Hepatitis B 1 Chronic Hepatitis B Is a
Hepatitis B 1
Chronic Hepatitis B Is a Global Health Problem HBV infection is the most common chronic viral infection in the world 1 HBs. Ag prevalence ≥ 8% High 2%-7% Intermediate <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. 1. Trepo C, et al. Lancet. 2014; 384; 2053 -2063; 2. WHO. Hepatitis B Fact Sheet. July 2014. www. who. int/mediacentre/factsheets/fs 204/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: e 98 -e 104. 2
Prevalence of CHB in the United States It is estimated that as high as 2 million persons are living with CHB in the United States 1 5% 62. 8% Percentage of foreign-born persons with CHB in the United States who originated from the indicated WHO regions (2001 -2010) 2 13. 5% 14. 1% 4. 6% WHO regions Africa Americas (without US) 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 endemicity 3 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. Kowdley KV, et al. Hepatology. 2012; 56: 422 -433. 3
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, 000 receive 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. 4
Chronic Hepatitis B Can Be Asymptomatic 2 About 2 out of 3 persons with CHB in the United States are unaware of their infection 1 • Persons with CHB can be without symptoms for many years 2 • Unaware of their infection, CHB patients are at risk for transmitting the virus to others and for developing serious liver disease later in life 2 • Identification and management of CHB-infected individuals can help prevent serious sequelae of chronic liver disease 2 1. Cohen C, et al. J Viral Hepat. 2011; 18: 377 -383; 2. CDC. Morb Mortal Wkly Rep. 2008; 57: 1 -20. 5
Virology of HBV Infection • HBV is a partially double-stranded DNA virus which primarily infects liver cells 1 viral envelope – Up to 1011 to 1013 virions/day may be produced in an infected person 2 polymerase • Liver inflammation and fibrosis/cirrhosis are consequences of host’s immune response 1 DNA • The virus can evade the immune system during early phases of infection – Therefore, acute infections are primarily asymptomatic 1 • The genomic template for active viral propagation, ccc. DNA, can persist in infected cells, even after clearance of infection marker 1 Figure adapted from Toronto Centre for Liver Disease. Hepatitis B. www. torontoliver. ca/hepatitis-b/. ccc. DNA=covalently closed circular DNA. 1. Busch K, Thimme R. Med Microbiol Immunol. 2015; 204: 5 -10; 2. Margeridon-Thermet S, Shafer RW. Viruses. 2010; 2: 2696 -2739. 6
Routes of HBV Transmission HBV Carrier Horizontal transmission 1 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 CHB 1 Child Up to 90% of infants born to HBe. Agpositive mothers develop CHB 2 HBe. Ag=hepatitis B e antigen. 1. CDC. Morb Mortal Wkly Rep. 2008; 57: 1 -20. 2. Buchanan C, Tran TT. Clin Liver Dis. 2010; 14: 495 -504. 7
Progression and Complications of CHB 0. 1%-3%1 HCC 10%-17%1 Acute Infection Chronic Infectiona 8%-38%1 Cirrhosis Liver Transplantation Death 15%1 Liver Failure (Decompensation) Figure adapted from Fattovich G, et al. In: Marcellin P, (ed. ) Management of Patients With Viral Hepatitis. Paris: APMAHV; 2004. 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. 70%-85%1 a. Chronic 1. Fattovich G, et al. J Hepatol. 2008; 48: 335 -352; 2. CDC. Morb Mortal Wkly Rep. 2008; 57: 1 -20. 8
Risk Factors Associated With CHB Disease Progression in Asian Patients HCC Development Non-HCC Liver Deaths • Increased ALT 1 • Reduced albumin 1, 2 • Reduced platelets • Ascites 1 • Encephalopathy 1 1, 2 • • Older age Male sex 3, 4 Cirrhosis 2 Increased HBV DNA 3, 4 • HBe. Ag status 1 3 • High level of HBs. Ag 5 • HBV genotype C/D 5 • Precore mutation 3 • Basal core promoter mutation 3 • Increased AFP 1 • Decreased baseline ALT 1 • Family history of HCC 6 • Alcohol consumption 4 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
HBV Disease Progression Chronic HBV Infection 1 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 • • >40 years of age 2 Male gender 2 Family history of HCC 2, 3 African or Asian race 2, 3 Viral / disease factors • • High HBV DNA level 2 • • Genotype C or D 2, 5 High HBs. Ag level 4 Prolonged time to HBe. Ag seroconversion 2 Development of HBe. Ag– CHB 2 BCP mutations 4, 5 Environmental factors • Coinfection with HCV, HDV, or HIV 2 • Alcohol consumption 2 • Cigarette smoking 2 • Aflatoxin 2 • Obesity and/or diabetes 2 Elevated ALT 2 Presence of fibrosis 4 or cirrhosis 2 ALT=alanine aminotransferase; BCP=basal core promoter; HBe. Ag=hepatitis B e antigen; HCV=hepatitis C virus; HDV=hepatitis D virus; HIV=human immunodeficiency virus. 1. 2. 3. 4. 5. 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: a 024935. Martin P, et al. Clin Gastroenterol Hepatol. 2015; 13: 2071 -2087. 10
Higher HBV DNA Levels Are Associated With Increased Risk of Cirrhosis and HCC Over Time (REVEAL Study) Previously Untreated Patients With CHB k is R Copies/m. L 1 <300 300 -9999 10, 00099, 999 100, 000 - ≥ 1 million 999, 999 IU/m. L 3, c <60 60 -<2000<20, 000 - ≥ 200, 000 <200, 000 C H C of N=3653 k C f o h ri r is N=3582 R s i os HCC 2 Crude Hazard Ratiob for HCC Adjusted Relative Riska of Cirrhosis 1 Copies/m. L 2 <300 300 -9999 10, 00099, 999 100, 000 - ≥ 1 million 999, 999 IU/m. L 3, c <60 60 -<2000<20, 000 - ≥ 200, 000 <200, 000 Viral Load a. Adjusted for age, sex, cigarette smoking, and alcohol consumption. HBV DNA level is a strong risk predictor of HCC, independent of HBe. Ag, ALT level, and liver cirrhosis; relative risk of an endpoint at any given time. c 1 IU/m. L is equivalent to 5 -6 copies/m. L. b. Elevated 1. Iloeje UH, et al. Gastroenterology. 2006; 130: 678 -686. 2. Chen CJ, et al. JAMA. 2006; 295: 65 -73. 3. Martin P, et al. Clin Gastroenterol Hepatol. 2015; 13: 2071 -2087. 11
Serologic Markers of HBV Infection HBs. Ag Hepatitis B Virus • Hallmark of • Major tool for screening and diagnosis of CHB 2 (if present ≥ 6 months 3) infection 1 HBV DNA • Measure of viral load; indicates ongoing viral replication 1 • Correlates with infectivity 4 and risk of major liver disease 2 Anti-HBs • Antibody to HBs. Ag 4 • Marker of immunity to HBV 4 • Only detectable marker of successful immunization 4 Anti-HBc HBe. Ag • Marker of risk of transmission of infection 4 • Antibody to HBV core antigen 4 • Marker of prior exposure 4 − Ig. M anti-HBc is a marker of recent infection 4 anti-HBs=antibody to HBs. Ag; anti-HBc=antibody to hepatitis B core antigen; Ig. M=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. 12
Serologic Profiles of Progression from Acute Infection to CHB Progression from acute infection to chronic hepatitis B Acute (6 months) Chronic (years) HBe. Ag Titer HBs. Ag anti-HBe Total anti-HBc Ig. M anti-HBc 0 4 8 12 16 20 24 28 32 36 52 Years Weeks after exposure • Antigens and antibodies associated with HBV infection include HBs. Ag, anti-HBs, anti-HBc, HBe. Ag, and anti-HBe • Serologic assays are available to test for these markers CDC. Morb Mortal Wkly Rep. 2008; 57; 1 -20. 13
Course of HBV Infection HBs. Ag+ HBe. Ag+ HBs. Ag− 2 million have CHB Anti-HBe+ HBV DNA ALT Immune Tolerant Immune Activation Minimal Inflammation Active Inflammation Figure adapted from Tong MJ, et al. 1 50, 000 receive Low Replicative treatment Mild Inflammation Reactivation Remission Active Inflammation Inactive PC/BCP Mutation Reactivation CHB follows a variable clinical course – not all patients will go through each phase (including remission) 2 Wild-type Reactivation ALT=alanine aminotransferase; anti-HBe=antibody to HBe. Ag; HBe. Ag=hepatitis B e antigen; HBs. Ag=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. 14
Immune Tolerant: High HBV DNA Levels at the Onset of CHB HBs. Ag+ HBe. Ag HBs. Ag– Anti-HBe HBV DNA ALT Immune tolerant Immune clearance Inactive carrier Reactivation Resolution • Often seen in perinatally infected children; may last for several decades 1 – In infection acquired during childhood or in adult, the phase is short or absent 2 • Very high serum HBV DNA levels and HBe. Ag positivity with very low rate of HBe. Ag seroclearance 1, 3 • Normal ALT levels with minimal or absence of inflammation or fibrosis 1 – A recent retrospective study showed that, despite having normal ALT, a substantial number of HBe. Ag+ Asian/Chinese patients had significant fibrosis 4 • As older age may predict adverse outcomes, it is important to monitor older immune tolerant patients who show minimally or intermittently elevated ALT 1 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 Harb Perspect Med. 2014; 4: a 024935; 4. Liao B, et al. PLo. S ONE. 8: e 78672. 15
Immune Clearance: Fluctuating HBV DNA Levels With Active Liver Damage HBs. Ag+ HBs. Ag– HBe. Ag Anti-HBe HBV DNA ALT Immune tolerant Immune clearance Inactive carrier Reactivation Resolution • Intermittent or persistent elevation of ALT levels and high HBV DNA levels 1 • Typically occurs during the 2 nd and 3 rd decades of life; may last for years, leading to progressive liver damage 2 – Presence of necroinflammation on liver biopsy and varying degrees of fibrosis are the result of immune-mediated liver damage 1 • HBe. Ag seroconversion is a serologic marker of the end of the immune clearance phase 2 – 10%-20% of patients will have annual spontaneous HBe. Ag seroconversion • Patients with active liver disease in the immune clearance phase are potential candidates for treatment 2 -4 1. Croagh CMN, Lubel JS. World J Gastroenterol. 2014; 20: 10395 -10404; 2. Burns GS, Thompson AJ. Cold Spring Harb Perspect Med. 2014; 4: a 024935; 3. Lok ASF, Mc. Mahon BJ. Hepatology. 2009; 50: 1 -36; 4. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008; 6: 1315 -1341. 16
Inactive Carrier: Low HBV DNA Levels with Minimal Liver Damage HBs. Ag+ HBs. Ag– HBe. Ag Anti-HBe HBV DNA ALT Immune tolerant Immune clearance Inactive carrier Reactivation Resolution • Characterized by HBe. Ag seroconversion, suppression of HBV DNA (low or undetectable), and normalization of ALT 1 • Usually mild hepatitis and minimal fibrosis, but more severe liver damage, including cirrhosis, may have already accumulated from the preceding immune clearance phase 2 • 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 HCC 2 • 20%-30% of patients will experience reactivation after HBe. Ag seroconversion 3 1. Croagh CMN, 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. 17
Reactivation and Resolution: Reactivation of Viral Replication and Resolving Infection HBs. Ag+ HBs. Ag– HBe. Ag Anti-HBe HBV DNA ALT Immune tolerant Immune clearance Inactive carrier Reactivation Resolution • Reactivation may occur spontaneously or due to immunosuppression 1, 2 • Patients with reactivation of HBV replication are usually older, with more advanced liver disease 2 – Those with active disease have increased risk of liver cirrhosis and HCC 1 • Treatment is recommended for HBe. Ag-negative CHB patients who experience HBV reactivation 3, 4 • HBs. Ag 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 B 5, 6 – Some patients may still have detectable HBV DNA in serum and are vulnerable to reactivation 5 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, Mc. Mahon 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: 1039518 10404; 6. Burns GS, Thompson AJ. Cold Spring Harb Prespect Med. 2014; 4: a 024935.
HBV Infection Can Be Prevented Screen for HBV Infection Involves simple blood tests for serologic markers of infection 1 Identify CHB-infected patients 1, 2 Identify unprotected patients for HBV vaccination 1, 2 • Counsel to prevent transmission of infection to others • Provide appropriate medical management • Hepatitis B vaccination is the most effective measure to help prevent HBV infection and its consequences 3 • It is important to screen for HBV infection before vaccination 1 1. Asian Liver Center. 2013 Physician’s Guide to Hepatitis B. http: //liver. stanford. edu/media/publications/Handbook/2013 Handbook. 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. 19
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 infection 1 -3 • All pregnant women 2 -4 • Men who have sex with men 1 -3 • Injection drug users 1 -3 • Individuals infected with human immunodeficiency virus (HIV)1 -3 • People with certain medical conditions 2, 3, 5 – Needing immunosuppressive therapy – Undergoing hemodialysis AASLD=American Association for the Study of Liver Diseases. For a complete list of screening recommendations, please see: 1. Le. Fevre ML; USPSTF. Ann Intern Med. 2014; 161: 58 -66. CDC=Centers for Disease Control and Prevention. 2. CDC. Morb Mortal Wkly Rep. 2008; 57: 1 -20. USPSTF=United States Preventative Services Task Force. 3. Lok ASF, Mc. Mahon BJ. Hepatology. 2009; 50(3): 1 -36. 4. USPSTF. Ann Intern Med. 2009; 150: 869 -873. 5. USPSTF. Consumer Fact Sheet. May 2014. http: //www. uspreventiveservicestaskforce. org/uspstf/uspshepb. htm. Accessed March 25, 2015. 20
HBV Screening Tests Screening tests for virologic markers of HBV infection include HBs. Ag, anti-HBs, and anti-HBc 1, 2 Screening Tests 1, 2 Recommended Follow-up HBs. Ag Anti-HBs Anti-HBca Interpretation + − + Acute or chronic infectionb Contact patient for evaluation and further testing − − − + + − − Patient has immunity from previous infection Follow up as appropriatec, d Patient has immunity from vaccination No further action required Patient is at-risk for HBV infection Vaccinate a. Anti-HBc refers to total anti-HBc. 2 is chronically infected if HBs. Ag+ for ≥ 6 months. 3 c. Patients who are anti-HBc positive should be monitored closely during and after the administration of cytotoxic chemotherapy for signs of HBV reactivation. 1 d. Patients with cirrhosis may need to be monitored for hepatocellular carcinoma per the AASLD guidelines. 4 b. Patient 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/HCCUpdate 2010. pdf. Accessed March 25, 2015. 21
HBV Vaccination Populations recommended for HBV vaccination by the CDC 1 • 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 months 2 • A full 3 -dose vaccine series is associated with immunity in >90% of healthy adults 2 First dose (0 month) Second dose (1 month) 75% 30%-55% with protective immunity a. Infants Third dose (6 months) 1 month with protective immunity >90% 5 months with protective immunity born to HBs. Ag-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-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. 22
Significant Disparity Between Self-Reported Vaccination and Actual Immunity A recent study showed significant disparity between self-reported vaccination and actual immunity 1 0. 4% Other 2% Infected 60. 4% Immune due to vaccination 26. 3% • History of vaccination has been cited as one of the main reasons for not ordering screening 2, a Immune due to natural infection • Vaccination is not beneficial for already infected or immune (resolved acute infection) persons 3 10. 8% • HBV screening is important to avoid false perception of protection 1 and unnecessary vaccination 3 Susceptible Serological diagnoses of 240 self-declared vaccinated Korean adults 1 a. Data 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/2013 Handbook. pdf. Accessed March 25, 2015. 23
Medical Management of CHB Initial evaluation of patients should include a thorough history and physical examination, followed by laboratory tests 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) • Screen for HCC in high-risk patients • HBe. Ag and anti-HBe • Liver biopsya • Liver function tests • Urinalysis • Tests for antibodies to HAV, HCV, HDV, and HIV • HBV genotype a. Noninvasive 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 HAV= hepatitis A virus; HCV=hepatitis C virus; HDV=hepatitis D virus. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008; 6: 1315 -1341. 24
Existing CHB Guidelines and Algorithms Overview HBe. Ag+ HBe. Ag− HBV DNA (IU/m. L) ALT (U/L) AASLD 20091 >20, 000 AASLD 20091 >2 x ULNa or biopsy (+) AASLD 20091 >20, 000 or >2000 if biopsy (+) AASLD 20091 >2 x ULNa or biopsy (+) US Treatment Algorithm 20152 ≥ 2000 US Treatment Algorithm 20152 >ULNa or TE*/biopsy (+) EASL 20123 >2000 EASL 20123 >ULNa and biopsy (+) APASL 20124 ≥ 20, 000 APASL 20124 ≥ 2 x ULNa or biopsy (+) APASL 20124 ≥ 2000 APASL 20124 >2 x ULNa or biopsy (+) a. ULN for US Treatment Algorithm (2015) and AASLD (2009): 30 U/m. L (men) and 19 U/m. L (women); ULN for EASL (2012): 40 U/m. L; 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, Mc. Mahon 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
Asian American Treatment Algorithm Indicators for Monitoring HBe. Ag− HBe. Ag+ Immune Tolerant Inactive Carrier • HBV DNAa >2000 IU/m. L • ALT ≤ ULNb • HBV DNA ≤ 2000 IU/m. L • ALT ≤ ULNb MONITOR HBe. Ag+ HBe. Ag− Compensated Cirrhosis • Undetectable HBV DNA • Any ALT level a. HBV DNA usually 107 -1012 copies/m. L. b. ALT normal range is based on local laboratory reference range. Tong MJ, et al. Dig Dis Sci. 2011; 56: 3143 -3162. 26
Asian American Treatment Algorithm Indicators for Treatment HBe. Ag+ HBe. Ag− Chronic Hepatitisa • HBV DNA >2000 IU/m. L • ALT > ULNb TREAT HBe. Ag− HBe. Ag+ Compensated Cirrhosisc • Detectable HBV DNA • Any ALT level a. Liver biopsy grade 1 -3 and/or stage 1 -3. normal range is based on local laboratory reference range. c. Patients with decompensated cirrhosis should be treated regardless of HBV DNA and ALT levels, and immediately referred to a liver transplant center. b. ALT Tong MJ, et al. Dig Dis Sci. 2011; 56: 3143 -3162. 27
Asian American Treatment Algorithm Indicators for “Gray Zone” Considerations HBe. Ag− Chronic Hepatitis • HBV DNA >2000 IU/m. L • ALT ≤ ULN HBe. Ag+ Chronic Hepatitis • HBV DNA ≤ 2000 IU/m. L • ALT > ULN ASSESS GRAY ZONE CONSIDERATIONS HBe. Ag− Chronic Hepatitis • HBV DNA ≤ 2000 IU/m. L • ALT > ULN Tong MJ, et al. Dig Dis Sci. 2011; 56: 3143 -3162. 28
Asian American Treatment Algorithm Risk Assessment for Patients in the “Gray Zone” Total Score Conduct liver biopsy if possible. If not, calculate Risk Impact Scorea Risk Factors Impact Score Age ≥ 40 yr 1 Male gender 1 Male ALT >30 U/L or Female ALT >19 U/L 1 Basal core promoter mutation 2 HCC in first-degree relative 3 Albumin ≤ 3. 5 g/d. L or Platelets ≤ 130, 000 mm 3 3 Total Score a. This ____ points <3 ≥ 3 HBV DNA >2000 IU/m. L Recommend Treatmentb HBV DNA ≤ 2000 IU/m. L Monitor scoring system is based on expert opinion and warrants further clinical experience and validation. see reference for detailed information on first- and second-line antiviral treatment choices. b. Please Adapted from Tong MJ, et al. Dig Dis Sci. 2011; 56: 3143 -3162. 29
Asian American Treatment Algorithm On-Treatment Monitoring 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 HBe. Ag+ HBe. Ag− HBe. Ag Every 6 months until negative Once sustained suppression of HBV DNA is achieved – Anti-HBe + HBs. Ag Every 12 months Tong MJ, et al. Dig Dis Sci. 2011; 56: 3143 -3162. 30
Asian American Treatment Algorithm When to Stop Treatment Stopping Treatment HBe. Ag+ HBe. Ag− Cirrhosis • Treat until seroconversion to anti. HBe • Continue antiviral treatment for life • Continue with consolidation therapy for at least 1 -2 years • If HBs. Ag becomes negative, then treatment may be stopped • After stopping therapy, monitor for relapse − − − Seroreversion to HBe. Ag positivity Reappearance of HBV DNA ALT elevation − Monitor closely for relapse Tong MJ, et al. Dig Dis Sci. 2011; 56: 3143 -3162. 31
Asian American Treatment Algorithm HCC Surveillance in Asian Americans With CHB Surveillance Tests • AFP • Abdominal ultrasound Surveillance Interval • Every 6 months • High-risk patients − Cirrhosis − HCC in blood relatives Surveillance Candidates a. If • Low- to moderate-risk patientsa − − Inactive carriers Immune tolerant patients HBs. Ag+ males <40 years, females <50 years Patients with HBs. Ag loss (especially in patients with cirrhosis) 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. 32
Summary • In the US, the majority of CHB patients are unaware of their infections 1 • The clinical course of CHB consists of the immune tolerant, immune clearance, inactive carrier, reactivation, and resolution phase 2 ─ Not all patients will go through every phase of infection; however, CHB patients are at risk for serious liver disease 2, 3 • HBV screening is important to identify chronically infected persons who may need treatment and to allow for intervention to reduce transmission to others 4 – HBV screening consists of simple blood tests for serologic markers of infection 5 • Screening, vaccination, and appropriate management of persons with CHB are important steps to help prevent hepatitis B and its liver complications 3 1. Cohen C, et al. J Viral Hepatitis. 2011; 18: 377 -383; 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 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/2013 Handbook. pdf. Accessed March 25, 2015. 33
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