Hepatitis B: Chronic Hepatitis and Inactive Carriers - Management Raymond S. Koff, M.D. Clinical Professor of Medicine University of Connecticut Health Science Center Farmington, Connecticut

Epidemiology: United States Chronic HBV Infection Epidemiology: United States HBsAg seroprevalence: 0.2% - 1.0% HBsAg prevalence highest in Asians and Asian-Americans (3-20%) HBsAg prevalence intermediate in African- Americans Accounts for up to 15% of chronic liver disease

Morbidity and Mortality, U.S. Chronic HBV Infection Morbidity and Mortality, U.S. Previously infected individuals: ~10 million Actively infected individuals: ~1-1.25 million (chronic hepatitis B and carriers) Annual cirrhosis deaths: ~4,000 Annual HCC deaths: ~1,000-1,500

Disease Burden of Hepatitis B Infection HBV - Epidemiology U.S. Global Estimated new infections 58,000 Uncertain per year Number of persons with 1.25 million 350 million chronic infection Deaths from chronic liver 5,000 500,000 disease per year Percent ever infected <4.9% 30% Disease Burden of Hepatitis B Infection Slide 63 Disease burden of Hepatitis B infection In the United States, the latest population survey - NHANES III estimated that the prevalence of chronic HBV infection was 0.42% and that of previous infection was 4.9%. It is estimated that 1.25 million Americans have chronic HBV infection and about 5,000 die yearly of complications from chronic hepatitis B. According to the WHO, a third of the world’s population have been exposed to hepatitis B, approximately 350 million persons worldwide have chronic HBV infection, and about 500,000 die yearly from chronic hepatitis B. www.cdc.gov www.who.org McQuillan GM, Coleman PJ, Kruszon-Moran D, et al. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys, 1976 through 1994. Am J Public Health 1999;89:14-8. Kane M. Global programme for control of hepatitis B infection. Vaccine 1995;13:S1:S47-S49. CDC and WHO

Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration Immigration Numbers Summed by Continent From 1996–2002 HBsAg Prevalence High (>8%) Intermediate (2–8%) Low (<2%) ~2 million Asians ~400,000 South Americans ~350,000 Africans ~930, 000 Europeans Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration The frequency of HBV infection and patterns of HBV transmission vary dramatically in different parts of the world. Approximately 45% of the world’s population live in areas where the prevalence of chronic HBV infection is high (>8% of the population is HBsAg positive), 43% live in areas of intermediate prevalence (2% to 7% of the population is HBsAg positive), and only 12% of the world’s population live in areas of low endemicity (<2% of the population is HBsAg positive). In areas of high endemicity, the lifetime risk of HBV infection is >60%. Such areas include most of Asia (except Japan and India), most of the Middle East, the Amazon Basin of South America, most Pacific Island Groups, Africa, and other special populations, such as Native Alaskans, Australian Aborigines, and Maoris in New Zealand. Most infections occur at birth or during early childhood when the risk of acquiring chronic infection is the greatest. There is little recognition of acute disease, as most early childhood HBV infections are asymptomatic. In areas of intermediate endemicity, the lifetime risk of HBV infection is 20% to 60% and infections occur in all age groups. Acute disease is commonly recognized as many infections occur in adolescents and young adults. Additionally, high rates of HBV-related chronic liver disease occur due to the high prevalence of chronic HBV infection. In areas of low endemicity, the lifetime risk of infection is <20% and most infections occur among adults in well-defined risk groups. In the United States, prevalence of HBsAg may be impacted by migratory trends from regions of high endemicity. From 1996 (when the data were gathered for the HBsAg prevalence) to 2002, approximately 1.9 million, 933,000, 337,000, and 401,000 persons have immigrated from Asia, Europe, Africa, and South America, respectively. References World Health Organization. Geographic Prevalence of HBsAg. http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm. Accessed: July 8, 2005. 2002 Yearbook of Immigration Statistics. http://uscis.gov/graphics/shared/aboutus/statistics/yearbook/2002.pdf. Accessed: July 8, 2005. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. World Health Organization. Available at: http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm. Accessed July 8, 2005. 2002 Yearbook of Immigration Statistics. Available at: http://uscis.gov/graphics/shared/aboutus/statistics/yearbook/2002.pdf. Accessed July 8, 2005. Mahoney FJ. Clin Microbiol Rev. 1999;12:351–366.

Estimates of HBV Infectivity in Body Fluids Blood Blood Cervicovaginal secretions Semen Semen Saliva Breast milk Urine CSF Tears Lowest Infectivity Most

HBV Infection Modes of Transmission Transfusion (blood, blood products) Tattoos; Body piercing Mother to infant Hepatitis B Shared needles & syringes Fluids (blood, semen) Transmission of HBV Infection HBV is present in blood, saliva, and semen of infected individuals, with the highest concentration of HBV found in blood and serous fluids.1 The major modes of acquisition of this virus include: Vertical transmission1,2: Mother to baby Horizontal transmission1,2: Blood transfusions Other body fluids (such as semen) Organ and tissue transplantation Contaminated needles and syringes Child to child, or other close physical contact with an infected individual 1. Moyer LA and Mast EE. Hepatitis B: Virology, epidemiology, disease, and prevention, and an overview of viral hepatitis. Am J Prev Med. 1994;10(suppl):45-55. 2. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: Evolving epidemiology and implications for control. Sem Liver Dis. 1991;11:84-92. Please see accompanying complete Prescribing Information. Organs & tissue transplantation Child to child

Risk Factors for Hepatitis B Infection Percutaneous Injection drug use Transfusion or transplant Occupational exposure Parenteral practices Permucosal Perinatal Sexual Household contact Risk Factors for Hepatitis B Infection Slide 65 Risk factors for hepatitis B infection HBV is transmitted by percutaneous and permucosal exposure to infectious blood or body fluids. Although HBsAg has been detected in a wide variety of body fluids, only serum and semen have been demonstrated to be infectious. Percutaneous exposures include injection drug use, transfusion of blood or blood products, organ transplant, needle stick injuries, contacts with contaminated equipment, tattooing, and acupuncture. Permucosal transmission results from sexual contact, perinatal transmission, and mucous membrane exposures to infectious blood or serum among household contact. Alter HJ, Purcell RH, Gerin JL, et al. Transmission of hepatitis B to champanzees by hepatitis B surface antigen positive saliva and semen. Infect Immun 1977;16:928-33. Alter HJ, Holland PV, Morrow AG, et al. Clinical and serological analysis of transfusion-associated hepatitis. Lancet 1975;2:838-41.

Age Distribution in the United States Acute Hepatitis B Age Distribution in the United States Reported cases (%) Age in Years

Risk Factors for Acute HBV infection in the U.S. Injection drug use Men having sex with men Multiple sex partners Sexual contact with HBV carriers Contact with HBV carriers Blood transfusion Occupational / hemodialysis Unknown Slide 66 Risk factors for acute HBV infection in U.S. Injection drug use is the predominant risk factor reported, followed by sexual exposure. Employment in the medical or dental field, blood transfusions, and dialysis account for less than 3% of cases. The widespread use of hepatitis B vaccine among health-care workers has reduced their incidence of hepatitis B, from 9% of reported cases in 1985 to 0.8% in 1994-1995. Although more than half of the cases reported in 1995 denied a recognized exposure, data from the Sentinel Counties study indicate that most persons who deny a specific exposure have some lifetime history of high-risk drug or sexual behaviors. Centers for Disease Control and Prevention: Hepatitis Surveillance Report No. 57. Atlanta, GA:DHHS; Sept. 2000:12. Mast EE, Mahoney FJ, Alter MJ, Margolis HS. Progress toward elimination of hepatitis B virus transmission in the United States. Vaccine 1998;16 S:S48-51. Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination strategies. JAMA 1990;263:1218-22. CDC

Chronic Hepatitis B Natural History Ranges from mild infection (inactive carrier, with normal ALT) to severe chronic liver disease Fibrosis and subsequent cirrhosis Liver failure Hepatocellular carcinoma Premature death Natural History of Chronic Hepatitis B The clinical course of chronic infection with HBV is variable, ranging from mild, asymptomatic infection to severe chronic liver disease. The more serious sequelae of HBV infection include: Fibrosis and subsequent cirrhosis Liver failure Hepatocellular carcinoma (HCC) Mortality Dusheiko G, Hoofnagle JH. Hepatitis B. In: McIntyre N, Benhamou J-P, Bircher J, Mizzetto M, Rodes J, eds. Oxford Textbook of Clinical Hepatology. 1st ed. New York, NY: Oxford University Press, Inc.; 1991:571-592. Please see accompanying complete Prescribing Information.

HBV Disease Progression Acute infection Chronic infection Cirrhosis Death 5–10%1,3 Liver failure 30%1 >90% of children <2% of adults1 25% in 5 years2 Cancer (HCC) Chronic HBV is the 6th leading cause of liver transplantation in the US4 Liver transplant-ation 1. Torresi J. Gastroenterology. 2000;118(2 suppl 1):S83–S103. 2. Fattovich G. Hepatology. 1995;21:77–82. 3. Moyer LA. Am J Prev Med. 1994;10:45–55. 4. Perrillo R. Hepatology. 2001;33:424–432.

Factors Influencing Risk of Cirrhosis Chronic Hepatitis B Higher HBV DNA levels (>104 copies/mL) HBeAg-positivity Persistent ALT elevation HIV, alcohol, immunosuppression Factors Influencing Risk of Cirrhosis Slide 87 Chronic hepatitis B Definition of chronic hepatitis B includes presence of HBsAg in serum for more than 6 months, with evidence of active viral replication (serum HBV DNA more than 105 copies/ml), and active inflammation of the liver (elevated aminotransferases and/or active inflammation on histology). Chronic hepatitis B is divided into HBeAg positive and HBeAg negative. Lok AS and McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-41. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000--summary of a workshop. Gastroenterology 2001;120:1828-53.

Cumulative Incidence of Cirrhosis for Five HBV DNA Categories (n=3,774) 6 5 6.5 4 3 5.6 P value for log-rank test, <0.001 2.5 1.4 1.0 Iloeje UH et al, Gastroenterology 2006;130:678-86: The Taiwan Natural History Study

HBV DNA Levels and Risk of Hepatocellular Carcinoma: The Taiwan Natural History Study* Serum HBV DNA Incidence Adj. Rel Risk p (copies/mL) (per 100,000) >1.0 x 106 1150 11.6 <.001 >1.0 x 105 - <1.0 x 106 952 7.2 <.001 >1.0 x 104 - <1.0 x 105 315 2.4 <.008 >300 - <1.0 x 104 112 0.9 NS <300 145 1.0 --- Slide 87 Chronic hepatitis B Definition of chronic hepatitis B includes presence of HBsAg in serum for more than 6 months, with evidence of active viral replication (serum HBV DNA more than 105 copies/ml), and active inflammation of the liver (elevated aminotransferases and/or active inflammation on histology). Chronic hepatitis B is divided into HBeAg positive and HBeAg negative. Lok AS and McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-41. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000--summary of a workshop. Gastroenterology 2001;120:1828-53. * Chen C-J et al. JAMA, 2006

Hepatocellular Carcinoma Among solid tumors, 5th highest incidence worldwide and 3rd most common cause of cancer deaths In the U.S. in 2007, 13th most common cancer and increasing faster than all others from 1995 to 2004; 8th most common cause of cancer deaths Despite advancing technology and available treatments, 5-year survival rates are generally less than 5%

Strategies for Eliminating HBV Transmission in the U.S. Maternal screening for HBsAg and providing post-exposure prophylaxis to infants of HBsAg-positive women Routine vaccination of all infants Catch-up vaccination for children aged <19 yrs Targeting high risk children, adolescents, adults

Natural History of Chronic Hepatitis B Annual risk of Phase of disease cirrhosis Chronic hepatitis B: HBeAg-positive ~2-6 % HBeAg-negative ~8-10% Inactive carrier: ~0.5%

Inactive HBsAg Carriers Chronic HBV Infection Inactive HBsAg Carriers HBsAg-positive/HBeAg-negative Normal serum ALT levels <104 copies/mL by PCR Generally mild histology Absence of evidence of effective therapy Very low risk of progression Management of Chronic Hepatitis B The goals of managing patients with chronic hepatitis B are: Suppression of viral replication Improvement in hepatic necroinflammatory disease Reduction in the likelihood of long-term sequelae of HBV infection, such as cirrhosis and hepatocellular carcinoma Please see accompanying complete Prescribing Information.

Natural History of HBV: Development of HBeAg-Negative Chronic HBV Hadziyannis SJ, Vassilopoulos D. Hepatology. 2001;34(4 pt 1):617–624.

Natural History of HBeAg-positive Disease Chronic Hepatitis B Natural History of HBeAg-positive Disease Annual Change in Status Probability Chronic hepatitis B cirrhosis ~ 2-6 % Cirrhosis decompensation ~ 6 % Cirrhosis hepatocellular ~ 2.5 % carcinoma Hepatocellular carcinoma death ~ 85%

Natural History of HBeAg-negative Disease Chronic Hepatitis B Natural History of HBeAg-negative Disease Older than HBeAg-positive patients Lower circulating HBV DNA levels More extensive hepatic injury Lower rates of spontaneous remission Pre-core and/or core promoter mutants in 90%

HBsAg Present? Is IgM anti-HBc present? Is HBeAg or HBV DNA present? Yes Is IgM anti-HBc present? No No Yes Chronic hepatitis Acute hepatitis Is HBeAg or HBV DNA present? Is anti-HBs present? Yes No Yes No Replicative HBV infection Nonreplicative HBV infection (carrier) Recovered/vaccinated ± anti-HBc No HBV infection

Evaluation of the HBsAg-positive Patient HBV DNA level HBeAg/anti-HBe status Serum ALT Clinical/laboratory/imaging evidence of cirrhosis or HCC Testing for viral resistance/genotype ?Histology

Treatment of Chronic HBV

Candidates for Treatment Chronic Hepatitis B Candidates for Treatment Elevated or Normal ALT levels and: HBeAg-positive and HBV DNA ≥105 copies/mL by PCR HBeAg-negative and HBV DNA ≥104 copies/mL by PCR Cirrhosis with detectable HBV DNA Management of Chronic Hepatitis B The goals of managing patients with chronic hepatitis B are: Suppression of viral replication Improvement in hepatic necroinflammatory disease Reduction in the likelihood of long-term sequelae of HBV infection, such as cirrhosis and hepatocellular carcinoma Please see accompanying complete Prescribing Information.

Goals of Therapy HBeAg-positive HBeAg-negative Suppression of HBV DNA to low or undetectable levels HBeAg loss  seroconversion Sustained response after seroconversion ALT normalization HBsAg loss ± seroconversion HBeAg-negative Suppression of HBV DNA to low or undetectable levels and ALT normalization HBeAg seroconversion not an endpoint Goals of Therapy: Two Distinct Patient Populations Taking into account the available data, the panel recommends that patients be treated after HBeAg seroconversion as long as HBV levels are decreasing until they have undetectable HBV DNA levels by PCR. The endpoint of therapy for HBeAg-negative patients with chronic HBV infection is more difficult to assess than for HBeAg-positive patients because HBeAg seroconversion cannot be used. Thus HBV DNA suppression and ALT level normalization are the only practical measures of response to therapy. Reference Keeffe et al. Clin Gastroenterol Hepatol. 2004;2:87-106.

HBV Treatment Options in 2008 Pegylated interferon alfa-2a Interferon alfa-2b Nucleoside analogs Entecavir Lamivudine Telbivudine Nucleotide analog Adefovir Tenofovir

Comparing Oral Antivirals and Interferon Chronic Hepatitis B Comparing Oral Antivirals and Interferon Orals IFN Oral administration: Yes No Side effects: minimal frequent Duration of treatment: prolonged finite Flares during treatment: rare yes Resistant mutant: yes no Impact of genotype: no yes Rate of HBsAg clearance: low higher

Interferon Therapy for HBeAg-positive HBV: Long-term Follow-up* Meta-analysis of 12 studies (n=1975) 765 interferon treated/1210 untreated Follow-up range: 2.1–8.9 yrs (mean 6.1)† Distribution of probabilities: Interferon Untreated Loss of HBsAg 11.4% 2.6% Disease decompensation 9.9% 13.3% Development of HCC 1.9% 3.2% Liver-related death 4.9% 8.7% *Long term response in treatment-free follow-up †Treatment duration: 4–6 months Craxi et al. EASL 2002.

Length of Therapy (month) Effect of Lamivudine on Incidence of HCC in Chronic HBV and Advanced Fibrosis P = 0.047 Placebo 10 Diagnosis of HCC (%) Lamivudine Incidence of HCC in Cirrhotics In the study headed by Liaw et al, 651 patients with CHB with histologically confirmed cirrhosis or advanced fibrosis were randomized (2:1, active treatment: placebo). The study was planned for a maximum of 5 years. The primary end point of the trial was time to disease progression, which was defined by hepatic decomposition, HCC, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. The study was terminated at a median duration of treatment of 32.4 months, owing to a significant difference in the primary endpoint between the active treatment arm and placebo. HCC occurred in 17 (3.9%) patients in the active treatment group and in 16 (7.4%) patients in the placebo arm (P = .047). The hazard ratio was 0.49. Reference Liaw YF, Sung JJY, Chow WC, et al. N Engl J Med. 2004;351:1521-1531. 6 12 18 24 30 36 Length of Therapy (month) Liaw YF, et al. N Engl J Med 2004;351:1521–1531.

Comparing Oral Agents and Peg-IFN alfa-2a Chronic Hepatitis B , HBeAg-Positive Comparing Oral Agents and Peg-IFN alfa-2a 1-year of Treatment Seroconversion HBeAg HBsAg Lamivudine: 18% 0% Telbivudine: 22% 0% Adefovir: 12% 0% Entecavir: 21% 0% Tenofovir: 21% 3% Peg-IFN alfa-2a: 32% 3%

Comparing Oral Agents and Peg-IFN alfa-2a Chronic Hepatitis B Comparing Oral Agents and Peg-IFN alfa-2a 1-year of Treatment HBV DNA <300-400 cp/mL at end of Rx Lamivudine: 38% Telbivudine: 60% Adefovir: 21% Entecavir: 69% Tenofovir: 80% Peg-IFN alfa-2a: 25-63%

Adefovir: Long-Term Efficacy in HBeAg-positive Patients Serum HBV <400 Copies/mL HBeAg Seroconversion Loss ALT Normalization Two patients (3.1%) developed resistance (N236T, 1; A181V, 1) through week 144. Kaplan Meier estimates of time to confirmed event. Marcellin P, Asselah T. J Hepatol. 2005;43:920–923.

HBsAg loss was 5% at 96 weeks for entecavir. Entecavir: Average Response Rates in Chronic Hepatitis B (HBeAg Positive) at 2 years of Treatment Entecavir 0.5 mg (n = 314 nucleoside- naïve patients) Lamivudine 100 mg (n = 314 nucleoside-naïve patients) Response at 96 Weeks (%) HBsAg loss was 5% at 96 weeks for entecavir. Gish B, et al. AASLD. 2005. Abstract 181.

Current Treatment Strategies Clinical Form Drug Therapy Chronic hepatitis B: PEG-IFN alfa-2a or tenofovir, entecavir, adefovir, telbivudine, lamivudine or ?combinations HBV-cirrhosis Compensated: same as above Decompensated: tenofovir, entecavir, adefovir, telbivudine, lamivudine, or transplantation

Key Issues in HBV Therapy Efficacy Duration of therapy Resistance Combination therapy Genotyping

Manifestations of Antiviral Resistance HBV DNA 8 ALT 6 Hepatitis flare Viral breakthrough HBV DNA (log10 IU/mL); ALT (U/L) 4 Biochemical breakthrough Genotypic resistance Is this correct -- that the units for both DNA and ALT can use the same 0-8 scale? 2 Upper limit of normal -1 1 2 3 Length of Antiviral Therapy (year)

The Risk of Resistance Antiviral potency: the emergence of resistant mutants is reduced when viral replication is highly suppressed – no virus, no resistance Genetic barrier: the number of mutations required to decrease susceptibility to an antiviral drug Viral fitness: the ability of a mutant virus to replicate

Cumulative Incidence of HBV Genotypic Resistance ADV resistance1 LAM resistance2 ETV resistance in LAM-refractory pts3 Incidence of Resistance (%) 71% 20 40 60 80 Year 1 Year 2 Year 3 Year 4 LAM ADV 29%-42%4 ETV 25% Year 5 Hepsera exhibits an excellent resistance profile over long-term treatment with no resistance at Year 1 and small increases over time. 10% ETV in naïve:<1% 1. Qi YL, et al. EASL. 2005. Abstract 57. 2. Lai CL, et al. Clin Infect Dis. 2003;36:687–696. 3. Tenney DJ, et al. AASLD. 2004. Abstract 184. 4. In HBeAg-negative pts; higher resistance in HBeAg-positives

Antiviral-Resistant HBV: Treatment Recommendations Resistant Drug Rescue Therapy Lamivudine-R Add adefovir (may be preferred over switch) Switch to entecavir (risk of entecavir-R) Add tenofovir or switch to FTC/tenofovir Adefovir-R Add lamivudine (may be preferred over switch) Switch to entecavir (if no prior lamivudine-R) Switch to FTC/tenofovir Entecavir-R Add or switch to adefovir or tenofovir Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936–962.

HBV Roadmap Schema CVR PVR IVR Assessment of Primary Non-Response at week 12 Early Predictors of Efficacy at week 24 CVR PVR IVR PCR- negative (<50 copies/mL) <103 copies/mL <104 copies/mL ≥104 copies/mL

Current and FutureTreatment of HBV Patients Focus on HBV DNA suppression Treatment decisions based on HBV DNA levels, disease severity, drug efficacy and resistance patterns (for oral agents) Combination oral therapy emerging New agents with prolonged activity after end-of-treatment, e.g. clevudine, may become available