For more information about the AHF and its members, please visit:

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2 The Asian Health Foundation (AHF) is a nonprofit organization that comprises more than 40 physicians dedicated to improving the health of Asian Americans and Pacific Islanders. For more information about the AHF and its members, please visit:

3 Christopher Bui, MD Gastroenterologist Fountain Valley Regional Hospital Huntington Beach Hospital Westminster, CA Danny Chu, MD Clinical Instructor Albert Einstein College of Medicine New York, NY Son T. Do, MD Past Chairman National Task Force for Hepatitis B, API University of Texas Southwestern Medical School Dallas, TX Hie-Won Hann, MD Professor of Medicine Jefferson Medical College of Thomas Jefferson University Director, Liver Disease Prevention Center Thomas Jefferson University Hospital Philadelphia, PA Kris V. Kowdley, MD Director, Liver Center of Excellence Virginia Mason Medical Center Seattle, WA Albert Min, MD Professor of Clinical Medicine Albert Einstein College of Medicine Director of Hepatology Beth Israel Medical Center New York, NY Mindie Nguyen, MD, MAS Assistant Professor, Gastroenterology and Hepatology Stanford University Palo Alto, CA Helen Te, MD Associate Professor of Medicine University of Chicago Medicine Medical Director, Adult Liver Transplantation Chicago, IL Tram T. Tran, MD Associate Professor of Medicine Geffen UCLA School of Medicine Medical Director, Liver Transplant Program Cedars-Sinai Medical Center Los Angeles, CA Naoky Tsai, MD Naoky Tsai, MD Professor of Medicine, University of Hawaii Director, Liver Center at Queens Medical Center Honolulu, HI

4 Christopher Bui, MD, has no real or apparent conflicts of interest to report, nor any financial relationships to disclose. Danny Chu, MD Consulting Fees: Bristol-Myers Squibb; Gilead Sciences, Inc. Fees for Non-CME Services: Bristol-Myers Squibb; Gilead Sciences, Inc. Son T. Do, MD Consulting Fees: Bristol-Myers Squibb; Gilead Sciences, Inc. Contracted Research: Bristol-Myers Squibb; National Institutes of Health Fees for Non-CME Services: Asian Health Foundation; Bristol-Myers Squibb; Gilead Sciences, Inc. Hie-Won Hann, MD Consulting Fees: Bristol-Myers Squibb; Gilead Sciences, Inc; Novartis Contracted Research: Bristol-Myers Squibb; Gilead Sciences, Inc. Other (Spouse): Gilead Sciences, Inc. Kris V. Kowdley, MD Consulting Fees: Abbott; Gilead Sciences, Inc; Novartis; Vertex (payable to the institution)

5 Albert Min, MD Consulting Fees: Bayer; Gilead Sciences, Inc; Vertex Contracted Research: Bristol-Myers Squibb; Gilead Sciences, Inc; Vertex Fees for Non-CME Services: Bristol-Myers Squibb; Gilead Sciences, Inc; Merck; Salix; Vertex Mindie Nguyen, MD, MAS Consulting Fees: Bristol-Myers Squibb; Novartis Contracted Research: Bristol-Myers Squibb; Gilead Sciences, Inc; Novartis Helen Te, MD has no real or apparent conflicts of interest to report, nor any financial relationships to disclose. Tram T. Tran, MD Consulting Fees: Bristol-Myers Squibb; Gilead Sciences, Inc. Naoky Tsai, MD Consulting Fees: Bristol-Myers Squibb; Genentech; Gilead Sciences, Inc. Contracted Research: Bristol-Myers Squibb; Gilead Sciences, Inc. Fees for Non-CME Services: Bristol-Myers Squibb; Genentech; Gilead Sciences, Inc.

6 After completing this CME/CE activity, the participant will be better able to: Explain the natural history of hepatitis B virus (HBV) infection in light of its clinical implications for treatment Evaluate currently approved treatments for chronic hepatitis B (CHB) in terms of safety and efficacy Formulate individualized treatment strategies for the duration of therapy

7 This activity is supported by independent educational grants from Bristol-Myers Squibb and Gilead Sciences Medical Affairs.

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9 55 years old/m, born in China, came to the United States at age 40 years, visited a physician for a life-insurance checkup

10 Persons 2 million 1.5 million 1 million 1.4 million- 2 million Having more potent drugs will not improve effectiveness if diagnosis and access to care are not improved High estimate Low estimate 500, , , , , , ,000 0 Chronically Infected Aware of Infection Potentially Eligible for Treatment Entering Care 50,000 Annual HBV Prescriptions Cohen C, et al. J Viral Hepat. 2011;18:

11 Blood, organ, plasma, semen, tissue donors Hemodialysis patients All pregnant women Infants born to HBsAg-positive women Household contacts, needle-sharing, or sex partners of HBV-infected persons Sources of blood or body-fluid exposures that might warrant postexposure prophylaxis Persons born in countries with HBsAg prevalence 2% HIV-infected persons Persons with select medical conditions (eg, elevated ALT or AST levels of unknown etiology) Persons with behavioral exposures (eg, IDUs, MSM) Unvaccinated children of persons from countries with 8% prevalence AST, aspartate aminotransferase; IDU, injection drug user; MSM, men who have sex with men. Centers for Disease Control and Prevention. MMWR. 2008;57:1-20.

12 HBsAg Prevalence 8% - high 2% 7% - intermediate <2% - low Centers for Disease Control and Prevention. MMWR. 2008;57:1-20.

13 Phase ALT Liver Histology HBV DNA HBeAg HBsAg Immunetolerance phase Normal or minimally elevated Minimal activity; absent or scant fibrosis High levels: HBV DNA >20,000 IU/mL Positive; anti- HBe negative Positive >6 months Immune - clearance phase (HBeAg positive) Elevated, persistently or intermittently Active; liver biopsy showing chronic hepatitis High levels: HBV DNA >20,000 IU/mL Positive; anti- HBe negative Positive >6 months Inactive HBsAg carrier state Persistently normal Inactive; liver biopsy showing variable, usually minimal, fibrosis Low or undetectable levels: HBV DNA negative or <2000 IU/mL Negative; anti- HBe positive Positive >6 months Resolution Normal Inactive; scant fibrosis No detectable HBV DNA Negative; anti- HBe positive Negative Reactivation phase (HBeAg negative) Elevated, often fluctuating levels Active: liver biopsy showing variable amounts of fibrosis Moderate, often fluctuating levels: HBV DNA >2000 IU/mL Negative; anti- HBeAg positive Positive >6 months Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:

14 HBV DNA HBeAg Anti-HBe HBsAg Anti-HBc Anti-HBc IgM Months Years Anti-HBc, antibody to the hepatitis B core antigen; IgM, immunoglobulin M. Centers for Disease Control and Prevention. MMWR. 2008;57:1-20.

15 Test for both HBsAg and anti-hbs Lok ASF, et al. Hepatology. 2009;50:1-36. Patient Status Test Result Chronic infection Susceptible Immune HBsAg positive Anti-HBs negative HBsAg negative Anti-HBs negative HBsAg negative Anti-HBs positive

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17 Screening test results: HBsAg positive, anti-hbs negative Additional tests showed: ALT 36 HBeAg negative, anti-hbe positive HBV DNA 110 IU/mL (about 550 copies/ml) After 6 months of follow-up: ALT 59 HBV DNA 7375 IU/mL A decision to treat the patient was made Because of HBeAg-negative infection, duration of therapy was indefinite

18 First-line agents Pegylated interferon (PegIFN) alfa-2a (Pegasys ) Injectable Entecavir (ETV) (Baraclude ) Oral Tenofovir (TDF) (VIREAD ) Oral Second-line agents Pegylated intereron (PegIFN) alfa-2b (Intron ) Injectable Lamivudine (LAM) (Epivir HBV ) Oral Adefovir (ADV) dipivoxil (Hepsera ) Oral Telbivudine (TBV) (Tyzeka ) Oral

19 HBeAg+ HBeAg- Patients, % a,b ADV ETV TDF c d a Marcellin P, et al. Hepatology. 2008;48: b Hadziyannis SJ, et al. Gastroenterology. 2006;131: c Han S et al, Hepatology. 2008;48:705A. d Marcellin P, et al. Hepatology. 2011;54:1011A.

20 HBeAg Seroconversion, % HBeAg Seroconversion, % At 1 Year b >1 Year b PegIFN LAM ADV ETV TBV TDF PegIFN LAM ADV ETV (3.5 y) (3 y) (5 y) (5 y) TBV TDF (4 y) (5 y) c a Not head-to-head trials. b Scaglione SJ, et al. Gastroenterology. 2012;142: c Marcellin P, et al. Hepatology. 2011;54:1011A.

21 60 Year 1 Patients With Seroconversion, % b b c c c Year 2 Year 3 Year 4 Year 5 0 ETV 1-5 TDF 6-9 a Not head-to-head trials; different patient populations and trial designs; b includes only patients from TDF study arm; c includes patients in Year 1 ADV study arm who were switched to TDF at end of Year 1 plus patients who had been on TDF from Day 1. 1 Chang TT, et al. N Engl J Med. 2006;354: Gish R, et al. Gastroenterology. 2007;133: Chao Y-C, et al. Hepatology. 2006;44:229A. 4 Han S, et al. Hepatology. 2007;46:654A. 5 Chang TT, et al. Hepatology. 2010;52: Marcellin P, et al. N Engl J Med. 2008;359: Heathcote EJ, et al. Hepatology. 2008;48:376A. 8 Heathcote EJ, et al. Gastroenterology. 2011;140: Heathcote EJ, et al. Hepatology. 2010;52:556A-557A. 10 Marcellin P, et al. Hepatology. 2011;54:1011A.

22 HBsAg Loss, % HBsAg Loss, % PegIFN (3.5 y) 8 PegIFN (3 y) 3 0 NA 2 LAM ADV ETV (2-3 y) (5 y) (5 y) LAM (4 y) HBeAg+ Patients a 5 NA 5 HBeAg- Patients a ADV (5 y) NA ETV TBV TDF (2 y) (5 y) TBV (2 y) TDF (5 y) a Not head-to-head trials. Scaglione SJ, et al. Gastroenterology. 2012;142:

23 Bridging fibrosis or cirrhosis, HBeAg+/HBV DNA >700,000 meq/ml 25 Increased CTP score, liver failure, or HCC Persons With Disease Progression, % Placebo 21% n = 43 P =.001 n = 173 9% n = 198 n = 385 LAM n = Time to Disease Progression, Months Placebo (n = 215) ITT population LAM (n = 436) P =.001 CTP, Child-Turcotte-Pugh; HCC, hepatocellular carcinoma; ITT, intent to treat. Liaw YF, et al. N Engl J Med. 2004;351:

24 Subjects, % (n = 10) (n = 126) (n = 79) (n = 37) (n = 19) (n = 77) Baseline Ishak Fibrosis Score 96% (335/348) of patients with paired biopsies either improved ( 1 unit decrease in fibrosis score) or did not change at Year 5 96% (318/331) who did not add FTC either improved or did not change at Year 5 98% of patients on TDF treatment had undetectable HBV DNA <400 copies/ml at Year 5 FTC, emtricitabine. Marcellin P, et al. AASLD 2011; San Francisco, CA; November 4-8, Poster Year 5 Response Improvement No change Worsening

25 The patient asks about the SEs of the medication and the safety of the indefinite duration of therapy What would you tell him? SE, side effect.

26 AEs Frequency (n = 1051) Myalgia 54 (5%) Neuropathy 42 (4%) Increased lipase 24 (2%) Increased serum creatinine 8 (<1%) Lactate increase or bicarbonate decrease 6 (<1%) Hypophosphatemia 5 (<1%) Muscular weakness 4 (<1%) Pancreatitis 3 (<1%) Creatinine phosphokinase elevation 2 (<1%) Manns MP, et al. Expert Opin Drug Saf. 2012;11:

27 ETV 31% lactic acidosis in 1 case series of decompensated cirrhosis (particularly MELD 20) 1 TDF 15% decreased bone mineral density in HIV patients 2 Nephrotoxicity, 3 better defined (34%) in HIV patients 4 ADV 3%-21% nephrotoxicity 5-7 TVD 1.4% myopathy, 0.3% peripheral neuropathy 8,9 MELD, model for end-stage liver disease. 1 Lange CM, et al. Hepatology. 2009;50: Vigano et al. Hepatology. 2011;54:1016A. 3 Gara et al. Hepatology. 2011;54:479A. 4 Scherzer R, et al. AIDS. 2012; in press. 5 Schiff E, et al. Liver Transpl. 2007;13: Marcellin P, et al. Hepatology. 2008;48: Hadziyannis SJ, et al. Gastroenterology. 2006;131: Fleischer Rd, et al. J Hepatology. 2009;51: Goncalves J, et al. J Hepatology. 2009;50:S329.

28 Year 1 Year 2 72 Weeks Year 3 Year 4 Year 5 Year 6 LAM 1 23% 46% 55% 71% 80% ADV a,1 0% 3% 11% 18% 29% TBV b,2,3 5% 25% TDF c,4 0% 0% c 0% c 0% c 0% ETV d,5 <1% <1% 1.2% 1.2% 1.2% 1.2% a Naive HBeAg-; b naive HBeAg+; c patients with HBV DNA 400 copies/ml at Week 72 could add FTC to TDF; d cumulative probabilities of resistance taken. 1 Locarnini S. Hepatol Int. 2008;2: ; 2 Lai CL, et al. N Engl J Med. 2007;357: ; 3 Liaw YF, et al. Gastroenterology. 2009;136: ; 4 Marcellin P, et al. Hepatology. 2011;54:1011A-1012A; 5 Tenney DJ, et al. Hepatology. 2009;49:

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30 Efficacy Utility of a medical treatment evaluated under optimal conditions Highly selected, motivated patients Experienced physicians: standardized algorithm for monitoring and management of suboptimal response or breakthroughs Free medications, evaluations, and tests Effectiveness Utility of a medical treatment in routine clinical settings, ie, real life All comers All physicians Costs borne by health insurance and/or patients Scaglione SJ, et al. Gastroenterology.2012;142:

31 Aware of Diagnosis IOM About 35% Diagnosis Referred and Linked to Care About 40%, Lower in Community Screening Programs Evaluation Barriers to Diagnosis and Linkage to Care Providers Knowledge, recognition of risk factors Resources, reimbursement Infected Persons Awareness of risks, consequences, and availability of treatment Fear of social stigmatization Language and cultural barriers Access to care IOM, Institute of Medicine. Scaglione SJ, et al. Gastroenterology. 2012; 142:

32 Meet criteria for treatment Physician knowledge Evaluation Follow-up of those who do not meet criteria for treatment Do not meet criteria for treatment Treatment recommended Patients acceptance Treatment started Concerns about: Need Duration of treatment SEs Costs Scaglione SJ, et al. Gastroenterology. 2012; 142:

33 Virologic Response Patient: Immune status Virus: HBV genotype, baseline HBV DNA Disease: ALT, cirrhosis Medication: potency, genetic barrier to resistance Treatment initiated HBV DNA suppressed Clinical benefit Medication Adherence Tolerance/AEs Affordability/costs Scaglione SJ, et al. Gastroenterology. 2012;142:

34 Phase III clinical trials 13%-100% of patients with VBTs not associated with emergence of drug-resistant mutations Medication nonadherence may be responsible for VBT in these patients Adherence in clinical practice likely lower Patients less motivated, have more comorbid conditions Monitoring less frequent Medications have to be paid for VBT, virologic breakthrough. Scaglione SJ, et al. Gastroenterology. 2012; 142:

35 Pharmacy-claims database in the United States 3 cohorts of CHB patients receiving LAM, ADV, ETV, or TDF (2009 cohort only) in January 2007, 2008, and 2009 followed for 1 year New patients = patients started on treatment in January of that year (n = 458) Existing patients = patients who had been on treatment in the prior year (n = 10,295) Persistence = percentage of patients who continued to refill the medication during that year Adherence = percentage of days during that year in which patients had medications Chotiyaputta W, et al. J Hepatol. 2011;54:12-18.

36 Pharmacy refill rates declined sharply in first 6 months, particularly among patients newly started on treatment Pharmacy refill persisted until the end of the year in: 73.4% of new patients 81.4% of existing patients Chotiyaputta W, et al. J Hepatol. 2011;54: Persistence Rate, % Persistence Rate, % Time, Months Existing Patients LAM (n = 88) ADV (n = 210) ETV (n = 195) TDF (n = 25) ALL (n = 518) Time, Months New Patients LAM (n = 88) ADV (n = 210) ETV (n = 195) TDF (n = 25) ALL (n = 518)

37 New Patients (n = 458) Existing Patients (n = 10,295) >95% %-95% 81%-90% 71%-80% 61%-70% 51%-60% <50% About 20% of patients had <80% adherence over a 1-year study period Chotiyaputta W, et al. J Hepatol. 2011;54:12-18.

38 Prospective study of 111 patients treated in a tertiary liver center Adherence assessed by provider inquiry and patient selfreporting in questionnaire Adherence defined as number of missed doses in past 30 days 73% patients reported 100% adherence in questionnaire 84% patients reported 100% adherence to health care providers Chotiyaputta W, et al. J Hepatol. 2011;54:12-18.

39 20 Patients With VBT Percentage % in 3/3 Adherence <100% in 2/3 <100% in 1/3 Questionnaire Chotiyaputta W, et al. J Viral Hepat. 2012;19:

40 Discontinuation of and nonadherence to HBV nucleos(t)ide analogs during long-term treatment of CHB is common and may result in VBT, treatment failure, and drug resistance Adherence rates reported to health care providers may be inflated

41 Pharmacy Reminders to patients Alerts to health care providers Health care providers Directed inquiries into adherence Education, counseling, repeated emphasis Education materials More frequent clinic visits and drug refills Patients Place medication in a prominent location Take medication at the same time each day Organize medications in a pillbox Family and caregivers Reminders Organize medications in a pillbox

42 Costs Medications (average wholesale price) TDF/ETV x 1 year about $10,000 (copay $240-$3600) Average duration of treatment >5 years PegIFN x 48 weeks $30,000 Lab monitoring HBV DNA, HBeAg, HBsAg Chemistry: ALT (liver panel), creatinine, phosphorus CBC, TSH (for IFN) Physician visits CBC, complete blood count; IFN, interferon; pegifn, pegylated interferon; TSH, thyroid-stimulating hormone.

43 Increasing the effectiveness of HBV management in clinical practice requires: Awareness of the risk for the disease to allow for diagnosis Access to medical care after diagnosis has been made Appropriate evaluation to determine the need for therapy Initiation of appropriate drugs and ability to procure medication Adherence to medication during therapy Continuing access to medical care to allow for consistent monitoring and follow-up during therapy

44 Long-term therapy with nucleos(t)ides requires adherence to medication and the use of drugs with high barrier to resistance Long-term therapy also requires surveillance for AEs of the drugs