1. Hepatitis B State of the Art
Joanna Ready, M.D.
SGNA
September, 2013

2. 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

3. 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

4. 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

5. Geographic Distribution of Chronic HBV Infection
Country
HBsAg+ (%)
China
South Korea
India
Taiwan
Vietnam
Japan
Africa
5-192
Russia
1.4-82
US/Europe
Core Slide
Lecture Notes
Hepatitis B virus (HBV) is one of the most common infectious diseases in the world. The geographical prevalence of hepatitis B varies from a highly endemic disease in Asia and Africa, with a carrier rate of up to 20%, to a disease of low prevalence in North America and Western Europe, with a carrier rate of less than 2%.1,2,3
References
1. World Health Organization. Hepatitis B Available at: Accessed: February 10, 2005.
2. Custer B, Sullivan SD, Hazlet TK, Iloeje U, Veenstra DL, Kowdley KV. Global epidemiology of hepatitis B virus. J Clin Gastroenterol. 2004;38(10 suppl): S158-S168.
3. World Health Organization. Seroprevalence of hepatitis B in WPRO. Available at: Accessed: February 28, 2005.
HBsAg Prevalence (%)1
8: High
2–8: Intermediate
<2: Low
1. WHO. Hepatitis B Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S WHO/WPRO data.

6. Geographic Distribution of HBV Genotypes
Greenland:
A, B, D
Ae, Bj, C,
D, F
B, A/Bj Ae D
B,C,A,D C G A D Bj G D Ba B
F1, H
F & H E B3 H F2 B C Aa D

7. 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

8. How to test for HBV?
HBsAg
Anti-HBs
Anti-HBc

9. What to do with results? HBsAg HBsAb HBcAb + - + refer to care
past infection
vaccinate
vaccinated

10. 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 yrs
1998: vaccination of all persons age 0-18 yrs not previously vaccinated
The HBV vaccine was licensed 20 years ago. Vaccines were initially derived from plasma, although recombinant vaccines are currently used. The 3-dose series is associated with high efficacy and an excellent safety record. Since 1982, vaccination has been recommended for adolescents and adults at high risk. In 1991, a comprehensive strategy was developed to eliminate hepatitis B transmission. The program initially focused on infants and later expanded to include adolescents. Currently, HBV vaccination is recommended for all unvaccinated persons 18 years of age and younger and for adults at high risk of infection.

11. 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
Acute HBV infection has declined significantly in the past decade, reflecting the effects of routine vaccination. Vaccination rates are high among infants and young children but lower among adolescents and adults. Indeed, while HBV incidence has declined slowly in adults, it has increased among some subgroups, indicating a missed opportunity for vaccination among these groups. The risk of serious complications of chronic hepatitis B is also declining, a trend that is likely due to vaccination efforts.
Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:

12. HBeAg –ve active chronic hepatitis
The phases of chronic hepatitis B
Immune
Immune
Immune
Immune
tolerance
clearance
control
escape
HBeAg+ve
HBeAg–ve
<
>
<
>
HBV-DNA
ALT
HBeAg +ve
chronic hepatitis
Inactive (carrier)
state*
HBeAg –ve active chronic hepatitis
*Previously considered to be ‘healthy carriers’

13. 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

14. Who should be considered for treatment?
Immune
escape
<
>
HBeAg+ve
HBeAg–ve
ALT
HBV-DNA
Inactive (carrier)
state
HBeAg –ve/+ve active chronic hepatitis
HBeAg +ve
chronic hepatitis
tolerance
clearance
control
treat

15. 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
Slide: Chronic HBV Treatment: Simplified Flow Chart
In evaluating patients with chronic HBV infection, HBeAg status is important to determine, because patients who are e-antigen negative have a lower threshold for therapy. In particular, e-antigen negative patients should be considered for treatment if they have viral load of one order of magnitude lower than e-antigen positive patients.1
For HBeAg+ patients, HBV DNA levels above 20,000 IU/mL (approximately 104 copies/mL) should be considered as potential candidates for therapy. Patients who are HBeAg- should be considered for therapy if HBV DNA levels are above 2,000 IU/mL (approximately 103 copies/mL). Patients below these viral load thresholds should be monitored every 6 to 12 months.1
Antigen status and viral load determinations should be combined with an assessment of alanine aminotransferase (ALT). Patients with elevated viral loads above threshold levels and elevated ALT levels should be treated. Patients with normal ALT may be monitored. Alternatively, especially in older patients, a liver biopsy may be considered in order to determine whether there is ongoing damage from HBV. Abnormal histology, even in the face of normal ALT levels and/or viral loads below the treatment thresholds are indications to provide antiviral therapy.1
Reference
Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:
Monitor ALT Q3mos for 1y
Consider Liver Biopsy If >40yrs
Significant fibrosis or inflammation
Treat
Lok AS et al Hepatology, 2009

16. Approved HBV treatments 2013
Interferon alfa-2b – 1991
Lamivudine – 1998
Adefovir – 2002
Entecavir – 2005
Peginterferon alfa-2a – 2005
Telbivudine – 2006
Tenofovir
For HIV:
Emtricitabine
Tenofovir + emtricitabine (single pill co-formulation) 16 16

17. Therapeutic endpoints over time
Improved histology
Improved survival
Anti-HBs+
Loss of
HBsAg
Anti-HBe+
Loss of
HBeAg
Loss of
HBV DNA
TIME

18. Treatment Goals in CHB: Remission
Differences between the two strategies
On-therapy maintained response =
Off-therapy sustained response
Low viremia
ALT normalization
Continued need for
antiviral drugs
Immune control,
no antiviral drugs

19. HBV Nucs: Nonresponse, Suboptimal Response, and Virologic Breakthrough
1.0
Antiviral Drug
Primary nonresponse
Virologic breakthrough
-1.0
Change in HBV DNA
(log10 IU/mL)
Suboptimal response
-2.0
This figure is a simple demonstration of what one might see utilizing these different definitions. In a primary nonresponse, as shown in the yellow line, you can see that there is less than a 1 log reduction at the end of 6-12 months. Shown in the green line is a suboptimal response and where there is a reduction in the HBV DNA, but it does not go to low levels or to undetectability. The blue line is an example of an individual who has virologic breakthrough. First of all, there is a substantial reduction in serum HBV DNA to very low or undetectable levels, but then over time—for example at Month 12—there is breakthrough, defined as a 1 log increase, that becomes apparent very quickly and this represents failure of therapy after it has initially been begun—what we call “virologic breakthrough.” We want to recognize this early so we can intervene with therapy, as we will see later. We do not want to wait until there is biochemical breakthrough because there then could be clinical deterioration associated with this virologic breakthrough.
-3.0
1 log
Nadir
-4.0 6 12 18
Months
Lok AS, et al. Hepatology. 2007;45:

20. 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 Limited Duration (1 Yr) Peginterferon Treatment
100 80
Entecavir Tenofovir Peginterferon 60
HBeAg Seroconversion (%) 39 40 35 31
29-32 26 26
22-27 21 22
HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.
In HBeAg-positive patients, use of the 3 recommended first-line agents—entecavir, tenofovir, and peginterferon—has resulted in HBeAg seroconversion rates between 21% and 27% at 1 year of treatment. Rates have been observed to increase over time so that by Year 3-4, seroconversion rates were 39% with entecavir, 26% with tenofovir, and 35% with peginterferon. Note that the increase in seroconversion rates in patients who were treated with peginterferon continued long after treatment had been discontinued.
For more information, go online to: 20
1.0 Yr
Yrs
Yrs
*With sustained undetectable HBV DNA.
Chang TT, et al. J Viral Hepat. 2009;16: Chang TT, et al. AASLD Abstract 109. Lau GK, et al. N Engl J Med. 2005;352: Marcellin P, et al. N Engl J Med. 2008;359: Buster EH, et al. Gastroenterology. 2008;135; Heathcote J, et al. AASLD Abstract 158. Heathcote J, et al. AASLD Abstract Janssen HL, et al. Lancet. 2005;365; 20

21. HBsAg Loss 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 1 Yr Peginterferon Treatment
100 80
Entecavir Tenofovir Peginterferon 60
HBsAg Loss (%) 40
HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
A similar pattern has been reported for surface antigen loss in HBeAg-positive patients treated with recommended first-line agents, albeit at lower levels. At the first year of treatment, the level of surface antigen loss was low, between 2% and 5%. This rate increased through the second, third, and fourth years of therapy so that by Year 3-4, surface antigen loss was reported in 8% of patients treated with tenofovir or peginterferon. 20 8 8 3 5 5 6 6 2 NA
1.0 Yr
Yrs
Yrs
*With sustained undetectable HBV DNA.
Chang TT, et al. N Engl J Med. 2006;354: Marcellin P, et al. N Engl J Med. 2008;359: Buster EH, et al. Gastroenterology. 2008;135; Gish R, et al. Gastroenterology. 2007;133: Heathcote J. AASLD Abstract 158. Heathcote J, et al. AASLD Abstract 483. Janssen HL, et al. Lancet. 2005;365: 21

22. 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*
100 93 96 90 91 87 80
Entecavir Tenofovir Peginterferon 63 60
Undetectable HBV DNA (%) 40
HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.
Among HBeAg-negative patients receiving recommended first-line therapies, viral suppression rates vary among agents. In trials evaluating the use of entecavir and tenofovir in this setting, between 87% and 100% of patients sustained undetectable HBV DNA over the first 3 years of therapy.
Use of peginterferon in HBeAg-negative patients has resulted in HBV DNA negativity in 63% of patients at the end of Year 1. However, this rate fell significantly over the second and third years of follow-up to 15% to 16%. Note that this reduction occurred as patients discontinued their peginterferon therapy, whereas patients treated with oral agents remained on therapy in Years 2 and 3.
For more information, go online to:
For more information, go online to: 20 15 16 NA
1 Yr
2 Yrs
3 Yrs
*Single center study.
Lok AS, et al. Hepatology. 2009;50: Marcellin P, et al. AASLD Abstract 146. Marcellin P, et al. AASLD Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136: Baqai S, et al. AASLD Abstract 476. Lai CL, et al. Hong Kong International Liver Congress 2006. 22

23. 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*
Vs 1 Yr Peginterferon Treatment
100 80
Entecavir Tenofovir Peginterferon 60
Patients (%) 40
HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
Loss of HBsAg is reported in HBeAg-negative patients after initiation of antiviral therapy, but the rate of loss over time is relatively low. During the first year of therapy, surface antigen loss has been reported in 4% of patients treated with peginterferon and < 1% of patients receiving tenofovir or entecavir. This rate increased to 9% at Year 3 for patients on peginterferon but remained < 1% for patients on entecavir and tenofovir.
For more information, go online to: 20 9 4 7
< 1
< 1 NA
1.0 Yr
Yrs
Yrs
*With sustained undetectable HBV DNA.
Lai CL, et al. N Engl J Med. 2006;354: Marcellin P, et al. N Engl J Med. 2008;359: Marcellin P, et al. AASLD Abstract 146. Shouval D, et al. J Hepatol. 2009;50: Marcellin P, et al. AASLD Abstract 481. Brunetto M, et al. EASL Abstract 683. 23

24. 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

25. Selection of Entecavir vs Tenofovir
Log HBV DNA ↓ at Wk 48-52
HBeAg pos
6.9
6.2
HBeAg neg
5.0
4.6
Genotypic resistance, %
NA naive
1.2 (Yr 5)
0 (Yr 3)
Lamivudine experienced
51 (Yr 5) NR
Pregnancy rating
Class C
Class B
AEs
None
Renal toxicity;
↓ BMD 25 21 21 20
Entecavir
Tenofovir 15
Response at Wk (%) 10 5
AE, adverse event; BMD, bone mineral density; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA nucleos(t)ide  analogue.
Available data suggest that first-line use of entecavir or tenofovir results in similar virologic response rates in HBeAg-positive and HBeAg-negative patients. Rates of e-antigen seroconversion in HBeAg-positive patients are also similar between the 2 agents, as is the rate of surface-antigen loss. In HBeAg-negative patients, rates of surface-antigen loss are also comparable between treatments.
The resistance profiles of entecavir and tenofovir are broadly similar, particularly in patients who are treatment naive. However, in patients who have previously received lamivudine, entecavir resistance rates can be as high as 51% after 5 years of entecavir treatment. Both drugs have favorable pregnancy ratings: tenofovir is rated class B and entecavir is class C. Use of entecavir has not been associated with a risk of major adverse events, whereas a risk of renal toxicity and possibly a decline in bone mineral density is associated with tenofovir treatment in some patients.
 should this be nucleos(t)ide throughout? 3 2
< 1
HBeAg
seroconversion
HBsAg
loss
HBsAg
loss
HBeAg Positive
HBeAg Neg
Lok AS. Hepatology. 2010;52: 25

26. 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)

27. 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

28. 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
Entecavir
Tenofovir
LAM/LdT resistance
Decreased
Active
ETV resistance --
ADV resistance
TDF resistance
ADV, adefovir; ETV, entecavir; HBV, hepatitis B virus; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir.
Treatment history must be considered when choosing an oral agent for patients with hepatitis B. For patients who have never received antivirals, both entecavir and tenofovir have proven efficacy with little apparent risk of emergent resistance.
In patients with lamivudine or telbivudine resistance, the activity of entecavir is decreased, and risk is increased for developing entecavir resistance. Entecavir remains active in patients who have adefovir or tenofovir resistance. The converse appears to be true for tenofovir: tenofovir is highly effective in patients who have lamivudine and telbivudine resistance and in patients who have entecavir resistance. In patients with adefovir resistance, tenofovir activity is somewhat decreased.
Lok AS. Hepatology. 2010;52: 28

29. NAs: Potency versus resistance
Nucleoside analogue
Nucleotide analogue
TDF
ETV
LdT
LAM
Potency of HBV DNA suppression
ADV
Likelihood of resistance development

30. Antiviral resistance increases over time80
Lamivudine1
24%
42%
53%
70%
65%
Adefovir2 60
Entecavir (LAM-resistant)3
Entecavir (naive)3 ***
Telbivudine4
Incidence of resistance (%)
12%
20%
25%
40% 40 0% 2%
11%
18%
29% 20 5%
15%
0.3%
0.4%
0.1%
0.8%
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

31. Special Populations with HBV
Cirrhosis
Decompensated cirrhosis
Organ transplantation
Acute hepatitis B
Pregnancy
Co infection with HCV or HDV
Chronic renal failure
Children

32. 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

33. Treatment decreases HBV disease progression
even with YMDD mutant status 25
Placebo (n=215)
21%
YMDD mutants (n=209) (49%) 20
Wild-type (n=221) 15
13%
Patients with disease progression (%) 10 5%
Time to Disease Progression According to YMDD Mutant Status
Around half the patients treated with lamivudine developed YMDD mutations which were associated with virological breakthrough and an increased likelihood of disease progression in terms of increased Child-Pugh score. However, clinical endpoints among patients with YMDD mutants occurred at a lower frequency than among patients receiving placebo. . 5 6 12 18 24 30 36
Time after randomisation (months)
Liaw et al. N Engl J Med 2004

34. Lamivudine in Decompensated Cirrhosis
23 consecutive UCSF patients compared with 23 historical controls
100 80 60 40 20
Lamivudine treated
Survival (%)
P < .001
Controls
Time (mo)
Cumulative probability of survival without liver transplantation
Yao FY, et al. Hepatology. 2001;34:411.

35. Liver Transplantation and HBV Progress in Past Decade
HBIG LAM
Era 1 ( ) 1
0.9
0.8
0.7
0.6
0.5
Era 3 ( ) 1
0.9
0.8
0.7
0.6
0.5
P < 0.01
HBV
P = .14
Survival %
Other
Survival %
Other
HBV
Time (years)
Time (years)
5-year survival rates ~50%
Many centers consider HBV to be contraindication for LT
5-year survival rates as good or better than for other indications for LT
Kim WR, et al. Liver Transpl. 2004;10:968.

36. 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

37. 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

38. Pregnancy (cont)
All current drugs have the potential for mitochondrial toxicity  lactic acidosis syndrome; deleterious effects on organogenesis; no study has reported long-term 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

39. 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 % in arm B no significant difference
No study has reported increased adverse fetal events with lamivudine

40. Pregnancy (cont) Tenofovir Telbivudine
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

41. 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

42. Pregnancy (cont) When to begin treatment? When to end 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

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

46. 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

47. 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
? 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
Current AASLD guidelines
Screening for liver cancer is critically important for patients with hepatitis B although there is a lack of consensus on some aspects of screening. All patients with cirrhosis should be screened, as cirrhosis is associated with an increased risk of HCC. However, HBV-infected individuals without cirrhosis are also at risk for HCC. There is some debate regarding the optimal age of initiating liver cancer screening. Although hepatitis-related HCC can develop at any age, the risk increases with longer duration of infection. Data from countries where infection occurs during infancy and childhood indicate that patients older than 35 years of age are at higher risk for HCC than patients younger than 35 years of age. In practice, most screening is initiated between the ages of 35 and 40 years.
1. Lok AS, and McMahon BJ. Hepatology. 2001; 34:
2. Liaw YF, et al. Gastroenterology. 1986;90:

48. 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

49. 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

50. Serology of HBV (addendum)
Infection
ALT
HBeAG
Anti-HBeAb
HBV DNA IU.ml
histology
Immune tolerant nl
Pos+
Neg-
High
normal
Chronic hepatitis HBeAg + up
>20,000
Active
Inactive carrier
<2,000
Chronic hepatitis HBeAg-
>2,000
active