Understanding and Implementing the AASLD’s HBV Practice Guidelines

Understanding and Implementing the AASLD’s HBV Practice Guidelines
Understanding and Implementing the AASLD’s HBV Practice Guidelines* and Other Recent Guidelines and Recommendations on the Diagnosis, Management, and Treatment of Hepatitis B AASLD, American Association for the Study of Liver Diseases; HBV, hepatitis B virus. Welcome to this program entitled, “Understanding and Implementing the American Association for the Study of Liver Diseases’ (AASLD) Hepatitis B Virus (HBV) Practice Guidelines and Other Recent Guidelines and Recommendations on the Diagnosis, Management, and Treatment of Hepatitis B.” *The AASLD 2009 Practice Guidelines were developed solely by AASLD without industry funding or influence. This program is supported by educational grants from

Hepatitis B Screening, Diagnosis, and Treatment Candidacy
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF Director, Center for Liver Disease Virginia Mason Medical Center Clinical Professor of Medicine University of Washington Seattle, Washington I am Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF, and I am Director of the Center for Liver Disease at Virginia Mason Medical Center in Seattle, Washington. In this CME-certified presentation, we will review hepatitis B screening, diagnosis, and treatment candidacy.

About These Slides The full program accompanying these slides is available on the Clinical Care Options Hepatitis Web site: clinicaloptions.com/GuidelinesHBV Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials. 3

Program Faculty Program Director W. Ray Kim, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota Faculty Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF Director, Center for Liver Disease Virginia Mason Medical Center Clinical Professor of Medicine University of Washington Seattle, Washington This slide lists the faculty for this program.

AASLD Practice Guidelines: Chronic Hepatitis B 2009 Update
AASLD: leading medical organization for advancing science and practice of hepatology AASLD guidelines a key reference on best practices for care of patients with hepatitis B Previous edition in 2007 Current edition in 2009 Evidence-based recommendations approved by the AASLD and endorsed by the Infectious Diseases Society of America AASLD, American Association for the Study of Liver Diseases. The AASLD is the leading medical organization for advancing the science and practice of hepatology. The AASLD guidelines are a key reference on best practices for the care of patients with hepatitis B, with the most current edition published in These evidence-based recommendations have been approved by the AASLD and have been endorsed by the Infectious Diseases Society of America. Lok AS, et al. Hepatology. 2009;50:

Grading System for Quality of Evidence Upon Which Recommendation Is Based
Grade I: based on randomized, controlled trials Grade II-1: based on controlled trials without randomization Grade II-2: based on cohort or case-control analytic studies Grade II-3: based on multiple time series, dramatic uncontrolled experiments Grade III: based on opinions of respected authorities, descriptive epidemiology The grading system for the quality of evidence upon which the recommendations are based is standardized. Grade I recommendations are based on randomized, controlled trials; grade II-1 recommendations are based on controlled trials without randomization; grade II-2 recommendations are based on cohort or case-controlled analytic studies; grade II-3 recommendations are based on multiple time series or dramatic, uncontrolled experiments; and grade III recommendations are largely based on the opinions of respected authorities and descriptive epidemiology. Lok AS, et al. Hepatology. 2009;50:

Other Reports and Guidelines Consulted
Institute of Medicine Consensus Report[1] Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C EASL Clinical Practice Guidelines: management of chronic hepatitis B[2] Panel of experts chosen by the EASL governing board Peer reviewed by external expert reviewers, approved by EASL governing board APASL Guidelines for HBV Management[3] Based on expert meeting Findings presented at and finalized after 2008 APASL meeting APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; HBV, hepatitis B virus. In the preparation of this program, other reports and guidelines were also consulted, including the recent consensus report, Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C, from the Institute of Medicine; the European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: management of chronic hepatitis B; and the Asian Pacific Association for the Study of the Liver (APASL) Guidelines for HBV Management. 1. Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C EASL. J Hepatol. 2009;50: Liaw YF, et al. Hepatol Int. 2008;2:

Burden of HBV Disease HBV, hepatitis B virus.
The presentation will begin with a review of the current burden of HBV-related disease.

IOM Report: Burden of HBV Disease[1]
15% to 25% risk of early death caused by liver cancer or end-stage liver disease among patients with chronic HBV infection[2,3] WHO global HBV estimates[3] ~ 2 billion people infected with HBV ~ 350 million people living with chronic HBV infection ~ 600,000 deaths annually caused by HBV-related liver disease or HCC HBV, hepatitis B virus; HCC, hepatocellular carcinoma; IOM, Institute of Medicine; WHO, World Health Organization. As recently reviewed in the Institute of Medicine report, the burden of HBV disease is highly substantial with a 15% to 25% risk of early death caused by liver cancer or end-stage liver disease among patients with chronic HBV infection. According to the World Health Organization, the global estimates of chronic HBV infection are astounding: it is estimated that approximately one third of the world’s population has been infected with HBV and that approximately 350 million people are living with chronic HBV infection. Approximately 600,000 deaths are attributable to HBV-related liver disease or hepatocellular carcinoma (HCC) annually. For more information on the WHO Hepatitis B Fact Sheet, go online to (accessed November 8, 2010). 1. Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C Beasley R, et al. In: Hollinger FB, Margolis H, Lemon SM, editors. Viral hepatitis and liver disease. Proceedings of the 1990 international symposium on viral hepatitis and liver disease: contemporary issues and future prospects WHO. Hepatitis B fact sheet.

Geographic Distribution of Chronic HBV Infection
HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. Worldwide, the endemicity of chronic hepatitis B varies by geographic region as shown on this slide. High endemic regions are defined by a hepatitis B surface antigen (HBsAg) prevalence of 8% or higher; regions of intermediate endemicity demonstrate 2% to 7% HBsAg seropositivity; and low endemic regions are defined as populations with < 2% HBsAg seropositivity. HBsAg Prevalence ≥ 8% (high) 2% to 7% (intermediate) < 2% (low) Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. 10

Transmission Routes and Endemicity
Most primary HBV infections in highly endemic countries occur during infancy or early childhood[1] Vertical transmission (from infected mother via perinatal exposure) or horizontal transmission Involves highest chronic infection risk Most primary HBV infections in low prevalence countries occur during adolescence/young adulthood[1] Transmission routes: unsafe sex practices or injection drug use ~ 21 million HBV infections worldwide in 2000 attributable to unsafe injection administration in healthcare settings[2] HBV, hepatitis B virus. Most primary HBV infections in highly endemic countries occur during infancy or early childhood. Vertical transmission from an infected mother via perinatal exposure and horizontal transmission early in life represent the most important sources of transmission. The timing of infection has a critical impact on the development of chronic infection with the risk of chronicity inversely related to the age at infection. Therefore, a neonate exposed to HBV during birth has a > 90% risk of developing chronic hepatitis B in the absence of vaccination and hepatitis B immune globulin, particularly if the mother has active viremia. By contrast, an adult who is exposed to HBV has a very low, approximately 5%, risk of chronic infection. Most primary HBV infections in low-prevalence countries occur during adolescence or young adulthood, with injection drug use and sexual contact being the major sources of transmission. In addition, approximately 21 million HBV infections worldwide in 2000 were attributable to unsafe injection administration in healthcare settings. 1. Shepard CW, et al. Epidemiol Rev. 2006;28: Hauri AM, et al. Int J STD AIDS. 2004;15:7-16.

HBV Incidence by Year: United States (1966-2005)
HBsAg screening of pregnant women recommended 14 12 Vaccine licensed Infant immunization recommended 10 OSHA rule enacted 8 Adolescent immunization recommended Cases per 100,000 Population 6 HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCW, healthcare worker; IDU, injection drug user; MSM, men who have sex with men; OSHA, Occupational Safety and Health Administration. This slide shows the dramatic impact of vaccination on the incidence of chronic hepatitis B in the United States. Shortly after the hepatitis B vaccine was licensed in 1982, the incidence of hepatitis B infections peaked and subsequently decreased over time as larger proportions of the population were recommended for screening and vaccination. These preventive measures included HBsAg screening of pregnant women, infant vaccination, vaccination through the Occupational Safety and Health Administration rule, and adolescent immunization. During this time, the incidence of HBV infection also declined among healthcare workers, men who have sex with men, and individuals who use injection drugs. 4 2 Decline among MSM & HCWs Decline among IDUs 1967 1971 1975 1979 1983 1987 1991 1995 1999 2003 Yr Wasley A, et al. MMWR Surveill Summ. 2008;57(2):1-24. Wasley A, et al. MMWR Surveill Summ. 2007;56(3):1-24. OSHA. Available at:

Reduced Incidence of HBV Infection in US
Incidence of acute HBV infection reduced 82% from to 2007 2007: 43,000 new infections Largest % declines were among younger populations More effective strategies needed for adult population Estimates limited by underreporting because acute infection is frequently asymptomatic or resembles other illnesses 16 < 15yrs 14 15-24 yrs 25-44 yrs 12 ≥ 45 yrs 10 Incidence (per 100,000) 8 6 4 HBV, hepatitis B virus. This slide shows that the incidence of acute HBV infection was reduced by 82% over a relatively short period of 17 years from 1990 to 2007, with only 43,000 new infections documented in As would be expected with universal vaccination in childhood, the largest proportional declines were among younger populations. More effective strategies are needed for adult populations, particularly when considering that many individuals with chronic HBV infection in the United States are immigrants and their family members may be at risk. It is important to note that incidence estimations of hepatitis B infection are limited by underreporting, because acute infection may be asymptomatic or may be confused with other illnesses. 2 1990 1995 2000 2005 Yr Daniels D, et al. MMWR Surveill Summ. 2009;58(3):1-27.

Incidence Among Persons Aged < 19 yrs (per 100,000)[1]
Reduced Incidence of HBV Infection Among Children of All Races in the US 7 Asian/Pacific Islander 6 Black American Indian/Alaska native 5 Hispanic White Incidence Among Persons Aged < 19 yrs (per 100,000)[1] 4 3 2 1 HBV, hepatitis B virus. The HBV incidence among persons younger than 19 years of age has decreased across all racial subgroups since However, despite this dramatic reduction in childhood infection rates, approximately 1000 cases of perinatal HBV infection are still estimated to occur each year, representing an important intervention opportunity for healthcare providers to prevent the high rates of chronic infection associated with perinatal transmission. 1990 1992 1994 1996 1998 2000 2002 2004 Yr Despite dramatic reduction in childhood infection rates, ~ 1000 cases of perinatal HBV infection are estimated to occur each yr[2] 1. Mast EE, et al. MMWR Recomm Rep. 2005;54(RR-16): Ward JW. Am J Public Health. 2008;98:

Impact of Immigration on US HBV Prevalence
Immigration Numbers by Continent: [1] ~ 3.6 million Asians ~ 1.3 million Europeans ~ 875,000 South Americans HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. Immigration has a substantial impact on the prevalence of chronic hepatitis B in the United States. This slide depicts the numbers of individuals who have immigrated to the United States from different regions of the world over a 10-year period from 2000 to Although a substantial proportion of immigration to the United States is from Europe, the largest proportion is from Asia, with approximately 3.6 million Asians immigrating to the United States during this time. In addition, approximately 1.6 million individuals immigrated from South America and Africa. These immigration patterns are significant because many of the source countries have a high (≥ 8%) prevalence of HBV infection. Based on these data, it is anticipated that the number of individuals with chronic hepatitis B in the United States is larger than previously estimated and is likely to continue to increase. For more information on the US Department of Homeland Security Yearbook of Immigration Statistics, download a copy from (accessed November 8, 2010). HBsAg Prevalence[2] ≥ 8% (high) ~ 804,000 Africans 2% to 7% (intermediate) < 2% (low) 1. US Department of Homeland Security. Yearbook of Immigration Statistics: Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. 15

Estimated Prevalence of HBsAg-Positive Persons in the US by Population Segment
Population Group CHB Prevalence, %[1,2] US-born API 1.40 Foreign-born API 8.90 Non-Asian Americans 0.42 Correctional institutions 2.00 Other group living quarters 0.50 Prevalence reflects patterns of HBV infection in regions of origin Potential for immigration from highly endemic countries to ↑ US HBV prevalence despite ↓ incidence of new infections Age-adjusted prevalence of anti-HBc and HBsAg in the US statistically similar during vs [3] ~ 40,000 persons with chronic HBV infection immigrate to US each yr[4] anti-HBc, hepatitis B core antibody; API, Asian/Pacific Islander; CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. Estimated chronic HBV infection prevalence in the United States by population segment demonstrates that foreign-born Asian/Pacific Islanders have a substantially higher prevalence than other populations including US-born Asian/Pacific Islanders, non-Asian Americans, residents of correctional institutions, and residents of other group-living quarters. This slide also demonstrates that prevalence patterns reflect the HBV prevalence within the countries of origin. Therefore, the potential for immigration from highly endemic countries to increase US hepatitis B prevalence remains substantial despite the reduced incidence of new infections attributed to vaccination strategies. For example, age-adjusted prevalence of individuals with previous exposure to HBV, as demonstrated by a positive anti–hepatitis B core antibody (anti-HBc) and positive HBsAg, in the United States was statistically similar between and Approximately 40,000 persons with chronic HBV infection immigrate to the United States each year, thereby potentially offsetting the reduction in incidence resulting from vaccination. 1. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8): Cohen C, et al. J Viral Hepat. 2008;15: Wasley A, et al. J Infect Dis. 2010;202: Mast EE, et al. MMWR Recomm Rep. 2006;55(RR-16):1-33.

Burden of HBV Among Asian/Pacific Islander Americans
API Americans represent 4.5% of overall US population, but constitute > 50% of Americans with chronic HBV infection[1,2] Birth in highly HBV endemic country a strong risk factor for chronic HBV infection among US API population[3] HCC is a leading cause of cancer mortality among API men in California[4] Ranks second in Vietnamese Americans and Cambodian Americans Ranks fourth in Chinese Americans and Korean Americans API, Asian/Pacific Islander; HBV, hepatitis B virus; HCC, hepatocellular carcinoma. Asian/Pacific Islander Americans bear a disproportionate burden of chronic HBV infection. This group represents 4.5% of the overall US population but more than 50% of Americans with chronic HBV infection. Birth in a highly endemic country (≥ 8% prevalence) is a strong risk factor for chronic hepatitis B among Asian/Pacific Islander populations in the United States. Alarming data demonstrate that HCC is a leading cause of cancer mortality among Asian/Pacific Islander men in California, ranking second among Vietnamese and Cambodian Americans and fourth among Chinese and Korean Americans. Healthcare providers need to be aware of populations who are at very high risk of HBV infection and related complications based on the endemicity of their countries of origin. For more information on the Asian Liver Center, Stanford University School of Medicine FAQ About Hepatitis B, go online to (accessed November 8, 2010). For more information on the US Census Bureau Fact Sheet , go online to (accessed November 8, 2010). 1. US Census Bureau Fact Sheet CDC. MMWR Morb Mortal Wkly Rep. 2009;58(18): Lin SY, et al. Hepatology. 2007;46: Asian Liver Center, Stanford University School of Medicine. FAQ About Hepatitis B.

CHB Prevalence Among Asian-Americans in San Francisco From 2001-2006
Prevalence of chronic HBV infection among 3163 Asian American adults: 8.9% Among chronically infected individuals, 65.4% were unaware of their serostatus Among individuals without evidence of chronic infection, % showed no evidence of protective antibodies and, therefore, were at risk for future infection CHB, chronic hepatitis B; HBV, hepatitis B virus. For instance, the chronic HBV prevalence among 3163 Asian Americans in San Francisco between 2001 and 2006 was found to be 8.9%, similar to the estimated prevalence in their countries of origin. Even more concerning, among individuals chronically infected with HBV, two thirds were unaware of their serostatus. Among individuals without evidence of chronic infection, 44.8% showed no evidence of protective antibodies and were thus at risk for future infection. Therefore, this population represents an enormous opportunity and also a substantial population at risk for acquisition and exposure to HBV; healthcare providers must be cognizant of the importance of counseling these individuals about vaccination. Lin SY, et al. Hepatology. 2007;46:

HBV Screening and Counseling
HBV, hepatitis B virus. The next part of the presentation will review HBV screening and counseling.

Risk Factors Associated With HBV in the United States: 2007
Cases,* % Multiple sex partners 38.3 Injection drug use 15.0 Surgery 11.7 Men who have sex with men 10.5 Sexual contact with hepatitis B patient 6.2 Percutaneous injury 4.3 Household contact of hepatitis B patient 2.3 Medical employee with blood contact 0.6 Blood transfusion 0.5 Hemodialysis 0.2 Unknown 58.0 HBV, hepatitis B virus. This slide lists risk factors associated with HBV based on the total number of cases for which data on a particular exposure type were reported in Multiple sex partners represented the most frequently reported risk factor, followed by injection drug use, surgery, men who have sex with men, sexual contact with a hepatitis B patient, percutaneous injury, household contact with a hepatitis B patient, medical employee with blood contact, blood transfusion, and hemodialysis. However, in the majority of cases, 58%, the risk factor or exposure source to hepatitis B was unknown. *Percentage of cases calculated based on total number of cases for which any data for that exposure type were reported. Percentages do not total 100% because multiple risk factors could be reported by a single case. Daniels D, et al. MMWR Surveill Summ. 2009;58(3):1-27.

AASLD Guideline Recommendations for HBV Screening
“1. The following groups should be tested for HBV infection (Grade I)” Persons born in high* or intermediate† endemic areas Asia, Africa, and South Pacific Islands: all countries Middle East (except Cyprus and Israel) European Mediterranean: Malta and Spain The Arctic (indigenous populations of Alaska, Canada, and Greenland) South America: Ecuador, Guyana, Suriname, Venezuela, and Amazon regions of Bolivia, Brazil, Colombia, and Peru Eastern Europe: all countries except Hungary Caribbean: Antigua and Barbuda, Dominica, Granada, Haiti, Jamaica, St Kitts and Nevis, St Lucia, and Turks and Caicos Central America: Guatemala and Honduras AASLD, American Association for the Study of Liver Diseases; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. The AASLD guideline recommendations for hepatitis B screening state that persons born in countries with high or intermediate endemicity should be tested for HBV infection. This recommendation includes individuals born in the following countries or regions: any country in Asia, Africa, or the South Pacific Islands; all countries in the Middle East except Cyprus and Israel; Malta and Spain in the European Mediterranean; indigenous populations of Alaska, Canada, and Greenland; Ecuador, Guyana, Suriname, Venezuela, and the Amazon regions of Bolivia, Brazil, Colombia, and Peru in South America; all countries in Eastern Europe except Hungary; Antigua and Barbuda, Dominica, Granada, Haiti, Jamaica, St Kitts and Nevis, St Lucia, and Turks and Caicos in the Caribbean; and Guatemala and Honduras in Central America. *HBsAg prevalence ≥ 8%. † HBsAg prevalence 2% to 7%. Lok AS, et al. Hepatology. 2009;50: Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

AASLD Guideline Recommendations for HBV Screening
“1. The following groups should be tested for HBV infection (Grade I)” US-born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity Persons with chronically elevated aminotransferases Persons needing immunosuppressive therapy Men who have sex with men Persons with multiple sexual partners or history of sexually transmitted disease Inmates of correctional facilities Persons who have ever used injection drugs Dialysis patients HIV- or HCV-infected individuals Pregnant women Family members, household members, and sexual contacts of HBV-infected persons AASLD, American Association for the Study of Liver Diseases; HBV, hepatitis B virus; HCV, hepatitis C virus. Other individuals for whom HBV screening is indicated include the following: US-born persons who are not vaccinated as infants and whose parents were born in regions of high endemicity, individuals with chronically elevated liver enzyme levels, individuals who need immunosuppressive therapy, men who have sex with men, individuals with a history of multiple sexual partners or sexually transmitted disease, inmates of correctional facilities, individuals who have ever used injection drugs, individuals receiving dialysis, hepatitis C virus– or HIV-infected individuals, pregnant women, and family members, household members, and sexual contacts of HBV-infected persons. Lok AS, et al. Hepatology. 2009;50:

AASLD Guideline Recommendations for Screening
“ Testing for HBsAg and anti-HBs should be performed, and seronegative persons should be vaccinated (Grade I)” HBsAg Anti-HBs Total Anti-HBc IgM Anti-HBc Indicates that the person is infected Indicates recovery and immunity from HBV infection Develops in a person who has been successfully vaccinated against hepatitis B Indicates previous or ongoing infection with HBV in an undefined time frame Appears at the onset of symptoms in acute hepatitis B and persists for life Indicates recent infection with HBV (≤ 6 mos) This test is used to distinguish acute from chronic HBV infection AASLD, American Association for the Study of Liver Diseases; anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgM, immunoglobulin M. The AASLD guideline recommendations for screening state that testing for HBsAg and anti–hepatitis B surface antibody (anti-HBs) should be performed and that seronegative persons should be vaccinated. The presence of persistent HBsAg indicates that a person is infected. The presence of anti-HBs indicates recovery and immunity from HBV infection and generally develops in a person who has been successfully vaccinated against hepatitis B if they have an adequate response. The total anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame. Anti-HBc generally appears at the onset of symptoms in acute hepatitis B and persists for life. Although the anti-HBs titer may gradually decrease and may become undetectable, anti-HBc usually remains detectable throughout life following exposure to the virus. The immunoglobulin M anti-HBc antibody indicates recent infection with HBV, usually ≤ 6 months; this test is used to distinguish acute from chronic HBV infection. For more information on the Centers for Disease Control and Prevention (CDC) HBV FAQs for Health Professionals, go online to (accessed November 8, 2010). Lok AS, et al. Hepatology. 2009;50: CDC. Hepatitis B FAQs for Health Professionals.

Interpretation of Serologic Results
HBsAg Total Anti-HBc IgM Anti-HBc Anti-HBs Interpretation Negative -- Susceptible; offer vaccination Positive Immune due to natural infection Immune due to hepatitis B vaccination Chronic HBV infection Acute HBV infection Unclear; could be any one of the following: 1. Resolved infection (most common) 2. False-positive anti-HBc; susceptible 3. “Low-level” chronic infection 4. Resolving acute infection anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgM, immunoglobulin M. This slide demonstrates the appropriate interpretation of serologic test results for HBsAg, total anti-HBc, immunoglobulin M anti-HBc, and anti-HBs. If the results are negative for all of these markers, then the individual has not been vaccinated, has not been exposed to the virus, and is not immune. A person who tests negative for HBsAg, positive for total anti-HBc, and positive for anti-HBs has been exposed to the intact virus but has cleared the virus and is now immune. An individual who tests positive for anti-HBs but negative for anti-HBc could only have achieved that outcome by vaccination. Patients who persistently test positive for HBsAg either have acute HBV infection if they have immunoglobulin M anti-HBc or chronic HBV infection if they lack immunoglobulin M anti-HBc. There are a number of possible scenarios in patients who have an isolated anti-HBc test result: the infection may have resolved and the anti-HBs titer has become undetectable, which is the most common scenario; the test result may have been falsely positive; the patient may have low-level chronic infection, in which case they should be tested for HBV DNA; or, very rarely, this result may represent the window period between clearance of HBsAg and appearance of surface anti-HBs. For more information on the CDC HBV FAQs for Health Professionals, go online to (accessed November 8, 2010). CDC. Hepatitis B FAQs for Health Professionals.

AASLD Guideline Recommendations for Counseling
“2. Carriers should be counseled regarding prevention of transmission of HBV (Grade III) 3. Sexual and household contacts of carriers who are negative for HBV seromarkers should receive hepatitis B vaccination (Grade III) 4. Newborns of HBV-infected mothers should receive HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series (Grade I)” AASLD, American Association for the Study of Liver Diseases; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus. The AASLD guideline recommendations for counseling patients indicate that carriers should be counseled regarding prevention of transmission of HBV. Sexual and household contacts of carriers who are negative for HBV seromarkers should receive vaccination. Finally, newborns of HBV-infected mothers should receive hepatitis B immune globulin and hepatitis B vaccine at delivery and should complete the recommended vaccination series. Lok AS, et al. Hepatology. 2009;50:

Recommendations Regarding Prevention of Transmission of HBV to Others Persons who are HBsAg positive should: Have sexual contacts vaccinated Use barrier protection during sexual intercourse if partner not vaccinated or naturally immune Not share toothbrushes or razors Cover open cuts and scratches Clean blood spills with detergent or bleach Not donate blood, organs, or sperm Children and adults who are HBsAg positive: Can participate in all activities including contact sports Should not be excluded from daycare or school participation and should not be isolated from other children Can share food, utensils, or kiss others AASLD, American Association for the Study of Liver Diseases; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. Individuals who are HBsAg positive should be advised to have their sexual contacts receive the HBV vaccine. If the partner is not vaccinated or naturally immune, a barrier protection method should be used during sexual intercourse to reduce the risk of transmission. Any source of blood-borne transmission, such as shared toothbrushes or razorblades, open cuts or scratches, or blood spills, should be avoided. In addition, HBsAg-positive individuals should be advised not to donate blood, organs, or sperm. Children and adults who are HBsAg positive can participate in all activities, including contact sports, should not be excluded from daycare or school participation, and should not be isolated from others. They may share food and utensils and may kiss others. Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

Who Should Be Vaccinated for HBV?
Infants At birth Children Who were not vaccinated as infants At-Risk Adults Travelers to regions of intermediate/high endemicity Susceptible sex partners and household contacts of HBsAg-positive persons Persons seeking evaluation or treatment for an STD Persons with behavioral or occupational exposures Persons with end-stage renal disease, chronic liver disease, or HIV infection Residents/staff in certain settings with clients with known HBV risk factors HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; STD, sexually transmitted disease. Which individuals are appropriate for HBV vaccination? All infants should receive vaccination at birth. Children who were not vaccinated as infants and at-risk adults should be vaccinated. At-risk adults include travelers to regions of intermediate or high endemicity; susceptible sexual partners and household contacts of HBsAg-positive persons; persons who seek evaluation or treatment for a sexually transmitted disease; individuals who are at increased risk of exposure to the virus as a result of their occupation or behaviors; individuals who are at risk for increased complications in the setting of infection, such as persons with chronic liver disease, HIV infection, or end-stage renal disease; and residents and staff in certain settings where clients with known HBV risk factors reside. For more information on the CDC HBV FAQs for Health Professionals, go online to (accessed November 8, 2010). CDC. Hepatitis B FAQs for Health Professionals. 27

“5. Persons who remain at risk for HBV infection such as infants of HBsAg-positive mothers, healthcare workers, dialysis patients, and sexual partners of carriers should be tested for response to vaccination (Grade III) ● Postvaccination testing should be performed at 9-15 months of age in infants of carrier mothers and 1-2 months after the last dose in other persons (Grade III) ● Follow-up testing of vaccine responders is recommended annually for chronic hemodialysis patients (Grade III)” AASLD, American Association for the Study of Liver Diseases; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. The AASLD guidelines recommend that persons who remain at risk for HBV, such as infants of HBsAg-positive mothers, healthcare workers, dialysis patients, and sexual partners of carriers, should be tested for response to vaccination. The recommendation further states that postvaccination testing should be performed at 9-15 months of age in infants of carrier mothers and 1-2 months after the last dose in other persons. Similarly, follow-up testing of vaccine responders is recommended annually for chronic hemodialysis patients. The reasons for this recommendation are the very high risk of exposure and subsequent chronic infection in these settings as well as a possible lower likelihood of developing antibody in the setting of chronic hemodialysis. Lok AS, et al. Hepatology. 2009;50:

“6. Abstinence or only limited use of alcohol is recommended in hepatitis B carriers (Grade III) 7. Persons who are positive only for anti-HBc and who are from a low endemic area with no risk factors for HBV should be given the full series of hepatitis B vaccine (Grade II-2)” AASLD, American Association for the Study of Liver Diseases; anti-HBc, hepatitis B core antibody; HBV, hepatitis B virus. Chronic hepatitis B carriers should abstain from alcohol use or consume only limited quantities of alcohol. Persons who are positive only for anti-HBc and who are from a low endemic area with no risk factors for HBV should be given the full series of hepatitis B vaccine. Lok AS, et al. Hepatology. 2009;50:

Natural History and Initial Evaluation
The next section will review the natural history and initial evaluation of chronic hepatitis B.

Phases of Chronic HBV Infection
Immune Tolerance Immune Active/ HBeAg-Positive CHB Nonreplicative (Inactive Carrier) HBeAg-Negative CHB Typical HBV DNA, IU/mL > 200,000 and often > 107-8 200, x 109 < 2000 x 107 HBeAg Positive Negative ALT Normal Elevated or fluctuating Other observations Liver biopsy typically normal or minimal findings Active inflammation on liver biopsy HBsAg may become undetectable Treatment candidate? No Yes ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. Hepatitis B is characterized by several phases of infection, and patients may evolve from one phase to another or may cycle back to a previous phase. The phases of chronic HBV infection are as follows: immune tolerant; immune active with wild-type or hepatitis B e antigen (HBeAg)–positive infection; nonreplicative status, which is the preferred term to the previously used term, “inactive carrier”; and HBeAg-negative infection in which the virus harbors mutations in the precore or basal core promoter region and patients may not be able to develop anti–hepatitis B e antibody (anti-HBe). Patients who are in the immune tolerant phase are HBeAg positive and have very high HBV DNA levels, often > 108 IU/mL. Patients with immune active/HBeAg-positive chronic hepatitis B also typically have very high HBV DNA levels. By definition, patients who are inactive carriers have HBV DNA < 2000 IU/mL and are HBeAg negative. Patients with HBeAg-negative chronic hepatitis B (precore or basal core promoter mutation–associated chronic hepatitis B) typically have lower levels of HBV DNA than patients who have HBeAg-positive disease. Patients with immune tolerant chronic hepatitis B generally have minimal or normal findings on liver biopsy, especially if they are younger than 30 years of age. Patients with immune active/HBeAg-positive chronic hepatitis B who have elevated liver enzymes usually show active inflammation on liver biopsy; treatment is generally recommended in these patients. In fact, a liver biopsy is not necessary to initiate therapy for HBeAg-positive chronic hepatitis B. Patients with HBeAg-negative chronic hepatitis B are differentiated from patients with nonreplicative disease by the presence of elevated HBV DNA levels, often elevated liver enzymes, and active inflammation; patients with HBeAg-negative chronic hepatitis B should be considered for therapy. Lok AS, et al. Hepatology. 2009;50:

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; HBV, hepatitis B virus. The diagram on this slide shows the natural history of HBV infection. A patient who acquires HBV infection early in childhood typically goes through a period of immune tolerance during which the HBV DNA level is very high, liver enzymes are normal, and there is minimal histologic injury. At some point, the disease may evolve into active, HBeAg-positive chronic HBV infection during which liver injury occurs. Patients who are infected with HBV later in life and develop chronic infection may enter directly into the active, HBeAg-positive phase. From this phase, patients may enter into inactive carrier or nonreplicative status from which they may either have subsequent reactivation of wild-type HBeAg-positive disease or develop HBeAg-negative, precore or basal core promoter mutant chronic HBV infection. Ongoing liver injury from either HBeAg-positive or HBeAg-negative infection can lead to cirrhosis and progressive liver disease. Inactive Carrier Courtesy of W. Ray Kim, MD. Chen DS, et al. J Gastroenterol Hepatol. 1993;8: Seeff L, et al. N Engl J Med. 1987;316: 32

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; HBV, hepatitis B virus; HCC, hepatocellular carcinoma. Patients may also develop liver cancer in the absence of active infection; this is a key feature that differentiates HBV infection from other hepatotropic viral infections, in particular hepatitis C virus infection. Patients do not need to develop cirrhosis to develop HCC in the setting of HBV infection and, furthermore, even patients who are immune tolerant and have very high levels of virus but minimal liver injury may develop HCC. Inactive Carrier Courtesy of W. Ray Kim, MD. Chen DS, et al. J Gastroenterol Hepatol. 1993;8: Seeff L, et al. N Engl J Med. 1987;316: 33

Risk Factors for Progression to Cirrhosis or HCC in HBsAg-Positive Individuals
Host Older age (> 40 yrs) Male sex Asian/African ancestry HCC family history Clinical Cirrhosis HCV coinfection Viral HBeAg positive Higher HBV DNA Genotype B, C Precore mutation Basal core promoter mutation Other Smoking, alcohol Obesity, diabetes HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus. Investigators have conducted many studies during the last several years to identify risk factors for progression to cirrhosis or HCC in patients who are HBsAg positive, including host and viral factors. Host-specific risk factors include older age (older than 40 years), male sex, Asian or African ancestry, and a family history of HCC. Patients who have cirrhosis or coinfection with hepatitis C virus are also at increased risk of liver disease progression. Viral factors that drive progression of disease include HBeAg positivity, high HBV DNA levels, infection with HBV genotype B or C, and the presence of precore or, in particular, basal core promoter mutation. Additional risk factors include smoking, excess alcohol consumption, obesity, and diabetes. McClune AC, et al. Clin Liver Dis. 2010;14:

Pts With Chronic HBV Infection and Normal ALT May Have Significant Liver Disease
Retrospective review of pts with chronic HBV infection Persistently normal ALT ALT x ULN ALT > 1.5 x ULN 37% of pts with chronic HBV infection and persistently normal ALT had evidence of significant fibrosis (stage 2-4) or inflammation (grade 2-3) by liver biopsy ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, upper limit of normal. It is important to recognize that a normal alanine aminotransferase (ALT) level may not exclude the presence of significant liver disease. In a widely cited retrospective review of patients with chronic hepatitis B, patients were classified as having persistently normal ALT, ALT 1-1.5 times the upper limit of normal, or ALT > 1.5 times the upper limit of normal. A full 37% of patients with chronic HBV infection and persistently normal ALT had evidence of significant fibrosis (stage 2-4) or inflammation (grade 2-3) by liver biopsy. Lai M, et al. J Hepatol. 2007;47:

Normal Serum AST and ALT and Risk of Death From Liver Disease
Prospective, cohort study Cause of death based on death certificates 94,533 males and 47,522 females aged yrs with 8-yr follow-up Results 690 deaths from liver disease ALT or AST ≥ 20 IU/L significantly associated with increased risk for death from liver disease in men RR of Death From Liver Disease Men Women AST, IU/L < 20 1.0 20-29 2.5 3.3 30-39 8.0 18.2 ALT, IU/L 2.9 3.8 9.5 6.6 ALT, alanine aminotransferase; AST, aspartate aminotransferase; RR, relative risk. Furthermore, data have shown that even levels of aspartate aminotransferase (AST) and ALT previously considered well within the normal range may identify patients who have an increased risk of dying from liver disease. In this large, prospective, cohort study of approximately 140,000 individuals, causes of death were ascertained from death certificates to assess the association between liver enzyme levels and liver-related deaths. The results demonstrated that ALT or AST ≥ 20 IU/L was associated with a significantly increased risk of death from liver disease relative to ALT or AST < 20 IU/L in men. In fact, the risk increased with AST and ALT levels as low as 20-29 IU/L, with even more substantial increases at ALT and AST levels of IU/L. However, this study was conducted in Asia and it is unclear if the data would be similar in other populations. Kim HC, et al. BMJ. 2004;328:983.

Adverse Liver Outcomes (Cirrhosis and HCC) in Chronic HBV Infection
Long-term follow-up (median: 29 mos) of 3233 patients from Hong Kong with chronic HBV infection Cirrhosis-assoc complications: ascites, SBP, variceal bleeding, PSE, HCC *P < vs ALT < 0.5 x ULN. †P < .05 vs ALT < 0.5 x ULN. 40 ALT > 1 to 2 x ULN* ALT > 2 to 6 x ULN* ALT x ULN* 30 ALT > 6 x ULN† ALT < 0.5 x ULN Risk of Complications (%) 20 ALT, alanine aminotransferase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PSE, portosystemic encephalopathy; SBP, spontaneous bacterial peritonitis; ULN, upper limit of normal. The study shown on this slide examined the relationship between adverse liver outcomes and ALT levels in patients with chronic hepatitis B. In this analysis, the risk of cirrhosis-associated complications was significantly higher in patients with any level of ALT elevation, including patients with ALT levels > 1-2 times the upper limit of normal, relative to patients with ALT levels < 0.5 times the upper limit of normal. The results of these studies suggest that normal ALT levels may best be defined as ≤ 20 IU/L rather than the normal ranges used in standard laboratory testing. 10 30 60 90 120 150 180 Follow-up (Mos) Reproduced from Yuen MF, et al. Gut. 2005;54: © 2005 with permission from BMJ Publishing Group Ltd.

The REVEAL Study: Serum HBV DNA Level and Risk of HCC
Long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC among untreated HBsAg+ individuals in Taiwan 12 All participants (N = 3653) HBeAg negative (n = 3088) 10.6 10 8 6.6 6.1 6.1 Multivariable-Adjusted HR 6 4 HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HR, hazard ratio. The REVEAL study, a long-term follow-up analysis involving more than 3000 individuals with chronic HBV infection in Taiwan, provided valuable data on risk factors for liver cancer and cirrhosis. The power of this study stems from the fact that data were collected at 2 time points more than 11 years apart, with complete patient assessment including serum HBV DNA levels and ultrasonography to determine the extent of cirrhosis. When the investigators examined the relationship between the level of viral replication and subsequent complications, they found that the adjusted hazard ratio for the development of HCC increased dramatically with increasing HBV DNA levels in the overall population and in the subset of patients who were HBeAg negative. The HBV DNA level above which the risk of liver cancer increased was 10,000 copies/mL, providing support for focusing on this value as a potential target for therapy. For more information, go online to: 2.3 2.6 2 1 1 1.1 1 < 300 10,000- 99,999 100, ,999 ≥ 1 million HBV DNA (copies/mL) Chen CJ, et al. JAMA. 2006;295:65-73.

Risk of HCC and Cirrhosis According to Baseline HBV DNA
HBV DNA (copies/mL) HBV DNA (copies/mL) 1.4 3.0 < ,000-99, , ,999 ≥ 1 million < ,000-99, , ,999 ≥ 1 million 1.2 2.5 1.0 2.0 0.8 HCC (% per Yr)[1] Cirrhosis (% per Yr)[2] 1.5 0.6 HBV, hepatitis B virus; HCC, hepatocellular carcinoma. In addition to the correlation between HCC and HBV DNA level, the risk of cirrhosis was also related to the HBV DNA level. As shown on this slide, the relationship between the incidence of cirrhosis and HBV DNA was very similar to the relationship between the incidence of HCC and HBV DNA, with the risk of both complications beginning to increase at HBV DNA levels > 10,000 copies/mL. For more information, go online to: For more information, go online to: 1.0 0.4 0.5 0.2 1. Chen CJ, et al. JAMA. 2006;295: Iloeje UH, et al. Gastroenterology. 2006;130:

Diagnosis and Initial Evaluation
The next section reviews diagnosis and initial evaluation.

AASLD Guideline Recommendations for Initial Evaluation of CHB Patients
“8. Initial evaluation of persons newly diagnosed with chronic HBV infection should include history, physical examination, and laboratory testing (Grade III) 9. All persons with chronic hepatitis B not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6-18 months apart (Grade II-3)” AASLD, American Association for the Study of Liver Diseases; CHB, chronic hepatitis B; HBV, hepatitis B virus. The AASLD guideline recommendations for initial evaluation are as follows: initial evaluation of persons with newly diagnosed chronic HBV infection should include history, physical examination, and laboratory testing, and all individuals with chronic hepatitis B who are not immune to hepatitis A should receive 2 doses of hepatitis A vaccine. Lok AS, et al. Hepatology. 2009;50:

Initial Evaluation of Chronic HBV–Infected Patients
History and physical examination Family history of liver disease, HCC Laboratory tests to assess liver disease: CBC with platelets, hepatic panel, and prothrombin time Tests for HBV replication: HBeAg/anti-HBe, HBV DNA Tests to rule out viral coinfections: anti-HCV, anti-HDV (in persons from countries where HDV infection is common and in those with history of injection drug use), and anti-HIV in those at risk Tests to screen for HCC: AFP and ultrasound as appropriate Consider liver biopsy to grade and stage liver disease: for patients who meet criteria for chronic hepatitis AFP, alpha-fetoprotein; anti-HBe, hepatitis B e antibody; CBC, complete blood count; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus. This slide provides a more detailed outline of the initial evaluation requirements for patients with chronic hepatitis B, including a complete history and physical examination as noted on the previous slide. It is also important to document any family history of liver disease or HCC, as this information may factor into the therapeutic decision. Laboratory tests, including a complete blood count with platelets, a liver function panel, and prothrombin time, should be ordered to assess for the presence and severity of liver disease. Tests for HBV replication, including HBV DNA, HBeAg, and anti-HBe, should be obtained. Given the high rate of coinfections in certain populations, it is appropriate to request serology for hepatitis C virus antibody and, in persons from countries with high hepatitis delta virus prevalence or injection drug users, hepatitis delta virus antibody. In addition, HIV testing should be performed in at-risk patients. Screening tests for liver cancer should include alpha-fetoprotein and ultrasound as appropriate. A liver biopsy should be considered to grade and stage liver disease in patients who meet the criteria for chronic hepatitis. Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

Chronic HBV Infection: Diagnostic Criteria
Disease Phase Diagnostic Criteria Chronic hepatitis B HBsAg+ > 6 mos Serum HBV DNA > 20,000 IU/mL (105 copies/mL), lower values ,000 IU/mL ( copies/mL) often seen in HBeAg- disease Persistent or intermittent elevation in ALT/AST levels Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation Inactive HBsAg carrier state HBeAg-, anti-HBe+ Serum HBV DNA < 2000 IU/mL Persistently normal ALT/AST levels Liver biopsy confirms absence of significant hepatitis Resolved hepatitis B Previous known history of acute or chronic hepatitis B or presence of anti-HBc +/- anti-HBs HBsAg- Undetectable serum HBV DNA (very low levels may be detectable by sensitive PCR assays) Normal ALT levels ALT, alanine aminotransferase; anti-HBc, hepatitis B core antibody; anti-HBe, hepatitis B e antibody; anti-HBs, hepatitis B surface antibody; AST, aspartate aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction. This slide distinguishes the diagnostic criteria required to confirm the diagnosis of chronic HBV infection from the criteria indicating inactive HBsAg carrier state or resolved hepatitis B. The diagnostic criteria for chronic HBV infection include HBsAg positivity for > 6 months; serum HBV DNA > 20,000 IU/mL; persistent or intermittent ALT/AST elevations; and a liver biopsy, if obtained, showing ongoing moderate or severe necroinflammation. However, lower HBV DNA values of ,000 IU/mL are often observed in the setting of HBeAg-negative disease. By contrast, patients in the inactive HBsAg carrier state or with nonreplicative status have lower levels of HBV DNA (< 2000 IU/mL) and are HBeAg negative and anti-HBe positive. A liver biopsy generally will show lack of significant necroinflammatory activity. Individuals who were previously exposed to HBV and have become immune will have a known history of acute or chronic HBV infection or will test positive for anti-HBc, with or without anti-HBs. By definition, these individuals lack detectable HBsAg and serum HBV DNA, although very sensitive polymerase chain reaction assays may detect very low levels of circulating viremia. Liver enzymes are generally normal. Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

HBeAg-Negative Patients Require Frequent Monitoring
800 140 ALT 700 120 HBV DNA 600 100 500 80 ALT (IU/L) 400 Serum HBV DNA (pg/mL) 60 300 40 ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. Patients with HBeAg-negative disease in particular require frequent monitoring because their liver enzymes and HBV DNA levels may fluctuate dramatically over time, demonstrating significant elevation at one time point and spontaneous remission at a subsequent time point. 200 100 20 200 400 600 800 1000 1200 1400 1600 Days Hadziyannis SJ, et al. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin Liver Dis. 2006;26(2): Reprinted by permission.

Evaluating HBV DNA Levels
Serum HBV DNA quantification used for Evaluation of chronic HBV infection Assessment of antiviral efficacy Ideal assay is one that uses real-time PCR Improved sensitivity (down to 5-10 IU/mL) Wider dynamic range (up to 8-9 log10 IU/mL) Serial HBV DNA monitoring more important than specific cutoff value in determining prognosis, need for treatment Lower HBV DNA levels (3-5 log10 IU/mL) may be associated with progressive liver disease; could warrant treatment Especially for HBeAg-negative or cirrhotic patients HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction. When evaluating patients with HBV infection, serum HBV DNA quantification is useful to determine the presence of ongoing or chronic infection and to assess the efficacy of therapy. The ideal assay is one that utilizes a real-time polymerase chain reaction. Such assays provide improved sensitivity down to very low levels of virus and a wider dynamic range that extends to high HBV DNA levels. It is important to monitor HBV DNA serially over time rather than obtaining a single measurement and comparing it with a specific cutoff value; the former approach provides more information about an individual patient’s clinical course, their likelihood of developing complications, and the need for treatment. Given the significant oscillation in HBV DNA levels that may be observed in individual patients, it is important to obtain at least 2-3 measurements before initiating therapy unless the patient is clearly symptomatic. Relatively low HBV DNA levels, in the range of 3-5 log10 IU/mL, may be associated with progressive liver disease; therefore the decision to start therapy in patients with modest HBV DNA levels must be made in collaboration with a hepatologist to determine the presence and severity of concomitant liver disease. This is especially true in patients with HBeAg-negative disease and in patients who have cirrhosis. Lok AS, et al. Hepatology. 2009;50:

Role of Liver Biopsy in Evaluating Patients With Chronic HBV Infection
Purpose of the biopsy Establish baseline severity of liver disease Exclude other coexistent causes of liver disease (eg, fatty liver or alcoholic liver disease) Greatest utility in patients who do not meet clearly defined recommendations for treatment/no treatment[1] Liver biopsy decisions should consider age, HBeAg status, HBV DNA levels, clinical factors that suggest chronic liver disease or portal hypertension, new suggested definitions of normal ALT levels[1,2] ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. The role of liver biopsy in evaluating patients with chronic HBV infection has evolved over time and continues to be a subject of debate. The biopsy is less relevant for making a diagnosis at this time because of the availability of excellent serologic tests. The main purpose of the biopsy is to establish the baseline severity of liver disease and to exclude the presence of other concomitant liver diseases, such as fatty liver disease or alcoholic liver disease. The greatest utility of a liver biopsy at the present time appears to be in patients who do not meet clearly defined recommendations for treatment guidelines. In such patients, the presence of significant liver injury may assist in making the decision to treat, whereas the presence of minimal histologic disease may suggest a watchful waiting approach. The decision to pursue a liver biopsy must be individualized and should consider several factors, such as the patient’s age and HBeAg status, the level of HBV DNA, clinical factors that suggest chronic liver disease or portal hypertension, and updated definitions of normal ALT levels. 1. Lok AS, et al. Hepatology. 2009;50: Prati D, et al. Ann Intern Med. 2002;137:1-10.

What Is a “Normal” ALT Level?
9221 first-time potential blood donors 74% suitable donors after exclusion of anemia, serologic reactivity on screening assay, seizure, sexual, and other risk 57% determined to be at “low risk” for liver disease BMI < 25 Normal serum cholesterol, triglycerides, and glucose levels Absence of concurrent medication use Updated healthy ALT upper limits determined from the group of low-risk individuals Males: 30 IU/L Females: 19 IU/L ALT, alanine aminotransferase; BMI, body mass index. What is the definition of a normal ALT level? The results of a well-cited study examining ALT levels in 9221 first-time potential blood donors have modified current definitions of healthy ALT levels. A substantial proportion of the study population was excluded because of risk factors for blood-borne infections. Among individuals determined to be suitable blood donors, 57% were identified as being at low risk for liver disease. Using this low-risk group, revised healthy upper limits of ALT were established as 30 IU/L for men and 19 IU/L for women. These upper limits of normal are now almost universally accepted among hepatologists. Prati D, et al. Ann Intern Med. 2002;137:1-10. 47

Determining Treatment Candidacy
How is treatment candidacy determined for patients with chronic HBV infection?

AASLD CHB Guidelines: Treatment Candidacy for HBeAg-Positive Patients
HBsAg Positive HBeAg Positive ALT < 1 x ULN HBV DNA < 20,000 IU/mL ALT 1-2 x ULN HBV DNA > 20,000 IU/mL ALT > 2 x ULN HBV DNA > 20,000 IU/mL AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; Q, every; ULN, upper limit of normal. The AASLD HBV treatment guidelines provide recommendations for treatment candidacy in both HBeAg-positive and HBeAg-negative patients. For HBeAg-positive disease, patients with ALT > 2 times the upper limit of normal and HBV DNA > 20,000 IU/mL are potential candidates for therapy. It is recommended that the patient’s ALT level and HBeAg status be followed at least every 1-3 months before initiation of therapy and, if persistent, treatment should be undertaken. Liver biopsy is optional in such cases. However, if the patient is symptomatic (eg, jaundice or decompensated cirrhosis), as noted earlier, therapy should be initiated immediately without waiting for follow-up results. By contrast, patients with ALT < 1 times the upper limit of normal and HBV DNA < 20,000 IU/mL can be followed clinically with ALT and HBeAg monitoring every 3-6 months and 6-12 months, respectively. It is in the intermediate group of patients where liver biopsy may be helpful to determine the need for treatment. Such patients have modest liver enzyme elevation (ALT 1-2 times the upper limit of normal) with persistent viremia (HBV DNA > 20,000 IU/mL). The recommendation is to consider a biopsy for patients in this group if they have persistent elevation within this range or if they are older than 40 years of age. Q 3-6 mos ALT Q 6-12 mos HBeAg Q 3 mos ALT Q 6 mos HBeAg Consider biopsy if persistent or age > 40 Rx as needed Q 1-3 mos ALT, HBeAg Treat if persistent Liver bx optional Immediate Rx if jaundice or decompensated Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases. 49

AASLD 2009 Guideline Recommendations for Treatment of HBeAg-Positive Patients
HBV DNA (PCR), IU/mL ALT Treatment Strategy > 20,000 ≤ 2 x ULN Low efficacy with current treatment Observe; consider treatment when ALT becomes elevated Consider biopsy in persons > 40 yrs, ALT persistently high normal-2 x ULN, or with family history of HCC Consider treatment if HBV DNA > 20,000 IU/mL and biopsy shows moderate/severe inflammation or significant fibrosis > 2 x ULN Observe for 3-6 mos and treat if no spontaneous HBeAg loss Consider liver biopsy prior to treatment if compensated Immediate treatment if icteric or clinical decompensation Endpoint of treatment: seroconversion from HBeAg to anti-HBe AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; anti-HBe, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PCR, polymerase chain reaction; ULN, upper limit of normal. The recommended treatment strategies for HBeAg-positive patients are outlined on this slide. If the ALT level is ≤ 2 times the upper limit of normal, current treatment options have low efficacy and therefore watchful waiting would be reasonable. If the ALT level becomes persistently elevated, treatment would be considered. If the patient is older than 40 years of age, has an ALT level that is persistently high normal to 2 times the upper limit of normal, or has a family history of liver cancer, liver biopsy should be considered. If the biopsy demonstrates significant inflammation or fibrosis, treatment would be appropriate. In patients with persistently elevated ALT > 2 times the upper limit of normal, observation for a short time period is appropriate, with treatment indicated if the patient remains HBeAg positive. Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

AASLD CHB Guidelines: Treatment Candidacy for HBeAg-Negative Patients
HBsAg Positive HBeAg Negative ALT < 1 x ULN HBV DNA < 2000 IU/mL ALT 1-2 x ULN HBV DNA ,000 IU/mL ALT ≥ 2 x ULN HBV DNA ≥ 20,000 IU/mL AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; Q, every; ULN, upper limit of normal. The recommendations for treatment of HBeAg-negative patients are shown on this slide. For HBeAg-negative patients who have very low HBV DNA levels (< 2000 IU/mL) and ALT < 1 times the upper limit of normal, treatment is not recommended. However, close monitoring is appropriate, including HCC surveillance in patients who meet the corresponding criteria. By contrast, HBeAg-negative individuals who have persistently elevated ALT ≥ 2 times the upper limit of normal and HBV DNA ≥ 20,000 IU/mL clearly meet treatment criteria, and liver biopsy would be optional in these patients. For patients in the intermediate range, defined as HBV DNA ,000 IU/mL and ALT 1-2 times the upper limit of normal, watchful waiting is appropriate for a short period of time. If elevated ALT and HBV DNA levels persist, a liver biopsy should be considered to determine if there is sufficient histologic activity to warrant initiation of therapy. Q 3 mos ALT x 3, then Q 6-12 mos if ALT still < 1 X ULN Q 3 mos ALT and HBV DNA Consider biopsy if persistent Rx as needed Treat if persistent Liver biopsy optional Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases. 51

AASLD 2009 Guideline Recommendations for Treatment in HBeAg-Negative Patients
HBV DNA (PCR), IU/mL ALT Treatment Strategy[1] > 20,000* > 2 x ULN Treat; endpoint of treatment: not defined > 2000 1 to > 2 x ULN Consider liver biopsy and treat if liver biopsy shows moderate/severe necroinflammation or significant fibrosis ≤ 2000 ≤ ULN Observe; treat if HBV DNA or ALT becomes higher *Treatment may be considered in patients with HBV DNA ,000 IU/mL, particularly if they are older or have cirrhosis. Although several studies including the REVEAL study showed a correlation between serum HBV DNA and clinical outcomes such as HCC, only patients with 1 or both samples at baseline and last follow-up with serum HBV DNA > 100,000 copies/mL (> 20,000 IU/mL) had significantly increased risk of HCC.[2] AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PCR, polymerase chain reaction; ULN, upper limit of normal. In HBeAg-negative patients initiating therapy, there is not a clear endpoint of treatment. For patients who are HBeAg positive, the goal is to achieve seroconversion from HBeAg positivity to anti-HBe positivity. Following HBeAg seroconversion, therapy can be discontinued and most patients will not experience relapse. Because relapse is common among HBeAg-negative patients, most experts agree that the duration of therapy needs to be longer; however, the ideal duration has not yet been characterized. As indicated on the previous slide, in HBeAg-negative patients who have modestly elevated liver enzymes and HBV DNA levels, watchful waiting is appropriate with consideration of liver biopsy to assist in the decision to continue monitoring or to start therapy. For more information, go online to: 1. Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases. 2. Chen CJ, et al. JAMA. 2006;295:65-73.

AASLD 2009 Guideline Recommendations for Treatment of Pts With HBV Cirrhosis
HBeAg HBV DNA (PCR), IU/mL ALT Treatment Strategy +/- Detectable Cirrhosis Compensated HBV DNA > 2000 IU/mL: treat HBV DNA < 2000 IU/mL: consider treatment if ALT elevated Decompensated Coordinate treatment with transplant center; refer for liver transplant Undetectable Compensated: observe Decompensated: refer for liver transplant. AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction. The HBV management approach is different for patients with cirrhosis because such patients have already progressed to advanced disease. As a result, the threshold for treatment candidacy is much lower. In the setting of compensated cirrhosis, regardless of HBeAg status, treatment initiation is recommended if HBV DNA levels are > 2000 IU/mL, and it should be considered in patients with HBV DNA < 2000 IU/mL if they have elevated ALT levels. Patients with decompensated cirrhosis related to chronic hepatitis B should be referred to a liver transplantation center and treatment should be coordinated with the center. Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

Treatment Criteria for Chronic Hepatitis B: Comparison of Liver Society Guidelines
Recommended HBV DNA and ALT levels outlined in the following table Liver Society Guidelines* HBeAg Positive HBeAg Negative HBV DNA, IU/mL ALT HBV DNA, IU/mL† EASL 2009[1] > 2000 > ULN‡ APASL 2008[2] ≥ 20,000 > 2 x ULN‡ ≥ 2000 AASLD 2009[3] > 20,000 > 2 x ULN§ or positive biopsy ≥ 2 x ULN§ or AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ULN, upper limit of normal. How do the AASLD treatment guidelines compare to the guidelines from the other societies? An important difference is in the recommended HBV DNA threshold levels. The EASL guidelines recommend that therapy should be considered in HBeAg-positive and HBeAg-negative patients with HBV DNA levels > 2000 IU/mL, whereas the AASLD guidelines recommend an HBV DNA threshold of 20,000 IU/mL for both groups. The HBV DNA threshold recommended in the APASL guidelines is 2000 IU/mL for HBeAg-negative patients and 20,000 IU/mL for HBeAg-positive patients. Furthermore, the EASL guidelines suggest that any elevation of liver enzymes be considered an indication for treatment, whereas the APASL and the AASLD guidelines recommend initiation of therapy at ALT levels > 2 times the upper limit of normal. *Although ALT and HBV DNA are primary tests used to determine treatment candidacy, the levels of elevation that warrant consideration of treatment are not universally agreed upon. †Some experts recommend in patients older than 40 yrs of age, 2000 IU/mL should be considered as a cutoff for treatment. ‡Laboratory normal. §30 U/L for men and 19 U/L for women. 1. EASL. J Hepatol. 2009;50: Liaw YF, et al. Hepatol Int. 2008;3: Lok AS, et al. Hepatology. 2009;50: 54

Further Patient Evaluation
The final section of this presentation reviews additional guidelines for patient evaluation.

Monitoring of Patients Not Considered for Therapy
Disease State Recommended Follow-up HBeAg positive HBV DNA > 20,000 IU/mL Normal ALT ALT every 3-6 mos, more often if ALT becomes elevated If ALT levels between 1-2 x ULN, recheck ALT every 1-3 mos; consider liver biopsy if older than 40 yrs of age, ALT borderline or mildly elevated on serial tests. Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis If ALT > 2 x ULN for 3-6 mos and HBeAg positive, HBV DNA > 20,000 IU/mL, consider liver biopsy and treatment Consider screening for HCC in relevant population ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ULN, upper limit of normal. Continued monitoring of patients who do not meet the criteria for therapy is a critical component of chronic HBV infection management. Such patients may experience HBV DNA increases, have progressive disease, and develop liver cancer. For HBeAg-positive patients who have normal ALT and high HBV DNA levels (> 20,000 IU/mL), the recommended follow-up includes ALT assessment every 3-6 months and consideration of therapy if levels become elevated. In patients with borderline or mildly elevated ALT levels or who are older than 40 years of age, liver biopsy should be considered to determine if treatment is warranted. Screening for HCC should also be conducted in relevant populations. Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

Monitoring of Patients Not Considered for Therapy
Disease State Recommended Follow-up Inactive HBsAg carrier state ALT every 3 mos for 1 yr; if persistently normal, ALT every 6-12 mos If ALT > 1-2 x ULN, check serum HBV DNA level and exclude other causes of liver disease. Consider liver biopsy if ALT borderline or mildly elevated on serial tests or if HBV DNA persistently ≥ 2000 IU/mL. Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis Consider screening for HCC in relevant population ALT, alanine aminotransferase; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ULN, upper limit of normal. For patients who are in the inactive HBsAg carrier state, it is recommended that liver enzymes be checked every 3 months for the first year and less frequently thereafter if they are persistently normal. If the liver enzymes become elevated and the HBV DNA level remains low, other causes of liver disease should be considered, such as drug-induced toxicity, fatty liver, etc. Among patients who have persistent HBV DNA ≥ 2000 IU/mL or borderline or mildly elevated ALT on serial tests, liver biopsy should be considered to determine the need for treatment. Lok AS, McMahon BJ. Hepatology. 2009;50: Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

AASLD Guideline Recommendations for HCC Screening
“13. HBV carriers at high risk for HCC such as Asian men over 40 yrs and Asian women over 50 yrs of age, persons with cirrhosis, persons with a family history of HCC, Africans over 20 yrs of age, and any carrier over 40 yrs with persistent or intermittent ALT elevation and/or high HBV DNA level > 2000 IU/mL should be screened with US examination every 6-12 mos (Grade II-2) 14. For HBV carriers at high risk for HCC who are living in areas where US is not readily available, periodic screening with AFP should be considered (Grade II-2)” AASLD, American Association for the Study of Liver Diseases; AFP, alpha-fetoprotein; ALT, alanine aminotransferase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; US, ultrasound. The AASLD guideline recommendations for HCC screening indicate that HBV carriers at high risk for liver cancer, such as Asian men older than 40 years of age and Asian women older than 50 years of age, individuals with cirrhosis, persons with a family history of HCC, Africans older than 20 years of age, and any HBV carrier older than 40 years of age with persistent or intermittent ALT elevation and/or high HBV DNA levels, should be screened with an ultrasound examination every 6-12 months. For HBV carriers at high risk for HCC who reside in areas where ultrasound is not readily available, periodic screening with alpha-fetoprotein should be considered. Lok AS, et al. Hepatology. 2009;50:

HBV Patients for Whom HCC Surveillance Is Recommended
Subgroup HCC Incidence per Yr Asian male HBV carriers > 40 yrs of age 0.4% to 0.6% Asian female HBV carriers > 50 yrs of age 0.3% to 0.6% Hepatitis B carrier with HCC family history Higher than no family history African/N American blacks with HBV HCC occurs at younger age Cirrhotic HBV carriers 3% to 8% HBV, hepatitis B virus; HCC, hepatocellular carcinoma. Recommendations regarding HCC surveillance for patients with HBV infection are based on incidence rates within different subgroups. Among HBV carriers, Asian males older than 40 years of age and Asian females older than 50 years of age experience HCC incidence rates of approximately 0.3% to 0.6% per year; therefore, surveillance is recommended regardless of the presence of cirrhosis. Because the risk of liver cancer is higher in chronic HBV carriers who have a family history of liver cancer compared with carriers who do not have a family history of liver cancer, HCC surveillance is also recommended in this group. African and North American black patients with chronic HBV infection develop HCC at a younger age than other racial subgroups and, therefore, are recommended for HCC screening. Finally, the highest risk of HCC is observed among patients with HBV-related cirrhosis, who have an annual incidence of 3% to 8% per year; surveillance should begin in this population when patients first establish medical contact. For more information on the AASLD HCC guidelines, go online to Practice Guidelines/HCCUpdate2010.pdf (accessed November 8, 2010). Bruix J, et al. AASLD HCC guidelines. July 2010.

AASLD Surveillance Guidelines
Surveillance recommended in at-risk groups Specific hepatitis B carriers Nonhepatitis B cirrhosis HCC surveillance should be performed with ultrasound Patients should be screened at 6-mo intervals Increased surveillance interval in patients at higher risk not needed AASLD, American Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma. Surveillance for HCC is recommended in at-risk groups of HBV carriers, as noted on the previous slide, and all patients with cirrhosis not related to HBV should also undergo surveillance. The current recommendation is that surveillance should be performed with ultrasonography at 6-month intervals; more frequent surveillance in patients at higher risk is not needed. For more information on the AASLD HCC guidelines, go online to Practice Guidelines/HCCUpdate2010.pdf (accessed November 8, 2010). Bruix J, et al. AASLD HCC guidelines. July 2010.

Summary and Conclusions
Despite dramatic reductions in HBV incidence in US, prevalence will likely remain the same or increase as a result of immigration from high endemicity regions Screening and vaccination according to guidelines remains essential Important to follow established guidelines for monitoring and treating patients with chronic hepatitis B Ongoing surveillance required in both treatment candidates and individuals who do not require therapy Although not required, liver biopsy may play important role in patients who do not meet clearly defined recommendations for treatment/no treatment HBV, hepatitis B virus. In conclusion, although the incidence of HBV infection has decreased dramatically in the United States as a result of comprehensive vaccination strategies, the number of patients with chronic HBV infection is likely underestimated and will likely remain steady or even increase given the high rates of immigration from countries with high HBV endemicity. It is important for all practitioners to be alert to the possibility of HBV exposure and advise screening and vaccination to any at-risk individuals. The AASLD and other learned societies have established clear guidelines for monitoring patients with chronic HBV infection and for determining when to initiate therapy. Epidemiologic data from Asia have shown that ongoing viral replication is independently associated with the development of cirrhosis and HCC. Patients with chronic HBV infection should be carefully monitored, even if they are not candidates for therapy, given the significant risk of HCC. Furthermore, based on the dynamic nature of chronic HBV infection with waxing and waning HBV DNA and ALT levels, changing serologic status, and prolonged periods of inactivity followed by periods of increased activity, ongoing HBeAg status and liver enzyme monitoring is strongly encouraged. Finally, it is very important to remember that although liver biopsy is no longer required to make a decision to start therapy in patients with chronic HBV infection, it may play a very useful role in cases that do not meet well-defined criteria for therapy. In such cases, liver biopsy results can assist in making the decision to continue watchful waiting or, in the setting of significant necroinflammatory disease or fibrosis, to proceed with therapy.

Go Online to Access More of the 2009 AASLD HBV Guidelines Program!
Interactive Virtual Presentation: Using HBV Treatment Guidelines in Determining How to Treat Interactive Case Challenges: Management of an HBeAg-Positive Korean American Male With Decompensated Cirrhosis, Management of an HBeAg-Positive Woman of Childbearing Age, Management of an HBeAg-Negative Chinese Patient Downloadable Slidesets clinicaloptions.com/GuidelinesHBV 62

Go Online to Access All of AASLD’s Practice Guidelines!*
AASLD promotes preferable methods of approaching diagnostic, therapeutic, and preventive aspects of care through the development of practice guidelines Portal Hypertension Guidelines Viral Hepatitis Guidelines Metabolic/Genetic/Autoimmune Liver Disease Guidelines End-Stage Liver Disease/Surgery Guidelines Position Papers on Other Disorders aasld.org/practiceguidelines *AASLD guidelines represent the official opinion of the Association, as reflected in the evidence-based reviews and recommendations of the individuals involved in developing the guidelines.

Understanding and Implementing the AASLD’s HBV Practice Guidelines

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Understanding and Implementing the AASLD’s HBV Practice Guidelines

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