1. HBV Core Curriculum: Epidemiology, Prevention and Treatment of Hepatitis B
Norah Terrault, MD, MPH
Adjunct Assistant Professor,
Medicine/Gastroenterology
University of California, San Francisco

2. About These Slides
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These slides may not be published or posted online without permission from Clinical Care Options.
We are grateful to Norah Terrault, MD, MPH, University of California San Francisco, who aided in the content creation of these slides.
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3. Global Burden of HBV 2 billion current or past infections
million with chronic HBV disease
1.25 million in the US
25%-40% of persons with chronic HBV disease die from cirrhosis or HCC
Over 300,000 cases/year of HBV-related HCC
HBV is second most important carcinogen behind tobacco
Hepatitis B virus (HBV) is one of the most important causes of chronic liver disease in the world. An estimated 2 billion individuals have current or past infection, and 300 to 400 million individuals, including 1.25 million people in the United States, are chronically infected. Between 25% and 40% of individuals with chronic hepatitis B die from cirrhosis or liver cancer, and more than 300,000 cases of HBV-related cancer occur each year. This makes hepatitis B the second most important carcinogen after tobacco.
World Health Organization. Fact sheet. Available at: Accessed January 31, Centers for Disease Control. Fact sheet. Available at: Accessed January 31, Lai CL, et al. Lancet. 2003;362:

4. Hepatitis B Disease Burden in the United States
Percent ever infected
4.9%
New infections
78,000/year
Highest rate of disease
20-49 year olds
Greatest decline in disease
Children and adolescents
In the United States, 78,000 new cases of HBV infections occur each year. The highest rate of disease is among year olds. Children and adolescents have seen the greatest decline in disease, largely because of vaccination programs.
Centers for Disease Control. Hepatitis B fact sheet. Available at: Accessed January 31, Mahoney FJ. Clin Microbiol Rev. 1999;12: Hepatitis B Foundation. Hepatitis B statistics. Available at: Accessed January 31, 2996.

5. Prevalence of Chronic Hepatitis B
~ 2 million Asians
~ 930, 000 Europeans
~ 400,000
South Americans
HBsAg Prevalence
Immigration patterns play an important role in the demographics of chronic hepatitis B in the United States. Although hepatitis B is not highly prevalent in the United States, individuals from areas where hepatitis B is highly prevalent have been immigrating to the United States, particularly during the past years. This has resulted in a population of HBV-infected individuals in the United States from various backgrounds.
> 8% - High
~ 350,000 Africans
2-8% - Intermediate
< 2% - Low
Immigration numbers summed by continent from
Centers for Disease Control. Hepatitis B fact sheet. Available at: Accessed January 31, Mahoney FJ. Clin Microbiol Rev. 1999;12: Hepatitis B Foundation. Hepatitis B statistics. Available at: Accessed January 31, 2006.

6. HBV Seroprevalence Among Asian Americans
5 large US cities ( )
Chinese
Korean
Vietnamese
Median age
43 yrs (12-80)
HBsAg+, overall
558/5341 (10.4%)
Proportion of Individuals HBsAg+ 0% 4% 8%
12%
16%
Philadelphia
11%
San Francisco
14%
Boston
10%
Chicago
11%
The prevalence of HBV among individuals who have immigrated to the United States from areas of high HBV prevalence was recently investigated in a study by Guan and colleagues. From , the overall prevalence of HBV in Asian Americans in 5 large US cities was 10.4%, which is higher than that expected for the general US population. This finding highlights the impact of immigration on HBV demographics in the United States.
For more information, please go online to:
Coverage/Boston 2004/Capsules/1269.aspx
NY(1)
15%
NY(2)
11%
Overall
10.4%
Guan R, et al. AASLD Abstract 1269.

7. Clinical Consequences of HBV Acquisition
Acute Infection
Major risk of death related to development of fulminant liver failure (rare)
Chronic Infection
Progressive liver disease
Risk of cirrhosis, liver failure, hepatocellular carcinoma (HCC)
Rarely extrahepatic manifestations
HBV is associated with clinical consequences in both the acute and chronic phases of infection. Acute HBV infection can cause fatal fulminant liver failure, which is a rare but present risk. The bigger burden of disease is caused by chronic infection. Progressive liver disease can culminate in cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Extrahepatic manifestations of hepatitis B are rare but can include polyarteritis nodosum and glomerular nephritis.

8. Reducing the Burden of Chronic HBV Disease
Prevention of infection
Vaccination!
Prevention of liver-related complications
Modify lifestyle: weight control, limit alcohol
Anti-HBV therapies: interferon, lamivudine, adefovir, entecavir
HCC surveillance
Efforts to reduce the burden of chronic hepatitis B disease have focused on 2 major strategies: vaccination and prevention of complications. The HBV vaccine is safe and effective and has significantly reduced the incidence of new infections. For patients already infected with chronic hepatitis B, several strategies are used to prevent liver-related complications. These strategies include lifestyle modifications—in particular, limiting alcohol intake and controlling weight—administering anti-HBV therapies if appropriate, and performing surveillance for HCC.

9. Incidence of Acute Hepatitis B: United States, 1978-1995
Safer Injection and Sexual Practices 80 70
Infant
immunization 60 50
Cases/100,000 40
Vaccine
licensed
HBsAg screening
of pregnant women
Vaccination is the best strategy for reducing the burden of chronic hepatitis B worldwide. The impact of vaccination, along with other prevention strategies, is evidenced by the decreasing incidence of acute hepatitis B in the United States during the past 20 years. Incidence of new infections began to decline in the mid-1980s, partly as a result of safer injection and sexual practices prompted by the HIV epidemic. Screening of pregnant women for hepatitis B began in the late 1980s, followed by the introduction of vaccinations for infants and then adolescents in the early to mid-1990s. 30 20
Adolescent immunization 10 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95
Year
Available at: Accessed February 5, 2006.

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. Annual Incidence of Liver Cancer in Children Aged 6-15 Years
Age at Diagnosis
Before Program Cohort
( ),
Incidence per 100,000
After Program Cohort
( ), 6
0.46
0.00 7
0.53
0.15 8
0.48
0.31 9
0.61
Total
0.52
0.13*
The impact of vaccination on the incidence of childhood HCC in HBV-endemic areas is evident in this study by Chang and colleagues, which compared incidence of liver cancer in Taiwanese children before and after the implementation of a vaccination program in In the decade before the vaccine program, the overall incidence of HCC in children aged 6-9 years was 0.52 cases per 100,000 persons. The incidence decreased significantly to 0.13 cases per 100,000 persons in the after-program cohort. Updated data show a continuation of this trend, indicating that prevention of HBV infection can influence the important endpoints of chronic disease such as liver cancer.
*P < .001 for comparison between birth cohort.
Vaccination program in effect since July 1984
Chang MH, et al. N Engl J Med. 1997;336:

13. Issues Related to HBV Vaccination
Poor or nonresponse to vaccination
Strategies to maximize likelihood of response
Durability of vaccine response
Need for booster vaccinations?
Missed opportunities for vaccination
Especially among adults at risk
During : ~ 110,000 adults acquired chronic HBV infection due to lack of adult hepatitis B immunization
HBV vaccination is still associated with several challenges. First, a small proportion of individuals fails to respond effectively to the vaccine. Ongoing strategies are attempting to maximize the likelihood of response in these individuals. Second, questions remain regarding the durability of the vaccine response and the need for booster vaccinations. Third, given the slight trend of increasing incidence of HBV infection among certain adult subgroups, some high-risk adults are apparently not receiving the needed vaccination.
Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:

14. Factors Associated with Reduced Vaccine Responses
Patient-Related
Older age (> 50 years)
Male gender
Smoking
Obesity
Immune deficiency
HIV
Transplant recipients
Dialysis
Compliance
Vaccine-Related
Schedule (accelerated vs 0, 1, 2, 6 months)
Double vs single dose
Use of “adjuvants”
GCSF, levamisole
IM versus ID
The reduced vaccine response noted in some individuals has been extensively studied, and both patient- and vaccine-related factors appear to be involved. The most important patient-related factors include older age, male sex, history of smoking and obesity, and issues related to immune deficiency that can influence the likelihood of achieving an effective vaccine response. Although vaccine-related factors are less important, altering the dose, schedule, and route of vaccination and using adjuvants may enhance responses in patients who fail to respond to the first series of vaccines.

15. HBV Vaccination Durability of Response
Durable immunity years
84% of Alaskan natives at 15 years[1]
85% of MSM (some HIV+) at 7 years[2]
> 50% of Chinese children at 15 years[3]
Immunity preserved in anti-HBs-negative persons
Amnestic response with booster dose
Preserved T cell responses in PBMCs in vitro
Studies investigating the durability of the vaccine response have documented years of immunity in different populations. Even in individuals who test antibody negative, immunity appears to be preserved with responses demonstrated after booster doses, and in vitro studies have showed preserved T-cell responses in peripheral blood mononuclear cells. For these reasons, booster vaccinations are not currently recommended for individuals demonstrating initial responses to the vaccine.
1. McMahon BJ, et al. Ann Intern Med. 2005;142: Hadler SC, et al. N Engl J Med. 1986;315: Ni YH, et al. Ann Intern Med. 2001;135:

16. HBV Vaccination: Durability of Response
Vaccines With Specific
Anti-HBs Titers
Predictors of decline in anti-HBs titers over 15 yrs
Low initial antibody response
Female gender
Younger age (0-4 yrs greatest decline) 40 38 30 28
Percentage of Patients
McMahon and colleagues recently published a study outlining factors in HBV vaccination durability. Fifteen years after vaccination, 28% of individuals had anti-HBs antibody titers greater than 100 IU/L, whereas 38% had titers greater than 10 IU/L, and the remainder had lower levels. Low initial antibody response, younger age at vaccination, and female sex were all predictive of a decline in HBV antibody titers over the 15-year period.
For more information, please go online to:
Options/Articles/McMahon-AIM /Capsule.aspx 20 18 16 10
< 2IU/L
≥ 2 IU/L
≥ 10 IU/L
≥ 100 IU/L
McMahon B, et al. Ann Intern Med. 2005;143:

17. Hepatitis B Vaccination in Adults: Missed Opportunities
Of all individuals with reported acute hepatitis B infection
56% have been treated for an STD and/or were incarcerated prior to their illness
89% are IDUs
35% are MSM
70% are persons with multiple sexual partners
Overlapping risks: IDU and sexual activities
Effective HBV vaccination in adults requires properly identifying high-risk individuals. Data indicate that individuals who present with acute hepatitis B generally have risk factors that would have supported prior vaccination. Fifty-six percent of patients with acute hepatitis B have had a sexually transmitted disease or been incarcerated. Eighty-nine percent have a history of injection drug use. Thirty-five percent are men having sex with men, and 70% are individuals with multiple sexual partners. These statistics highlight the overlapping risks between injection drug use and high-risk sexual activities that increase the risk for HBV infection and suggest the need for vaccination.
Goldstein ST, et.al. JID. 2002;185: Khan A, et al. Antiviral Therapy. 2000:5(suppl 1):21.

18. Prevention of HBV Infection Summary
Vaccine is highly effective – HBV incidence is declining
Infants and children vaccination rates high
In countries endemic for HBV, infant vaccination has reduced rates of liver complications
Missed opportunities among adults
If sexually active, IDU  at risk
HBV-related HCC is vaccine-preventable cancer
In summary, the HBV vaccine is highly effective and has resulted in a declining incidence of HBV infection. Vaccination rates among infants and children are high, and the implementation of infant vaccination programs is leading to declining incidence in countries endemic for HBV. This has been borne out in the reduced rates of serious liver complications, including liver cancer. In the United States, adults and adolescents at risk should be offered vaccination; this will reduce the number of missed opportunities for preventing infection. Finally, as a result of the development of a vaccine, HBV-related HCC is now a vaccine-preventable cancer.

19. Outcomes of Acute HBV Infection
Recover
Acute Hepatitis
Subclinical
Hepatitis
Fulminant
Hepatitis
5-20%
ACUTE
INFECTION
< 1% %
DEATH
The risk of developing chronic HBV infection is closely related to the age at time of infection. Among neonates infected with hepatitis B, 90% develop chronic infection and only 10% develop acute infection and then recover. By contrast, 95% or more of adults infected with hepatitis B develop acute infection and recover, and only 5% or fewer develop chronic infection.
Chronic Infection
Risk is Related to Age at Infection
Outcome
Neonates, %
Children, %
Adults, %
Chronic carrier 90 20
< 5
Recover 10 80
> 95
Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.

20. Clinical-Epidemiologic Correlations
HBV Endemicity
Location
Age of Infection
Mode of Transmission
Chronicity
HCC Risk
High 10-15%
Asia
Sub-Sahara Africa
Birth
Toddler
Perinatal
Horizontal
Likely
High
Low < 2%
N. America
W. Europe
Scandinavia
Early
Adulthood
Percutaneous
Sexual
Rare
Low
The age at time of infection influences the epidemiology of HBV infection worldwide. In areas where HBV is endemic, such as Asia and sub-Saharan Africa, individuals are generally exposed to the virus at the time of birth, perinatally, or early in childhood. The rate of chronicity is therefore high, which perpetuates the burden of chronic HBV infection in the population.
In areas of low HBV endemicity, such as North America, individuals are typically exposed to the virus as adults through sexual contact or percutaneous exposure. Because these individuals are likely to clear the virus spontaneously, the risk of chronicity is low and the burden of chronic liver disease related to cirrhosis and liver cancer is also low.
Available at: Accessed February 6, 2006.

21. Natural History of Chronic HBV Infection
Years
Serology
HBeAg
Anti-HBe
ALT level
HBV DNA level
(viremia)
Disease
Chronic active hepatitis
Cirrhosis/HCC
Immune tolerant (phase I)
Immune Active (phase II)
Non-Replicative (phase III)
Chronicity Stage
Minimal inflammation
Resolved
Normal to cirrhosis/HCC
HBsAg
Anti-HBs
Understanding the natural history of chronic hepatitis B is critical to managing infected patients and making treatment decisions. Upon developing chronic HBV infection, individuals are HBsAg positive and have detectable HBeAg. In the initial “immune tolerant” phase, alanine aminotransferase (ALT) levels are normal and HBV DNA levels are typically high. Patients are often asymptomatic and liver biopsies indicate minimal inflammation. Duration of the immune tolerant phase varies and can last for several decades. It is typically long-lasting in individuals infected as infants or children but short-lived in those infected during adulthood.
Patients then enter the immune active phase, in which ALT levels become abnormal, HBV DNA levels fluctuate and are often elevated, and biopsy would indicate inflammation and necrosis of the liver. Fibrosis can eventually develop, which may culminate in the development of cirrhosis. Individuals in the immune active phase are at the greatest risk for liver disease progression and are the target group for treatment. A prolonged immune active phase is associated with an increased risk for fibrosis and, ultimately, cirrhosis.
During the immune active phase, patients may seroconvert, becoming anti-HBe positive. This milestone, which can occur spontaneously or with treatment, typically signals progression from the immune active phase to the nonreplicative phase. In this third phase, anti-HBe is present, ALT levels have returned to normal, and HBV DNA levels are low. Liver biopsy would reveal minimal necroinflammation, although residual fibrosis or cirrhosis may still be present. Patients in the nonreplicative phase may spontaneously lose HBsAg and thereby move into the final phase of resolved infection.
Depending on the length of time spent in each phase, individuals may present to their physicians with either mild or active liver disease, and some patients may already have cirrhosis. Understanding where each patient falls in the natural history helps clinicians make optimal treatment decisions and anticipate future events.

22. Possible Outcomes of HBeAg+ Chronic HBV Infection
Spontaneous seroconversion
(n = 283)
33% ALT elevation (> 2 x ULN)
67% Sustained remission
Although seroconversion from HBeAg-positive to anti-HBe status typically signals a transition from the immune active to the nonreplicative phase, this does not always occur. Spontaneous seroconversion from HBeAg-positive to anti-HBe status is typically sustained. Hsu and colleagues found that 67% of individuals who spontaneously seroconvert remain anti-HBe positive. These patients experience reductions in ALT levels and declines in HBV DNA levels. However, in 33% of patients, ALT levels remain elevated, in most cases because of the evolution to HBeAg-negative chronic hepatitis B disease, which results from mutations in the precore or core promoter regions of the HBV genome. These patients are HBeAg negative and anti-HBe positive, yet have abnormal ALT levels and elevated HBV DNA levels, and are at risk for liver injury.
24% HBeAg-negative CHB with detectable HBV DNA
5% Undetermined causes
4% HBeAg
reversion
Hsu YS, et al. Hepatology. 2002;35:

23. Possible Outcomes of HBeAg+ Chronic HBV Infection
Patient Populations in Chronic Hepatitis B
Marker
Immune Tolerant
HBeAg+ CHB
Inactive HBsAg Carrier
HBeAg– CHB (Precore Mutant)
HBsAg +
HBeAg –
Anti-HBe
ALT
Normal 
HBV DNA (copies/mL)
> 105
< 103
> 104
Histology
Normal/Mild
Active
Most patients presenting to clinicians in practice fall into 1 of 4 groups. All of these individuals have chronic HBV infection as indicated by the presence of HBsAg. Those in the immune tolerant phase are HBeAg positive, have normal ALT levels, high levels of HBV DNA, and mild or normal histology. Current treatment strategies are not focused on these patients.
Two groups have active disease: those with HBeAg-positive chronic hepatitis B and those with HBeAg-negative chronic hepatitis B with promoter mutations. Both groups exhibit abnormal ALT levels, elevated HBV DNA levels, and necroinflammation with varying degrees of fibrosis. Because these patients are at the greatest risk for disease progression and liver disease complications, they are the target groups for treatment.
Finally, patients with inactive chronic HBV infection carry HBsAg but lack HBeAg. They are anti-HBe positive but exhibit normal ALT levels, low HBV DNA levels, and may have residual fibrosis on histology.
Lai CL, et al. Lancet. 2003:362: Lok AS, et al. Gastroenterology. 2001;120:

24. Natural Clearance of HBsAg
Occurs in ~ 0.5% of HBsAg carriers/year
Duration of infection is primary determinant of HBsAg loss
~ 50% of carriers who clear HBsAg have HBV DNA present in sera in low titer (1–2 logs)
Resolution of HBV infection is marked by the loss of HBsAg and the acquisition of anti-HBs. Natural clearance occurs in approximately 0.5% of HBsAg carriers each year. The primary determinant of HBsAg loss is the duration of infection. Patients diagnosed before they are 20 years of age are more likely to lose HBsAg than those infected at an older age.
McMahon and colleagues found that half of individuals who clear surface antigen and develop anti-HBs still maintain low but detectable serum HBV titers.
McMahon BJ, et al. Ann Intern Med. 2001;135:

25. Annual Risk of HBV Progression
HBeAg+ chronic
hepatitis B
HBeAg-Neg chronic
hepatitis B
All HBsAg +
individuals
5.0%
1.0%-2.0%
Cirrhosis
3.0%
2.0%
0.4%
For patients with chronic hepatitis B, the annual risk of developing cirrhosis varies from 5% for HBeAg-positive patients to 1% to 2% for HBeAg-negative, seroconverted patients. Individuals with cirrhosis have a 3% risk of developing liver decompensation and a 2% risk of developing HCC.
Although patients with cirrhosis are at greatest risk for developing HCC, patients who are noncirrhotic but chronically infected have some risk of developing HCC. This should be considered in developing an HCC surveillance strategy.
The longer an individual is in the immune active phase, the greater the risk of complications such as cirrhosis, decompensation, and cancer. Other factors associated with progressive disease are heavy alcohol use and the presence of immune suppression, specifically coinfection with HIV.
Decompensation
HCC
Factors linked with progression
Duration of “active”disease
Heavy alcohol use
Immune suppression (HIV)
Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.

26. Initial Evaluation of HBsAg+ Patient
History and PE
Assess risk factors (coinfection)
Alcohol use
Family history of HBV and HCC
Physical findings of cirrhosis
Investigations
Liver disease activity
Serologic and virologic markers
Screening for HCC (AFP and ultrasound)
In the initial evaluation of a patient with HBV infection, a detailed history and physical exam are extremely important. The history should focus on the likely mode of acquisition in order to estimate the duration of infection and predict the risk of complications. For example, patients with HBV infection and a family history of HCC are at greater risk for developing HCC and therefore require special surveillance. The physical exam focuses on determining disease stage and the possible presence of cirrhosis or decompensated liver disease. Use of alcohol should be discussed as it can influence disease progression and should be avoided in patients with chronic hepatitis B. Investigations should focus on assessing liver disease activity, serologic and virologic markers of disease, and screening tests for HCC.
Lok AS, et al. Hepatology 2001;34:
Tsai NC. Sem Liver Dis. 2004;24(suppl 1):71-76.

27. Categorization of Disease
HBeAg positive or negative
Replication high or low (HBV DNA)
ALT elevated or normal
Liver histology
It is important to identify where each patient lies in the natural history of HBV infection. This categorization is made based on the presence or absence of HBeAg, the HBV DNA level, ALT level, and liver histology. These assessments help define each patient’s profile and determine the best treatment strategy.

28. Role of Baseline Liver Biopsy
Confirm diagnosis of chronic hepatitis B
Establish baseline severity
Grade: severity of necroinflammation
Stage: amount of fibrosis
Clarify diagnosis when ALT and HBV DNA levels are discordant
Exclude other coexistent causes of liver disease (eg, fatty liver or alcoholic liver disease)
Guide decision regarding initiation of treatment
Although a liver biopsy is not required to establish a diagnosis of chronic hepatitis B, it has several uses in the diagnostic process and can help guide treatment decisions. Biopsy analysis can reveal the degree of necroinflammation and the extent of fibrosis, which may be important in deciding whether to treat a patient and how to proceed with future screenings for complications. Biopsy analysis can clarify diagnosis when ALT and HBV DNA levels are discordant or borderline elevated. Additionally, histology is important for assessing patients at risk for other causes of liver test abnormalities such as metabolic fatty liver disease and alcohol-related liver disease.
Ferrell L, et al. in McSween, et al, editors. Pathology of the liver, 4th ed. London:Churchill Livingstone; 2002: Buckley A ,et al. Can J Gastroenterol 2000;14: Park A , et al. Minerva Gastroenterol Dietol. 2004;50:

29. Indications for Treatment of Chronic HBV
Patients with active liver disease:
Abnormal liver function tests (AST, ALT)
HBeAg positive and > 105 HBV DNA
HBeAg negative and > 104 HBV DNA
Biopsy if HBV DNA < 104 with  ALT
Treat if active hepatitis (biochemical or histologic)
Patients in the immune active phase of disease represent the target group for treatment, as they are at greatest risk for disease progression. These patients have abnormal liver tests and elevated HBV DNA levels. They may be HBeAg positive or HBeAg negative, depending on the presence of promoter variances. HBeAg-positive patients tend to have HBV DNA levels greater than 105 copies/mL, whereas HBeAg-negative patients may have slightly lower levels of at least 104 copies/mL. Biopsies may be helpful in characterizing patients with borderline HBV DNA levels and abnormal ALT levels. Based upon the liver tests and the HBV DNA levels, a treatment decision can be made.
Lok AS, et al. Hepatology. 2001;34:

30. 2 Distinct Patient Populations With Chronic HBV
HBeAg+ (wild-type), HBV DNA+
HBeAg loss
Seroconversion to anti-HBe
Durability of response ~ 80%
HBeAg-/anti-HBe+/HBV DNA+ (precore mutant)
HBeAg seroconversion not an endpoint
Long-term therapy the rule
Treatment endpoints differ between the 2 distinct chronic hepatitis B patient populations. For HBeAg-positive patients, HBeAg loss and seroconversion to anti-HBe are primary goals of therapy. Seroconversion is accompanied by a decline in ALT levels to normal and an HBV DNA decline to low levels. Achievement of seroconversion typically helps define the duration of therapy.
For HBeAg-negative patients, seroconversion is not an endpoint. In general, patients with HBeAg-negative chronic hepatitis B require longer therapy than HBeAg-positive patients to achieve improvements in ALT levels and histology although there is significant overlap in treatment duration between the 2 groups.

31. Endpoints of Treatment
Sustained suppression of HBV DNA replication
HBeAg seroconversion
Improvement in liver histology
Reduced rates of liver complications
The most important goal of therapy is a reduction in the rate of liver-related complications. Treatment progress is measured by the attainment of important endpoints including sustained HBV DNA suppression, HBeAg seroconversion, and improved liver histology. These can result in the important endpoint of reduced rates of liver complications.

32. Histologic Improvement in Cirrhosis: 3 Years of Lamivudine Therapy
Pre-Rx
Post-Rx
Many clinical trials investigating new antiviral agents for chronic hepatitis B have shown histologic benefits of reduced necroinflammation and improvements in fibrosis in some patients. These histologic images show the reversal of cirrhosis made possible by effective antiviral therapy, which in this case was a 3-year course of lamivudine. At the beginning of treatment, this patient had established cirrhosis with broad bands of fibrosis, shown in blue, forming nodules in the liver. After 3 years of treatment, fibrosis is no longer visible, and there is a reversal in cirrhosis.
Wild-Type HBV

33. Long-Term Benefit of Lamivudine in Compensated Cirrhosis30
All P values ≤ .05
Placebo (n = 215)
Lamivudine (n = 436) 20
18%
Patients, %
In another study evaluating the efficacy of lamivudine, Liaw and colleagues treated 651 patients with cirrhosis with lamivudine (n = 436) or placebo (n = 215) for just more than 3 years. They evaluated the disease progression in terms of the development of decompensated liver disease and liver cancer. Treatment with lamivudine was associated with a significantly lower risk of disease progression. These data support the treatment of individuals with chronic HBV infection in order to prevent the serious complications of advanced disease. 10 9% 8% 7% 4% 3%
Overall Disease
Progression
CPT
Increase
HCC
Liaw et al. N Engl J Med. 2004;351:

34. Screening for Liver Cancer: Lack of Consensus
At what age should HCC screening be initiated?
1) Among HBV-infected individuals, HCC can occur at any age, including childhood
2) Optimal age for initiation of screening unknown1
3) Patients ≥ 35 yrs are at much higher risk for HCC than those < 35 years2
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:

35. Screening for Liver Cancer: Alpha-fetoprotein (AFP)
Up to 1/3 of patients with HCC have normal AFP
AFP may be elevated in 1/3 of patients with cirrhosis without HCC
Very high level of AFP (> 1000 ng/mL) diagnostic of HCC, with few exceptions
Persistently rising AFP levels highly suggestive of HCC but not often seen
The use of alfa-fetoprotein (AFP) for HCC screening has been studied extensively. Up to one third of patients with liver cancer have normal AFP levels. Therefore, using only AFP screening would miss many cases of HCC. False-positive results are also an issue, as AFP may be elevated in cirrhotic patients without HCC. However, AFP levels above 1000 ng/mL are diagnostic of HCC with few exceptions. Persistently rising AFP levels are also highly suggestive of HCC, but this pattern is not commonly seen.

36. Screening for Liver Cancer: Patients With Chronic HBV
Cancer screening strategies:
High Risk- AFP + U/S every 6 months
Cirrhosis
Family history HCC
Medium Risk- AFP + U/S every year
Age ≥ 30-40
Active disease (ALT)
If rising AFP or high AFP > 20 ng/mL, spiral CT or MRI at least once
Although there are many recommendations for liver cancer screening, the most common practices include a combination of AFP and ultrasound every 6-12 months in high-risk individuals, as defined by cirrhosis or family history. Medium-risk individuals, including those aged years and those with active disease, should receive AFP with an ultrasound every year.
A high or rising AFP along with a negative ultrasound may still indicate cancer, and consideration should be given to alternative imaging studies in these patients.

37. Chronic HBV Infection: Recent Advances
4 antiviral drugs now available
Longer term benefits of treatment known
Resistance emerging as issue with oral antivirals
Combination therapy under study
Several new nucleos/tides in development
Four different drugs are now approved for the treatment of HBV. The long-term benefits are well understood in terms of improving histology and reducing the risk of liver cancer. However, the long-term use of these antiviral agents is associated with the development of drug resistance. Combination therapy is therefore a likely strategy for the future.

38. Go Online to View More CCO Programs!
Conference Coverage of all the key data presented at major hepatitis meetings
News and Capsule Summaries covering the latest findings in the field of hepatitis
Downloadable Slides, and much more!
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