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Best Primary Care Practices for Hepatitis B Infection: Focus on Therapeutic Strategies

Best Primary Care Practices for Hepatitis B Infection: Focus on Therapeutic Strategies. Larry Culpepper, MD, MPH Professor of Family Medicine Department Family Medicine Boston University School of Medicine. Learning Objectives.

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Best Primary Care Practices for Hepatitis B Infection: Focus on Therapeutic Strategies

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  1. Best Primary Care Practices for Hepatitis B Infection: Focus on Therapeutic Strategies Larry Culpepper, MD, MPH Professor of Family Medicine Department Family Medicine Boston University School of Medicine

  2. Learning Objectives Increase the rate at which family physicians screen at-risk patients for hepatitis B infection Provide accurate patient education and counseling to HBsAg-positive patients Devise or refer for ongoing monitoring, follow-up, and determination of treatment candidacy

  3. Why Care About Hepatitis B Virus (HBV) Infection? • HBV infection is: • A public health problem • Prevalent • Underdiagnosed and undertreated • Associated with signifcant morbidity and mortality • Family physicians are well positioned to reach at-risk communities

  4. HBV is a Public Health Problem • Institute of Medicine (IOM) • Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C1 • US Department of Heath and Human Services (HHS) • Combating The Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care & Treatment of Viral Hepatitis2 1. Institute of Medicine Committee on the Prevention and Control of Viral Hepatitis Infections. 2011. www.iom.edu/viralhepatitis 2. US Department of Heath and Human Services. 2011. www.hhs.gov/ash/.../hepatitis/actionplan_viralhepatitis2011.pdf

  5. IOM Report: Key Findings • Inadequate disease surveillance systems • At-risk unaware • Poor access • preventive services • testing • social support • medical management services • Chronically infected do not know they are infected • Many health-care providers do not • screen for risk factors • know how to manage infected people • Institute of Medicine Committee on the Prevention and Control of Viral Hepatitis Infections. 2011. www.iom.edu/viralhepatitis

  6. HBV Infection is Prevalent Globally • 2 billion infected • >400 million have chronic infection United States • In 2009, estimated 38,000 newly infected • ~1.4 million persons have chronic infection • Minority properly diagnosed (~500,000) • Only half are receiving care (~250,000) • ~50,000 receiving antiviral treatment WHO. 2012. http://www.who.int/mediacentre/factsheets/fs204/ en/index.html CDC Division of Viral Hepatitis. 2012. http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm Cohen C, et al. J Viral Hepat. 2011;18(6):377-383. PMID: 21143343.

  7. HBV Morbidity and Mortality • 50-100 x more infectious than HIV • Chronic HBV develops in 90% infected as infants and 1-10% infected as adults • Chronic infection can lead to cirrhosis, liver failure, and cancer (usually over 20-30+ years) • Premature death in 15-25% of chronically infected • A leading cause of cirrhosis and hepatocellular carcinoma (HCC) • 620,000 each year worldwide die from HBV related disease • CDC Division of Viral Hepatitis. 2012. http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

  8. Family Physicians Positioned to Reach At-Risk Communities • 1° and 2° prevention • Combattingstigma • ProvidingVaccine • LaboratoryScreening • Treatmentor referral • Long-term Follow-up

  9. HBV Risk Assessment Screening Serology Results Interpretation

  10. Screening: Use the CDC Guideline CDC. 2008. http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf

  11. Persons at High Risk are Candidates for HBV Screening • Persons born in regions of high and intermediate HBV endemicity (HBsAg prevalence (≥2%) • US born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity(≥8%) • Household and sexual contacts of HBV carriers • Persons who have injected drugs • Persons with multiple sexual partners or history of STDs • Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. PMID: 18802412.

  12. Persons at High Risk are Candidates for HBV Screening • All pregnant women • Infants born to HBV carrier mothers • Individuals with chronically elevated ALT/AST • Patients undergoing immunosuppressive therapy • Individuals infected with HIV or HCV • Men who have sex with men • Inmates of correctional facilities • Patients undergoing hemodialysis • Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. PMID: 18802412.

  13. HBV Screening Recommendations by Risk Group Centers for Disease Control and Prevention. 2008. http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf

  14. HBV Screening Recommendations by Risk Group Centers for Disease Control and Prevention. 2008. http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf

  15. Chronic HBV Centers for Disease Control and Prevention. 2008. http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf

  16. HBV Infection: Possible Outcomes Acute HBV infection 3-5% adult-acquired 95% infant-acquired Chronic HBV infection Chronic Hepatitis 12-25% in 5 yrs Cirrhosis 6-15% in 5 yrs 20-23% in 5 yrs Hepatocellular carcinoma (HCC) Liver failure Liver transplant Death Death

  17. Acute HBV Infection withRecovery Typical Serologic Course Symptoms HBeAg anti-HBe Total anti-HBc Titre anti-HBs IgM anti-HBc HBsAg 0 4 8 12 16 24 28 32 52 100 20 36 Weeks after Exposure

  18. Acute (6 months) Chronic (Years) HBeAg Anti-HBe HBsAg Total anti-HBc Titer IgM anti-HBc Years 0 4 8 12 16 20 24 28 32 36 52 Weeks after Exposure Acute HBV Infection with Progression to Chronic Infection: Typical Serologic Course

  19. HBV Serologic Markers HBeAg and Anti-Hbe NOT used for screening Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. PMID: 18802412.

  20. CDC Division of Viral Hepatitis. 2012. http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm

  21. Serologic Results Guide Next Steps

  22. Counseling of HBV Susceptible Patients • Counsel patients on • Modes of transmission • Found in semen, saliva, vaginal mucus, and tears • Not found in urine, sweat, or stool • Prevention strategies • Condoms • Avoid IV drug use

  23. HBV Vaccination is Highly Effective 80% Decline in Incidence Since Universal Infant Vaccination Begun in 1991 14 12 10 Incidence (Cases per 100,000 population) 8 6 4 2 0 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 Year • Wasley A, et al. MMWR SurveillSumm. 2008;57(SS-2):1-24.

  24. Further Test Patients Who Are HBsAg Positive • Assess for liver disease • CBC • Hepatic panel • INR • Assess HBV replication • HBeAg • anti-HBe • HBV DNA • Rule out HCV and HIV • anti-HCV • anti-HDV* • anti-HIV • Screen for HCC • Ultrasound preferred (AFP as alternative) • Consider liver biopsy to grade & stage liver disease AASLD * In persons from countries where HDV infection is common and in those with history of injection drug use • Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

  25. Surveillance for Hepatocellular Carcinoma in Chronic HBV • Cost effective at annual incidence • Without cirrhosis: >0.2% • With cirrhosis: 1.5-2% Age Related • Asian men ≥age of 40 • Asian women ≥ age 50 • Caucasians with viral load ≥ 20,000 IU and active inflammation • Men ≥ age 40 • Women ≥ age 50 At Time of Diagnosis • Africans and North American Blacks • Patients with a family history of HCC • Patients with cirrhosis • No Surveillance: Caucasians with low HBV titers and not cirrhosis

  26. Surveillance Techniques for HCC in Chronic HBV • Ultrasound sensitivity • 94% overall • 63% for early HCC • Ultrasound surveillance interval • 6 months • Based on tumor growth rate, not degree of risk • Alpha-fetoprotein (AFP) no data on which to base use – not recommended • Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53:1020

  27. Making the Decision to Treat or Refer • Consider referral to a specialist • For HBV-infected patients who are • Coinfected with HIV or HCV • Pregnant • At an advanced stage of disease • And when you are concerned about • Antiviral resistance • How best to manage a patient

  28. Treatment

  29. Goals and Benefits of Hepatitis B Treatment Prevent long-term outcomes (cirrhosis, liver transplantation, HCC, death) by durable suppression of HBV DNA • Primary endpoint • Sustained decrease in serum HBV DNA level to undetectable • Secondary endpoints • Decrease or normalize serum ALT • Improve liver histology • Induce HBeAg loss or seroconversion in HBeAg-positive disease • Induce HBsAg loss or seroconversion Treatment often long term or lifelong, particularly in HBeAg-negative patients • Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

  30. Management:HBsAg+ and HBeAg+ AASLD 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 q3-6 mos ALT q6-12 mosHBeAg q3 mos ALT q6 mosHBeAg Consider biopsy if persistent or older than 40 yrs of age Treat as needed q1-3 mos ALT, HBeAg Treat if persistent Liver biopsy optional Immediate rx if jaundice or decompensated • Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

  31. Management: HBsAg+ and HBeAg- AASLD ALT < 1 x ULN HBV DNA < 2000 IU/mL ALT 1-2 x ULN HBV DNA 2000-20,000 IU/mL ALT ≥ 2 x ULN HBV DNA ≥ 20,000 IU/mL q3 mos ALT x 3, then q6-12 mos if ALT still < 1 x ULN q3 mos ALT and HBV DNA Consider biopsy if persistent Treat as needed Treat if persistent Liver biopsy optional • Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

  32. Other Guidelines • European Association For The Study Of The Liver (EASL) guidelines1 • Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update2 • Indications for therapy in HBV3 • US treatment algorithm for chronic HBV in the US 4 • Management of chronic HBV in Asian Americans5 1. EASL. B. JHepatol. 2009;50(2):227-242. PMID: 19054588. 2. Liaw YF, et al. HepatolInt. 2008;2(3):263-283. PMID: 19669255. 3. DegertekinB, LokAS. Hepatology. 2009;49(5 Suppl):S129-137. PMID: 19399799 4. KeeffeEB, et al. ClinGastroenterolHepatol. 2006;4(8):936-962. PMID: 16844425. 5. Tong MJ, et al.. Dig Dis Sci. 2011;56(11):3143-3162. PMID: 21935699.

  33. Mr. Huỳnh • 38-yo Asian-American man in for CPE • emigrated from Vietnam at age 7 • Routine preventive care labs normal • Agreed to HBV testing Chronic HBV infection

  34. Mr. Huỳnh: Lab Evaluation Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720

  35. 4 Phases of Chronic HBV Infection HBeAg Anti-HBe Mr. Huỳnh HBV DNA ALT Optimal treatment times

  36. Treatment Candidacy for HBeAg-Positive PatientsAASLD Guidelines < 1 x ULN 1-2 x ULN > 2 x ULN ALT and and and > 20,000 IU/mL > 20,000 IU/mL < 20,000 IU/mL HBV DNA Monitor Q3-6 mos ALT Q6-12 mos HBeAg Monitor Q3 mos ALT Q6 mos HBeAg Consider biopsy if persistent or aged > 40 yrs and Treat as needed MONITOR Q1-3 mos ALT and HBeAg and treat if elevations persist TREAT immediately if jaundice or decompensated APPROACH Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

  37. Treatment Candidacy for HBeAg-NegativePatientsAASLD Guidelines < 1 x ULN 1-2 x ULN ≥ 2 x ULN ALT and and and ≥ 20,000 IU/mL 2000-20,000 IU/mL < 2000 IU/mL HBV DNA Monitor Q3 mos ALT x 3, then Q6-12 mos if ALT still < 1 X ULN Monitor Q3 mos ALT and HBV DNA Consider biopsy if persistent and treat as needed Treat if elevations persist APPROACH Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

  38. Mr. HuỳnhFamily Follow-up • Wife tested not immune • They used condoms until she completed vaccine series • Following that, they started trying to conceive • Healthy boy 2 years later  HBV vaccines and was immune • Sister was tested and was positive • Sees a doctor regularly now • Thankful her brother asked her to get tested • Mr. Huynh hasinactive disease for the next 10 years

  39. Mr. Huỳnh10 Years Later • Presents to his family physician with symptoms of morning stiffness in feet and ankles and ankle pain • Diagnosed with rheumatoid arthritis • Began therapy with methotrexate • Monitored for HBV Reactivation Q 3 months • HBV DNA <2,000 IU/mL at start of therapy • 4,500 IU/mL within three months

  40. HBV Reactivation: Loss of HBV immune control in a patient with inactive HBV infection • Abrupt reappearance or increase in viral replication • Rise in HBV DNA • Return of HBeAg in some • Subsequent liver damage • Increase in ALT • May progress to liver failure and death, even with antiviral therapy Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.

  41. Chronic HBV Infection Reactivation HBeAg Anti-HBe HBV DNA ALT Optimal treatment times

  42. HBV Reactivation:Risk Factors • Malignancy • Solid tumors (e.g., breast cancer): 20% to 41% of HBsAg positive have flair • Lymphoma: 40% to 58% of HBsAg positive have flair • Chemotherapy • Related to potency of immunosuppression • HBV DNA > 3 × 105 copies/mL • Elevated if HBeAg positive • Male Yeo W, et al. Hepatology. 2006;43:209-220.

  43. Agents Reported to Cause HBV Reactivation Roche B, et al. Liver Int. 2011;31(suppl 1):104-110.

  44. HBV Therapy:Therapeutic Goals • Primary goal • Prevention of long-term negative clinical outcomes (e.g., cirrhosis, HCC, death) achievable by durable suppression of HBV DNA to low or undetectable levels • Secondary goals • Decrease or normalize serum ALT • Seroconversion from HBeAg+ to HBeAg- • Seroconversion from HBsAg+ to HBeAgs Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

  45. HBV Chronic HBV Therapy:FDA-Approved Agents • Entecavir, peginterferon alfa-2a, and tenofovir recommended as first-line therapy • Rapid onset of action • Low rate of drug resistance with prolonged use • Favorable safety profiles • Adefovir, interferon alfa-2b, lamivudine, and telbivudine also approved Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

  46. Overview of First-Line Therapies Scaglione SJ, Lok AS. Gastroenterology. 2012;142(6):1360-1368. PMID: 22537444.

  47. HBV DNA and HCC REVEAL: long-term follow-up (mean 11.4 yrs) cohort study to determine risk of cirrhosis and HCC among untreated HBsAg+ N = 3653 Taiwanese patients 14 Baseline HBV DNA Level, copies/mL ≥ 1 million 100,000-999,999 10,000-99,999 300-9999 < 300 12 10 Cumulative Incidence of HCC (%) 8 6 4 2 0 Chen CJ, et al. JAMA. 2006;295:65-73. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years of Follow-up

  48. Summary • Family physicians well positioned to: • Recognize risk factors • Screen if indicated • Immunize • Diagnose • Assess disease stage, need for therapy • Manage treatment • Surveilfor reactivation if immune status compromised • Monitor disease progression and for hepatocellular carcinoma

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