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Hepatitis B

Hepatitis B. Chronic Hepatitis B Is a Global Health Problem. HBsAg prevalence. High. ≥8% . Intermediate. 2%-7% . <2%. Low. An estimated 240 million people worldwide are living with chronic hepatitis B (CHB) 2. Map adapted from the CDC. 3. HBV=hepatitis B virus.

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Hepatitis B

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  1. Hepatitis B

  2. Chronic Hepatitis B Is a Global Health Problem HBsAg prevalence High ≥8% Intermediate 2%-7% <2% Low An estimated 240 million people worldwide are living with chronic hepatitis B (CHB)2 Map adapted from the CDC.3 HBV=hepatitis B virus. HBV infection is the most common chronic viral infection in the world1 1. TrepoC, et al. Lancet. 2014;384;2053-2063; 2. WHO. Hepatitis B Fact Sheet. July 2014. www.who.int/mediacentre/factsheets/fs204/en/. Accessed March 25, 2015;3. CDC. Morb Mortal Wkly Rep. 2008;57:1-20; 4. Vijayadeva V, et al. Am J Manag Care. 2014;20:e98-e104.

  3. Prevalence of CHB in the United States 5% 62.8% 13.5% WHO regions Percentage of foreign-born persons with CHB in the United States who originated from the indicated WHO regions (2001-2010)2 14.1% Africa Americas (without US) 4.6% Europe Eastern Mediterranean Western Pacific and Southeast Asia Approximately 90% of foreign-born persons with CHB in the United States migrated from regions of intermediate and high endemicity3 It is estimated that as high as 2 million persons are living with CHB in the United States1 WHO=World Health Organization. 1. Cohen C, et al. J Viral Hepatitis. 2011;18:377-383; 2. Liu SJ, et al. J Immigr Minor Health. 2015;17:7-12; 3. KowdleyKV, et al. Hepatology. 2012;56:422-433.

  4. CHB in the US: Continuum of Care 2 million have CHB 600,000 are aware of their infection 500,000 are potentially eligible for treatment 300,000 diagnosed and entered into care 50,000receive treatment 1.4 million people in the US are unaware of their CHB infection Based on epidemiologic studies in the US. Numbers presented are the upper end of estimated ranges. Cohen C, et al. J Viral Hepat. 2011;18:377-383.

  5. 2 Chronic Hepatitis B Can Be Asymptomatic About2 out of 3 persons with CHB in the United States are unaware of their infection1 Persons with CHB can be without symptoms for many years2 Unaware of their infection, CHB patients are at risk for transmitting the virus to others and for developing serious liver disease later in life2 Identification and management of CHB-infected individuals can help prevent serious sequelae of chronic liver disease2 1. Cohen C, et al. J Viral Hepat. 2011;18:377-383; 2. CDC. Morb Mortal Wkly Rep. 2008;57:1-20.

  6. Virology of HBV Infection viral envelope polymerase DNA Figure adapted from Toronto Centre for Liver Disease. Hepatitis B. www.torontoliver.ca/hepatitis-b/. • HBV is a partially double-stranded DNA virus which primarily infects liver cells1 • Up to 1011 to 1013 virions/day may be produced in an infected person2 • Liver inflammation and fibrosis/cirrhosis are consequences of host’s immune response1 • The virus can evade the immune system during early phases of infection • Therefore, acute infections are primarily asymptomatic1 • The genomic template for active viral propagation, cccDNA, can persist in infected cells, even after clearance of infection marker1 cccDNA=covalently closed circular DNA. • Busch K, Thimme R. Med Microbiol Immunol. 2015;204:5-10; 2. Margeridon-Thermet S, Shafer RW. Viruses. 2010;2:2696-2739.

  7. Routes of HBV Transmission HBV Carrier Horizontal transmission1 Sexual contact Prolonged close contact (eg, household) Exposure to blood or body fluid Organ, blood, and semen donors Hemodialysis Injection drug use Vertical transmission via mother Approximately 25%-50% of acute infections in children aged 1-5 years and <5% in older children and adults progress to CHB1 Child Up to 90% of infants born to HBeAg-positive mothers develop CHB2 HBeAg=hepatitis B e antigen. • CDC. Morb Mortal Wkly Rep. 2008;57:1-20. 2. Buchanan C, Tran TT. Clin Liver Dis. 2010;14:495-504.

  8. Progression and Complications of CHB 0.1%-3%1 HCC 10%-17%1 Cirrhosis Liver Transplantation Death Chronic Infectiona Acute Infection 8%-38%1 15%1 Liver Failure(Decompensation) 70%-85%1 Figure adapted from Fattovich G, et al. In: Marcellin P, (ed.) Management of Patients With Viral Hepatitis. Paris: APMAHV; 2004. aChronic infection is defined as the persistence of positive test results for hepatitis B surface antigen or HBV DNA for at least 6 months.2 Percentages are 5-year cumulative incidence rates. HCC=hepatocellular carcinoma. 1. Fattovich G, et al. J Hepatol. 2008;48:335-352; 2. CDC. Morb Mortal Wkly Rep. 2008;57:1-20.

  9. Risk Factors Associated With CHB Disease Progression in Asian Patients HCC Development Non-HCC Liver Deaths • High level of HBsAg5 • HBV genotype C/D5 • Precore mutation3 • Basal core promoter mutation3 • Increased AFP1 • Decreased baseline ALT1 • Family history of HCC6 • Alcohol consumption4 • Increased ALT1 • Reduced albumin1,2 • Reduced platelets1,2 • Ascites1 • Encephalopathy1 • Older age3 • Male sex3,4 • Cirrhosis2 • Increased HBV DNA3,4 • HBeAg status1 AFP=alpha fetoprotein. 1. Tong MJ, et al. Dig Dis Sci. 2009;54:1337-1346; 2. Tong MJ, et al. Gastroenterol Hepatol. 2006;2:41-47; 3. Tong MJ, et al. World J Gastroenterol. 2006;12:6620-6626; 4. Chen C-J, et al. JAMA. 2006;295:65-73; 5. Lin CL, Kao JH. J Gastroenterol Hepatol. 2013;28:10-17; 6. Yang HI, et al. World J Gastroenterol. 2014;20:6244-6251. 9

  10. HBV Disease Progression Chronic HBV Infection1 8%-38% 0.1%-3% 10%-17% Cirrhosis HCC Percentages are 5-year cumulative incidence rates.1 Progression to HBV-related complications depends on multiple risk factors Host factors Viral / disease factors Environmental factors • >40 years of age2 • Male gender2 • Family history of HCC2,3 • African or Asian race2,3 • High HBV DNA level2 • High HBsAg level4 • Prolonged time to HBeAg seroconversion2 • Development of HBeAg– CHB2 • Genotype C or D2,5 • BCP mutations4,5 • Elevated ALT2 • Presence of fibrosis4 or cirrhosis2 • Coinfection with HCV, HDV, or HIV2 • Alcohol consumption2 • Cigarette smoking2 • Aflatoxin2 • Obesity and/or diabetes2 ALT=alanine aminotransferase; BCP=basal core promoter; HBeAg=hepatitis B e antigen; HCV=hepatitis C virus; HDV=hepatitis D virus; HIV=human immunodeficiency virus. • Fattovich G, et al. J Hepatol. 2008;43:335-352. • Terrault NA, et al. Hepatology. 2015 Nov 13. [Epub ahead of print]. • Trepo C, et al. Lancet. 2014;384:2053-2063. • Burns GS, Thompson AJ. Cold Spring Harb Perspect Med. 2014;4:a024935. • Martin P, et al. Clin Gastroenterol Hepatol. 2015;13:2071-2087.

  11. Higher HBV DNA Levels Are Associated With Increased Risk of Cirrhosis and HCC Over Time (REVEAL Study) Previously Untreated Patients With CHB Cirrhosis1 HCC2 N=3653 N=3582 Risk of HCC Risk of Cirrhosis Adjusted Relative RiskaofCirrhosis Crude Hazard Ratiob for HCC IU/mL3,c IU/mL3,c <60 <60 60-<2000 60-<2000 2000-<20,000 2000-<20,000 20,000-<200,000 20,000-<200,000 ≥200,000 ≥200,000 10,000-99,999 10,000-99,999 100,000-999,999 100,000-999,999 ≥1 million ≥1 million <300 <300 300-9999 300-9999 Copies/mL1 Copies/mL2 Viral Load Viral Load aAdjusted for age, sex, cigarette smoking, and alcohol consumption. bElevated HBV DNA level is a strong risk predictor of HCC, independent of HBeAg, ALT level, and liver cirrhosis; relative risk of an endpoint at any given time. c1 IU/mL is equivalent to 5-6 copies/mL. • Iloeje UH, et al. Gastroenterology. 2006;130:678-686. • Chen CJ, et al. JAMA. 2006;295:65-73. • Martin P, et al. Clin Gastroenterol Hepatol. 2015;13:2071-2087.

  12. Serologic Markers of HBV Infection HBsAg Hepatitis B Virus HBV DNA • Hallmark of infection1 • Major tool for screening and diagnosis of CHB2 (if present ≥6 months3) • Measure of viral load; indicates ongoing viral replication1 • Correlates with infectivity4and risk of major liver disease2 Anti-HBs • Antibody to HBsAg4 • Marker of immunity to HBV4 • Only detectable marker of successful immunization4 HBeAg Anti-HBc • Marker of risk of transmission of infection4 • Antibody to HBV core antigen4 • Marker of prior exposure4 • IgM anti-HBc is a marker of recent infection4 anti-HBs=antibody to HBsAg; anti-HBc=antibody to hepatitis B core antigen; IgM=immunoglobulin M. 1. Trepo C, et al. Lancet. 2014;384:2053-2063. 2. Niederau C. World J Gastroenterol. 2014;20:11595-11617. 3. CDC. Morb Mortal Wkly Rep. 2008;57:1-20; 4. Kao JH. Expert Rev Gastroenterol Hepatol. 2008;2:553-562.

  13. Serologic Profiles of Progression from Acute Infection to CHB Progression from acute infection to chronic hepatitis B Acute(6 months) Chronic(years) HBeAg anti-HBe HBsAg Total anti-HBc Titer IgM anti-HBc 52 Years 0 4 8 12 16 20 24 28 32 36 Weeks after exposure Antigens and antibodies associated with HBV infection include HBsAg, anti-HBs, anti-HBc, HBeAg, and anti-HBe Serologic assays are available to test for these markers CDC. Morb Mortal Wkly Rep. 2008;57;1-20.

  14. Course of HBV Infection HBsAg+ HBsAg− HBeAg+ Anti-HBe+ Anti-HBe+ 2 million have CHB HBV DNA ALT 50,000receive treatment Immune Tolerant Immune Activation Low Replicative Reactivation Remission MinimalInflammation ActiveInflammation MildInflammation ActiveInflammation Inactive Figure adapted from Tong MJ, et al.1 PC/BCP Mutation Reactivation Wild-type Reactivation CHB follows a variable clinical course – not all patients will go through each phase (including remission)2 ALT=alanine aminotransferase; anti-HBe=antibody to HBeAg; HBeAg=hepatitis B e antigen; HBsAg=hepatitis B surface antigen; PC/BCP=precore/basal core promoter. 1. Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162; 2. Martin P, et al. Clin Gastroenterol Hepatol. 2015;13:2071-2087.

  15. Immune Tolerant:High HBV DNA Levels at the Onset of CHB HBsAg+ HBsAg– HBeAg Anti-HBe HBV DNA ALT Immune tolerant Immune clearance Inactive carrier Reactivation Resolution • Often seen in perinatally infected children; may last for several decades1 • In infection acquired during childhood or in adult, the phase is short or absent2 • Very high serum HBV DNA levels and HBeAg positivitywith very low rate of HBeAg seroclearance1,3 • Normal ALT levels with minimal or absence of inflammation or fibrosis1 • A recent retrospective study showed that, despite having normal ALT, a substantial number of HBeAg+ Asian/Chinese patients had significant fibrosis4 • As older age may predict adverse outcomes, it is important to monitor older immune tolerant patients who show minimally or intermittently elevated ALT1 1. Croagh CMN, Lubel JS. World J Gastroenterol. 2014;20:10395-10404; 2. Sarin Sk, Kumar M. In: Shetty L, Wu GY (eds). Clinical Gastroenterology: Chronic Viral Hepatitis. Totowa, NJ: Humana Press. 2009;185-241; 3. Burns GS, Thompson AJ. Cold Spring HarbPerspect Med. 2014;4:a024935; 4. Liao B, et al. PLoS ONE. 8:e78672.

  16. Immune Clearance:Fluctuating HBV DNA Levels With Active Liver Damage HBsAg+ HBsAg– HBeAg Anti-HBe HBV DNA ALT Immune clearance Inactive carrier Reactivation Resolution Immune tolerant • Intermittent or persistent elevation of ALT levels and high HBV DNA levels1 • Typically occurs during the 2nd and 3rd decades of life; may last for years, leading to progressive liver damage2 • Presence of necroinflammation on liver biopsy and varying degrees of fibrosis are the result of immune-mediated liver damage1 • HBeAg seroconversion is a serologic marker of the end of the immune clearance phase2 • 10%-20% of patients will have annual spontaneous HBeAg seroconversion • Patients with active liver disease in the immune clearance phase are potential candidates for treatment2-4 • CroaghCMN, Lubel JS. World J Gastroenterol. 2014;20:10395-10404; 2. Burns GS, Thompson AJ. Cold Spring HarbPerspect Med. 2014;4:a024935; 3. Lok ASF, McMahon BJ. Hepatology. 2009;50:1-36; 4. Keeffe EB, et al. Clin GastroenterolHepatol. 2008;6:1315-1341.

  17. Inactive Carrier:Low HBV DNA Levels with Minimal Liver Damage HBsAg+ HBsAg– HBeAg Anti-HBe HBV DNA ALT Inactive carrier Reactivation Resolution Immune tolerant Immune clearance Characterized by HBeAgseroconversion, suppression of HBV DNA (low or undetectable), and normalization of ALT1 Usually mild hepatitis and minimal fibrosis, but more severe liver damage, including cirrhosis, may have already accumulated from the preceding immune clearance phase2 The term “healthy carrier” is an erroneous term, as a significant proportion of patients may have high viral load, hepatic fibrosis, and other liver-related complications such as HCC2 20%-30% of patients will experience reactivation after HBeAg seroconversion3 1. CroaghCMN, Lubel JS. World J Gastroenterol. 2014;20:10395-10404 ; 2. Sarin SK, Kumar M. In: Shetty K, Wu GY (eds). Clinical Gastroenterology: Chronic Viral Hepatitis. Totowa, NJ: Humana Press. 2009;185-241; 3. Trepo C, et al. Lancet. 2014;384:2053-2063.

  18. Reactivation and Resolution:Reactivation of Viral Replication and Resolving Infection HBsAg+ HBsAg– HBeAg Anti-HBe HBV DNA ALT Reactivation Resolution Inactive carrier Immune tolerant Immune clearance 1. Trepo C, et al. Lancet. 2014;384:2053-2063; 2. Sarin SK, Kumar M. In: Shetty K, Wu GY (eds). Clinical Gastroenterology: Chronic Viral Hepatitis. Totowa, NJ: Humana Press. 2009;185-241; 3. Lok ASF, McMahon BJ. Hepatology. 2009;50:1-36; 4. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341; 5. Croagh CMN, Lubel JS. World J Gastroenterol. 2014;20:10395-10404; 6. Burns GS, Thompson AJ. Cold Spring Harb Prespect Med. 2014;4:a024935. • Reactivation may occur spontaneously or due to immunosuppression1,2 • Patients with reactivation of HBV replication are usually older, with more advanced liver disease2 • Those with active disease have increased risk of liver cirrhosis and HCC1 • Treatment is recommended for HBeAg-negative CHB patients who experience HBV reactivation3,4 • HBsAg loss may occur in 0.5%-2% of Western patients and 0.1%-0.8% of Asian populations annually; this is considered resolution of hepatitis B5,6 • Some patients may still have detectable HBV DNA in serum and are vulnerable to reactivation5

  19. HBV Infection Can Be Prevented Screen for HBV Infection Involves simple blood tests for serologic markers of infection1 Identify CHB-infected patients1,2 Identify unprotected patients for HBV vaccination1,2 • Hepatitis B vaccination is the most effective measure to help prevent HBV infection and its consequences3 • It is important to screen for HBV infection before vaccination1 • Counsel to prevent transmission of infection to others • Provide appropriate medical management 1. Asian Liver Center. 2013 Physician’s Guide to Hepatitis B. http://liver.stanford.edu/media/publications/Handbook/2013Handbook.pdf. Accessed March 25, 2015; 2. CDC. Morb Mortal Wkly Rep. 2008;57:1-20; 3. CDC. Morb Mortal Wkly Rep. 2006;55:1-33.

  20. Alignment of HBV Screening Recommendations From USPSTF, CDC, and AASLD USPSTF CDC AASLD • People born in regions with prevalence of HBV infection of ≥2%1-3 • US-born people not vaccinated as infants whose parents were born in regions with prevalence of HBV infection of ≥8%1-3 • Household and sexual contacts of persons with HBV infection1-3 • All pregnant women2-4 • Men who have sex with men1-3 • Injection drug users1-3 • Individuals infected with human immunodeficiency virus (HIV)1-3 • People with certain medical conditions2,3,5 • Needing immunosuppressive therapy • Undergoing hemodialysis AASLD=American Association for the Study of Liver Diseases. CDC=Centers for Disease Control and Prevention. USPSTF=United States Preventative Services Task Force. • For a complete list of screening recommendations, please see: • LeFevre ML; USPSTF. Ann Intern Med. 2014;161:58-66. • CDC. Morb Mortal Wkly Rep. 2008;57:1-20. • Lok ASF, McMahon BJ. Hepatology. 2009;50(3):1-36. • USPSTF. Ann Intern Med. 2009;150:869-873. • USPSTF. Consumer Fact Sheet. May 2014. http://www.uspreventiveservicestaskforce.org/uspstf/uspshepb.htm. Accessed March 25, 2015.

  21. HBV Screening Tests Screening Tests1,2 aAnti-HBc refers to total anti-HBc.2 bPatient is chronically infected if HBsAg+ for ≥6 months.3 cPatients who are anti-HBc positive should be monitored closely during and after the administration of cytotoxic chemotherapy for signs of HBV reactivation.1 dPatients with cirrhosis may need to be monitored for hepatocellular carcinoma per the AASLD guidelines.4 1. Keeffe EB, et al. Gastroenterol Hepatol. 2008;6:1315-1341; 2. CDC. Interpretation of Hepatitis B Serologic Test Results. http://www.cdc.gov/hepatitis/HBV/testingchronic.htm. Updated December 11, 2013. Accessed March 25. 2015; 3. CDC. Morb Mortal Wkly Rep. 2008;57:1-20; 4. Bruix J, Sherman M. Hepatology. 2011;53. http://www.aasld.org/sites/default/files/ guideline_documents/HCCUpdate2010.pdf. Accessed March 25, 2015. Screening tests for virologic markers of HBV infection include HBsAg, anti-HBs, and anti-HBc1,2

  22. HBV Vaccination Populations recommended for HBV vaccination by the CDC1 • All newbornsa • All unvaccinated children and adolescents through 18 years of age • All unvaccinated adults at risk for infection and those requesting protection from HBV infection • Primary vaccination consists of 3 intramuscular doses given at 0, 1, and 6 months2 • A full 3-dose vaccine series is associated with immunity in >90% of healthy adults2 First dose (0 month) Second dose (1 month) Third dose (6 months) 30%-55% 75% >90% with protective immunity with protective immunity with protective immunity 1 month 5 months aInfants born to HBsAg-positive mothers should also receive hepatitis B immune globulin ≤12 hours of birth.3 1. CDC. Vaccination and Immunizations: Hepatitis B In-Short. http://www.cdc.gov/vaccines/hcp/vis/vis-statements/hep-b.html. February 2, 2012. Accessed March 25, 2015; 2. CDC. Morb Mortal Wkly Rep. 2006;55:1-33; 3. CDC. Morb Mortal Wkly Rep. 2005;54:1-33.

  23. Significant Disparity Between Self-Reported Vaccination and Actual Immunity A recent study showed significant disparity between self-reported vaccination and actual immunity1 0.4%Other 2% Infected • History of vaccination has been cited as one of the main reasons for not ordering screening2,a • Vaccination is not beneficial for already infected or immune (resolved acute infection) persons3 • HBV screening is important to avoid false perception of protection1 and unnecessary vaccination3 26.3% Immune due to natural infection 60.4% Immune due to vaccination 10.8% Susceptible Serological diagnoses of 240 self-declared vaccinated Korean adults1 aData based on a survey of 217 Asian/Asian American primary care practitioners from New York, Los Angeles, San Francisco, Houston, and Chicago areas.2 1. Navarro N, et al. BMC Infect Dis. 2014;14:269; 2. Chu D, et al. Gut Liver. 2013;7:450-457; 3. Asian Liver Center. 2013 Physician’s Guide to Hepatitis B. http://liver.stanford.edu/media/publications/Handbook/2013Handbook.pdf. Accessed March 25, 2015.

  24. Medical Management of CHB Pretreatment Evaluation and Initial Follow-Up Evaluation tests History and physical examination • Risk factors for viral hepatitis • Risk factors for HIV coinfection • Duration of infection • Route of transmission • History of alcohol use • Presence of comorbid diseases • Family history of liver cancer • Serial testing for HBV DNA and ALT (6-month period) • HBeAg and anti-HBe • Liver function tests • Tests for antibodies to HAV, HCV, HDV, and HIV • HBV genotype • Screen for HCC in high-risk patients • Liver biopsya • Urinalysis aNoninvasive methods for assessing fibrosis may be helpful on a case-by-case basis. Patients should also be counseled on risk of transmission, screening of family members, vaccination of at-risk household and sexual contacts, and family planning Initial evaluation of patients should include a thorough history and physical examination, followed by laboratory tests HAV= hepatitis A virus; HCV=hepatitis C virus; HDV=hepatitis D virus. Keeffe EB, et al. Clin GastroenterolHepatol. 2008;6:1315-1341.

  25. Existing CHB Guidelines and AlgorithmsOverview HBeAg+ HBeAg− HBV DNA (IU/mL) HBV DNA (IU/mL) ALT (U/L) ALT (U/L) AASLD 20091>20,000 AASLD 20091>2x ULNa or biopsy (+) AASLD 20091>20,000 or >2000 if biopsy (+) AASLD 20091>2x ULNa or biopsy (+) US Treatment Algorithm 20152≥2000 US Treatment Algorithm 20152>ULNa or TE*/biopsy (+) US Treatment Algorithm 20152≥2000 US Treatment Algorithm 20152>ULNa or TE*/biopsy (+) EASL 20123>2000 EASL 20123>ULNa and biopsy (+) EASL 20123>2000 EASL 20123>ULNa and biopsy (+) APASL 20124≥20,000 APASL 20124≥2x ULNa or biopsy (+) APASL 20124≥2000 APASL 20124>2x ULNa or biopsy (+) aULN for US Treatment Algorithm (2015) and AASLD (2009): 30 U/mL (men) and 19 U/mL (women); ULN for EASL (2012): 40 U/mL; ULN for APASL (2012): dependent on the laboratory reference. AASLD=American Association for the Study of Liver Diseases; APASL=Asian Pacific Association for the Study of the Liver; EASL=European Association for the Study of the Liver; *TE=transient elastography;ULN=upper limit of normal. 1. Lok ASF, McMahon BJ. Hepatology. 2009;50:1-36; 2. Martin P, et al. Clin Gastroenterol Hepatol. 2015;13:2071-2087; 3. EASL. J Hepatol. 2012;57:167-185; 4. Liaw YF, et al. Hepatol Int. 2012;6:531-561. 25

  26. Asian American Treatment AlgorithmIndicators for Monitoring HBeAg− HBeAg+ • ImmuneTolerant • HBV DNAa >2000 IU/mL • ALT ≤ ULNb • Inactive Carrier • HBV DNA ≤2000 IU/mL • ALT ≤ ULNb MONITOR HBeAg− HBeAg+ • Compensated • Cirrhosis • Undetectable HBV DNA • Any ALT level • Compensated • Cirrhosis • Undetectable HBV DNA • Any ALT level aHBV DNA usually 107-1012 copies/mL. bALT normal range is based on local laboratory reference range. Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.

  27. Asian American Treatment AlgorithmIndicators for Treatment HBeAg− HBeAg+ • ChronicHepatitisa • HBV DNA >2000 IU/mL • ALT > ULNb • ChronicHepatitisa • HBV DNA >2000 IU/mL • ALT > ULNb TREAT HBeAg− HBeAg+ • Compensated • Cirrhosisc • Detectable HBV DNA • Any ALT level • Compensated • Cirrhosisc • Detectable HBV DNA • Any ALT level aLiver biopsy grade 1-3 and/or stage 1-3. bALT normal range is based on local laboratory reference range. cPatients with decompensated cirrhosis should be treated regardless of HBV DNA and ALT levels, and immediately referred to a liver transplant center. Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.

  28. Asian American Treatment AlgorithmIndicators for “Gray Zone” Considerations HBeAg− • Chronic Hepatitis • HBV DNA >2000 IU/mL • ALT ≤ ULN HBeAg+ • Chronic Hepatitis • HBV DNA ≤2000 IU/mL • ALT > ULN ASSESS GRAY ZONE CONSIDERATIONS HBeAg− • Chronic Hepatitis • HBV DNA ≤2000 IU/mL • ALT > ULN Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.

  29. Asian American Treatment AlgorithmRisk Assessment for Patients in the “Gray Zone” Total Score <3 ≥3 HBV DNA >2000 IU/mL HBV DNA ≤2000 IU/mL Recommend Treatmentb Monitor aThis scoring system is based on expert opinion and warrants further clinical experience and validation. bPlease see reference for detailed information on first- and second-line antiviral treatment choices. 29 Adapted from Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.

  30. Asian American Treatment AlgorithmOn-TreatmentMonitoring of HBV DNA, ALT, and Serologic Markers • HBV DNA • Every 3 months until undetectable • Every 3-6 months thereafter Monitoring of CHB Patients on Treatment • ALT • Every 3 months until normalization • Every 3-6 months thereafter – • HBeAg • Every 6 months until negative HBeAg+ Anti-HBe + Once sustained suppression of HBV DNA is achieved • HBsAg • Every 12 months HBeAg− Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162. 30

  31. Asian American Treatment AlgorithmWhen to Stop Treatment Stopping Treatment • HBeAg+ • Treat until seroconversion to anti-HBe • Continue with consolidation therapy for at least 1-2 years • After stopping therapy, monitor for relapse • Seroreversion to HBeAg positivity • Reappearance of HBV DNA • ALT elevation • HBeAg− • Continue antiviral treatment for life • If HBsAg becomes negative, then treatment may be stopped • Monitor closely for relapse • Cirrhosis • Continue antiviral treatment for life Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.

  32. Asian American Treatment AlgorithmHCC Surveillance in Asian Americans With CHB • AFP • Abdominal ultrasound Surveillance Tests • Every 6 months Surveillance Interval • High-risk patients • Cirrhosis • HCC in blood relatives • Low- to moderate-risk patientsa • Inactive carriers • Immune tolerant patients • HBsAg+ males <40 years, females <50 years • Patients with HBsAg loss (especially in patients with cirrhosis) Surveillance Candidates aIf clinically active chronic hepatitis, cirrhosis, or other risk factors for HCC are present in these patients. Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.

  33. Summary • In the US, the majority of CHB patients are unaware of their infections1 • The clinical course of CHB consists of the immune tolerant, immune clearance, inactive carrier, reactivation, and resolution phase2 • Not all patients will go through every phase of infection; however, CHB patients are at risk for serious liver disease2,3 • HBV screening is important to identify chronically infected persons who may need treatment and to allow for intervention to reduce transmission to others4 • HBV screening consists of simple blood tests for serologic markers of infection5 • Screening, vaccination, and appropriate management of persons with CHB are important steps to help prevent hepatitis B and its liver complications3 1. Cohen C, et al. J Viral Hepatitis. 2011;18:377-383; 2. Keeffe EB, et al. Clin GastroenterolHepatol. 2008;6:1315-1341; 3. CDC. Morb Mortal Wkly Rep. 2008;57:1-20; 4. Rajbhandari R, Chung RT. Ann Intern Med. 2014;161:76-77; 5. Asian Liver Center. 2013 Physician’s Guide to Hepatitis B. http://liver.stanford.edu/media/publications/Handbook/2013Handbook.pdf. Accessed March 25, 2015.

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