Treatment of Hepatitis B

Marion Peters MD
University of California
San Francisco

Slide 1
 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 2
 Who should be tested for HBV?new
• Blood and organs donors
• Hemodialysis patients
• Pregnant women
• Infants of HBsAg + mothers
• Behavioural contacts:
o Household and sexual contacts
o HIV+, MSM, IDU
• Individuals from countries where prevalence is ≥2%
• Patients receiving immunosuppressive therapy
• Abnormal ALT of unknown cause

CDC 2008

Slide 3
 Overlapping HIV and HBV
Epidemics

HBV
HIV
HBsAg+

35-40 million

350-400 million
400 million

3.5- 4 million
4 million

Slide 5
Geographic Distribution of HBV Genotypes
Greenland:
A, B, D
Ae, Bj, C,
D, F
B, A/Bj A
e D
B,C,A,D G C
Bj
G
D A D B
FF&
1, H
B
H
a
H
E B3

F2 A BC D
a

Slide 6
Natural history of HBV

Slide 7
The phases of chronic hepatitis B
Immune Immune Immune Immune
tolerance clearance control escape

HBeAg+ve HBeAg–ve
< >< >
HBV-DNA

ALT

HBeAg +ve Inactive (carrier) HBeAg –ve active

chronic hepatitis state* chronic hepatitis

*Previously considered to be ‘healthy carriers’ Slide 8

HBV Control
• Inflammatory: normalize serum ALT, biopsy
• Virologic: decrease HBV DNA
• Immune: seroconversion
o HBeAg to HBeAb
o HBsAg to HBsAb
• HBV never “cured” but controlled

Slide 9
 Therapeutic endpoints over time
Improved Improved
histology Anti-HBs+ survival

Anti-HBe+ Loss of
HBsAg
Loss of
HBeAg
Loss of
HBV DNA

TIME

Slide 10
Who should be considered for treatment?
Immune Immune Immune Immune
tolerance clearance control escape

HBeAg+ve HBeAg–ve
< >< >
HBV-DNA

ALT

treat treat
HBeAg +ve Inactive (carrier) HBeAg –ve/+ve active
chronic hepatitis state chronic hepatitis

Slide 11
Overview of Algorithm Used to Determine
Need for Treatment of HBV

HBeAg Positive HBeAg Negative

HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL

ALT Level

Elevated ALT Normal ALT

Monitor ALT Consider Liver

Q3mos for 1y Biopsy If >40yrs

Significant fibrosis or
Treat
inflammation

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008

Lok AS et al Hepatology,Slide
2009 12
Approved HBV treatments 2009
• Interferon alfa-2b – 1991
• Lamivudine – 1998
• Adefovir – 2002
• Entecavir – 2005
• Peginterferon alfa-2a – 2005
• Telbivudine – 2006
• Tenofovir - 2008
For HIV:
o Emtricitabine
o Tenofovir + emtricitabine (single pill co-formulation)

Slide 13
 HBV Nucs: Nonresponse, Suboptimal
Response, and Virologic Breakthrough

1.0
Antiviral Drug
0 Primary
nonresponse Virologic
breakthrough
-1.0
ange in HBV DNA
(log10 IU/mL) Suboptimal response
-2.0

-3.0
1 log
-4.0 Nadir

0 6 12 18
Months
Lok AS, et al. Hepatology. 2007;45:507-539.
Slide 15
 HBeAg Seroconversion Rates Over
Time in HBeAg-Positive Patients

Not head-to-head trials; different patient populations and trial designs

Extended Treatment With Nucleos(t)ide Analogues* vs

100
1 Yr Peginterferon Treatment
80 Entecavir
Tenofovir
60 Peginterferon
Ag Seroconversion (%)
39 35
40 31
26 29-32 26
21 22 22-27
20

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. CCO Hepatitis
Slide 16
 HBsAg Loss Over Time in HBeAg-
Positive 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
80 Entecavir
Tenofovir
60 Peginterferon
HBsAg Loss (%)
40

20
5 5 6 6 8 8
2 3
NA
0
1.0 Yr 1.5-2.0 Yrs 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. CCO Hepatitis
Slide 17
 Predictors of HBsAg Loss in
HBeAg-Positive Patients
• Race: whites > nonwhites[1]
• Genotype[1-3]
o Nucleos(t)ide analogues: A and D
o Peginterferon: A
• Serum HBsAg decline during first 24 wks with
nucleos(t)ide analogues[1]
• HBeAg negative at or within 26 wks of completing
peginterferon treatment[3]

1. Heathcote EJ, et al. EASL 2009. Abstract 909. 2. Gish RG, et al. J Viral Hepat. 2010;17:16-22.
3. Buster EH, et al. Gastroenterology. 2008;135;459-467. CCO Hepatitis
Slide 18
 Undetectable HBV DNA Over Time in
HBeAg-Negative Patients
Not head-to-head trials; different patient populations and trial designs

Extended Treatment With Nucleos(t)ide Analogues vs

1 Yr Peginterferon Treatment
100 93 96 100*
90 91 87
80 Entecavir
63 Tenofovir
60 Peginterferon
etectable HBV DNA (%)
40

20 15 16
NA
0
*Single center study. 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. CCO Hepatitis
Slide 19
 HBsAg Loss Over Time in
HBeAg-Negative Patients

Not head-to-head trials; different patient populations and trial designs

Extended Treatment With Nucleos(t)ide Analogues*

100
Vs 1 Yr Peginterferon Treatment
80
Entecavir
60 Tenofovir
Patients (%) Peginterferon
40

20 9
4 7
<1 0 <1 0 NA 0
0
1.0 Yr 1.5-2.0 Yrs 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. CCO Hepatitis
Slide 20
 HBsAg Levels at Wk 12 of PegIFN Predict
Off-Therapy SVR in HBeAg-Negative Pts
• 48 pts pegIFN alfa-2a for 48 wks
• SVR: undetectable HBV DNA (< 29 IU/mL) at Wk 24 following
treatment completion
• Change in HBsAg level from baseline to Wk 12 evaluated as
predictor of SVR
o Cutoff: 0.5 log10 IU/mL decrease
o PPV: 89% – NPV: 90%

Decrease in HBsAg From Baseline to Wk 12

Outcome, % (n) ≥ 0.5 log10 IU/mL < 0.5 log10 IU/mL
(n = 9) (n = 39)
SVR 89 (8) 10 (4)
No SVR 11 (1) 90 (35)

Moucari R, et al. Hepatology. 2009;49:1151-1157. CCO Hepatitis Slide 21

 NAs: Potency versus resistance

Nucleoside analogue
Nucleotide analogue

TDF ETV
LdT
LAM
otency of HBV DNA suppression
ADV

Likelihood of resistance
development

Slide 22
 Antiviral resistance increases over time
80
Lamivudine1 70%

Adefovir2 65%

60 Entecavir (LAM-resistant)3
53%
Entecavir (naive)3 ***
Telbivudine4 42%
40%
40
of resistance (%)
29%
24% 25%
20%
20
15% 18%
12% 11%
5%
0.1% 0% 0.3% 2% 0.4% 0.8%
0
Year 1 Year 2 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, EASL 2006
Slide 25
Special Populations with HBV
• Cirrhosis
• Decompensated cirrhosis
• Organ transplantation
• Acute hepatitis B
• Pregnancy
• Co infection with HCV or HDV
• Chronic renal failure
• Children

Slide 26
 Cirrhosis
• 5 y Survival 84% for compensated
• 5 y Survival 14-35% for decompensated6
• Interferons are safe and effective in compensated HBV
cirrhosis only1 (I)
• Nucleoside analogues have been shown prospectively
to be safe, decrease rates of liver decompensation and
to decrease the development of HCC2 (I)
• All cirrhotic patients with HBV DNA>2000 IU/mL should
be treated regardless of ALT3-5 (III)
• Many experts recommend treating compensated
cirrhotics with any detectable viral load3 (III)

1Buster, 2007; 2Liaw, 2004; 3Keeffe, 2008; 4Liaw 2008 (APASL); 5Lok 2007; 6Kim 2004
Slide 27
 Treatment decreases HBV disease progression
even with YMDD mutant status
25
Placebo (n=215)
YMDD mutants (n=209) (49%) 21%
20 Wild-type (n=221)

15
Patients with disease 13%
progression (%)
10

5%
5

0
0 6 12 18 24 30 36

Time after randomisation (months)

Liaw et al. N Engl J Med 2004
Slide 28
Lamivudine in
Decompensated Cirrhosis
23 consecutive UCSF patients compared with
23 historical controls
100
80
60
40
20 Lamivudine treated
0
Survival (%)
P < .001

Controls

0 6 12 18 24 30 36 42 48
Time (mo)
Cumulative probability of survival without liver transplantation
Yao FY, et al. Hepatology. 2001;34:411.
Slide 29
 Liver Transplantation and HBV
Progress in Past Decade

HBIG
Era 1 (1987-1991) LAM
1
1 Era 3 (1997-2002)
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
0.5
P < 0.01 HBV P = .14
vival % Other Survival %
Other
HBV

012345 012345
Time (years) Time (years)

• 5-year survival rates ~50% • 5-year survival rates as

• Many centers consider HBV good or better than for
to be contraindication for LT other indications for LT

Kim WR, et al. Liver Transpl. 2004;10:968.

Slide 30
Pregnancy
• Many patients with CHB are immune tolerant when pregnant
• Children born to HBsAg positive mothers should receive HBIG
within 12 hours of birth and the first dose of HBV vaccination,
with subsequent vaccination at 1 and 3-6 months of age1
o >95% of children then immune to HBV
• Vaccine failure associated with
o inadequate therapy
o infants of mothers with very high HBV DNA (>8 Log10 IU/mL)
• Treatment to decrease mother to child transmission (MTCT)
o Lam for one month decreased MTCT (12.5% cf 28% historical
controls) in women with >109 g equiv/mL2 (III)
• Pregnant women with chronic active hepatitis B should be
treated per standard guidelines:
o Category B: Telbivudine, TDF
o Category C: Lam, ADV, ETV

1Lok, 2007; 2van Zonneveld, 2003

Slide 31
 Reactivation of HBV
• High rate of reactivation in
immunosuppressed patients
o Chemotherapy
o HIV after immune reconstitution
o Post organ transplant
o Biologic response modifiers: rituximab (anti-
CD20), TNF- inhibitors: GI, hematologists,
rheumatologists, dermatologists
• Reactivation can occur in immunocompetent
treated with steroids, BRMs

Slide 32
 Reactivation of HBV
• Highest in HBV active disease
1.HBsAg pos, HBeAg pos, high HBV DNA
2.HBsAg pos, HBeAb pos, low HBV DNA
3.HBsAg neg, anti-HBs pos, anti-HBc pos
o Deaths occur in all groups
• ALL patients undergoing chemotherapy
must have tested HBsAg, HBsAb and
HBcAb prior to treatment

Slide 33
 HBV is a dynamic disease
• Diagnose
• Initial evaluation includes education
o Family and sexual contacts should be tested
o counsel drugs to avoid- steroids, chemo, BRM
• Monitor as status changes over time
• Selection of patients to treat
o Individualize treatment decisions
o Change if no/ poor response
• Long term monitoring
o HCC, special populations, reactivation

Slide 35
 HBV: The importance of monitoring

HBV is a dynamic disease!!!

Require treatment
40%
60%

Require monitoring…
• Inactive disease may not remain inactive
• Liver damage may occur if HBV
reactivates
HBV can be controlled but not cured
Slide 36