1. Hepatitis B: Chronic Hepatitis and Inactive Carriers - Management
Raymond S. Koff, M.D.
Clinical Professor of Medicine
University of Connecticut
Health Science Center Farmington, Connecticut

2. Epidemiology: United States
Chronic HBV Infection
Epidemiology: United States
HBsAg seroprevalence: 0.2% - 1.0%
HBsAg prevalence highest in Asians and
Asian-Americans (3-20%)
HBsAg prevalence intermediate in African-
Americans
Accounts for up to 15% of chronic liver
disease

3. Morbidity and Mortality, U.S.
Chronic HBV Infection
Morbidity and Mortality, U.S.
Previously infected individuals: ~10 million
Actively infected individuals: ~ million
(chronic hepatitis B and carriers)
Annual cirrhosis deaths: ~4,000
Annual HCC deaths: ~1,000-1,500

4. Disease Burden of Hepatitis B Infection
HBV - Epidemiology
U.S Global
Estimated new infections , Uncertain
per year
Number of persons with million million
chronic infection
Deaths from chronic liver , ,000 disease per year
Percent ever infected <4.9% %
Disease Burden of Hepatitis B Infection
Slide 63
Disease burden of Hepatitis B infection
In the United States, the latest population survey - NHANES III estimated that the prevalence of chronic HBV infection was 0.42% and that of previous infection was 4.9%. It is estimated that 1.25 million Americans have chronic HBV infection and about 5,000 die yearly of complications from chronic hepatitis B.
According to the WHO, a third of the world’s population have been exposed to hepatitis B, approximately 350 million persons worldwide have chronic HBV infection, and about 500,000 die yearly from chronic hepatitis B.
McQuillan GM, Coleman PJ, Kruszon-Moran D, et al. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys, 1976 through Am J Public Health 1999;89:14-8.
Kane M. Global programme for control of hepatitis B infection. Vaccine 1995;13:S1:S47-S49.
CDC and WHO

5. Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration
Immigration Numbers Summed by Continent From 1996–2002
HBsAg Prevalence
High (>8%)
Intermediate (2–8%)
Low (<2%)
~2 million Asians
~400,000
South Americans
~350,000 Africans
~930, 000 Europeans
Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration
The frequency of HBV infection and patterns of HBV transmission vary dramatically in different parts of the world. Approximately 45% of the world’s population live in areas where the prevalence of chronic HBV infection is high (>8% of the population is HBsAg positive), 43% live in areas of intermediate prevalence (2% to 7% of the population is HBsAg positive), and only 12% of the world’s population live in areas of low endemicity (<2% of the population is HBsAg positive).
In areas of high endemicity, the lifetime risk of HBV infection is >60%. Such areas include most of Asia (except Japan and India), most of the Middle East, the Amazon Basin of South America, most Pacific Island Groups, Africa, and other special populations, such as Native Alaskans, Australian Aborigines, and Maoris in New Zealand. Most infections occur at birth or during early childhood when the risk of acquiring chronic infection is the greatest. There is little recognition of acute disease, as most early childhood HBV infections are asymptomatic.
In areas of intermediate endemicity, the lifetime risk of HBV infection is 20% to 60% and infections occur in all age groups. Acute disease is commonly recognized as many infections occur in adolescents and young adults. Additionally, high rates of HBV-related chronic liver disease occur due to the high prevalence of chronic HBV infection.
In areas of low endemicity, the lifetime risk of infection is <20% and most infections occur among adults in well-defined risk groups.
In the United States, prevalence of HBsAg may be impacted by migratory trends from regions of high endemicity. From 1996 (when the data were gathered for the HBsAg prevalence) to 2002, approximately 1.9 million, 933,000, 337,000, and 401,000 persons have immigrated from Asia, Europe, Africa, and South America, respectively.
References
World Health Organization. Geographic Prevalence of HBsAg Accessed: July 8, 2005.
2002 Yearbook of Immigration Statistics. Accessed: July 8, 2005.
Mahoney FJ. Clin Microbiol Rev. 1999;12:
World Health Organization. Available at: Accessed July 8, 2005.
2002 Yearbook of Immigration Statistics. Available at: Accessed July 8, 2005.
Mahoney FJ. Clin Microbiol Rev. 1999;12:351–366.

6. Estimates of HBV Infectivity in Body Fluids
Blood
Blood
Cervicovaginal
secretions
Semen
Semen
Saliva
Breast
milk
Urine
CSF
Tears
Lowest Infectivity Most

7. HBV Infection Modes of Transmission
Transfusion
(blood, blood products)
Tattoos; Body
piercing
Mother to infant
Hepatitis B
Shared needles
& syringes
Fluids
(blood, semen)
Transmission of HBV Infection
HBV is present in blood, saliva, and semen of infected individuals, with the highest concentration of HBV found in blood and serous fluids.1 The major modes of acquisition of this virus include:
Vertical transmission1,2:
Mother to baby
Horizontal transmission1,2:
Blood transfusions
Other body fluids (such as semen)
Organ and tissue transplantation
Contaminated needles and syringes
Child to child, or other close physical contact with an infected
individual
1. Moyer LA and Mast EE. Hepatitis B: Virology, epidemiology, disease, and prevention, and an overview of viral hepatitis. Am J Prev Med ;10(suppl):45-55.
2. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: Evolving epidemiology and implications for control. Sem Liver Dis ;11:84-92.
Please see accompanying complete Prescribing Information.
Organs &
tissue transplantation
Child to child

8. Risk Factors for Hepatitis B Infection
Percutaneous
Injection drug use
Transfusion or transplant
Occupational exposure
Parenteral practices
Permucosal
Perinatal
Sexual
Household contact
Risk Factors for Hepatitis B Infection
Slide 65
Risk factors for hepatitis B infection
HBV is transmitted by percutaneous and permucosal exposure to infectious blood or body fluids. Although HBsAg has been detected in a wide variety of body fluids, only serum and semen have been demonstrated to be infectious.
Percutaneous exposures include injection drug use, transfusion of blood or blood products, organ transplant, needle stick injuries, contacts with contaminated equipment, tattooing, and acupuncture.
Permucosal transmission results from sexual contact, perinatal transmission, and mucous membrane exposures to infectious blood or serum among household contact.
Alter HJ, Purcell RH, Gerin JL, et al. Transmission of hepatitis B to champanzees by hepatitis B surface antigen positive saliva and semen. Infect Immun 1977;16:
Alter HJ, Holland PV, Morrow AG, et al. Clinical and serological analysis of transfusion-associated hepatitis. Lancet 1975;2:

9. Age Distribution in the United States
Acute Hepatitis B
Age Distribution in the United States
Reported
cases (%)
Age in Years

10. Risk Factors for Acute HBV infection in the U.S.
Injection drug use
Men having sex with men
Multiple sex partners
Sexual contact with HBV carriers
Contact with HBV carriers
Blood transfusion
Occupational / hemodialysis
Unknown
Slide 66
Risk factors for acute HBV infection in U.S.
Injection drug use is the predominant risk factor reported, followed by sexual exposure. Employment in the medical or dental field, blood transfusions, and dialysis account for less than 3% of cases. The widespread use of hepatitis B vaccine among health-care workers has reduced their incidence of hepatitis B, from 9% of reported cases in 1985 to 0.8% in Although more than half of the cases reported in 1995 denied a recognized exposure, data from the Sentinel Counties study indicate that most persons who deny a specific exposure have some lifetime history of high-risk drug or sexual behaviors.
Centers for Disease Control and Prevention: Hepatitis Surveillance Report No. 57. Atlanta, GA:DHHS; Sept. 2000:12.
Mast EE, Mahoney FJ, Alter MJ, Margolis HS. Progress toward elimination of hepatitis B virus transmission in the United States. Vaccine 1998;16 S:S48-51.
Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination strategies. JAMA 1990;263:
CDC

11. Chronic Hepatitis B Natural History
Ranges from mild infection (inactive carrier, with normal ALT) to severe chronic liver disease
Fibrosis and subsequent cirrhosis
Liver failure
Hepatocellular carcinoma
Premature death
Natural History of Chronic Hepatitis B
The clinical course of chronic infection with HBV is variable, ranging from mild, asymptomatic infection to severe chronic liver disease. The more serious sequelae of HBV infection include:
Fibrosis and subsequent cirrhosis
Liver failure
Hepatocellular carcinoma (HCC)
Mortality
Dusheiko G, Hoofnagle JH. Hepatitis B. In: McIntyre N, Benhamou J-P, Bircher J, Mizzetto M, Rodes J, eds. Oxford Textbook of Clinical Hepatology. 1st ed. New York, NY: Oxford University Press, Inc.; 1991:
Please see accompanying complete Prescribing Information.

12. HBV Disease Progression
Acute infection
Chronic infection
Cirrhosis
Death
5–10%1,3
Liver
failure
30%1
>90% of children
<2% of adults1
25% in 5 years2
Cancer (HCC)
Chronic HBV is the 6th leading cause of liver transplantation in the US4
Liver transplant-ation
1. Torresi J. Gastroenterology. 2000;118(2 suppl 1):S83–S103.
2. Fattovich G. Hepatology. 1995;21:77–82.
3. Moyer LA. Am J Prev Med. 1994;10:45–55.
4. Perrillo R. Hepatology. 2001;33:424–432.

13. Factors Influencing Risk of Cirrhosis
Chronic Hepatitis B
Higher HBV DNA levels (>104 copies/mL)
HBeAg-positivity
Persistent ALT elevation
HIV, alcohol, immunosuppression
Factors Influencing Risk of Cirrhosis
Slide 87
Chronic hepatitis B
Definition of chronic hepatitis B includes presence of HBsAg in serum for more than 6 months, with evidence of active viral replication (serum HBV DNA more than 105 copies/ml), and active inflammation of the liver (elevated aminotransferases and/or active inflammation on histology). Chronic hepatitis B is divided into HBeAg positive and HBeAg negative.
Lok AS and McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:
Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: summary of a workshop. Gastroenterology 2001;120:

14. Cumulative Incidence of Cirrhosis for Five HBV DNA Categories (n=3,774)6 5
6.5 4 3
5.6
P value for log-rank test, <0.001
2.5
1.4
1.0
Iloeje UH et al, Gastroenterology 2006;130:678-86: The Taiwan Natural History Study

15. HBV DNA Levels and Risk of Hepatocellular Carcinoma: The Taiwan Natural History Study*
Serum HBV DNA Incidence Adj. Rel Risk p
(copies/mL) (per 100,000)
>1.0 x <.001
>1.0 x <1.0 x <.001
>1.0 x <1.0 x <.008
>300 - <1.0 x NS
<
Slide 87
Chronic hepatitis B
Definition of chronic hepatitis B includes presence of HBsAg in serum for more than 6 months, with evidence of active viral replication (serum HBV DNA more than 105 copies/ml), and active inflammation of the liver (elevated aminotransferases and/or active inflammation on histology). Chronic hepatitis B is divided into HBeAg positive and HBeAg negative.
Lok AS and McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:
Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: summary of a workshop. Gastroenterology 2001;120:
* Chen C-J et al. JAMA, 2006

16. Hepatocellular Carcinoma
Among solid tumors, 5th highest incidence worldwide and 3rd most common cause of cancer deaths
In the U.S. in 2007, 13th most common cancer and increasing faster than all others from 1995 to 2004; 8th most common cause of cancer deaths
Despite advancing technology and available treatments, 5-year survival rates are generally less than 5%

17. Strategies for Eliminating HBV Transmission in the U.S.
Maternal screening for HBsAg and providing
post-exposure prophylaxis to infants of
HBsAg-positive women
Routine vaccination of all infants
Catch-up vaccination for children aged <19 yrs
Targeting high risk children, adolescents, adults

18. Natural History of Chronic Hepatitis B
Annual risk of
Phase of disease cirrhosis
Chronic hepatitis B:
HBeAg-positive ~2-6 %
HBeAg-negative ~8-10%
Inactive carrier: ~0.5%

19. Inactive HBsAg Carriers
Chronic HBV Infection
Inactive HBsAg Carriers
HBsAg-positive/HBeAg-negative
Normal serum ALT levels
<104 copies/mL by PCR
Generally mild histology
Absence of evidence of effective therapy
Very low risk of progression
Management of Chronic Hepatitis B
The goals of managing patients with chronic hepatitis B are:
Suppression of viral replication
Improvement in hepatic necroinflammatory disease
Reduction in the likelihood of long-term sequelae of HBV infection, such as cirrhosis and hepatocellular carcinoma
Please see accompanying complete Prescribing Information.

20. Natural History of HBV: Development of HBeAg-Negative Chronic HBV
Hadziyannis SJ, Vassilopoulos D. Hepatology. 2001;34(4 pt 1):617–624.

21. Natural History of HBeAg-positive Disease
Chronic Hepatitis B
Natural History of HBeAg-positive Disease
Annual
Change in Status Probability
Chronic hepatitis B cirrhosis ~ 2-6 %
Cirrhosis decompensation ~ 6 %
Cirrhosis hepatocellular ~ 2.5 % carcinoma
Hepatocellular
carcinoma death ~ 85%

22. Natural History of HBeAg-negative Disease
Chronic Hepatitis B
Natural History of HBeAg-negative
Disease
Older than HBeAg-positive patients
Lower circulating HBV DNA levels
More extensive hepatic injury
Lower rates of spontaneous remission
Pre-core and/or core promoter mutants in 90%

23. HBsAg Present? Is IgM anti-HBc present? Is HBeAg or HBV DNA present?
Yes
Is IgM anti-HBc present? No No
Yes
Chronic hepatitis
Acute hepatitis
Is HBeAg or HBV DNA present?
Is anti-HBs present?
Yes No
Yes No
Replicative HBV
infection
Nonreplicative HBV infection (carrier)
Recovered/vaccinated ± anti-HBc
No HBV infection

24. Evaluation of the HBsAg-positive Patient
HBV DNA level
HBeAg/anti-HBe status
Serum ALT
Clinical/laboratory/imaging evidence of cirrhosis or HCC
Testing for viral resistance/genotype
?Histology

25. Treatment of Chronic HBV

26. Candidates for Treatment
Chronic Hepatitis B
Candidates for Treatment
Elevated or Normal ALT levels and:
HBeAg-positive and HBV DNA ≥105 copies/mL
by PCR
HBeAg-negative and HBV DNA ≥104 copies/mL by PCR
Cirrhosis with detectable HBV DNA
Management of Chronic Hepatitis B
The goals of managing patients with chronic hepatitis B are:
Suppression of viral replication
Improvement in hepatic necroinflammatory disease
Reduction in the likelihood of long-term sequelae of HBV infection, such as cirrhosis and hepatocellular carcinoma
Please see accompanying complete Prescribing Information.

27. Goals of Therapy HBeAg-positive HBeAg-negative
Suppression of HBV DNA to low or undetectable levels
HBeAg loss  seroconversion
Sustained response after seroconversion
ALT normalization
HBsAg loss ± seroconversion
HBeAg-negative
Suppression of HBV DNA to low or undetectable levels and ALT normalization
HBeAg seroconversion not an endpoint
Goals of Therapy: Two Distinct Patient Populations
Taking into account the available data, the panel recommends that patients be treated after HBeAg seroconversion as long as HBV levels are decreasing until they have undetectable HBV DNA levels by PCR.
The endpoint of therapy for HBeAg-negative patients with chronic HBV infection is more difficult to assess than for HBeAg-positive patients because HBeAg seroconversion cannot be used. Thus HBV DNA suppression and ALT level normalization are the only practical measures of response to therapy.
Reference
Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:

28. HBV Treatment Options in 2008
Pegylated interferon alfa-2a
Interferon alfa-2b
Nucleoside analogs
Entecavir
Lamivudine
Telbivudine
Nucleotide analog
Adefovir
Tenofovir

29. Comparing Oral Antivirals and Interferon
Chronic Hepatitis B
Comparing Oral Antivirals and Interferon
Orals IFN
Oral administration: Yes No
Side effects: minimal frequent
Duration of treatment: prolonged finite
Flares during treatment: rare yes
Resistant mutant: yes no
Impact of genotype: no yes
Rate of HBsAg clearance: low higher

30. Interferon Therapy for HBeAg-positive HBV: Long-term Follow-up*
Meta-analysis of 12 studies (n=1975)
765 interferon treated/1210 untreated
Follow-up range: 2.1–8.9 yrs (mean 6.1)†
Distribution of probabilities:
Interferon
Untreated
Loss of HBsAg
11.4%
2.6%
Disease decompensation
9.9%
13.3%
Development of HCC
1.9%
3.2%
Liver-related death
4.9%
8.7%
*Long term response in treatment-free follow-up
†Treatment duration: 4–6 months
Craxi et al. EASL 2002.

31. Length of Therapy (month)
Effect of Lamivudine on Incidence of HCC in Chronic HBV and Advanced Fibrosis
P = 0.047
Placebo 10
Diagnosis of HCC (%)
Lamivudine
Incidence of HCC in Cirrhotics
In the study headed by Liaw et al, 651 patients with CHB with histologically confirmed cirrhosis or advanced fibrosis were randomized (2:1, active treatment: placebo). The study was planned for a maximum of 5 years. The primary end point of the trial was time to disease progression, which was defined by hepatic decomposition, HCC, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. The study was terminated at a median duration of treatment of 32.4 months, owing to a significant difference in the primary endpoint between the active treatment arm and placebo.
HCC occurred in 17 (3.9%) patients in the active treatment group and in 16 (7.4%) patients in the placebo arm (P = .047). The hazard ratio was 0.49.
Reference
Liaw YF, Sung JJY, Chow WC, et al. N Engl J Med. 2004;351: 6 12 18 24 30 36
Length of Therapy (month)
Liaw YF, et al. N Engl J Med 2004;351:1521–1531.

32. Comparing Oral Agents and Peg-IFN alfa-2a
Chronic Hepatitis B , HBeAg-Positive
Comparing Oral Agents and Peg-IFN alfa-2a
1-year of Treatment Seroconversion
HBeAg HBsAg
Lamivudine: % 0%
Telbivudine: % %
Adefovir: % %
Entecavir: % %
Tenofovir: % %
Peg-IFN alfa-2a: % %

33. Comparing Oral Agents and Peg-IFN alfa-2a
Chronic Hepatitis B
Comparing Oral Agents and Peg-IFN alfa-2a
1-year of Treatment HBV DNA < cp/mL at end of Rx
Lamivudine: %
Telbivudine: %
Adefovir: %
Entecavir: %
Tenofovir: %
Peg-IFN alfa-2a: %

34. Adefovir: Long-Term Efficacy in HBeAg-positive Patients
Serum HBV <400 Copies/mL
HBeAg
Seroconversion
Loss
ALT
Normalization
Two patients (3.1%) developed resistance (N236T, 1; A181V, 1) through week 144.
Kaplan Meier estimates of time to confirmed event. Marcellin P, Asselah T. J Hepatol. 2005;43:920–923.

35. HBsAg loss was 5% at 96 weeks for entecavir.
Entecavir: Average Response Rates in Chronic Hepatitis B (HBeAg Positive) at 2 years of Treatment
Entecavir 0.5 mg (n = 314 nucleoside- naïve patients)
Lamivudine 100 mg
(n = 314 nucleoside-naïve patients)
Response at 96 Weeks (%)
HBsAg loss was 5% at 96 weeks for entecavir.
Gish B, et al. AASLD Abstract 181.

36. Current Treatment Strategies
Clinical Form Drug Therapy
Chronic hepatitis B: PEG-IFN alfa-2a or
tenofovir, entecavir,
adefovir, telbivudine,
lamivudine or ?combinations
HBV-cirrhosis
Compensated: same as above
Decompensated: tenofovir, entecavir, adefovir,
telbivudine, lamivudine, or
transplantation

37. Key Issues in HBV Therapy
Efficacy
Duration of therapy
Resistance
Combination therapy
Genotyping

38. Manifestations of Antiviral Resistance
HBV DNA 8
ALT 6
Hepatitis flare
Viral
breakthrough
HBV DNA (log10 IU/mL); ALT (U/L) 4
Biochemical
breakthrough
Genotypic
resistance
Is this correct -- that the units for both DNA and ALT can use the same 0-8 scale? 2
Upper limit of normal -1 1 2 3
Length of Antiviral Therapy (year)

39. The Risk of Resistance
Antiviral potency: the emergence of resistant mutants is reduced when viral replication is highly suppressed – no virus, no resistance
Genetic barrier: the number of mutations required to decrease susceptibility to an antiviral drug
Viral fitness: the ability of a mutant virus to replicate

40. Cumulative Incidence of HBV Genotypic Resistance
ADV resistance1
LAM resistance2
ETV resistance in LAM-refractory pts3
Incidence of Resistance (%)
71% 20 40 60 80
Year 1
Year 2
Year 3
Year 4
LAM
ADV
29%-42%4
ETV
25%
Year 5
Hepsera exhibits an excellent resistance profile over long-term treatment with no resistance at Year 1 and small increases over time.
10%
ETV in naïve:<1%
1. Qi YL, et al. EASL Abstract 57.
2. Lai CL, et al. Clin Infect Dis. 2003;36:687–696.
3. Tenney DJ, et al. AASLD Abstract 184.
4. In HBeAg-negative pts; higher resistance in HBeAg-positives

41. Antiviral-Resistant HBV: Treatment Recommendations
Resistant Drug
Rescue Therapy
Lamivudine-R
Add adefovir (may be preferred over switch)
Switch to entecavir (risk of entecavir-R)
Add tenofovir or switch to FTC/tenofovir
Adefovir-R
Add lamivudine (may be preferred over switch)
Switch to entecavir (if no prior lamivudine-R)
Switch to FTC/tenofovir
Entecavir-R
Add or switch to adefovir or tenofovir
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936–962.

42. HBV Roadmap Schema CVR PVR IVR
Assessment of Primary Non-Response at week 12
Early Predictors of Efficacy at week 24
CVR
PVR
IVR
PCR-
negative
(<50 copies/mL)
<103
copies/mL
<104
copies/mL
≥104
copies/mL

43. Current and FutureTreatment of HBV Patients
Focus on HBV DNA suppression
Treatment decisions based on HBV DNA levels, disease severity, drug efficacy and resistance patterns (for oral agents)
Combination oral therapy emerging
New agents with prolonged activity after end-of-treatment, e.g. clevudine, may become available