Hepatitis B: An Update COPYRIGHT

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1 Hepatitis B: An Update Sanjiv Chopra, M.D. Professor of Medicine Harvard Medical School James Tullis Firm Chief Department of Medicine Beth Israel Deaconess Medical Center

2 A Tale of Serendipity Baruch Blumberg, M.D. and the Discovery of Australia Antigen

3 Polymorphism Occurrence in the natural habitat of two or more discontinuous and presumably inherited forms of a species in such proportions that the rarest of them cannot be maintained merely by recurrent mutation. E.B. Ford

4 Hepadnaviruses Tree squirrel Ground squirrel Woodchuck HBV Stork Woodly monkey Heron Arctic ground squirrel Ross Goose Duck

5 HBV Transmission From Colour Atlas of Liver Disease, Sherlock S, Summerfield JA. Mosby 1991

6 Unusual Mode of HBV Transmission Orienteering

7 Question 1 (ARS) Choose the one correct statement: 1. Chronic Hepatitis B afflicts 170 million people worldwide % of Primary Hepatocellular Carcinoma related to Chronic Hepatitis B occurs in patients without cirrhosis.

8 What is the Current Burden of Hepatitis B Worldwide? Chronic HBV afflicts 400 million people Annually, 500,000 people die from cirrhosis and Primary Hepatocellular Carcinoma Annually, 40,000 die from Acute Hepatitis B Hepatitis B related hospitalizations cost more than $1 Billion each year

9 What is the Natural History of Acute Hepatitis B? Infections in newborns are most often asymptomatic Incubation period is typically 3 months Proclivity to chronicity is dependent upon age of acquisition of Acute HBV Perinatal period: 90% Between 1-5 years: 50% Adults: Less than 5%

10 What is the Natural History of Chronic Hepatitis B? Chronic HBV Infection has 3 major phases: 1. Immuno-tolerant phase 2. Immuno-active phase 3. Inactive carrier phase

11 Immuno-tolerant Phase Occurs in all children infected perinatally High levels of serum HBV DNA Liver biopsy is normal or reveals minimal inflammation Can last up to several decades, then transitions to immuno-active phase

12 Immuno-Active Phase Elevated serum ALT and AST Often, HBe Antigen positive and high levels of serum HBV DNA Liver biopsy reveals inflammation with or without fibrosis

13 Inactive Carrier Phase Seroconversion from HBe Ag positive to anti-hbe positive Low or undetectable levels of serum HBV DNA Normal ALT, reduced liver inflammation on biopsy Lower risk of Primary Hepatocellular Carcinoma Disease may be reactivated by immunosuppression

14 Question 2 (ARS) Choose the one correct statement: 1. Patients with persistently normal ALT (defined as normal ALT on 3 consecutive occasions over a 6 month period) have mild or negligible disease on biopsy. 2. The higher the pre-treatment ALT, the better the response to anti-viral treatment.

15 What is the significance of serum ALT in patients with Chronic Hepatitis B?

16 ALT Level in Chronic Hepatitis B ALT levels are often elevated by as much as 50% at follow-up visits Normal ALT has been associated with Stage 2 firbrosis in 12-43% of patients Age more than 45 years is a predictor of significant fibrosis The higher the pre-treatment ALT level, the better the response to treatment

17 What is the Proper Interpretation of an Isolated Anti-HBc? Reported in 1% of blood donors in low prevalence areas and 15% of population in endemic countries Can occur in two settings: 1. During the window period of Acute Hepatitis B (IgM) 2. Many years after recovery from Acute Hepatitis B at which point anti-hbs becomes undetectable Transmission of HBV infection reported from blood and organ donors with isolated anti-hbc Evaluation of individuals with isolated anti-hbc should include repeat testing for HBsAg, anti-hbc and anti-hbs

18 What is the Significance of HBV Genotypes? Eight genotypes (A H) identified Prevalence varies geographically: USA Genotypes A and C common Asia Genotypes B and C common Mid-East Genotype D common Genotypes may have clinical significance, i.e., response to treatment, risk for Fulminant Hepatic Failure, risk for PHCC Not ready for routine clinical use at present!

19 What to do with Non-Responders to Hepatitis B Vaccination? Recognize that non-responders include individuals with chronic kidney disease, immunosuppressed patients, patients with celiac sprue and a small percentage of healthy subjects. Those who fail to respond to the primary vaccine series, should be administered one or more additional doses: 15-25% will have adequate antibody response after one dose. 50% will have adequate antibody response after 3 additional doses. Consider double dose if subjects at high risk and still non-responders.

20 An Individual Who Travels Fequently To China, Japan, Phillipines and Thailand Was Vaccinated 15 Years Ago. Should He Receive a Booster Dose? Somewhat of a controversial subject: Practice varies from country to country Germany, Spain, France, Belgium, Netherlands booster dose recommended depending upon postvaccination anti-hbs titer In the USA, it is recommended that dialysis patients have an annual anti-hbs titer checked. If below 10 m I/U/mL, patient should receive booster.

21 Are the Concerns about Hepatitis B Vaccine Side Effects Valid? Most common side effect is pain at the injection site and mild fever. No association with Multiple Sclerosis. No association with SIDS. No association with Chronic Fatigue Syndrome. Millions and millions of doses administered world wide a three decade long experience!

22 Question 3 (ARS) Choose the one correct statement: 1. An adult patient who acquires acute Hepatitis B has a 60-70% chance of becoming chronically infected. 2. An adult patient who acquires acute Hepatitis B has a 2-3% chance of becoming chronically infected. 3. Patients with chronic Hepatitis B who are Hepatitis B e antigen negative are not infectious.

23 CDC Recommends HBV Vaccination for Patients with Diabetes CDC Investigated several outbreaks of HBV infection. Patients with Diabetes found to have higher rates of infection. HBV vaccination recommended for all unvaccinated diabetic patients under 60 years of age.

24 Sequelae Of Acute HBV < 1% fulminant 95-98% recover (adults) 2-5% chronic (adults)

25 HBV - Natural History Clinical Outcome of Chronic Hepatitis B

26 33

27 Is There Any Significance to Serum HBV DNA? HBV DNA levels highest in HBeAg positive patients Risk of cirrhosis and PHCC proportional to serum HBV DNA levels Response to nucleoside/nucleotide agents proportional to serum HBV DNA levels

28 What Is The Risk of PHCC in Chronic HBV?

29 Risk of PHCC in Chronic Hepatitis B Risk present in both cirrhotics and non-cirrhotics. Risk higher in patients with high serum levels of HBV DNA, HBeAg(+) individuals and with HCV coinfection. Individuals infected with HBV genotype 6 (more common in Asia and Pacific Islands) appear to have an increased risk of cirrhosis and PHCC. Adults with HBV infection acquired in the perinatal period have a 100 fold higher risk of developing PHCC compared to uninfected individuals.

30 Risk Of PHCC In Asymptomatic Carriers No. of PHCC cases 3,454 HBsAg (+) men 152* 19, 253 HBsAg (-) men 9 * Relative risk is 94 Beasley, RP, Hwang, L-Y Viral Hepatitis and Liver Disease Grune and Stratton, 1984, pp

31 PHCC in Chronic HBV 25

32 Management Of Chronic HBV Stage of liver disease Candidacy for treatment Risk of PHCC Family ramifications Lifestyle modifications

33 Goals of Therapy Primary Goal Prevention of Cirrhosis, HCC and death* Secondary Goals in Clinical Practice Decrease in serum HBV DNA Normalization of serum ALT HBeAg seroconversion HBsAg seroconversion * May be achievable by durable suppression of serum HBV DNA to undetectable levels

34 Costs of Treatment Drug Name Annual Cost Lamivudine (100 mg) $ 2,482. Emtricitabine (200 mg) $ 3,872. Adefovir (10 mg) $ 6,647. Entecavir (0.5 mg) $ 8,694. Tenofovir (300 mg) $ 5,811. Peginterferon alfa-2a (180 mcg) $ 18,480.

35 Factors to Consider in Choosing Treatment 1. Patient preference: Pill vs. injection 2. Duration of treatment 3. Rates of resistance 4. Previous treatment 5. Cost Promise of combination therapies has yet to be realized!

36 Current Treatment Landscape Generic Name Trade Name Manufacturer Interferon alfa-2b INTRON A Schering Corporation Date Approved for Hepatitis B 1991 Lamivudine EPIVIR-HBV GlaxoSmithKline 1998 Adefovir dipivoxil HEPSERA Gilead Sciences 2002 Entecavir BARACLUDE Bristol-Myers Squibb Peginterferon alfa- 2a Telbivudine 2005 PEGASYS Hoffmann La-Roche 2005 TYZEKA Idenix & Novartis Pharmaceuticals 2006 Tenofovir Viread Gilead Sciences 2008

37 Towards a cure for Hepatitis B? Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis. G. Ebert et al., PNAS, 2015, 112(18): Promising study in a mouse model of chronic HBV in which there was preferentially killing of HBV infected hepatocytes.

38 Question 4 (ARS) Choose the correct answer: 1. Chronic Hepatitis B is associated with Essential Mixed Cryoglobulinemia. 2. Chronic Hepatitis B is associated with Polyarteritis Nodosa.

39 Infant Hepatitis B Vaccine Series Duration of protection extends through the adolescent years. Middleman AB, et al. Duration of protection after hepatitis B vaccination series. Pediatrics May 2014.

40 Updated Hepatitis B Screening Patients At High Risk Should Be Screened Persons from regions with high rates of HBV infection Household contacts of HBV + individuals HIV positive patients Injection drug users Men who have sex with men Lack of vaccination during infancy of U.S. born persons with parents from a high risk region.

41 Patients with Diabetes should be vaccinated The Advisory Committee on Immunization Practices recommends that HBV vaccination be given to unvaccinated adults with diabetes mellitus who are ages 19 to 59. Recommendation was based on outbreaks of HBV in patients who were undergoing assisted blood glucose monitoring, a subsequent analysis of the risk of acquiring HBV among all diabetics in the United States, and a costeffectiveness analysis. MMWR Morb Mortal Wkly Rep. 2011;60(50):1709.

42 Summary of Key Points and Notable Comparisons with Hepatitis C 1. Hepatitis B afflicts 400 million individuals worldwide and Hepatitis C afflicts 200 million individuals 2. The Hepatitis B vaccine is truly the first anti-cancer vaccine! There is no available vaccine for Hepatitis C 3. In contrast to HCV, pts with chronic HBV are at substantial risk for developing PHCC even in the absence of cirrhosis 4. The goal of treatment in chronic HBV is to have sustained suppression of HBV DNA to undetectable levels while in chronic HCV it is to cure patients!

43 Summary of Key Points and Notable Comparisons with Hepatitis C 5. Cryoglobulinemia is associated with chronic Hepatitis C and Polyarteritis Nodosa is associated with chronic Hepatitis B. 6. Anti-viral treatment for Hepatitis B prevents progressiion, may reverse fibrosis, improves Child s classification and decreases the need for liver transplantation. 7. Hepatitis B virus Genotypes not ready for prime time use. Hepatitis C virus genotype is the most important predictor of sustained virological response (cure).