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 Larry Culpepper, MD, MPH Professor of Family Medicine Department Family Medicine Boston University School of Medicine

2. Learning Objectives 1.Increase the rate at which family physicians screen at-risk patients for hepatitis B infection 2.Provide accurate patient education and counseling to HBsAg-positive patients 3.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 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 C 1 US Department of Heath and Human Services (HHS) Combating The Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care & Treatment of Viral Hepatitis 2 Institute of Medicine (IOM) Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C 1 US Department of Heath and Human Services (HHS) Combating The Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care & Treatment of Viral Hepatitis 2 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 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 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 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 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.htmhttp://www.cdc.gov/hepatitis/hbv/hbvfaq.htm Cohen C, et al. J Viral Hepat. 2011;18(6):377-383. PMID: 21143343. 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.htmhttp://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 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 Providing Vaccine 1° and 2° prevention Combatting stigma Laboratory Screening Treatment or 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/ChronicHepBTe stingFlwUp.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 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 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 Chronic HBV infection 3-5% adult-acquired95% infant-acquired Cirrhosis Chronic Hepatitis 12-25% in 5 yrs Liver failure Hepatocellular carcinoma (HCC) Liver transplant 6-15% in 5 yrs20-23% in 5 yrs Death

17. Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 0481216 20 242832 36 52100 Acute HBV Infection with Recovery Typical Serologic Course Weeks after Exposure Titre

18. Acute HBV Infection with Progression to Chronic Infection: Typical Serologic Course

19. HBV Serologic Markers Marker Interpretation HBsAg Chronic hepatitis B when > 6 mos Anti-HBs Immunity HBeAg Active viral replication and high infectivity Anti-HBe Recovery phase or reactivation phase Anti-HBc Past and possibly current infection Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. PMID: 18802412. HBeAg and Anti-Hbe NOT used for screening

20. PatternInterpretation HBsAg anti-HBc anti-HBs − Susceptible HBsAg anti-HBc anti-HBs − + Immune due to natural infection HBsAg anti-HBc anti-HBs − + Immune due to HB vaccination HBsAg anti-HBc IgM anti-HBc anti-HBs + − Acutely infected HBsAg anti-HBc IgM anti-HBc anti-HBs + − Chronically infected HBsAg anti-HBc anti-HBs − + − 1. Resolved infection (most common) 2. False-positive anti-HBc, thus susceptible 3. “Low level” chronic infection 4. Resolving acute infection 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 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 Incidence (Cases per 100,000 population) Year 14 12 10 8 6 4 2 0 1982198419861988199019921994199619982000200220042006 80% Decline in Incidence Since Universal Infant Vaccination Begun in 1991 Wasley A, et al. MMWR Surveill Summ. 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 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 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 * In persons from countries where HDV infection is common and in those with history of injection drug use AASLD Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

25. Surveillance for Hepatocellular Carcinoma in Chronic HBV 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 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 At Time of Diagnosis Africans and North American Blacks Patients with a family history of HCC Patients with cirrhosis Cost effective at annual incidence Without cirrhosis: >0.2% With cirrhosis: 1.5-2% 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 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 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 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 Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720. Treatment often long term or lifelong, particularly in HBeAg- negative patients

30. Management: HBsAg+ and HBeAg+ q3-6 mos ALT q6-12 mos HBeAg q3 mos ALT q6 mos HBeAg 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 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 Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

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

32. Other Guidelines European Association For The Study Of The Liver (EASL) guidelines 1 Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update 2 Indications for therapy in HBV 3 US treatment algorithm for chronic HBV in the US 4 Management of chronic HBV in Asian Americans 5 European Association For The Study Of The Liver (EASL) guidelines 1 Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update 2 Indications for therapy in HBV 3 US treatment algorithm for chronic HBV in the US 4 Management of chronic HBV in Asian Americans 5 1. EASL. B. J Hepatol. 2009;50(2):227-242. PMID: 19054588. 2. Liaw YF, et al. Hepatol Int. 2008;2(3):263-283. PMID: 19669255. 3. Degertekin B, Lok AS. Hepatology. 2009;49(5 Suppl):S129-137. PMID: 19399799 4. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4(8):936-962. PMID: 16844425. 5. Tong MJ, et al.. Dig Dis Sci. 2011;56(11):3143-3162. PMID: 21935699. 1. EASL. B. J Hepatol. 2009;50(2):227-242. PMID: 19054588. 2. Liaw YF, et al. Hepatol Int. 2008;2(3):263-283. PMID: 19669255. 3. Degertekin B, Lok AS. Hepatology. 2009;49(5 Suppl):S129-137. PMID: 19399799 4. Keeffe EB, et al. Clin Gastroenterol Hepatol. 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 HBsAgAnti-HBsAnti-HBc +-+ Chronic HBV infection

34. Mr. Huỳnh: Lab Evaluation AssessUsingMr. Huỳnh Liver function CBC & platelets Normal LFTs Normal INR Normal HBV replication HBV DNA <2000 IU/mL HBeAg/anti-HBe Negative HCV & HIV anti-HCV Negative anti-HIV Negative HCC Ultrasound Negative Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720

35. PhaseImmune Tolerant Immune ClearanceInactive Carrier State Reactivation Liver Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Active inflammation Anti-HBe HBV DNA 4 Phases of Chronic HBV Infection HBeAg ALT Optimal treatment times Mr. Huỳnh

36. 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 1-2 x ULN Treatment Candidacy for HBeAg-Positive Patients AASLD Guidelines < 1 x ULN> 2 x ULN ALT > 20,000 IU/mL < 20,000 IU/mL > 20,000 IU/mL HBV DNA and APPROACH Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

37. 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 1-2 x ULN Treatment Candidacy for HBeAg-Negative Patients AASLD Guidelines < 1 x ULN ≥ 2 x ULN 2000-20,000 IU/mL < 2000 IU/mL ≥ 20,000 IU/mL and ALT HBV DNA APPROACH Lok AS, et al. Hepatology. 2009;50(3):661-662. PMID: 19714720.

38. Mr. Huỳnh Family Follow-up

39. Mr. Huỳnh 10 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. PhaseImmune Tolerant Immune ClearanceInactive Carrier State Reactivation Liver Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Active inflammation Optimal treatment times Anti-HBe HBV DNA Chronic HBV Infection Reactivation HBeAg ALT

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 × 10 5 copies/mL ● Elevated if HBeAg positive ● Male Yeo W, et al. Hepatology. 2006;43:209-220.

43. Agents Reported to Cause HBV Reactivation Cortico- steroids Prednsone Budesonide Anti-TNF Infliximab A dalimumab Etanercept Antimeta- bolite Methotrexate Purine Analogues Azathioprine 6-MP Other Rituximab Cyclosporine 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. Interferon Entecavir/Tenof ovir AdministrationParenteralOral Side-effectsSignificantMinimal Duration of therapyShortLong Use in decompensated patients or pregnancy Contraindicated Yes (TF in pregnancy) HBV DNA suppression (HBeAg negative, 1 yr) 63%90-93% HBeAg seroconversion 1 yr27%21% HBsAg loss (3-5 yrs)8-11%0-10% Drug resistanceNone0-1.2% 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+ Chen CJ, et al. JAMA. 2006;295:65-73. Years of Follow-up Cumulative Incidence of HCC (%) N = 3653 Taiwanese patients 0 2 4 6 8 10 12 14 012345678910111213 Baseline HBV DNA Level, copies/mL ≥ 1 million 100,000-999,999 10,000-99,999 300-9999 < 300

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