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Viral Hepatitis: State of the Art

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Viral Hepatitis: State of the Art

  1. 1. Viral Hepatitis: State of the Art Rudy Rai, MD Gastroenterology & Hepatology
  2. 2. Human Hepatitis Viruses <ul><li>Enterically Transmitted </li></ul><ul><ul><li>HAV </li></ul></ul><ul><ul><li>HEV </li></ul></ul><ul><li>Percutaneous/ permucosally Transmitted </li></ul><ul><ul><li>HBV </li></ul></ul><ul><ul><li>HCV </li></ul></ul><ul><ul><li>HDV </li></ul></ul><ul><li>Non-Hepatotrophic agents </li></ul><ul><ul><li>SEN </li></ul></ul><ul><ul><li>TTV </li></ul></ul><ul><ul><li>HGV </li></ul></ul><ul><ul><li>? </li></ul></ul>*DNA viruses *RNAViruses
  3. 3. Other agents in Acute Hepatitis (non A-E) <ul><li>CMV </li></ul><ul><li>EBV </li></ul><ul><li>VZV </li></ul><ul><li>HSV </li></ul><ul><li>Parvovirus B19 </li></ul><ul><li>Reovirus </li></ul><ul><li>Mumps </li></ul><ul><li>Yellow fever </li></ul><ul><li>Coxsackie B </li></ul><ul><li>Syncytial Giant cell </li></ul><ul><li>Adenovirus </li></ul><ul><li>Rubella </li></ul><ul><li>Hemorrhagic fevers </li></ul>
  4. 4. Hepatitis A Virus <ul><li>Single strand RNA virus </li></ul><ul><li>Family: Picornaviridae </li></ul><ul><li>Genus: Hepatovirus </li></ul><ul><li>Phases </li></ul><ul><ul><li>Replicative </li></ul></ul><ul><ul><li>Necroinflammatory </li></ul></ul><ul><li>Outcome </li></ul><ul><ul><li>Worse in older patients </li></ul></ul><ul><ul><li>Mild in children </li></ul></ul><ul><ul><li>Superinfection in Hep C (40% mortality) </li></ul></ul>
  5. 5. Hepatitis A: Age Dependent Jaundice <6 6-14 >14 Age in Years Anicteric Icteric
  6. 6. Acute Hepatitis A: Age specific Case Fatality Rates 0-14 15-39 40-49 >50 0.1 0.4 1.1 2.7 Case Fatality Rate (%) Age in Years
  7. 7. Hepatitis A <ul><li>HAV vaccine protects against all human HAV strains </li></ul><ul><li>No reservoir of viremic/intestinal “carriers” </li></ul><ul><li>Infection occurs from acutely infected to susceptibles </li></ul><ul><li>Oral-fecal transmission </li></ul><ul><ul><li>Water </li></ul></ul><ul><ul><li>Food- seafood, mollusks </li></ul></ul><ul><ul><li>Intimate </li></ul></ul><ul><ul><li>Institutional </li></ul></ul><ul><ul><li>Household </li></ul></ul>
  8. 8. Hepatitis A: Sequence Fecal HAV Serum HAV Elevated ALT ! 30 ! 90 ! 60 Days after Exposure IgG IgM
  9. 9. Hepatitis A vaccine: Recommendations ACIP (1999) <ul><li>Community attack rate >20/100,000 </li></ul><ul><ul><li>consider routine childhood vaccination </li></ul></ul><ul><li>High HAV Endemic areas </li></ul><ul><ul><li>Travelers, military, Native Americans </li></ul></ul><ul><li>Outbreaks </li></ul><ul><ul><li>Children/young adults </li></ul></ul><ul><li>Other </li></ul><ul><ul><li>Chronic liver disease </li></ul></ul><ul><ul><li>IDUs </li></ul></ul><ul><ul><li>Men who have sex with men </li></ul></ul><ul><ul><li>Patients with clotting factor disorders </li></ul></ul>
  10. 10. Parvovirus B19 <ul><ul><li>Erythema infectiosum </li></ul></ul><ul><ul><li>Acute Hepatitis </li></ul></ul><ul><ul><li>Fulminant liver failure </li></ul></ul><ul><ul><li>Transient dysfunction </li></ul></ul><ul><ul><li>Aplastic anemia </li></ul></ul>
  11. 11. Herpes Simplex <ul><ul><li>Immunocompromised or pregnant </li></ul></ul><ul><ul><li>Diagnosis: IgM Ab </li></ul></ul><ul><ul><li>Mucocutaneous lesions/ DIC common </li></ul></ul><ul><ul><li>Liver Biopsy: confluent coagulative necrosis, eosinophilic ground-glass inclusions w/clear halo </li></ul></ul><ul><ul><li>Rx: Acyclovir, OLTx </li></ul></ul><ul><ul><li>20-40% survival </li></ul></ul>
  12. 12. Hepatitis E <ul><ul><li>Developing world </li></ul></ul><ul><ul><li>Largely waterborne </li></ul></ul><ul><ul><li>Incubation 6-7 weeks </li></ul></ul><ul><ul><li>Virus shed 2-3 weeks before symptoms </li></ul></ul><ul><ul><li>Transient ALT elevation </li></ul></ul><ul><ul><li>*** Pregnant- Acute Liver Failure </li></ul></ul>
  13. 13. Treatment <ul><li>Hepatitis A and E </li></ul><ul><ul><li>No chronic form </li></ul></ul><ul><ul><li>May need supportive care </li></ul></ul><ul><ul><li>Passive (Immunoglobin) and/or active (Hep A vaccine) immunization for contacts in infectious period </li></ul></ul><ul><ul><li>Recommend preventative vaccine for Hep A w/underlying liver disease* </li></ul></ul><ul><ul><li>Caution for pregnant women traveling to Hep E endemic areas* </li></ul></ul>
  14. 14. Serodiagnosis of Acute Viral Hepatitis <ul><li>Hepatitis A </li></ul><ul><ul><li>HAV IgM </li></ul></ul><ul><li>Hepatitis B </li></ul><ul><ul><li>HBSAg(+); HBCore Ab IgM (+) </li></ul></ul><ul><li>Hepatitis C </li></ul><ul><ul><li>HCV RNA (PCR/TMA); HCV Ab (50-60%) </li></ul></ul><ul><li>Hepatitis D </li></ul><ul><ul><li>HDV Ab IgM; HepBSAg (+)* </li></ul></ul><ul><li>Hepatitis E </li></ul><ul><ul><li>HEV Ab IgM </li></ul></ul>
  15. 15. Model of Human Hepatitis C Virus Lipid Envelope Capsid Protein Nucleic Acid Envelope Glycoprotein E2 Envelope Glycoprotein E1 Reprinted with permission. Henderson, LE. Available at www.hepcprimer.com.
  16. 16. Projected Public Health Burden for HCV <ul><li>The HCV disease burden is projected to peak with an estimated 14,000-19,000 deaths/year </li></ul>Year Deuffic-Burban et al. AASLD; October 24-28, 2003; Boston, MA. Abstract 552. 0 10000 20000 30000 40000 50000 60000 1990 2010 2030 2050 2070 HCV-related mortality, maximal HCV-related mortality, minimal HIV-related mortality, maximal HIV-related mortality, minimal Annual Incidence
  17. 17. Hepatitis C: A Global Health Problem United States 3-4 M Americas 12-15 M Africa 30-40 M Southeast Asia 30-35 M Australia 0.2 M World Health Organization. Weekly epidemiological record. 1999;74:421-428. Western Europe 5 M 170-200 Million (M) Carriers Worldwide Eastern Europe 10 M Far East Asia 60 M
  18. 19. Prevalence of HCV Infection: United States 1990 Alter et al. N Engl J Med . 1999;341:556-562. Anti-HCV+ (%) 0 1 2 3 4 5 6 7 Age (yr) Mexican American Caucasian 3.5% 1.1% African American 3.2% 6–11 12–19 20–29 30–39 40–49 50–59 70+ 60–69
  19. 22. Shiffman et al. J Infect Dis . 2000;182:1595-1601. Elevated ALT Normal ALT Cirrhosis 22% No Fibrosis (KS<5) 19% Inflammation (KS>5) 19% Portal 24% Bridging 16% No Fibrosis (KS<5) 40% Portal 26% Cirrhosis 6% Bridging 6% Inflammation (KS>5) 23% KS, Knodell score. Liver Histology in Patients With Elevated and Normal Serum ALT
  20. 23. Hepatitis C Scenarios <ul><li>HCV Ab </li></ul><ul><li>+ </li></ul><ul><li>- </li></ul><ul><li>+ </li></ul><ul><li>+ </li></ul>HCV RIBA + -/+ - + HCV PCR - + - + Interpretation True Ab, cleared infxn True infxn, Immune deficiency False + Ab, infants Chronic Infxn
  21. 25. Type 1 IFNs: Exhibit Multiple Activities Stark GR, et al. Annu Rev Biochem . 1998;67:227-264. Theofilopoulos AN, et al. Annu Rev Immunol . 2005;23:307-335. Brierley M, et al. J Interferon Cytokine Res. 2002;22:835-845. 0 Many cell types B lymphocytes Immunoregulatory Activity Proliferation, differentiation, activation of different cell types heavily involved in immune responses Natural killer cells T lymphocytes Activation Proliferation Survival Dendritic cells Muscle Fibroblasts Antifibrotic Antiviral Activity Many cell types Adipocytes IFN  /  Antiangiogenic Antiproliferative Activity
  22. 26. Neumann AU, et al. Science . 1998;282:103-107; Dixit NM, et al. Nature. 2004;432:922-924. Biphasic Decline of HCV Load During IFN  -2 b (10 mIU QD) Therapy Viral Load (log 10 HCV RNA eq/mL) Days of Therapy Block in virus production: direct action of ISGs 0 Lag period: 4 – 12 hr (ISG expression) Clearance of infected cells: immune cell modulation Many weeks- months; selection for escape mutants 3 4 5 6 7 1 5 10 14 Ribavirin works in synergy with IFN during phase 2, especially in hard-to-treat patients
  23. 28. <ul><li>Disease acquisition at >40 years </li></ul><ul><li>Male gender </li></ul><ul><li>HIV coinfection </li></ul><ul><li>HBV coinfection </li></ul><ul><li>Fatty liver disease </li></ul>Factors That Speed Progression of Liver Disease Not Within Patient’s Control Hezode et al. EASL; April 14-18, 2004; Berlin, Germany. Abstract 68. Ivanova et al. EASL; April 14-18, 2004; Berlin, Germany. Abstract 484. NIH Consensus Development Conference Statement. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Poynard et al. Lancet. 1997;349:825-832.
  24. 30. <ul><li>ALT </li></ul><ul><li>Viral load </li></ul><ul><li>Mode of transmission </li></ul><ul><li>Genotype </li></ul>Factors That Do NOT Speed Progression of Liver Disease NIH Consensus Development Conference Statement. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Poynard et al. Lancet . 1997;349:825-832.
  25. 31. Role of Liver Biopsy <ul><li>Confirm clinical diagnosis </li></ul>Brunt et al. Hepatology . 2000;31:241-246. Assess severity of necroinflammation Evaluate possible concomitant disease processes Assess therapeutic intervention Assess fibrosis Utility of Liver Biopsy
  26. 32. Hepatic Histopathologic Evaluation <ul><ul><ul><li>Measure of severity and ongoing disease activity </li></ul></ul></ul><ul><ul><ul><li>May fluctuate with disease activity or therapeutic intervention </li></ul></ul></ul><ul><ul><ul><li>Indicates long-term disease progression </li></ul></ul></ul><ul><ul><ul><li>Relatively constant in relation to disease activity or therapeutic intervention </li></ul></ul></ul>Stage Fibrosis Brunt et al. Hepatology. 2000;31:241-246. Grade Necro- inflammation
  27. 33. Progression of Fibrosis on Biopsy No Fibrosis Stage 1: Fibrous expansion of some portal areas Stage 3: Fibrous expansion of most portal areas with occasional portal to portal bridging Stage 4: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) Stage 5,6: Cirrhosis, probable or defined Cirrhotic liver: Gross anatomy of cadaver Courtesy of Gregory Everson, MD.
  28. 34. Knodell Ishak METAVIR Absent 0 0 0 Portal fibrosis (some) 1 1 1 Portal fibrosis (most) 1 2 1 Bridging fibrosis (few) 3 3 2 Bridging fibrosis (many) 3 4 3 Incomplete cirrhosis 4 5 4 Cirrhosis 4 6 4 Hepatic Fibrosis Scoring Systems Brunt. Hepatology . 2000;31:241-246.
  29. 35. 0 10 20 30 1 2 3 4 Duration of infection (y) Fibrosis stage SLOW Women <40 years of age Alcohol <50 g/d RAPID Men >40 years of age Alcohol >50 g/d MEDIUM Rates of Fibrosis Progression Marcellin P, et al. Hepatology. 2002;36:S47-S56. 0
  30. 36. Serum Fibrosis Markers Is This a Viable Option to Liver Biopsy? <ul><li>Minimally-invasive algorithmic-based serum marker assays are being evaluated </li></ul><ul><ul><li>HCV FIBROSURE™ (LabCorp ® ) </li></ul></ul><ul><ul><li>FibroSpect SM (Prometheus Laboratories) </li></ul></ul><ul><li>Accurately reflect mild fibrosis </li></ul><ul><li>No utility demonstrated with intermediate fibrosis </li></ul><ul><li>Role in patient management remains controversial </li></ul>Poynard et al. 54th AASLD. October 24 - 28, 2003. Boston, Mass. Abstract 3. Ratziu et al. 39th EASL. April 14-18, 2004. Berlin, Germany. Abstract 597.
  31. 37. Treatment for Hepatitis C
  32. 38. Goals of Antiviral Therapy Viral clearance Prevent HCC Delay decompensation Prevent HCV recurrence after liver transplantation Target the disease Target the virus
  33. 39. Sustained Responder Nonresponder Relapser Nonresponder HCV RNA negative Time (wks) HCV RNA 12 24 48 72 Identifying Nonresponders and Relapsers: HCV Patterns of Response to Therapy Adapted from: Davis GL, et al. Hepatology. 2003;38:645-652. Fried MW, et al. N Engl J Med. 2002;347:975-982. 0
  34. 40. FDA Approved, Marketed HCV Drugs Pawlotsky JM, et al. Hepatology. 2004;39:554-567. *Ribavirin is not approved for monotherapy, but as part of combination with interferon alfa † Interferon relapsers and nonresponders 0.8 – 1.2 g/day, PO 0.8 – 1.2 g/day, PO Copegus ® (Roche) Rebetol ® (Schering-Plough) Ribavirin* 1.0 – 1.5  g/kg QW, SC Peg-Intron ® (Schering-Plough) Peginterferon alfa-2b 180  g QW, SC Pegasys ® (Roche) Peginterferon alfa-2a 9  g TIW, SC 15  g TIW, SC † Infergen ® (InterMune) Interferon alfacon-1 3 MU TIW, SC Intron A ® (Schering-Plough) Interferon alfa-2b 3 MU TIW, SC Roferon-A ® (Roche) Interferon alfa-2a Dosing Name (manufacturer) Product
  35. 41. SVR Rates in HCV Populations AA genotype 1 0 10 20 30 40 50 60 HCV Genotype 1 HVL (all genotypes) Advanced fibrosis and cirrhosis (stages 3 and 4) HIV/HCV HIV/HCV genotype 1 52% - 53% 41% - 44% 42% - 53% 43% - 44% 27% - 40% 17% - 9% 19% - 26% ITT Populations SVR (%) 0 SVR=sustained virologic response; HCV=hepatitis C virus; HIV=human immunodeficiency virus; ITT=intent-to-treat. Torriani FJ, et al. N Engl J Med. 2004;351:438-450. Jeffers LJ, et al. Hepatology. 2004;39:1702-1708. Carrat F, et al. JAMA. 2004;292:2839-2848. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. Fried MW, et al. N Engl J Med. 2002;347:975-982. Manns MP, et al. Lancet. 2001;358:958-965.
  36. 42. Key HCV Treatment Trials QW, once a week; TIW, three times a week; wks, weeks. Fried et al. N Engl J Med . 2002;347:975-982. Hadziyannis et al. Ann Int Med. 2004;140:346-357. Manns et al. Lancet. 2001;358:958-965. <ul><li>24 vs 48 weeks of therapy (N = 1311) </li></ul><ul><ul><li>PEG IFN 180 μ g + RBV 1000-1200 mg QD </li></ul></ul><ul><ul><li>PEG IFN 180 μ g + RBV 800 mg QD </li></ul></ul>Hadziyannis et al ( 2004) PEG IFN alfa-2a/ RBV 800/1000-1200 <ul><li>48 weeks of therapy (N = 1121) </li></ul><ul><ul><li>PEG IFN 180 μ g + RBV 1000-1200 mg PO QD </li></ul></ul><ul><ul><li>IFN alfa-2b 3 MU SC TIW + RBV 1000-1200 mg PO QD </li></ul></ul><ul><ul><li>PEG IFN 180 μ g SC QW + Placebo </li></ul></ul>Fried et al (2002) PEG IFN alfa-2a/ RBV 1000-1200 <ul><li>48 weeks of therapy (N = 1530) </li></ul><ul><ul><li>PEG IFN 1.5 µ g/kg + RBV 800 mg/day </li></ul></ul><ul><ul><li>PEG IFN 1.5 µ g/kg (4 wks), then 0.5 µ g/kg (44 wks) + RBV 1000-1200 mg/day </li></ul></ul><ul><ul><li>IFN alfa-2b 3 MU TIW + RBV 1000-1200 mg/day </li></ul></ul>Manns et al (2001) PEG IFN alfa-2b/ RBV 800
  37. 45. HCV RNA Structure Structural Non-Structural Structure Processing Replication 5 ' UTR IRES, Translation Transcription, Replication IRES = internal ribosomal entry site; UTR = untranslated region; C = nucleocapsid core; E1 = envelope protein 1; E2 = envelope protein 2; NS = non-structural Hoofnagle JH. Hepatology. 2002;36(5 suppl 1):S21-S29. 3 ' UTR C E1 E2 Nucleocapsid, Assembly Envelope Proteins, Assembly and Entry p7 Calcium Channel? NS2 NS3 NS4A Protease Serine Protease, Helicase NS3 cofactor NS4B NS5A NS5B Replication? Phosphoprotein, Replication RNA-dependent RNA polymerase
  38. 46. Potential HCV Therapies R803 Rigel Amantadine Endo Labs Solvay Multiferon Viragen Omega IFN Biomedicine ISIS 14803 Isis ANA245 ANADYS Albuferon Human Genome Sciences VX-950 Vertex HCV-086 ViroPharma/ Wyeth Phase III Phase II Phase I Viramidine Valeant Zadaxin SciClone Infergen/gamma IFN InterMune Oral IFN alpha Amarillo Biosciences NM283 Idenix JTK 003 AKROS Pharma HCV/MF59 Chiron SCH-6 Schering Civacir NABI HepX-C XTL IDN-6556 Idun VX-497 Vertex Ceplene Maxim Time to Market E-1 Innogenetics IP-501 Indevus REBIF Ares-Serono
  39. 47. Side Effects of Interferon <ul><li>Flu-like symptoms </li></ul><ul><ul><li>Headache </li></ul></ul><ul><ul><li>Fatigue or asthenia </li></ul></ul><ul><ul><li>Myalgia, arthralgia </li></ul></ul><ul><ul><li>Fever, chills </li></ul></ul><ul><li>Neuropsychiatric disorders </li></ul><ul><ul><li>Depression </li></ul></ul><ul><ul><li>Mood lability </li></ul></ul><ul><li>Alopecia </li></ul><ul><li>Thyroiditis </li></ul><ul><li>Nausea </li></ul><ul><li>Diarrhea </li></ul><ul><li>Injection-site reaction </li></ul><ul><li>Lab alterations </li></ul><ul><ul><li>Neutropenia </li></ul></ul><ul><ul><li>Anemia </li></ul></ul><ul><ul><li>Thrombocytopenia </li></ul></ul>
  40. 48. Side Effects of Ribavirin <ul><li>Hemolytic anemia </li></ul><ul><li>Teratogenicity </li></ul><ul><li>Cough and dyspnea </li></ul><ul><li>Rash and pruritus </li></ul><ul><li>Insomnia </li></ul><ul><li>Anorexia </li></ul>Rebetron  [package insert]. Kenilworth, NJ: Schering Corp; 2002.
  41. 49. Predictors of SVR <ul><li>Gt 2 </li></ul><ul><ul><li>Gt 3 more difficult to treat than Gt 2 </li></ul></ul><ul><li>Low baseline viral load </li></ul><ul><li>Early virologic response, Week 12-24 </li></ul><ul><ul><li>Modifiable through adherence </li></ul></ul><ul><li>Absence of cirrhosis </li></ul><ul><li>Female gender </li></ul><ul><li>Aged  40 years </li></ul><ul><li>Low hepatic iron stores </li></ul><ul><li>Short duration of disease (<5 years) </li></ul>Fried et al. N Engl J Med . 2002;347:975-982. Hadziyannis et al. Ann Int Med . 2004;140:346-357. Mangia et al. EASL; April 14-18, 2004; Berlin, Germany. Abstract 93. Manns et al. Lancet. 2001;358:958-965. McHutchison et al. Hepatology. 2000;32:223A. Poynard et al. Hepatology . 2000;31:211-218. Zeuzem et al. N Engl J Med . 2000;342:1666-1672.
  42. 50. Summary <ul><li>Hepatitis C is a complex but treatable disease </li></ul><ul><li>Early identification is key </li></ul><ul><li>Normal ALT does not equal mild or no disease </li></ul><ul><li>Treatment modalities are rapidly evolving </li></ul>
  43. 51. Hepatitis B
  44. 52. Chronic Hepatitis B <ul><li>Tenth leading cause of death worldwide </li></ul><ul><li>400 million worldwide </li></ul><ul><li>1.25 million in the US </li></ul><ul><ul><li>4 million in Western Europe </li></ul></ul><ul><ul><li>80% of HBV carriers in Asia </li></ul></ul><ul><li>4,000 to 5,500 deaths annually in the US </li></ul><ul><li>In ~30% of patients with chronic HBV </li></ul><ul><ul><li>Infection, cirrhosis or HCC will develop </li></ul></ul>
  45. 53. Hepatitis B – Historical perspective MMWR. 2004;52:1252-1254. HepB.Org . Available at: www.hepb.org/professionals/approved_hbv_drugs.htm. Accessed: June 16, 2005. <ul><li>Vaccine recommended for adults and adolescents with significant risk factors </li></ul><ul><li>Mass immunizations implemented in infants, pregnancy screening, infant post-exposure perinatal prophylaxis </li></ul><ul><li>Lamivudine first oral therapy approved </li></ul><ul><li>Adefovir approved </li></ul>2005 <ul><li>E ntecavir approved </li></ul><ul><li>Peginterferon alfa-2a injectable approved </li></ul><ul><li>α -interferon injection first treatment for hepatitis B approved </li></ul>1982 1991 1998 2002 Year
  46. 54. Questions Asked Before Treating <ul><li>Who do I treat? </li></ul><ul><li>HBV DNA (+) </li></ul><ul><li>HBeAg (+) or (-) </li></ul><ul><li>Elevated ALT or AST </li></ul><ul><li>Liver biopsy evidence of chronic hepatitis </li></ul><ul><li>What do I use? </li></ul><ul><li>Nucleoside? Which? </li></ul><ul><li>Interferon? </li></ul><ul><li>Combination therapy ? </li></ul>
  47. 55. Nucleoside Analogues Pros Cons Oral administration Long duration of treat- ment ( > 1 yr )“virustatic” Minimal side effects Drug-resistant mutants Useful in decompensated Type of response differs c irrhosis and post-OLT from IFN (HBsAg loss rare) Much less expensive Post-withdrawal ALT than IFN flares ( ~20-25%)
  48. 56. Incidence of Lamivudine Resistance in Chronic HBV Infection Percent Lamivudine Resistant Resistance > HBeAg loss Years of Lamivudine 90% HIV- Pos 53% 20% 49% 67% 38% 0% 20% 40% 60% 80% 1 2 3 4
  49. 57. Chronic Hepatitis B Treatment Options <ul><li>Interferon/ PEG IFN- FDA approved Jul 2005* </li></ul><ul><li>Nucleoside Analogues </li></ul><ul><ul><ul><ul><li>Lamivudine </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Adefovir </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Entecavir - FDA approved in Mar 2005 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Emtricitabine ** </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Tenofovir ** </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Telbivudine - Phase III enrollment completed </li></ul></ul></ul></ul>** Off label use
  50. 58. Questions? Thank You for your attention!

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