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Optimal Management of HBV: A Partnership Between Primary Care and Specialty Physicians

Optimal Management of HBV: A Partnership Between Primary Care and Specialty Physicians. Primary Care Specialist Screening Diagnostic testing Identification of treatment candidates Initiation of treatment On-treatment monitoring Long-term follow-up for

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Optimal Management of HBV: A Partnership Between Primary Care and Specialty Physicians

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  1. Optimal Management of HBV: A Partnership Between Primary Care and Specialty Physicians

  2. Primary Care Specialist Screening Diagnostic testing Identification of treatment candidates Initiation of treatment On-treatment monitoring Long-term follow-up for disease activation HCC screening Vaccination

  3. Hepatitis B: An Important Disease for Primary Care and Specialty Physicians

  4. Why Is HBV Relevant in Primary Care? • High global impact • High prevalence in specific risk groups • Risk of death/cancer • Effective prevention • Effective treatment • Improve liver disease outcomes • Decrease progression to cirrhosis or HCC and improve survival

  5. Global Impact of HBVA Significant Cause of Worldwide Morbidity and Mortality • >2 billion have been infected1 • 4 million acute cases per year1 • 1 million deaths per year1 • 350 million chronic carriers1 • 25% of carriers die from chronic active hepatitis, cirrhosis, or liver cancer1 • Nearly 75% of chronic carriers are Asian2 • 2nd most important carcinogen behind tobacco3 • Causes 60%–80% of all primary liver cancer1 • HBV is 100 times more contagious than HIV4 1. WHO. Hepatitis B. 2002. 2. Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc. 1988. 3. CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink Book.” 8th ed. 4. CDC. MMWR. 2001;50:RR-11.

  6. HBVA Global Health Problem HBsAg Prevalence (%)1 <8: High 2–8: Intermediate <2: Low 1. WHO. Hepatitis B. 2002. 2. Custer B. et al. J Clin Gastroenterol. 2004;38(10 suppl):S158. 3. WHO/WPRO data.

  7. HBV Disease Progression Liver Cancer (HCC) Death Liver Transplantation Chronic Infection Cirrhosis Liver Failure Torresi J, et al. Gastroenterology. 2000;118:S83. Fattovich G, et al. Hepatology. 1995;21:77. Perrillo RP, et al. Hepatology. 2001;33:424.

  8. Burden of HBV Infection in the United States 73,000 1,250,000 New Acute Infections per Year1 Chronic Infections1 5000 3100 230 Deaths per Year1 HCC per Year2 Liver Transplants per Year3 1. CDC. HBV Disease Burden. 2005. 2. El-Serag HB, et al. Arch Intern Med. 2000;160:3227. 3. UNOS/OPTN.

  9. Poor Survival inHBV-Related Cirrhosis 100 80 Cirrhosis1(n = 130) 60 55% Patients Surviving (%) 40 Decompensated Cirrhosis2 (n = 21) 20 14% 0 0 1 2 3 4 5 Years 1. Weissberg JI, et al. Ann Intern Med. 1984;101:613. 2. De Jongh FE, et al. Gastroenterology. 1992;103:1630.

  10. HBV Is Preventable

  11. Clinical-Epidemiologic Correlations Age of Mode of ESLD HCC Endemicity Location Infection Transmission Chronicity Risk Risk Low N. America Early Percutaneous Rare Low Low W. Europe Adulthood Sexual High Sub-Sahara Birth Perinatal Likely High High Far East Toddler Horizontal

  12. HBV VaccineIndications • Routine vaccination of infants • Regardless of mother’s HBsAg status • With HBIG for HBsAg positive mothers • Catch-up vaccination of children and adolescents • Vaccination of adults with risk factors for infection • High-risk sexual activity • Illegal injection drug use • Occupational exposure • Hemodialysis patients • Household contacts of infected persons HBIG = hepatitis B immune globulin. CDC. MMWR. 1991;40(RR-13):1.

  13. US Incidence of Viral Hepatitis Infection Over Time Incidence of Hepatitis A, US 180 Incidence of Acute Hepatitis B, US Incidence of Acute Hepatitis C, US 160 140 Estimated Number of Cases (Thousands) 120 100 80 60 40 20 0 1990 1992 1994 1996 1998 2000 2002 1991 1993 1995 1997 1999 2001 2003 Year CDC. Disease burden from viral hepatitis A, B, and C in the United States. 2003.

  14. HBV VaccinationEffect on HCC Incidence and Mortality* Incidence Mortality 1 1 0.80 0.8 0.8 0.70 Per 100,000 Children (6–14 Years) 0.58 0.57 Per 100,000 Children(6–14 Years) 0.6 0.6 0.36 0.34 0.4 0.4 0.2 0.2 0 0 1981–86 1986–90 1990–94 1981–86 1986–90 1990–94 *Nationwide vaccination in Taiwan, implemented 7/84 Chang M-H, et al. N Engl J Med. 1997;336:1855.

  15. Screening for HBV and Evaluating Infected Patients

  16. Who Should Be Screened? • Patients with abnormal ALT • Patients engaged in high-risk sexual behaviors • Injection drug users • Immigrants, refugees, or adoptees from areas of high endemicity • Immunocompromised patients • Dialysis patients • Recipients of organ/tissue transplants or blood transfusion • Household members or sexual partners of known HBV carriers • Occupational exposure (healthcare workers, police, EMTs) • Inmates in long-term correctional facilities or residents in institutions for the developmentally disabled • Pregnant women • Individuals infected with HCV or HIV Adapted from CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink Book.” 8th ed, 2005. Lok ASF, et al. Hepatology. 2001;34:1225.

  17. Prevalence of HBV Serologic Markers in Population Groups Who Should Be Tested for HBV Infection Prevalence of HBV Serologic Markers (%) Population HBsAg Any Marker Persons born in high endemic areas* 13 70–85 Men who have sex with men 6 35–80 Injection drug users 7 60–80 Dialysis patients 3–10 20–80 HIV infected patients 8–11 89–90 Pregnant females (USA) 0.4–1.5 Family/household and sexual contacts 3–6 30–60 *Africa; Southeast Asia, including China, Korea, Indonesia, and the Philippines; the Middle East, except Israel; South and Western Pacific Islands; the interior Amazon River basin; and certain parts of the Caribbean (Haiti and the Dominican Republic) Lok ASF, et al. Hepatology. 2001;34:1225. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

  18. Screening Tests • HBsAg • If positive, indicates infection • Anti-HBc • If positive, indicates HBV exposure • Anti-HBs • If positive, indicates immunity

  19. History and Physical Evaluation • Risk factors for coinfection • Alcohol use • Family history of HBV infection and HCC • Physical findings of advanced disease • Jaundice • Abdominal swelling • Upper GI bleeding Lok ASF, et al. Hepatology. 2001;34:1225. Tsai NCS, et al. Semin Liver Dis. 2004;24(suppl 1):71.

  20. Assessment ofLiver Disease Severity • Liver disease activity, biochemical • ALT • AST • Liver function/synthetic testing • Albumin • Bilirubin • Prothrombin time (INR) • Ultrasonography: morphologic assessment • Liver size, contour, and echogenicity • Splenomegaly Lok ASF, et al. Hepatology 2001;34:1225. Tsai NCS, et al. Semin Liver Dis. 2004;24(suppl 1):71. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87.

  21. 2nd-Phase Testing in HBsAg+ Patients • Anti-HBc • IgG: if positive, indicates HBV exposure • IgM: if positive, indicates acute HBV • HBeAg • If positive, indicates active HBV replication • If negative • If HBV DNA negative, suggests HBV replication is suppressed • If HBV DNA positive, most likely has precore mutation • Anti-HBe • HBV DNA quantification • Quantitative level correlates with level of HBV replication

  22. Further Testing for HBsAg+ Patients • HCV antibody in at-risk individuals • HIV antibody or RNA quantification in at-risk individuals • Consider screening for hepatitis delta virus (HDV) if adult-acquired HBV • Anti-HDV • Delta antigen • Delta RNA if any HDV testing is available

  23. Hepatitis Delta Virus (HDV) Clinical Scenario Outcome Acute HDV/acute HBV  Risk of acute liver disease Acute HDV/chronic HBV  Risk of progressive liver disease Chronic HDV/chronic HBV  Risk of cirrhosis and cancer

  24. Who Are Treatment Candidates?

  25. Natural History of HBV Infection Immune Tolerance Early Childhood >95% Adulthood <5% HBeAg- Chronic Hepatitis B HBeAg+ Chronic Hepatitis B Cirrhosis Inactive Carrier Courtesy of W. Ray Kim, MD Chen DS, et al . J. Gastroenterol Hep. 1993:8(5):470.Seeff L, et al. N Engl J Med. 1987;316(16):965.

  26. Phases of Chronic HBV Infection Immune Inactive HBeAg HBeAg Tolerant HBsAg Positive Negative Phase Carrier CHB CHB* HBsAg + + + + HBeAg + – + – Anti-HBe – + – + ALT Normal Normal  HBV DNA >105 >104 <105 >104† copies/mL copies/mL copies/mL copies/mL Histology Normal/Mild Inactive Active Active *Precore mutant †Expert opinions vary as to this value 1IU = ~5 copies/mL Lai CL, et al. Lancet. 2003:362:2089. Lok AS, et al. Gastroenterology. 2001;120:1828.

  27. HBV Disease Progression Liver Cancer (HCC) 5%–10%1 6% in 5 yr2 Liver Transplantation Death Chronic Infection 30%1 Cirrhosis 23% in 5 yr2 Acute Flare Liver Failure Chronic HBV is the 6th leading indication of liver transplantation in the US3~5% • Torresi J, et al. Gastroenterology. 2000;118:S83. 2. Fattovich G, et al. Hepatology. 1995;21:77. • 3. Perrillo RP, et al. Hepatology. 2001;33:424.

  28. HBeAg Negative Patients • HBeAg positive patients may develop antibodies (anti-HBe) • When HBeAg is lost, 2 possible scenarios • Inactive carrier (normal ALT, low or negative HBV DNA level) • Precore mutant chronic HBV (moderate to high HBV DNA, elevated ALT)

  29. Inactive Carriers • HBeAg negative, normal ALT, low/negative HBV DNA • “Healthy carriers” = oxymoron • All patients who are HBsAg positive need ongoing monitoring as part of management • Monitor for increased ALT or HBV DNA every 6 months • Monitor for HCC in at-risk groups Sherman M. Semin Liver Dis. 2005;25:143.

  30. Precore Mutant (HBeAg Negative) Chronic HBV • HBeAg negative, elevated ALT, moderate to high HBV DNA • Usually result of mutation in precore or basal core promoter regions of HBV • Potentially more severe and progressive chronic disease • Longer, more aggressive (suppression of HBV DNA) treatment needed • 29% risk of adefovir resistance at 5 years of therapy1 • Seen predominantly in genotypes B,C, and D 1. Borroto-Esoda K, et al. J Hepatol. 2006;44(Suppl 2):179.

  31. HBV DNA and Prognosis High viral load predicts • Progression of liver disease1 • Cirrhosis1 • Cirrhosis-related complications2 • HCC1,3 • Independent of HBeAg, ALT, and cirrhosis3 1. Chen G, et al. Abstract 996. Presented at: AASLD 2004. 2. Yuan JH, et al. J Viral Hepat. 2005;12:373. 3. Chen C-J, et al. JAMA. 2006;295:65.

  32. Baseline HBV DNA Level and Cumulative Incidence of HCCEntire Cohort 16 14.89 14 12.17 12 N = 3653, 13-year follow-up 10 Cumulative Incidence of HCC (%) 8 6 3.57 4 1.37 1.3 2 0 300–<104 104–<105 105–<106 ≥106 <300 HBV DNA (Copies/mL) 1IU = ~5 copies/mL Chen C-J, et al. JAMA. 2006;295:65.

  33. Baseline HBV DNA Level and Cumulative Incidence of HCCSubgroup of Noncirrhotic HBeAg– Patients with Normal ALT 16 13.50 14 12 N = 2925 10 Cumulative Incidence of HCC (%) 7.96 8 6 4 3.15 0.89 2 0.74 0 300–<104 104–<105 105–<106 ≥106 <300 HBV DNA (Copies/mL) Chen C-J, et al. JAMA. 2006;295:65.

  34. Baseline HBV DNA Level and Relative Risk of Cirrhosis Adjusted for gender, age, smoking, alcohol consumption 9.8 10 N = 3582, 11-year follow-up 9 8 7 5.9 6 Relative Risk 5 4 2.5 3 1.4 2 1 1 0 300–9.9x103 1.0–9.9x104 1.0–9.9x105 >105 <300 HBV DNA (Copies/mL) Iloeje UH, et al, Gastroenterology. 2006;130:678.

  35. HBV DNA and Prognosis Caveat Low HBV DNA does not rule out risk • In HBeAg positive patients, HBV DNA 20,000 IU (<105 copies/mL) predicted better histology • But 14.3% of patients withHBV DNA 20,000 IU (<105 copies/mL) still had fibrosis1 • In patients with cirrhosis, viral load was the best predictor of complications • But even with HBV DNA 20,000 IU (<104 copies/mL) complications continued to develop2 1. Yuen MF, et al. Am J Gastroenterol. 2004;99:2031. 2. Yuan HJ, et al. J Viral Hepat. 2005;12:373.

  36. Candidacy for anti-HBV TreatmentPrinciple In general, a patient with chronic HBV is a treatment candidate if there is evidence of • Liver disease (abnormal ALT) and • HBV replication (HBV DNA+)

  37. When Do You Initiate anti-HBV Therapy? • Parameters • HBV DNA levels >104-5 copies/mL • ALT levels >1–2 x ULN • Factors • HBeAg positive vs HBeAg negative • Cirrhosis vs no cirrhosis • Compensated vs decompensated disease

  38. Which Patients Should Be Treated?AASLD Guidelines1 HBV DNA HBeAg (Copies/mL) ALT Management + >105 ≤2 x ULN Follow + >105 >2 x ULN Treat – >105 >2 x ULN Treat – – ≤2 x ULN Follow +/– >105 Cirrhosis If compensated, treat; if decompensated*, refer for liver transplant +/– – Cirrhosis If compensated, observe; if decompensated*, refer for liver transplant *Do not use interferon or peginterferon if the patient has decompensated cirrhosis.2,3 Specific treatment recommendations are made elsewhere in this activity. 1. Lok ASF, et al. Hepatology. 2004;39:857. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. 2. INTRON® A (interferon alfa-2b) Product Information. Kenllworth, NJ: Schering Corporation: 2004. 3. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004.

  39. US Treatment Algorithm UpdateHBeAg Positive Compensated Disease HBeAg Positive HBV DNA <105 c/mL HBV DNA ≥105 c/mL ALT Normal ALT Elevated • No treatment • Monitor every 6–12 mo • Monitor every 3–12 mo (immune tolerant) • Consider biopsy, if age >35–40 y, and treat if significant disease Treat Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

  40. US Treatment Algorithm UpdateHBeAg Negative Compensated Disease HBeAg Negative HBV DNA <104 c/mL HBV DNA ≥104 c/mL ALT Normal ALT Elevated • No treatment • Monitor every 6–12 mo • Monitor ALT, or • Consider biopsy, since ALT often fluctuates, and treat if significant disease • Long-term treatment required • Treat • Long-termtreatment required Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

  41. US Treatment Algorithm UpdateCompensated Cirrhosis HBV DNA (PCR) HBV DNA ≥104 c/mL HBV DNA <104 c/mL May Choose to Treat or Observe Treat Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

  42. US Treatment Algorithm UpdateDecompensated Cirrhosis HBV DNA Detectable by PCR? No Yes • Observe • Wait list for transplant • Treat • Wait list for transplant Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

  43. Who May Not Need Referral to a Specialist? Noncirrhotic patients with persistently normal ALT • Inactive carrier • HBeAg negative • DNA <104 • Persistently normal ALT • Immune tolerant • HBeAg positive • Persistently normal ALT

  44. Who Is Likely to Benefit from Referral to a Specialist? • HBeAg positive chronic hepatitis B • Abnormal ALT • DNA >105 • HBeAg negative chronic hepatitis B • Abnormal ALT • HBV DNA may be variable • Cirrhosis • Regardless of HBeAg, DNA or ALT status

  45. Management of Chronic HBV Infection ALT <17–25* U/L ALT >17–25* U/L DNA<2000 IU/mL Observe† Biopsy‡<10,0000 c/mL DNA >2000 IU/mL Biopsy Treat:>10,000 c/mL and treat if eAg (+): >6 mo post Ag seroC active HBV eAg (–): prolonged Rx (at least 24 mo) beyond NAT negative§ (Consider biopsy or use noninvasive testing to stage disease) *Upper limits of normal for a person with normal BMI, 17 for women and 25 for men;†Treat any patient with cirrhosis who is NAT positive, refer to specialist; ‡Rule out fatty liver and other causes of CLD; §Consider 3–5 years. NAT = nucleic acid testing, such as PCR, bDNA or TMA. Reprinted from Gish R. Clin Liver Dis. 2005;9:541, with permission from Elsevier.

  46. Monitoring for Patients Not Considered for Treatment • Check ALT every 3–6 months • If ALT is persistently elevated, reevaluate for treatment • HCC surveillance in relevant population Lok ASF, et al. Hepatology. 2001;34:1225. Lok ASF, et al. Hepatology. 2004;39:857.

  47. HCC Surveillance Is Recommended for the Following Groups of Patients (Level III) Hepatitis B Carriers Asian males ≥40 years Asian females ≥50 years All cirrhotic hepatitis B carriers Family history of HCC Africans over age 20 For noncirrhotic hepatitis B carriers not listed above, the risk of HCC varies depending on the severity of the underlying liver disease and current and past hepatic inflammatory activity. Patients with high HBV DNA concentrations and those with ongoing hepatic inflammatory activity remain at risk for HCC. Nonhepatitis B Cirrhosis Hepatitis C Alcoholic cirrhosis Genetic hemochromatosis Primary biliary cirrhosis Although the following groups have an increased risk of HCC, no recommendations for or against surveillance can be made because a lack of data precludes an assessment of whether surveillance would be beneficial. Alpha1-antitrypsin deficiency Nonalcoholic steatohepatitis Autoimmune hepatitis Bruix J, Sherman M. Hepatology. 2005;42:1208. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.

  48. Counseling of HBV-Infected Patients • Limit use of alcohol1-3 • Prevent transmission1,4 • Screen and vaccinate sexual and household contacts1,4 • Vaccinate against hepatitis A1 1. Lok ASF, et al. Hepatology. 2001;34:1225. 2. Chevillotte G, et al. Gastroenterology. 1983;85:141. 3. Villa E, et al. Lancet. 1982;2:1243. 4. CDC. “The Pink Book.” 8th ed, 2005.

  49. Treatment of Hepatitis B

  50. Primary Goal of anti-HBV Therapy Preventing Cirrhosis, HCC, and Death Durable Suppressionof HBV Replication

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