1. Epidemiology and Natural History of HBV
This presentation will outline the epidemiology and natural history of hepatitis B virus (HBV) infections.
This program is supported by an unrestricted educational grant from

2. About These Slides
The full program accompanying these slides is available on the Clinical Care Options Hepatitis Web site: clinicaloptions.com/HBVCurriculum
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We are grateful to Robert G. Gish, MD, for his assistance in developing these slides
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. 2 2

3. Korean Mummy Found With HBV
Virus discovered in the liver of the South Korean Handong mummy
500-year-old child
First time HBV ever been found in a mummified body
Study of the genome of the 500-year-old virus under way
To see if there have been any significant changes to HBV over time
This slide shows a picture of the Korean mummy found with chronic hepatitis B infection. This is the mummy of a 500-year-old child who underwent laparoscopy and a liver biopsy. The child was found to have HBV genotype C, which is typical for Korean patients. We will talk more about genotypes later, but this discovery highlights how long hepatitis B has been present as a chronic disease in a variety of Asian populations. Interestingly, the liver pathology, as best it could be ascertained from this very old mummy, showed minimal liver disease.
Source: Seoul National University

4. Prevalence of HBV: Global Estimates
HBsAg
Positive, %
Taiwan
Vietnam
China
Africa
Philippines
Thailand
Japan
Indonesia
4.0
South Korea
India
Russia US
HBsAg, hepatitis B surface antigen.
This slide illustrates the prevalence of hepatitis B using global estimates by region and country. As seen on this slide, there are wide ranges of hepatitis B surface antigen (HBsAg) prevalence in different countries. However, some information on this slide may not fully reflect the current situation. For instance, in some communities in Vietnam and China, the prevalence is as high as 30%. Fortunately, in a number of countries that instituted vaccination, which will also be discussed later, there has been a declining prevalence of hepatitis B, especially in babies, infants, and young children.
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. 4 4

5. Geographic Diversity of HBV Infection: Clinical/Epidemiologic Correlations
North America/
Western Europe
Sub-Sahara Africa/
Far East
Endemicity
Low
High
Age of infection
Early adulthood
Birth, toddler
Primary mode of transmission
Percutaneous sexual
Perinatal horizontal
Chronicity
Rare
Likely
Risk of end-stage liver disease
Risk of hepatocellular carcinoma
This slide illustrates HBV infection in 2 areas of the world. In North America, Western Europe, and probably large areas of Central and South America, endemicity is low, and the age of infection is usually during early adulthood and occurs through percutaneous sexual exposure. Chronicity is typically less than 4%, especially in adults. The risk of end-stage liver disease and liver cancer is approximately 7%.
Conversely, in the Far East and sub-Saharan Africa, endemicity is high. As outlined in the previous slide, the age of infection is usually at birth, and approximately two thirds of the disease is due to mother-to-child transmission. However, after birth, the primary mode of transmission in children is horizontal or iatrogenic due to exposure to needles and sharp devices. Chronicity is also highly likely in patients from these areas. The risk of cirrhosis and cancer ranges from 25% to 30%. In sub-Saharan Africa, for example, liver cancer occurs relatively commonly even in patients without advanced fibrosis.
Mast EE, et al. MMWR Recomm Rep. 2006;55:1-33. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168. 5 5

6. 10 Leading Causes of Infectious Disease Deaths Worldwide (2000)
Deaths per Year
Lower respiratory tract infections
~ 3.5 million
HIV/AIDS
~ 3.0 million
Diarrheal diseases
~ 2.2 million
Tuberculosis
~ 2.0 million
Malaria
~ 1-3 million
Measles
~ 888,000
Hepatitis B
~ 500, ,000
Pertussis
~ 355,000
Neonatal tetanus
~ 300,000
Hepatitis C
~ 250,000
This slide shows the 10 leading causes of infectious disease deaths worldwide. Hepatitis B is number 7 and hepatitis C is number 10. If hepatitis B and C are grouped together, viral hepatitis is nearly number 5 in terms of the risk of infectious disease death. This, of course, relates to cirrhosis and cancer deaths for both of these chronic viral hepatitis infections.
WHO. Hepatitis B Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc CDC. Epidemiology & prevention of vaccine-preventable diseases. The Pink Book. 8th ed. CDC. MMWR. 2001;50:RR-11. 6

7. HBV: A Significant Cause of Worldwide Morbidity and Mortality
> 2 billion have been infected[1]
4 million acute cases per year[1]
1 million deaths per year[1]
million chronic carriers[1]
25% of carriers die from chronic hepatitis, cirrhosis, or liver cancer[1]
Nearly 75% of chronic carriers are Asian[2]
Second most important carcinogen behind tobacco[3]
Causes 60% to 80% of all primary liver cancer[1]
HBV is 100 times more contagious than HIV[4]
Core Slide
This slide outlines how hepatitis B is a significant cause of worldwide morbidity and mortality, with more than 2 billion infected. These individuals are typically hepatitis B surface antibody positive with or without core antibody positivity. Surface antibody indicates immunity, core antibody indicates exposure, and surface antigen indicates infection. There are approximately 400 million surface antigen-positive individuals worldwide, leading to approximately 1 million deaths per year. There are about 4 million acute cases per year; however, this number is probably an underestimate since many hepatitis B patients do not have symptoms and are not identified as true acute cases. Nearly 75% of chronic carriers worldwide are from the Asia-Pacific region. Hepatitis B virus is the second most important carcinogen behind tobacco in this region and is the cause of 60% to 80% of all primary liver cancer there. Since HBV is a DNA virus, it is much more contagious than HIV because it can live outside the body for significant periods of time on different blood-contaminated articles and the HBV DNA in infected patients can be very high (108 to 1011 IU/mL), whereas the HBV DNA in patients with HIV usually ranges from  copies/mL in untreated individuals.
1. WHO. Hepatitis B Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc CDC. Epidemiology & prevention of vaccine-preventable diseases. The Pink Book. 8th ed. 4. CDC. MMWR. 2001;50:RR-11. 7

8. Acute HBV Infection Incidence* in the US (1982-2006)
Universal vaccination of infants recommended in 1991
80% decline in incidence 14 12 10 8
Incidence 6 4 2
This slide looks at reported acute HBV infection in the United States. It shows a precipitous decline as universal vaccination of infants throughout the United States was instituted, starting in 1991.
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
Year
*Per 100,000 population.
MMWR: Surveillance Summary March 21, 2008 / Vol. 57 / No. SS—2. 8

9. Acute HBV Incidence* by Race and Year in the US (1990-2006)
Overall decline ~ 93%
Decline among Asian/Pacific Islanders ~ 95% 15
American Indian/ Alaska Native
Asian/Pacific Islanders
Black, non-Hispanic
Hispanic
White, non-Hispanic 10
Incidence 5
API, Asian/Pacific Islander.
Now, we will discuss hepatitis B incidence in the United States by race and by year. Again, this slide shows a precipitous decline in the incidence of HBV. Among Asian/Pacific Islanders specifically, this decline was 95%, which illustrates how preventative medicine can make a huge difference.
1990
1992
1994
1992
1996
1996
1998
2000
2002
2004
2006
Year
*Per 100,000 population.
MMWR: Surveillance Summary March 21, 2008 / Vol. 57 / No. SS—2.

10. Chronic HBV Prevalence: Asian/Pacific Island Immigrants in NYC (2005)30
21.4%
21.6% 20
16.0%
HBsAg+ Prevalence (%)
12.2% 10
Next, we will discuss hepatitis B prevalence in Asian/Pacific Island immigrants in New York City. This slide highlights the country of origin in the blue columns and the number of years in the United States in the orange columns. Among individuals from China, 21.4% were HBsAg positive. The rate was much lower for individuals from Korea or from other Asian/Pacific Island regions. Among those who had been in the United States for a short period of time (≤ 5 years), the prevalence of HBV was approximately 22%.
4.6%
4.3%
China
South Korea
Other
≤ 5
6-10
>10
Country of Origin
Years in the US
CDC. MMWR Morb Mortal Wkly Rep. 2006;55: 10

11. Chronic HBV Prevalence: Asian Americans in San Francisco (2001-2006)80 70
65.4% 60 50
44.8%
Prevalence (%) 40 30 20
This slide shows the prevalence of chronic HBV infection in Asian Americans in San Francisco, California. This included more than 3000 Asian American volunteers who were screened between 2001 and The blue column on the left shows that approximately 9% of Asian Americans in San Francisco were HBsAg positive. Among individuals unaware of their hepatitis serostatus, HBV testing was positive in 65%. In individuals not infected, 45% of patients lacked protective antibodies and were at risk for infection if not vaccinated. However, only 12% of patients reported being vaccinated and of these patients, 5.2% had chronic HBV infection. So, it appears that some individuals who would not benefit from vaccination, such as those patients who are already infected, are probably receiving the vaccination. This suggests that, in this population, testing for HBV infection might be warranted before intervening with a vaccine.
8.9% 10
Chronic HBV Positive
Chronic HBV Positive, Unaware of Serostatus
At Risk: Lack of Protective Antibodies
Lin SY, et al Hepatology. 2007;46: 11

12. Trends in Mortality in the US
Next, we will discuss trends in mortality in the United States. 12

13. Burden of HBV Infection in the US
> 14 million (~ 1 out of 20) persons in the US have been infected[1]
An estimated ~ 2 million are chronically infected in the US[2]
73,000
2,000,000
New Acute Infections per Year[3]
Chronic Infections[2]
5000
3100
230
HCC, hepatocellular carcinoma.
The first slide in this group evaluates the burden of HBV infection in the United States. This is important because more than 14 million people have been exposed to HBV, having at least 1 positive hepatitis B test. Currently, it is estimated that 2 million individuals in the United States are HBsAg positive.
Considerable data indicate that the potential burden associated with HBV infection in the United States is currently underestimated. Although acute infections do continue to decline, I believe that the number of deaths per year is underestimated because hepatitis B is not identified as the cause on death certificates. This is also true with liver cancer, such that a patient with hepatocellular carcinoma (HCC) may die of liver failure but the presence of HCC may not be identified before death—that is, not until autopsy or another later time. Consequently, HCC may not be listed in the medical information of the patient, leading to lower reported rates. The number of liver transplantations is low and continues to decline. Perhaps the reason the number of liver transplantations is not higher is because patients are diagnosed with liver cancer late, when they are no longer candidates for transplantation. Of course, all liver cancer patients could potentially be thought of as transplantation candidates. But with improved screening and surveillance, it is likely that more patients will receive a transplantation earlier because of liver cancer.
Deaths per Year[3]
Diagnosed HCC per Year[4]
Liver Transplants per Year[5]
1. CDC. Available at: Accessed May 20, Cohen C, et al. J Viral Hepat. 2008;15: CDC. HBV disease burden El-Serag HB, et al. Arch Intern Med. 2000;160: UNOS/OPTN. 13

14. Asian American Age-Adjusted Liver Cancer Rates (California, 2000-2002)
Approximately 3.7 million Asians in California; cancer data from California Cancer Registry
Incidence
Mortality 60
Male Female
54.3 60
Male Female 50 50 40
33.7 40
35.5 30
26.6
Rate (per 100,000)
Rate (per 100,000) 30
23.3
16.8
19.9 20
15.8
15.9 20
This slide displays Asian American age-adjusted liver cancer rates in California between 2000 and There are a number of important messages on this slide, which indicate that liver cancer is an important cause of death in Asian men. There are very high rates of both incidence and mortality in Vietnamese and Korean males. Although the rates are lower among Chinese, Filipino, and Japanese males, it is also a substantial issue in these populations. This is a powerful message for ethnic communities throughout the United States.
12.0
11.5
9.3
10.4
7.6
8.1
7.8
8.3 10
6.8 10
7.8
5.4
6.0
4.2
2.5
2.7
Chinese
Filipino
Korean
White
Chinese
Filipino
Korean
White
Vietnamese
Japanese
Vietnamese
Japanese
McCracken M, et al. CA Cancer J Clin. 2007;57: 14

15. Age- and Race-Specific HBV Mortality Rate in the US (1994-1998)6
Other race 5 4
Death Rate (per 100,000) 3 2
The next graph shows the age- and race-specific HBV mortality in the United States between 1994 and The line identified as “Other Race” is predominantly Asian/Pacific Islanders. There is a peak in this line at older ages, probably because patients are dying of other causes, such as cardiovascular disease and other cancers. Nonetheless, we need to intervene further and bring the Asian/Pacific Islander mortality down to a rate that approximates that of black and white individuals through the use of early intervention.
Black 1
White
< 25
25-34
35-44
45-54
55-64
65-74
75+
Age
CDC. MMWR Morb Mortal Wkly Rep. Underlying Cause of Death 15

16. Trend in Mortality From HBV by Race and Sex in the US (1979-1998)
2.0
2.0
Male
Female
Other race
1.5
1.5
Other race
Death Rate (per 100,000)
1.0
Death Rate (per 100,000)
1.0
Black
This slide shows the mortality from hepatitis B by race and sex in the United States, with men having a 2- to 3-fold higher mortality than women. This is attributed to higher testosterone levels and higher iron retention and deposition in the liver in men. Most recently another factor, interleukin-6, has been proposed. This cytokine may be protective against cancer, based on animal studies, and appears to be present at lower levels in men.
0.5
0.5
White
Black
White
0.0
0.0
'79-'83
'84-'88
'89-'93
'94-'98
'79-'83
'84-'88
'89-'93
'94-'98
Year
Year
CDC. MMWR Morb Mortal Wkly Rep. Underlying Cause of Death. 1979–1998. 16

17. Risk Factors Associated With Acute HBV Infection: US (2006)
This slide illustrates risk factors for HBV infection and shows that injection drug use, multiple sex partners, and sex between men are all important issues. This chart also lists other categories that are preventable. Clearly, we need to take interventions in our own communities to decrease these risks. The category “unknown” typically refers to probable vertical transmission that has not been clearly proven in that patient.
MMWR: Surveillance Summary March 21, 2008 / Vol. 57 / No. SS—2. 17

18. Vaccination
Now, we will discuss hepatitis B vaccination. 18

19. HBV Vaccine: Indications
Routine vaccination of infants
Regardless of mother’s HBsAg status
With HBIG for HBsAg+ mothers
Catch-up vaccination of children and adolescents
Vaccination of adults
End-stage renal disease
HIV infection
Chronic liver disease
At risk of occupational exposure
Household contacts or sex partner of persons with HBV
Illegal injection drug use
Sexually active persons with multiple partners
Current or recent injection-drug users
Vaccination of adults (cont)
Men who have sex with men
Travelers to countries with high or intermediate HBV prevalence
Staff and clients of :
STD treatment
HIV testing and treatment
Drug-abuse treatment and prevention
Health-care settings targeting services to injection-drug users or men who have sex with men
Correctional facilities
End-stage renal disease programs
Institutions for persons with developmental disabilities
Seeking evaluation or treatment for a STD
Any adult seeking protection from HBV infection
Core Slide
HBsAg, hepatitis B surface antigen.
Indications for vaccination are outlined on this slide. In addition to routine infant HBV vaccination, “catch-up” vaccination in children and adolescents is recommended, as is vaccination of adults with risk factors for infection. Primary care practitioners must obtain detailed risk histories of their adult patients during screening for hepatitis B to determine who needs hepatitis B vaccination. All individuals with the risk factors listed on this slide should also be checked for hepatitis C virus infection.
CDC. MMWR Morb Mortal Wkly Rep. October 19, 2007 / 56(41);Q1-Q4 19

20. HBV Vaccination: Effect on HCC Incidence and Mortality*1 1
0.80
0.8
0.8
0.70
0.57
0.58
0.6
0.6
Per 100,000 Children (6-14 Yrs)
Per 100,000 Children (6-14 Yrs)
0.36
Core Slide
0.4
0.4
0.34
HCC, hepatocellular carcinoma.
This slide examines hepatitis B vaccination using data from Taiwan. Although this information is approximately 10 years old, it shows the profound impact on incidence and mortality of HCC through early intervention that started in the early 1980s in Taiwan.
0.2
0.2
*Nationwide vaccination in Taiwan, implemented July 1984.
Chang MH, et al. N Engl J Med. 1997;336: 20

21. Hepatitis B Vaccine Coverage Among Children* in the US (1995-2003)
100
Asian/Pacific Islanders 95
Black 90 85
HepB3 Coverage (%) 80
Hispanic 75 70
This slide illustrates hepatitis B vaccination coverage among children in the United States. As shown, coverage is well over 90% in all racial groups. This is a profound achievement and shows that the United States has excellent healthcare regarding HBV vaccination. 65
White 60
1995
1996
1997
1998
1999
2000
2001
2002
2003
Year
*Aged months.
National Immunization Survey. Available at: stats-surv/imz-coverage.htm#nis. Accessed May 20, 2008. 21

22. Virology of HBV: A Primer
Now, we will discuss the virology of hepatitis B. The next couple of slides are going to highlight important issues relative to the virus and then to the immune system. 22

23. Life Cycle of HBV in the Hepatocyte
Subviral particles
Viral polymerase converts pregenomic RNA to partially ds DNA
Infectious HBV virion ER
Cytoplasm
Partially dsDNA
Minus strand DNA
HBeAg
Encapsulated pregenomic mRNA
HBsAg
cccDNA, covalently closed circular DNA; dsDNA, double-strand DNA; ER, endoplasmic reticulum; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBcAg, hepatitis B core antigen; mRNA, messenger RNA.
This slide illustrates the lifecycle of HBV in the hepatocyte. The infectious HBV virion is taken up into the liver cell and the viral polymerase converts pregenomic RNA into partially double-stranded DNA. This is then moved to the nucleus and covalently closed circular DNA is formed. Messenger RNA is formed from the covalently closed circular DNA and moved to the cytoplasm where it is packaged. A minor strand and then a partially double-stranded DNA is formed using both the polymerase and reverse transcriptase to make a complete viral particle. Precore/core protein is used and e antigen is formed in parallel to the core/precore protein. Surface antigen is also formed from the messenger RNA. This concludes complete viral packaging and release of complete virions or subviral particles of e-antigen as well as some core antigen and surface antigen, which serve as decoys to the immune system and probably modulate the immune system directly. Hepatitis B virus is not cytopathic, except in rare situations, such as liver transplantation, where the patient has high levels of immune suppression.
HBcAg
cccDNA
mRNA
Precore/core
Nucleus
Hepatocyte
Adapted from Lai CL, et al. J Med Virol. 2000;61: 23

24. HBV-Triggered Immune Response
Antigen- presenting cell
HBV
MHC class II
HBV antigens
CD4+ T cell
HBV peptides
HBV DNA
MHC class I
Down- regulations of viral replication
CD8+ T cell
Infected hepatocyte
HBV RNA
HBsAg, hepatitis B surface antigen; MHC, major histocompatibility complex; TNF-, tumor necrosis factor alfa.
The other part of this picture is the immune response to the HBV-infected hepatocyte expressing viral antigens. CD8+ T cells attach to the hepatocyte where major histocompatibility complex expression class I binds to antigen-presented molecules on the liver cell surface. Cytokines, such as tumor necrosis factor-alfa and interferon-gamma, stimulate a Th1 response interacting with antigen-presenting cells, both CD8+ cells and CD4+ cells, directly causing cell lysis. These immune response cytokines regulate inflammatory responses, which can result in the progression of liver disease and the worsening of fibrosis to cirrhosis. This immune and inflammatory response, either alone or in combination with advanced fibrosis and cirrhosis, can result in liver cancer.
TNF-α Interferon-gamma
HBV peptides
CD8+ T cell
HBV cores
HBsAg
MHC class I
Ganem D, et al. N Engl J Med. 2004;350: 24

25. Global Distribution of the 8 HBV Genotypes
A, B, C,
D, G
B, C
A, D, E D
H, F F
A, B, C, D
This slide shows the 8 HBV genotypes that are currently recognized. I have recently described a ninth genotype found in Vietnam; however, this still needs to be confirmed by other virologists. These genotypes have arisen through viral mutation as the virus moved from Central Africa and the area around Uganda, spreading worldwide. These mutations have created variants that are grouped based on similarities and are called genotypes. There are also other viral variant groups within the genotypes called subgenotypes. These arise because of recombination of the virus and can result in very different sequences, sometimes even within the same region. The clinical implications of different HBV genotypes will be discussed later.
Arauz-Ruiz P, et al. J Gen Virol. 2002;83: Bell SJ, et al. J Clin Virol. 2005;32:
Chu CJ, et al. Gastroenterology. 2003;125: Kidd-Ljunggren K, et al. J Gen Virol. 2002;83: Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2: 25

26. HBV Genotype Prevalence in the US (2001-2002)
Nationwide study of 694 consecutive chronic HBV-infected patients seen at 17 US liver centers
Prevalence of HBV genotypes
Prevalence of HBV genotypes by place of birth/ethnicity
100
100
China
Taiwan
Korea
Vietnam 78 80 80 64 60 61 60 60
Prevalence (%)
This slide shows in more detail the prevalence of different HBV genotypes in the United States. The prevalence of specific genotypes is strongly aligned by race; genotypes A and D are found more commonly in adult-acquired disease among white patients and genotypes B and C are associated with Asian patients. Among Asian patients, genotype B is most common in Vietnamese individuals and genotype C is much more highly prevalent in Korean individuals.
Prevalence (%)
34.7 35 40
30.8 40 32 32 22 20 14
10.4 20 6 5
0.4
0.6
1.1 2 3 1 2 A B C D E F G A B C D
Chu CJ, et al. Gastroenterology. 2003;125: 26

27. Natural History
The next slides discuss the natural history of hepatitis B. 27

28. Naturally Occurring Molecular Variants of HBV
HBeAg positive (wild type)[1]
Associated with higher serum HBV DNA levels and greater infectivity[2]
Basal core promoter mutations (44% US patients)[3]
Precore mutations (27% US patients)[3]
HBeAg negative (genetic mutations at precore or core promoter regions)
Associated with poorer long-term clinical response to therapy and lack of spontaneous remission
Abolishes HBeAg production (HBeAg-negative CHB)
Lower rate of HBeAg positivity
CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen.
There are a number of phases to HBV infection. Among patients with active HBV replication, that is, those who are HBV DNA positive, there are 2 distinct types of disease. The first is hepatitis B e antigen (HBeAg)–positive disease, which used to be regarded as wild-type infection because some patients can clear this type of infection by spontaneous seroconversion. However, Chu and colleagues found that almost one half of the HBeAg-positive patients thought to be infected with pure wild-type HBV actually harbored basal core promoter mutations and 27% had precore mutations. Therefore, HBeAg-positive patients should be considered as having a mixed infection and are probably transitioning to either viral clearance or to an HBeAg-negative phase of disease. HBeAg-negative disease is also characterized by active replication and is associated with a higher risk of progression to cirrhosis and cancer than HBeAg-positive infection. When core promoter or precore mutations occur, HBeAg production is lost but core and surface proteins continue to be produced and the virus is packaged. The HBeAg-negative virus is a little less efficient at viral production and patients with this type of infection typically have 1-2 log10 IU/mL lower HBV DNA levels than those with HBeAg-positive infection, a finding that has been corroborated across a wide number of studies.
1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:
2. Buchwold VE, et al. J Virol. 1996;70:
3. Chu CJ, et al. Gastroenterology. 2003;125: 28

29. HBeAg-Negative Chronic Hepatitis B
Most common in genotypes B, C, and D
Asia and Southern Europe
Not typically acquired as de novo infection
Precore and basal core promoter mutants emerge during immune clearance phase
2 main patterns
Persistently increased ALT, intermediate to high HBV DNA levels
30% to 40% of patients
High HBV DNA levels before ALT increases
Erratic ALT increases, low or negative HBV DNA
45% to 60% of patients
Sustained spontaneous remission is uncommon (6% to 15%) and long-term prognosis is poorer compared with HBeAg-positive patients
ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen.
This slide focuses on HBeAg-negative disease in more detail. This is most common in genotypes B, C, and D and is rarely seen in genotype A because of instability of certain parts of the viral proteins and the packaging process. It is almost never acquired as a de novo infection and, if it is acquired, it is typically cleared spontaneously. There are 2 main patterns associated with this stage of the disease. Some patients have persistently elevated HBV DNA with persistently increased alanine aminotransferase (ALT) levels. Other patients have erratic ALT increases with HBV DNA increasing, decreasing, or maybe clearing for a period of time, then returning to detectable levels. Patients in this second group almost never clear HBV DNA spontaneously.
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4: 29

30. Phases of Disease
The next slides consider the phases of disease from a slightly different perspective. 30

31. 4 Phases of Chronic HBV Infection
Immune-tolerance phase
HBeAg positive; high HBV DNA (2 x IU/mL); normal ALT
HBeAg-positive chronic hepatitis (immune clearance)
Intermediate to high HBV DNA (200, x 109 IU/mL); high or fluctuating ALT; active inflammation on liver biopsy
Inactive HBsAg carrier (low replication phase)
HBeAg negative; low HBV DNA (< 2000 IU/mL); normal ALT
HBsAg may become undetectable
HBeAg-negative chronic hepatitis (reactivation phase)
ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.
Early in life, HBV-infected children and young teenagers are in an immune-tolerant phase. The immune system does not respond to the virus and the HBV DNA is intermediate to high, with a normal ALT level. A normal ALT level is considered to be < 19 IU/mL in women and < IU/mL in men. In general, ALT levels < 30 IU/mL correlate with minimal or no liver disease.
The HBeAg-positive chronic hepatitis phase is characterized by immune clearance activity whereby the ALT level is a marker of T-cell activity. During this phase, clinicians almost always will see active inflammation on liver biopsy that correlates with fibrosis.
The inactive HBsAg carrier phase is characterized by normal and healthy ALT levels. In this phase, HBeAg is negative and HBV DNA is typically < 104 copies/mL or 2000 IU/mL.
Finally, the HBeAg-negative chronic hepatitis phase is characterized by intermediate levels of HBV DNA, typically elevated or fluctuating ALT levels, and active disease on liver biopsy.
Lok AS, et al. Hepatology. 2007;45:
Pungpapong S, et al. Mayo Clin Proc. 2007;82: 31

32. Phases of Chronic HBV Infection
Immune
Immune
Low Replicative
Reactivation
Tolerance
Clearance
Phase
Phase
HBeAg+
HBeAg-/anti-HBe+ (precore/core promoter variants)
<
>
<
>
> 2000 IU/mL
HBV DNA
< 2000 IU/mL
2 x x 1011 IU/mL
200, x 109 IU/mL
anti-HBe, antibody to hepatitis B e; HBeAg, hepatitis B e antigen.
The next 4 slides examine these phases of chronic hepatitis B moving from immune tolerance to immune clearance or immune stress, to the low replicative or nonreplicative state, then to the reactivation phase, which typically occurs as the precore/core promoter HBeAg-negative disease evolves.
Slide courtesy of A. S. F. Lok, MD. 32

33. Phases of Chronic HBV Infection
Immune
Immune
Low Replicative
Reactivation
Tolerance
Clearance
Phase
Phase
HBeAg+
HBeAg-/anti-HBe+ (precore/core promoter variants)
<
>
<
>
> 2000 IU/mL
HBV DNA
< 2000 IU/mL
2 x x 1011 IU/mL
200, x 109 IU/mL
ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; HBeAg, hepatitis B e antigen.
During this set of slides, the ALT levels oscillate then become normal and healthy in many patients, but not all. Some patients will move from immune clearance to HBeAg-negative disease.
ALT
Slide courtesy of A. S. F. Lok, MD. 33

34. Phases of Chronic HBV Infection
Immune
Immune
Low Replicative
Reactivation
Tolerance
Clearance
Phase
Phase
HBeAg+
HBeAg-/anti-HBe+ (precore/core promoter variants)
<
>
<
>
> 2000 IU/mL
HBV DNA
< 2000 IU/mL
2 x x 1011 IU/mL
200, x 109 IU/mL
ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen.
This section of the slide illustrates the histology. A patient can develop cirrhosis during any of these different phases but most commonly this occurs when the ALT is oscillating or elevated and HBV DNA is actively replicating.
ALT
Normal/mild CH
Moderate/severe CH
Normal/mild CH
Moderate/severe CH
Cirrhosis
Inactive cirrhosis
Cirrhosis
Slide courtesy of A. S. F. Lok, MD. 34

35. Phases of Chronic HBV Infection
Immune
Immune
Low Replicative
Reactivation
Tolerance
Clearance
Phase
Phase
HBeAg+
HBeAg-/anti-HBe+ (precore/core promoter variants)
<
>
<
>
> 2000 IU/mL
HBV DNA
< 2000 IU/mL
2 x x 1011 IU/mL
200, x 109 IU/mL
ALT
ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CH, chronic hepatitis; HBeAg, hepatitis B e antigen.
Finally, this section shows the HBeAg-positive phase, the inactive carrier phase, and the HBeAg-negative phase. It should be highlighted that a patient can move from the HBeAg-positive to HBeAg-negative phase with either no or a very brief period of the inactive carrier state.
Normal/mild CH
Moderate/severe CH
Normal/mild CH
Moderate/severe CH
Cirrhosis
Inactive cirrhosis
Cirrhosis
HBeAg+ chronic hepatitis
Inactive-carrier state
HBeAg- chronic hepatitis
Slide courtesy of A. S. F. Lok, MD. 35

36. Natural History of HBV Infection
Early Childhood
> 95%
Immune Tolerance
Adulthood
< 5%
HBeAg- Chronic Hepatitis B
HBeAg+ Chronic Hepatitis B
Cirrhosis
HBeAg, hepatitis B e antigen.
The next 2 slides show the 4 phases of HBV disease, including the HBeAg-positive and HBeAg-negative phases, both of which can move to cirrhosis. In addition, there is the inactive carrier phase, which is characterized by less active disease and rarely directly moves to cirrhosis. The percentages next to the early childhood box (> 95%) and the adulthood box (< 5%) denote the risk of developing a chronic carrier state.
Inactive Carrier
Courtesy of W. Ray Kim, MD. Chen DS, et al. J Gastroenterol Hep. 1993;8: Seeff L, et al. N Engl J Med. 1987;316: 36

37. Natural History of HBV Infection
Early Childhood
> 95%
Immune Tolerance
Adulthood
< 5%
HBeAg- Chronic Hepatitis B
HBeAg+ Chronic Hepatitis B
HCC
HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma.
This slide highlights the risk of cancer. A patient can progress to cancer from any of the 4 highlighted states.
Inactive Carrier
Courtesy of W. Ray Kim, MD. Chen DS, et al. J Gastroenterol Hep. 1993;8: Seeff L, et al. N Engl J Med. 1987;316: 37

38. Clinical Profiles of Chronic HBV Infection
Immune Tolerant
HBeAg+ CHB
Inactive HBsAg Carrier
HBeAg- CHB (Precore Mutant)
HBsAg +
HBeAg –
Anti-HBe
ALT
Normal 
HBV DNA
> 20,000 IU/mL (> 105 copies/mL)
> 20,000 IU/mL (> 105 copies/mL)
< 200 IU/mL (< 103 copies/mL)
> 2000 IU/mL (> 104 copies/mL*)
Histology
Normal/mild
Active
ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.
This table illustrates the clinical profiles of HBV infection. The field is moving to use of international units (IU/mL) rather than copies/mL when describing HBV DNA levels. This slide shows that, from a historical perspective, HBV DNA > 20,000 IU/mL correlated with the highest risk of progression in HBeAg-positive patients and HBV DNA > 2000 IU/mL correlated with the highest risk of progression with HBeAg-negative disease.
*Expert opinions vary as to this value.
Lai CL, et al. Lancet. 2003:362:2089. Lok AS, et al. Gastroenterology. 2001:120:1828. 38

39. Factors Associated With Disease Progression
The next section reviews factors associated with disease progression. 39

40. Risk Factors for Progression of Liver Disease (Cirrhosis, Liver Failure, HCC)
HBV genotype
HBeAg positivity
Presence of hepatic inflammation/ fibrosis/cirrhosis
Severity at presentation
Sustained activity of liver disease
Elevated ALT
Elevated HBV DNA
HBV/HCV and HBV/HDV coinfection
Liver iron
Liver fat
High geographic endemicity
Older age
Male sex
Immune status: HIV or organ transplant
Alcohol abuse
Smoking
Positive family history for liver cancer*
Aflatoxin exposure*
ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma.
This slide highlights risk factors for the progression of liver disease. These will be discussed in more detail in the context of the clinical significance of HBV DNA levels later in this presentation. It is important to consider carefully how to broach modifiable risk factors, including drinking and smoking cigarettes or marijuana, with your patients. Although aflatoxin exposure cannot easily be modified, it is relatively rare in the United States, although there are interventions available in areas such as Africa or southeastern China where this is more common. It is important to always take a family history for the presence or absence of liver cancer in HBsAg carriers, especially in Asian patients.
*HCC only
Fattovich G et al. Gastroenterology. 2004;127:S35-S50.
Yang HI, et al. N Engl J Med. 2002;347:
Tang B, et al. J Med Virol. 2004;72:35-40. 40

41. Historical Methods of Determining the Risk of HCC: HBeAg Status
HCC, hepatocellular carcinoma.
Regarding historical methods of determining the risk of HCC, in the past HBeAg was thought to be a good marker of risk, although this has changed in recent years, in part because of the data presented in the following slides. 41

42. HBeAg Seroconversion Not Always Associated With Outcomes in Asians
Chang Gung Memorial Hospital, Taiwan (N = 283)
Median age of seroconversion: 32 years
Patients without evidence for cirrhosis at time of HBeAg seroconversion
7.8% and 2.2% developed cirrhosis and HCC, respectively, over a median follow-up of 8.6 years
Queen Mary Hospital, Hong Kong (N = 3233)
Median age of seroconversion: 35 years
Median age for the development of HCC and/or cirrhosis: 57 years
73.3% of patients with clinical complications were anti-HBe positive
HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma.
This slide illustrates data from the Chang Gung Hospital in Taiwan and Queen Mary Hospital in Hong Kong from 2002 to 2005, which show that even patients with HBeAg seroconversion and clearance were still at substantial risk for developing cirrhosis and liver cancer. HBeAg does not impart any additional information on risk of liver cancer that supersedes that provided by the level of HBV DNA.
Hsu YS, et al. Hepatology. 2002;35: Yuen MF, et al. Gut. 2005;54: 42

43. Disease Progression After HBeAg Seroconversion in Asians
Prospective study in Taiwan
11,893 men without evidence of hepatocellular carcinoma
Newly diagnosed HCC
111 cases during 92,359 person-years of follow-up
Incidence rate per 100,000 person-years
HBsAg-, HBeAg-: 39.1
HBsAg+, HBeAg-: 324.3
HBsAg+, HBeAg+:
HBeAg positivity at enrollment was associated with an increased risk of HCC
HCC
HBsAg+, HBeAg+ RR: 60.2 (P < .001) 12 10 8
Cumulative Incidence (%) 6 4
HBsAg+, HBeAg- RR: 9.6 (P < .001)
HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; RR, relative risk; yrs, years.
By contrast, Yang and colleagues found that patients were at a lower risk of developing liver cancer when they became HBeAg negative. However, this study did not record HBV DNA levels in their main database. 2
HBsAg-, HBeAg- RR: 1.0
Follow-Up (Yrs)
Yang HI, et al. N Engl J Med. 2002;347: 43

44. Current Methods of Determining the Risk of HCC: HBV DNA Level
HCC, hepatocellular carcinoma.
What are the current methods of determining the risk of progression of liver disease and the development of HCC? 44

45. Low HBV DNA Level Does Not Rule Out Risk in Asian Patients
HBeAg-positive patients[1]
HBV DNA < 105 copies/mL predicted better histology
However, 14.3% of patients still had fibrosis
Patients with cirrhosis[2]
HBV DNA level was the best predictor of HBV-related complications (P = .02)
However, 24.5% of anti-HBe patients with complications had HBV DNA levels < 104 copies/mL
anti-HBe, antibody to hepatitis B e; HBeAg, hepatitis B e antigen.
This slide demonstrates that having low detectable HBV DNA levels does not completely eliminate the risk of serious liver disease in Asian patients. Among the HBeAg-positive patients, HBV DNA < 105 copies/mL predicted better histology, but 14% of these patients still had substantial fibrosis.
In patients with cirrhosis, HBV DNA was the best predictor of HBV-related complications, but 24% of patients with anti-HBe with complications had HBV DNA < 104 copies/mL.
For more information, go online to:
1. Yuen MF, et al. Am J Gastroenterol. 2004;99: Yuan HJ, et al. J Viral Hepat. 2005;12: 45

46. The REVEAL Study: Key FIndings
Patients with higher baseline HBV DNA levels had higher
cumulative risk of development of cirrhosis and HCC
Association observed across all stratified groups: all patients, HBeAg-negative patients only, HBeAg-negative patients with normal ALT with or without cirrhosis
Liver cancer mortality range
HBV DNA < 300 copies/mL: 72.8 per 100,000 person-years
HBV DNA ≥ 105 copies/mL: per 100,000 person-years
Multivariate analysis for risk of developing cirrhosis and HCC vs HBsAg-negative persons
Patients with HBV DNA < 300 copies/mL at baseline and during follow-up still at significantly increased risk
Age, cigarette smoking, alcohol consumption, and ALT > 15 IU/L during follow-up significantly associated with increased risk
ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma.
The REVEAL study was a large Taiwanese study that showed that liver cancer mortality range was still substantial in patients with HBV DNA < 300 copies/mL (~ 69 IU/mL), at 73/100,000 patient-years. However, in patients with HBV DNA > 105 copies/mL (~ 20,000 IU/mL), the mortality was more than 800/100,000 patient-years.
Multivariate analysis was conducted on the risk of developing cirrhosis and HCC in patients with chronic hepatitis B compared with HBsAg-negative individuals. Patients with HBV DNA < 300 copies/mL (~ 69 IU/mL) had a numerically higher risk of HCC and cirrhosis compared with HBsAg-negative controls. Interestingly, age (which serves as a marker for the duration of disease), use of cigarettes, alcohol exposure, and elevated ALT were significantly associated with the risk of cirrhosis and liver cancer.
For more information, go online to:
Chen CJ, et al. JAMA. 2006;295: Iloeje UH, et al. Gastroenterology. 2006;130: Iloeje UH, et al. Clin Gastroenterol Hepatol. 2007;5: 46

47. HBV DNA Associated With Increased Risk of HCC
3.9-fold greater risk of HCC in individuals with detectable HBV DNA vs those with undetectable HBV DNA
Risk associated with increasing HBV DNA levels
These data support possibility of reducing long-term risk of HCC by inducing sustained suppression of HBV replication
Caveats: Analysis of data only from a nested case–controlled subpopulation of HBsAg positive Taiwanese men
HCC, hepatocellular carcinoma.
Yang and colleagues conducted a subsequent analysis that showed that patients with detectable HBV DNA had a 4-fold greater risk of HCC than those with undetectable HBV DNA. Therefore, it is important that assessment of HBV DNA be part of the standard of care. Blood tests should be done in all patients who are HBsAg positive with follow-up testing every 6 months.
Yang HI, et al. N Engl J Med. 2002;347: 47

48. HCC Surveillance Is Recommended for the Following CHB Patients
Asian males 40 years of age or older
Asian females 50 years of age or older
All cirrhotic hepatitis B patients
Family history of HCC
Africans older than 20 years of age
For noncirrhotic hepatitis B carriers not listed above, the risk still exists but varies depending on a number of factors
CHB, chronic hepatitis B; HCC, hepatocellular carcinoma.
Surveillance of HCC is recommended for the following patients with chronic hepatitis B:
Asian men older than 40 years of age if they do not have cirrhosis
Asian women older than 50 years of age if they do not have cirrhosis
All cirrhotic patients with hepatitis B, anywhere in the world, should undergo liver cancer screening and surveillance; my recommendation, consistent with expert opinion including the article by Bruix and colleagues, is to follow a 6-month cycle
Patients with a family history of HCC; if a first-degree relative is diagnosed with liver cancer, surveillance screening should commence
Individuals born in sub-Saharan Africa older than 20 years of age should receive liver cancer surveillance
Furthermore, in hepatitis B patients, I assess alpha-fetoprotein at baseline and every 6 months. Although this is not necessarily a very specific test for incident cancers, it is generally felt to be a good test to predict long-term risk of liver cancer in an individual with hepatitis B.
Bruix J, et al. Hepatology. 2005;42: 48

49. Provider and Patient Knowledge About HBV
The next set of slides considers provider and patient knowledge about HBV. 49

50. Provider Screening Knowledge and Practice in Chinese-Speaking Patients
Retrospective cohort study
General Medical Practice at UCSF
55,000 adult visits per year
8% by Chinese-speaking patients
65% of Chinese patients were screened for HBV
Predictors for being screened
Being married (P < .001)
Years visiting the practice (P = .003)
Higher screen rates by physicians who spoke Chinese and those with a greater knowledge of HBV
These data emphasize the need to educate physicians on screening high-risk populations
Patients Screened for HBV
100 80 72 65 60
Patients Screened (%) 47 40 36 21 20
UCSF, University of California, San Francisco.
This slide describes results from a retrospective cohort study at a general medical practice at the University of California, San Francisco, at which there were approximately 50,000 adult visits per year, of which 8% were Chinese patients. Sixty-five percent of the Chinese patients were screened for hepatitis B. The likelihood that a specific patient would be screened increased if they were married and also increased with longer duration of attendance at that general medicine practice. Higher screening rates were identified among physicians who spoke Chinese and among those who had had substantial medical provider education about hepatitis B.
Korean
White
South East Asian/Pacific Islander
Filipino
Chinese Speaking Chinese
Lai CJ, et al. J Cancer Educ. 2007;22:37-41. 50

51. Knowledge of HBV and Liver Cancer: Among Asian Americans, SF Bay Area
Multilanguage survey of 199 adults undertaken in 2000
90% of respondents had heard of HBV and > 70% were aware of the liver morbidity and mortality associated with HBV infection but
< 60% had been tested
31% were vaccinated
44% had their children vaccinated
SF, San Francisco.
This slide shows the knowledge of hepatitis B and liver cancer among Asian Americans in the San Francisco Bay area. A total of 199 adults took the survey in Interestingly, 90% of the respondents had heard of hepatitis B and more than 70% were aware of the liver morbidity and mortality associated with hepatitis B. However, less than 60% of the respondents had been tested, only 31% had been vaccinated, and only 44% had had their children vaccinated. This clearly outlines a substantial community and clinical need.
Wu CA, et al. Asian Pacific J Cancer Prev. 2007;8: 51

52. Knowledge of HBV Transmission Among Asian Americans, SF Bay Area
100
Responses to Questions About HBV Transmission
Correct answer
Incorrect answer 90 80 70
63.3
59.3
58.8 60
56.3
53.3
50.8
Respondents (%) 50 40
27.1 30
25.1
25.6
26.6
21.6
22.1
23.6
22.1
20.1 20
14.0
15.1
14.6
SF, San Francisco.
This slide illustrates correct and incorrect answers to questions about HBV transmission. Along the x-axis, methods of transmission are listed, including contaminated food, contaminated blood, home devices such as razors and toothbrushes, intravenous drug use, unprotected sex, and birth to an infected mother.
The proportions of patients answering the questions correctly ranged from 50% to 60%, except for the small number correctly answering the question on contaminated food. It is known that contaminated food is extremely unlikely to transmit hepatitis B, but this suspicion can commonly result in individuals being ostracized from their families and friends. Handshakes, hugs, kisses, food sharing, and glass sharing are not risky and also not reasons to discriminate against these patients. The public should be informed to not be prejudiced and to not ostracize individuals who are HBsAg positive. However, they should be cautious with blood and sexual exposure. 10
Y N U
Y N U
Y N U
Y N U
Y N U
Y N U
Contaminated Food
Contaminated Blood
Shared Razors/ Toothbrushes
IDU
Unprotected Sex
Birth to Infected Mother
N, no; U, uncertain, Y, yes.
Wu CA, et al. Asian Pacific J Cancer Prev. 2007;8: 52

53. Knowledge of HBV Prevention Among Asian Americans, SF Bay Area
100
Responses to Questions About HBV Prevention
Correct answer
Incorrect answer 90 80
73.9
70.4 70 60
46.7
48.2
Respondents (%) 50
46.2 40
29.6
30.7
27.6 30
25.6
22.1
22.1
23.1
17.6 20
SF, San Francisco.
This slide shows correct and incorrect responses to questions designed to test knowledge of hepatitis B prevention in the same survey. Regarding proper cooking techniques and avoiding contaminated water, approximately one half of patients answered incorrectly. It is extremely unlikely for HBV to be transmitted in contaminated water, unlike hepatitis A virus. Fortunately, most respondents (but not 100%) knew to avoid infected needles. Interestingly, approximately one half of the individuals did not know that hepatitis B is not curable.
8.5
7.5 10
Y N U
Y N U
Y N U
Y N U
Y N U
Vaccination
Proper Cooking Techniques
Avoid Contaminated Water
Avoid Infected Needles
Availability of a Cure
N, no; U, uncertain, Y, yes.
Wu CA, et al. Asian Pacific J Cancer Prev. 2007;8: 53

54. Diagnostic Criteria and Patient Evaluation
The next slide reviews diagnostic criteria and patient evaluation. 54

55. Evaluation of Patients With Chronic HBV Infection
Initial evaluation
History and physical examination
Family history of liver disease, HCC
Laboratory tests to assess liver disease: complete blood counts with platelets, hepatic panel, and prothrombin time
Tests for HBV replication: HBeAg/anti-HBe, HBV DNA quantification
Ultrasound of liver and spleen
AFP
AFP, alpha-fetoprotein; anti-HBe, antibody to hepatitis B e; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma.
The initial evaluation of patients with chronic HBV infection should include the following steps:
Obtain a medical history and perform a physical exam; be sure to feel the spleen size, percuss the liver, and look for spider angiomata, palmar erythema, edema, encephalopathy, and jaundice
Obtain a family history, especially of liver cancer
Order laboratory tests to assess liver disease, including a complete blood count with platelets. A low white blood cell count and a low platelet count strongly suggest hypersplenism
Order a liver panel, which includes liver enzymes, such as aspartate aminotransferase (AST) and ALT. These are no longer called liver function tests; these are enzymes and do not relate to liver function, although an AST higher than ALT is often associated with a low platelet count and advanced fibrosis. The prothrombin time, albumin, and bilirubin are liver function tests and should be part of the clinical assessment
Determine HBeAg status and HBV DNA quantification
Obtain a baseline ultrasound of the liver; this should include a measurement of the portal vein diameter, spleen size, and vertical height
Measure the alpha-fetoprotein
Adapted from Lok AS, et al. Hepatology. 2007;45: 55

56. Evaluation of Patients With Chronic HBV Infection
Initial evaluation (cont’d)
Tests to rule out viral coinfections: HIV, HAV, HCV
HDV in persons from countries where HDV is common, any adult-acquired HBV, and in those with history of injection drug use
Tests to screen for HCC
Consider liver biopsy to grade and stage liver disease for patients who meet criteria for chronic hepatitis
AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma.
Initial evaluation should also include the following additional steps:
Evaluate the presence of any viral hepatitis coinfections
Assess for HIV coinfection
Start screening and surveillance for liver cancer
Consider a liver biopsy to grade and stage liver disease. A liver biopsy that shows fibrosis or cirrhosis can be a great motivator for patients to comply with long-term indefinite treatment with oral agents
Adapted from Lok AS, et al. Hepatology. 2007;45: 56

57. HBV DNA Testing
Indicates chronic hepatitis when still positive 6 months after diagnosis of acute HBV infection
Can differentiate chronic, inactive carrier (< 2000 IU/mL) vs resolved HBV infection (undetectable)
Change in viral levels used to monitor response to therapy
Increasing viral levels indicate emergence of resistant variants during antiviral therapy
Viral levels correlate with disease progression
Previous slides have reviewed the importance of and the recommended frequency for HBV screening. HBV DNA screening can be used to monitor for the emergence of resistant variants during antiviral therapy, to identify viral levels correlating with disease progression, and to assess the risk of cirrhosis and cancer. It is the standard of care in all HBsAg-positive patients. In my area, this information is being disseminated to the community, and it is now our job as clinicians to identify HBsAg-positive patients and to make sure they receive appropriate HBV DNA testing.
Adapted from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2: 57

58. Dynamic Ranges of HBV Viral Assays
Abbott RealTime HBV
HBV Digene Hybrid-Capture I
Versant HBV DNA 1.0
HBV Digene Hybrid-Capture II
Ultra-Sensitive Digene Hybrid-Capture II
Amplicor HBV Monitor
Versant HBV DNA 3.0
Cobas Amplicor HBV Monitor
PCR, polymerase chain reaction.
This slide shows the dynamic ranges of a variety of HBV DNA viral assays. In the United States, the most widely used test is the Cobas Taqman assay, shown in yellow. TMA testing, shown in purple, is used primarily in blood banks and is not commercially available. At the top of the chart is the Abbott RealTime HBV assay, but this is not commercially available in the United States at the current time. The Versant HBV DNA tests, both in green, are still clinically available but have poor sensitivity for low levels of HBV DNA. I do use this assay in patients with very high levels of HBV DNA because it gives a true value directly from the patient sample. It is common for other more sensitive assays to require dilution of the serum sample to get correct values.
HBV PCR Kit
TMA Assay LLQ 5 IU mL
Cobas Taqman 48 HBV
102
104
103
105
106
107
108
1010
109 10 1
HBV DNA (IU/mL)
Assay Product Documentation 58

59. Assessment for Treatment: Candidates for Therapy[1]
Immune-tolerant phase
HBeAg positive; HBV DNA high ( IU/mL); ALT normal
Consider biopsy in older patients
May be candidates for therapy in light of the Taiwanese data[2] but issue controversial
Immune-active phase (chronic hepatitis B)
HBeAg positive (wild type) or
HBeAg negative (mutants)
HBV DNA high ( IU/mL); ALT elevated; symptoms +/-
ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen.
This slide outlines candidates for hepatitis B treatment. As previously discussed, data indicate that patients with abnormal ALT levels are at high risk for liver disease progression in the setting of measurable HBV DNA. It is likely that that the criteria for treatment will be updated during the next National Institutes of Health guidelines meeting as a result of the REVEAL study data. Other data from Europe, Africa, Southeast Asia, Hong Kong, and mainland China will also be important in determining our future treatment strategies.
For more information, go online to:
1. Lok AS, McMahon BJ. Hepatology. 2007;45:
2. Chen CJ, et al. JAMA. 2006;295:65-73. 59

60. Impact of HBV Genotype on Disease Progression
Genotype C
More frequently associated with severe liver disease and HCC than with genotype B
Genotype B
Associated with seroconversion from HBeAg to anti-HBe at younger age than with genotype C
Genotypes A and B
Higher rates of antiviral response and HBeAg loss following peginterferon alfa-2b than with genotypes D and C, respectively
HBV Genotyping Line Probe Assay
marker line
conj. control 1
amp. control 2 3
Genotype A 4 5
Genotype B 6 7
Genotype C 8 9
Genotype D 10 11
Genotype E 12 13 14
anti-HBe, antibody to hepatitis B e; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma.
Regarding HBV genotyping, genotype C appears to be associated with a higher risk of development of cirrhosis and HCC, compared with genotype B. These are the 2 dominant genotypes in Asia. Conversely, genotype B is associated with a higher rate of seroconversion from HBeAg positivity to HBeAg negativity and is associated with greater HBV DNA suppression when treated. Genotype A and B are associated with a higher rate of response to interferon-based therapy, which is an important issue when managing adult-acquired hepatitis B.
Genotype F 15 16
Genotype G
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4: 60

61. Epidemiology in the Asian Community: Treatment Implications
Earlier age of HBV acquisition accounts for the major differences in natural history of HBV between Asian and white populations
Asian patients undergo approximately 2-3 decades of immune-tolerance phase
Whites enter immune-clearance phase shortly after establishment of chronic HBV infection
When predicting prognosis in Asians, consider
Age
Potential for disease progression
After HBeAg seroconversion
With HBV DNA levels < 105 copies/mL
With persistently normal ALT levels in the setting of viremia
ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen.
This slide considers the treatment implications of HBV epidemiology in the Asian community. As previously discussed, ALT and HBV DNA levels can be used to estimate risk of progression. White patients with adult-acquired disease enter the immune clearance phase shortly after establishment of chronic hepatitis B and clear the virus at a much higher rate because of active immune recognition of HBV infection.
When predicting an Asian patient's prognosis, HBV DNA and elevated ALT should be considered the most important factors. A liver biopsy should be considered in patients with intermediate ALT or HBV DNA levels.
Yuen MF, et al. J Gastroenterol Hepatol. 2007;22: 61

62. Role of ALT in Assessment of HBV Patients
ALT > 20 IU/L associated with increased risk for liver disease-related death[1]
Patients with mildly elevated ALT (> 1 to 2 x ULN) may be at increased risk of developing complications or fibrosis progression[2,3]
Up to 24% of patients with normal ALT have stage 2-4 fibrosis by biopsy[4,5]
AASLD position statement on ALT measurements:[6]
Useful in identifying significant liver disease and need for treatment
Useful for gauging the future course of natural history of HBV infection
ALT values > 1- 2 x ULN at the highest risk of complications
ALT, alanine aminotransferase.
This slide emphasizes the role of ALT in assessing hepatitis B patients. Using a large database of more than 150,000 people in Korea, ALT levels that ranged from 20-30 IU/mL were associated with a higher risk of liver disease-related death than lower ALT levels. Even a small increment of ALT elevation results in a much higher risk of liver disease-related death.
According to 2 different studies, patients with mildly elevated ALT, at 1-2 times the upper limit of normal, have increased risk of complications and fibrosis progression. In 2 other studies, up to 24% of patients with normal ALT had stage 2-4 fibrosis on biopsy. These data highlight a distinction between “normal” ALT and “healthy” ALT.
1. Kim HC, et al. BMJ 2004;328: Yuen MF, et al. Gut. 2005;54: Lai M, et al. J Hepatol. 2007;47: Lai M, et al. Hepatology 2005;42(suppl 1):720A. 5. Alberti A, et al. Ann Intern Med. 2002;137: Kim WR, et al. Hepatology. 2008;47: 62

63. Can HBV Infection Be Cured?
HBV is not curable but it is controllable
HBsAg seroconversion is the ultimate form of viral control
HBsAg, hepatitis B surface antigen.
This slide emphasizes an important point, that hepatitis B is not curable but is controllable with our powerful agents. A number of different medications can be used, and clinicians should be focused on achieving undetectable HBV DNA in all patients. However, HBsAg seroconversion is the ultimate goal for our patients. 63

64. Natural Clearance of HBsAg in Anti-HBe+, Asymptomatic HBsAg Carriers
Taiwanese Cohort
Chang Gung Memorial Hospital (N = 1965)
Minimum follow-up: 3 years
Calculated rate of hepatitis seroclearance
1.15% per year
Cumulative probabilities of HBsAg seroclearance
8.1%, 24.9%, and 44.7% after 10, 20, and 25 years, respectively
Correlated with age at entry and sustained remission of hepatitis (P < .0001)
Annual Rate of HBsAg Seroclearance
Age at entry, Yrs
Follow-Up, Person-Yrs
Annual Rate, %
< 30 (n = 510)
5936
0.77
30-39 (n = 890)
9869
1.07
40-49 (n = 394)
3880
1.65
≥ 50 (n = 171)
1582
1.83
Total
21267
1.15
anti-HBe, antibody to hepatitis B e; HBsAg, hepatitis B surface antigen.
This slide examines natural clearance of HBsAg in anti-HBe-positive, asymptomatic HBsAg carriers. There is a high rate of HBsAg seroclearance, at an annual rate of approximately 1% to 2%. This is a special population that has had undetectable HBV DNA for a long period. To achieve this, patients must have some level of immune recognition that clears HBV DNA levels from their blood. Patients who have been infected for more than 25 years can have up to approximately a 45% chance of HBsAg seroclearance. However, these patients should not be considered cured. If they receive immunosuppression, there is a substantial chance of HBV reactivation in these patients.
Chu CM, et al. Hepatology. 2007;45: 64 64

65. Presence of Occult HBV Among Patients Without Liver Disease
Occult HBV infection defined by presence of HBV DNA in liver of HBsAg-negative individuals
These individuals may be at increased risk of liver fibrosis progression and development of HCC if other causes of liver damage are present[1]
Immunosuppression may reactivate occult HBV
Individuals may transmit HBV infection to others
Prevalence of occult HBV infection studied in 98 Italian HBsAg-negative patients without liver disease[2]
16.3% of patients had occult HBV infection
62.5% (10/16) of anti-HBc positive patients vs 7.3% (6/82) of HBV marker-negative patients (P < .0001)
anti-HBc, antibody to hepatitis B core; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma.
This slide outlines the presence of occult HBV among patients without liver disease. These data show that HBV DNA was detectable in 16.3% of 98 Italian HBsAg-negative patients without liver disease. Corroborating data have been reported in Asian patients, in dialysis patients, and in other individuals using super-sensitive HBV DNA testing that allows the detection of occult HBV DNA in individuals at risk.
1. Squadrito G, et al. Cancer. 2006;106:
2. Raimondo G et al. J Hepatol. 2008;48:

66. Go Online for Additional Components of This Program!
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Treatment Initiation Guidance Tool
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clinicaloptions.com/HBVCurriculum