg-negative: until HBsAg clearance
— Normal ALT and HBV DNA low in 65-70% at 5 years
— ADV d/c Rx 5y: 18/33 inactive and 13/18 cleared HBsAg
— IFN f/u 5y 230 pts: 12% lost HBsAg
• Compensated cirrhosis: long-term treatment unless
confirmed HBsAg clearance
• Close monitoring for viral relapse and hepatitis flare is
mandatory if treatment is stopped
• Decompensated cirrhosis and post-liver transplantation:
life-long treatment
Lok AASLD 2009; Hadziyannis Gastro 2012
Slide 24
Selection of Entecavir vs Tenofovir
21 21
Response at Wk 48-52 (%)
Tenofovir
• HBeAg pos
6.9
6.2
• HBeAg neg
5.0
4.6
• NA naive
1.2 (Yr 5)
0 (Yr 3)
• Lamivudine
experienced
51 (Yr 5)
NR
Pregnancy
rating
Class C
Class B
None
Renal toxicity;
↓ BMD
Log HBV DNA
↓ at Wk 48-52
25
20
Entecavir
Tenofovir
15
10
5
2
0
Entecavir
HBeAg
seroconversion
3
<1 0
HBsAg
loss
HBeAg Positive
HBsAg
loss
Genotypic
resistance, %
AEs
HBeAg Neg
Lok AS. Hepatology. 2010;52:743-747.
Slide 25
HBV Therapy and Chronic renal
disease
• All nucleos(t)ide analogues must be dosed
according to GFR in patients with chronic
kidney disease (CKD)
• TDF can cause renal disease
— TDF filtered by glomerulus
— Toxicities reported:
• Acute tubular necrosis
• Fanconi’s
– Proteinuria/glucosuria/phophoturia/hypokalemic
RTA/bone loss
• Diabetes insipidus (rare)
Slide 26
Tenofovir Nephrotoxicity
• Exposure in 10,841 HIV+ VA pts on ART from 1997–
2007
— Events: 3400 proteinuria, 3078 GFR (>3ml/min/y) and
533 CKD (<60 ml/min)
— De novo appearance of 3 of 5 of proteinuria, glucosuria,
hypophosphatemia, hypouricemia, Cr.
• 51 HBV patients followed for mean 6.4y
• 7/51 had renal tubular dysfunction
— Associated with older patients, lower baseline GFR
— Improved with switch to ETV
Scherzer and Shlipak AIDS 2012; Gara and Hoofnagle AASLD 2011
Slide 27
Efficacy of Entecavir vs Tenofovir in the
Setting of Resistance
• Similar antiviral activity against nonresistant HBV;
efficacy against drug-resistant strains differs
Activity
According to
Resistance
LAM/LdT
resistance
ETV resistance
ADV resistance
TDF resistance
Entecavir
Tenofovir
Decreased
Active
-Active
Active
Decreased
Active
--
Lok AS. Hepatology. 2010;52:743-747.
Slide 28
Potency of HBV DNA suppression
NAs: Potency versus resistance
Nucleoside analogue
Nucleotide analogue
TDF
ETV
LdT
LAM
ADV
Likelihood of resistance development
Slide 29
Antiviral resistance increases over time
80
Incidence of resistance (%)
Lamivudine1
70%
65%
Adefovir2
60
Entecavir (LAM-resistant)3
53%
Entecavir
(naive)3 ***
Telbivudine4
40
42%
40%
29%
25%
24%
20%
20
18%
15%
12%
11%
5%
0
0.1% 0%
Year 1
0.3% 2%
Year 2
0.4%
0.8%
Year 3
Year 4
Year 5
Resistance to NAs…is it just a matter of time??
1
Lai, Clin Infect Dis 2003; 2 Westland, Hepatology 2003;
3
Colonno R, EASL 2007; 4 Gane, EASLSlide
2006
30
Special Populations with HBV
• Cirrhosis
• Decompensated cirrhosis
• Organ transplantation
• Acute hepatitis B
• Pregnancy
• Co infection with HCV or HDV
• Chronic renal failure
• Children
Slide 31
Cirrhosis
• 5 y Survival 84% for compensated
• 5 y Survival 14-35% for decompensated6
• Interferons are safe and effective in compensated HBV
cirrhosis only1
• Nucleoside analogues have been shown prospectively to
be safe, decrease rates of liver decompensation and to
decrease the development of HCC2
• All cirrhotic patients with HBV DNA>2000 IU/mL should
be treated regardless of ALT3-5
• Many experts recommend treating compensated
cirrhotics with any detectable viral load3
1Buster,
2007; 2Liaw, 2004; 3Keeffe, 2008; 4Liaw 2008 (APASL); 5Lok 2007; 6Kim 2004
Slide 32
Treatment decreases HBV disease progression
even with YMDD mutant status
Patients with disease
progression (%)
25
Placebo (n=215)
YMDD mutants (n=209) (49%)
Wild-type (n=221)
20
21%
15
13%
10
5%
5
0
0
6
12
18
24
30
36
Time after randomisation (months)
Liaw et al. N Engl J Med 2004
Slide 33
Lamivudine in
Decompensated Cirrhosis
23 consecutive UCSF patients compared with
23 historical controls
Survival (%)
100
80
Lamivudine treated
60
P < .001
40
Controls
20
0
0
6
12
18 24 30
Time (mo)
36
42
48
Cumulative probability of survival without liver transplantation
Yao FY, et al. Hepatology. 2001;34:411.
Slide 34
Liver Transplantation and HBV
Progress in Past Decade
HBIG
LAM
Era 1 (1987-1991)
1
0.9
0.9
0.8
0.8
P < 0.01
Survival %
Survival %
Era 3 (1997-2002)
1
Other
0.7
HBV
0.6
0.5
0
1
2
3
Time (years)
4
5
• 5-year survival rates ~50%
• Many centers consider HBV
to be contraindication for LT
HBV
0.7
P = .14
Other
0.6
0.5
0
1
2
3
Time (years)
4
5
• 5-year survival rates as
good or better than for
other indications for LT
Kim WR, et al. Liver Transpl. 2004;10:968.
Slide 35
Pregnancy and Hepatitis B
• Vertical transmission remains the most
frequent route of infection worldwide
— Endemic areas:
• 20% women of childbearing age infected with HBV
• Perinatal acquisition: 90% rate of chronicity
– In contrast to:
» Acquisition age 1-5: 20-30% chance of chronic
infection
» Acquisition as adult: < 5% chance of chronic infection
• Risk of infection to the infant:
— HBeAg + status of the mother
— Viral load of the mother
• >106 copies/mL; 200,000IU/ml
Slide 36
Pregnancy (cont)
• HBIg and HBV vaccination
— HBIg within 12 hrs of birth & HBV vaccination series by
month six:
• Beasley et (1981): reduction of HBV transmission from 90% to
26% with HBIg
• Follow up studies using active and passive immunization: 3-7%
rate of transmission to the infant
• Failures: eAg positive mothers with high viral loads
• Data on the Rx of HBV during pregnancy remains
limited:
Category B
Category C
telbivudine
lamivudine
tenofovir
entecavir
emtricitabine
adefovir
Slide 37
Pregnancy (cont)
• All current drugs have the potential for
mitochondrial toxicity  lactic acidosis
syndrome; deleterious effects on
organogenesis; no study has reported longterm effects (i.e. after one year)
• Safety data:
— Antiretroviral Pregnancy Registry (APR) & the
Development of Antiretroviral Therapy Study
(DART):
• 112 mono-infected patients Rx with antiretrovirals:
– 2.7% birth defects (APR); 3% (DART)
– 2.4% in all births reported by CDC
Slide 38
Pregnancy (cont)
•
Lamivudine most extensively studied agent
—
Suu et al (2003):
• 38 women who became pregnant on lamivudine
– None of the infants positive at 1 year
– 26% of historical controls
—
von Zonneveld et al (2003):
• 8 women eAg + with DNA >1.2 X 109 during the last 4 weeks of pregnancy
– 1 of 8 infants sAg positive at 1 year (12.5%) vs 28% of historical controls
—
Xu et al (2009):
• Double-blind, placebo-controlled trial of lamivudine and immunoprophylaxis
during the last 8 weeks of pregnancy vs HBIg and HBV vaccination alone
–
–
–
–
–
151 women
18% of babies in arm A were sAg positive at 1 year
39% of babies in arm B were sAg positive at 1 year
In large part due to a significant number of mothers/infants lost to follow-up
For those with complete data:
» At 1 year: 13% positive in arm A
31% in arm B
no significant difference
• No study has reported increased adverse fetal events
with lamivudine
Slide 39
Pregnancy (cont)
• Tenofovir
— Class B drug
— High genetic barrier to resistance
— No increased adverse fetal events
• Telbivudine
— Similar results
— Low genetic barrier to resistance
• No published studies using entecavir, adefovir,
emtricitabine to prevent vertical transmission
• Current CDC/AASLD guidelines have not made
specific recommendations regarding the treatment of
pregnant women with HBV
Slide 40
Pregnancy (cont)
• Effect on successful delivery
— Theoretical but not proven:
• Increased bleeding/abruption
• Gestational diabetes
• LBW
• Pregnancy’s effect on HBV
— Rare, usually eAg + mothers
• Effect of Rx on mother’s disease:
— No change in disease progression
— Stopping Rx after delivery:
• ALT flare 12-25%; rarely clinically significant; responds
to reinstitution of Rx
– 12-17% of women will have a mild flare after deliver without
withdrawal of drugs
Slide 41
Pregnancy (cont)
• When to begin treatment?
— No data available
• First/second trimester if mother has evidence of
significant liver impairment/ongoing damage
– High ALT and VL
– Evidence of fibrosis  low platelet count; radiographic
evidence
• Check VL at the end of the second trimester consider
Rx for VL>106 (200,000IU/ml) OR history of prior
children with chronic hepatitis B, regardless of the VL
• When to end treatment?
— Again, no data available
— Consider if in immunotolerant phase
— Risk  hepatic decompensation
Slide 42
Slide 43
Slide 44
Reactivation of HBV
• High rate of reactivation in
immunosuppressed patients
— Chemotherapy
— HIV after immune reconstitution
— Post organ transplant
— Biologic response modifiers: rituximab (antiCD20), TNF- inhibitors: GI, hematologists,
rheumatologists, dermatologists
• Reactivation can occur in immunocompetent
treated with steroids, BRMs
Slide 45
Reactivation of HBV
• Highest in HBV active disease
— HBsAg and HBeAg pos, high HBV DNA
— HBsAg and HBeAb pos, low HBV DNA
— HBsAg neg, anti-HBs neg, anti-HBc pos
• “occult HBV”
— Deaths occur in all groups
• ALL patients undergoing chemotherapy must
have tested HBsAg, HBsAb and HBcAb prior
to treatment
Slide 46
Screening for Liver Cancer:
Lack of Consensus
• Optimal age for initiation of screening unknown1
— Patients ≥ 35 yrs are at much higher risk for HCC than
those < 35 years2
— Asian males aged 40; females aged 50
— Sub-Saharan Africans > 20
— Cirrhosis, any age
— Co-infection with HCV/HIV
Current
AASLD
guidelines
— ? ETOH
• Among HBV-infected individuals, HCC can occur at any age,
including childhood (genotype B?)
• Up to 1/3 of patients with HCC have normal AFP
• AFP may be elevated in 1/3 of patients with cirrhosis without
HCC
1. Lok AS, and McMahon BJ. Hepatology. 2001; 34:1225-1241.
2. Liaw YF, et al. Gastroenterology. 1986;90:263-267.
Slide 47
HBV is a dynamic disease
•
Diagnose
•
Initial evaluation includes education
— Family and sexual contacts should be tested
— counsel drugs to avoid- steroids, chemo, BRM
•
Monitor as status changes over time
— ALT /HBV DNA may not remain normal over time
especially in anti-HBe
•
•
Selection who to treat
•
Individualize treatment decisions
•
Change if no/ poor response
Long term monitoring HCC, reactivation
Slide 48
HBV: The importance of monitoring
HBV is a dynamic disease!!!
Require treatment
60%
40%
Require monitoring…
• Inactive disease may not remain inactive
• Liver damage may occur if HBV reactivates
HBV can be controlled but not cured
Slide 49
Serology of HBV (addendum)
Infection
ALT HBeAG AntiHBV DNA
HBeAb IU.ml
histology
Immune tolerant
nl
Pos+
Neg-
High
normal
Chronic
hepatitis
HBeAg +
up
Pos+
Neg-
>20,000
Active
Inactive carrier
nl
Neg-
Pos+
<2,000
normal
Chronic
hepatitis
HBeAg-
up
Neg-
Pos+
>2,000
active
Slide 50