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UPDATE on HBV and HCV

UPDATE on HBV and HCV. 2009 Robert G Gish MD. Disclosures relevent to this lecture. Consultant and speaker Schering, Roche, BMS, Gilead, Pharmasset Research Grants Schering, Roche, BMS, Gilead, Pharmasset Investment position None . Update on HBV and HCV. Epidemiology Screening

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UPDATE on HBV and HCV

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  1. UPDATE on HBV and HCV 2009 Robert G Gish MD

  2. Disclosures relevent to this lecture • Consultant and speaker • Schering, Roche, BMS, Gilead, Pharmasset • Research Grants • Schering, Roche, BMS, Gilead, Pharmasset • Investment position • None

  3. Update on HBV and HCV • Epidemiology • Screening • Natural history • Treatment

  4. Chronic Liver Disease Prevalence in United States a. McCullough AJ. J Clin Gastroenterol 2006;40:S17-S29. b. Armstrong GL et al. Ann Intern Med. 2006;144:705-714. c. From http://www.acg.gi.org/patients/cgp/pdf/alcohol.pdf. Accessed 04/05/08. d. From http://www.nhlbi.nih.gov/new/press/01-09-25.htm. Accessed 04/05/08. e. From http://www.cdc.gov/ncidod/diseases/hepatitis/resource/PDFs/disease_burden.pdf. Accessed 04/05/08 f. From http://seer.cancer.gov/statfacts/html/livibd.html. Accessed 04/05/08

  5. Who should you testing for viral hepatitis? • Patients typically enter this diagnostic group with a history of • Elevated liver tests • or • Risk history • Also: few symptoms are specific for liver disease and thus an evaluation should take place if: • signs of liver failure

  6. Liver Tests • Liver Enzymes • AST • ALT • Alkaline Phosphatase • GGT • Liver Synthetic Tests • Bilirubin • Albumin • Protime/INR True “liver function tests”

  7. Elevated Liver TestsDifferential Diagnosis • Population based survey in US 1999-2002 estimated abnormal ALT (>45 IU/mL) in 8.9% of population • Symptomatic vs Asymptomatic? • Acute vs Chronic? • Hepatitic vs Cholestatic?

  8. Evaluation of Liver Enzymes • First step is to repeat the test!! • Many many things can cause a one-time elevation of liver tests • A mild elevations (<2x “Healthy”) should be monitored (2-3x) for at least 6 months before a full serologic work-up is done • After intervention: stop alcohol (example) • Exception is suspected viral hepatitis • Order serologies in high risk people • Abnormal Liver Function • Immediate evaluation !!!

  9. 6 key tests for increased liver enzymes • Alcohol history • CAGE, MAST • HCV antibody • HBsAg • Iron Sat • Medication and herbal, OTC history • metabolic syndrome tests • BMI • HTN • Lipids • Glc fasting • Waist circumference

  10. Hepatitic: Viral Hepatitis: A, B, C, D, E Alcoholic and Nonalcoholic Steatohepatitis Autoimmune Hemochromatosis Wilson’s disease Alpha-1 antitrypsin Cholestatic: Obstruction Gallstones, malignancy, parasites Primary Biliary Cirrhosis Primary Sclerosing Cholangitis Infiltrative diseases: metastatic cancer, sarcoidosis, amyloidosis Medications Differential Diagnosis Other: • Drugs • Thyroid disorders • Celiac disease • Vascular disease: CHF, Budd Chiari syndrome, Sinusoidal obstructive syndrome

  11. ALT Value According to Sex and BMIAfter Modeling by Neural Network ALT (IU/L) 45.56 RBF2 11.53 1.00 Sex 0.00 36.00 BMI 16.00 Piton A, et al. Hepatology. 1998;27:1213.

  12. Healthy ALT • <19 for women • <25-30 for men

  13. Normal Aminotransferase Levels and Risk of Mortality from Liver Diseases • Study design: Prospective cohort study; Korean Medical Insurance Corporation; 8-year follow-up; 94,533 men and 47,522 women aged 35 to 59 • Results: “...findings indicate that serum aminotransferase concentration is associated with mortality from liver disease, even within the current normal range“; best cut-off value by ROC of ALT for prediction of liver diease in men was 30 U/L • Conclusions: “People with slightly elevated aminotransferase activity, but still within the normal range, should be closely observed and further investigated for liver disease“ Kim HC, et al. BMJ 2004;328:983.

  14. Normal Aminotransferase Levels and Risk of Mortality from Liver DiseasesProspective Cohort Study ALT (IU/L) No (men) RR (95% CI) < 20 37425 1.0 (0.7-1.4) 20-29 36589 2.9 (2.4-3.5) 30-39 11975 9.5 (7.9-11.5) 40-49 4068 19.2 (15.3-24.2) 50-99 3887 30.0 (25.0-36.1)  100 589 59.0 (43.4-80.1) "Normal“ "Elevated“ Kim HC, et al. BMJ 2004;328:983.

  15. Hepatitis B • 2 Billion exposed • 400 million infected worldwide • 2 million infected in the US • Death rate due to cirrhosis or liver cancer • 25-30% in patients with vertically acquired HBV • 7% in patients with adult acquired HBV

  16. Concept • HBV is not curable • HBV is suppressible and controllable

  17. HBV Phase I • HBsAg Infection • Anti-HBs Immunity • Anti-HBc Exposure

  18. HBV Phase II • If a patient is HBsAg positive • Order • HBV DNA quant • HBeAg • Anti HBe • Also • HDV • Antigen • Antibody

  19. HBV Phase III • If a patient is HBsAg positive • Order • Anti HAV • Vaccinate if not immune • Also • HCV • HIV • No make sure patient is not coInfected

  20. HBV Serologies Acute infection Chronic infection Immunized Past Exposure/with Immunity/Clearance False pos or Past Exp

  21. HBV DNA: Quantification • Levels of HBV DNA important • To decide if patients liver disease is active or inactive • To define a patients long term risk of HCC and cirrhosis • To allocate patient to proper treatment and or monitoring status

  22. HBV Serologies: Interpretation when HBV DNA positive • HBeAg: only applicable in patients who are chronically infected or carriers • “Wild type” (or mixed infections wild type and precore and/or core promoter variants) • Negative: precore/core promoter mutant variant of virus, still can be infective, still has advancing disease • Positive: increased infectivity • When to consider stopping treatment if treatment is initiated

  23. HBV Role of Liver Biopsy in Patients With Normal ALT and High Viral Load Stage of Fibrosis by ALT Group 70 Stage 0 60 Stage 1 50 Stage 2 Stage 3 40 Patients, % Stage 4 30 24% 20 10 0 PNALT (n = 57) ALT 1-1.5 ULN (n = 23) ALT > 1.5 ULN (n = 110) Lai et al. AASLD 2005. Abstract 67571.

  24. Rationale for Screening for HBV • As many as 25% of children infected in their first year of life will eventually die from HBV-related complications, 7% of adult aquired disease will die of complications of cancer or cirrhosis • Less than 5% of adults acquiring acute infection develop chronic infection • Among children infected with HBV, ~90% become chronic carriers, although they rarely develop acute illness • Vast majority of individuals with chronic HBV are asymptomatic Centers for Disease Control and Prevention. MMWRMorb Mortal Wkly Rep. 2008;57 (No. RR-8):10 (A).

  25. Who Should Be Screened?Adult Indications for HBV Screening and/or Vaccination Centers for Disease Control and Prevention. MMWRMorb Mortal Wkly Rep. 2008;57 (No. RR-8):10 (A).

  26. Who Should Be Screened?Adult Indications for HBV Screening and/or Vaccination (cont’d) ALT/AST=alanine transaminase/aspartate transaminase. Centers for Disease Control and Prevention. MMWRMorb Mortal Wkly Rep. 2008;57 (No. RR-8):10 (A).

  27. Geographic Regions With HBV Surface Antigen (HBsAg) Prevalence of 2% aA complete list of countries in each region is available at http://www.cdc.gov/travel/destinationList.htm; bestimates of prevalence of HBsAg, a marker of chronic HBV infection, are based on limited data and might not reflect current prevalence in countries that have implemented childhood HBV vaccination. In addition, HBsAg prevalence might vary within countries by subpopulation and locality; cAsia includes 3 regions: Southeast Asia, East Asia, and Northern Asia. Centers for Disease Control and Prevention. MMWRMorb Mortal Wkly Rep. 2008;57 (No. RR-8):10 (A).

  28. Screening Programs • San Francisco HBV-free • A major collaborative involving city government, private health care and nonprofit community organizations—including California Pacific Medical Center and AsianWeek Foundation • Two-year campaign to screen all Asian and Pacific Islander residents for HBV infection • The largest health care campaign to target Asians and Pacific Islanders in the United States Hep B Free. http://www.sfhepbfree.org/news_042407.htm. Accessed September 25, 2008.

  29. Treating HBV Treatable but not curable

  30. Key Take Home Point • HBV DNA quantification • Correlates with risk of cancer and cirrhosis • Independent of ALT or HBeAg status

  31. HBV Risk (HCC and Cirrhosis) Score

  32. Approved Therapeutic Options in the United States • First line • Entecavir (Baraclude®) • Tenofovir (Viread®) • Pegylated interferon (Pegasys®) • Second line • Adefovir dipivoxil (Hepsera®) • Telbivudine (Tyzeka®, Sebivo®) • Third line • Lamivudine (Epivir-HBV®, Zeffix®, or Heptodin®) • Rarely used • Interferon alpha (Intron A®) Lok et al. Hepatol. 2007;45:507-539 (A). EASL Guidleines 2009, NIH Consensus Conf 2008

  33. Clinical Considerations for Treatment • Which criteria should be used to start, continue, switch, or stop therapy? • How long should therapy last? • How to prevent resistance? • Which agent to use? • Use of combination therapy • Is combination of agents more effective? • When should combination therapy be used as initial therapy?

  34. Who Needs Treatment? • Main parameters to determine indication • HBeAg and anti-HBe status • HBV DNA quantification • Liver enzymes (ALT, AST) • Liver biopsy • Assess fibrosis • Exclude concomitant liver disease (eg, fatty liver) Lok et al. Hepatol. 2007;45:507-539 (A).

  35. Management of Chronic HBV Infection ю ULN for a person with a normal BMI ФTreat any patient with cirrhosis who is NAT positive, refer to specialist Refer: patients with cirrhosis, resistance, liver cancer € Rule out fatty liver and other causes of CLD § Consider 3-5 years NAT, nucleic acid testing, such as PCR, bDNA or TMA As modified from Gish. Clin Liver Dis. 2005;9(4):541-565.

  36. Goals of Therapy • The overall goal of treatment in all HBV patients is • Suppression of HBV DNA levels to undetectable amounts to decrease progression to cirrhosis, HCC, and liver-related mortality • HBsAg seroconversion • Normalization of serum liver enzymes • Improvement of liver histology • Goals of therapy in HBeAg-positive patients • HBeAg seroconversion • Goals of therapy in HBeAg-negative patients • No clear end point of therapy • Relapse is common even when treatment is discontinued after 2 to 3 years of successful therapy • Resistance to antiviral agents is the primary consideration in choosing first-line therapy given the need for long-term treatment Modified from Lok et al. Hepatol. 2007;45:507-539 (A).

  37. Summary: Recommendations • HBV DNA positive= Treat • Efficacy, safety and resistance profile • First Line Therapy: 90% + are HBV DNA negative at 2-5 years • Entecavir • Tenofovir • Second Line Therapy: special cases • Adefovir (availability) • Telbivudine (preganancy, HIV co infection without ART therapy) • Third Line Therapy: pregnancy or very short term use is role • Lamivudine • Pursue HBsAg seroconversion

  38. Resistance is associated with Treatment failures with Liver disease flares Liver decompensation Death Urgent liver transplant HBV vaccine failure

  39. Resistance Rates Lok et al. Gastroenterology. 2003;125:1714-1722 (B); Hadziyannis et al. Gastroenterology. 2006;131:1743-1751 (A); Herpcera® (adefovir dipivoxil) prescribing information. Gilead Sciences, Inc.; 2008 (A); Presented at: 18th Conference of the APASL; March 23-26, 2008; Seoul, Korea (Bi).

  40. Definitions: Antiviral Resistance • Genotypic resistance • Presence of mutations associated with decreased susceptibility to antiviral agents • Phenotypic resistance • In vitro demonstration of decreased susceptibility (EC50) • Virologic breakthrough • Increase in viral levels (= secondary Tx failure) • Biochemical breakthrough • Increase in ALT Lok et al. Hepatol. 2007;45:507-539 (A).

  41. Summary • HBV is a serious US and Global health problem • Screen appropriate patients • Vaccinate patients at risk for infection • Treat patients at risk of progression • Although not curable, disease is suppressable with improved patient outcomes

  42. HCV: The “Facts” • Estimated 170,000,000 infected people worldwide (~ 3% of world population) • Risk of chronicity: 55% – 85% • Risk of cirrhosis: 20% within 20 years 30% within 30 years • Cirrhosis-related mortality: 2% – 5% / year • Incidence of liver cancer: 3% – 10% / year among patients with cirrhosis • HCV is curable

  43. Estimated HCV Prevalence in Select PopulationsUnited States Incarcerated, ~310,000 (15%)1;Ever incarcerated, ~1,400,000 Injection drug users~300,000 (80-90%)2,3 HIV-infected ~300,000 (30%)4 Alcoholics~240,000 (11-36%)5 Living below poverty level ~940,000 (2.4%)6 Homeless ~175,000 (22%)7 Veterans ~280,000 (8%)8 Children (6-19 years) ~100,000 (0.1%)9 1MMWR Recomm Rep. 2003;52(RR-1):1-36. 2Edlin. Hepatology. 2002;36(5 Suppl 1):210-9. 3NHSDA Report. 2003. 4Khalili and Behm. Clin Inf Dis. 2000;31:154-61. 5Labreque and Sandt. In Hepatitic C: Choices. 2002. 6Alter et al. N Engl J Med. 1999;341(8):556-562. 7Nyamathi et al. J Gen Intern Med. 2002;17(2):134-43. 8Bräu et al. Am J Gastroenterol. 2002;97(8):2071-8. 9Jonas. Hepatology. 2002;36(5 Suppl 1):S173-8.

  44. Rules for HCV • All patients with HCV Aby + need quantitative RNA test assessment • 20% will develop cirrhosis if HCV RNA positive and elevated liver enzymes above “healthy range” • increased risk of cirrhosis • if HIV+, Alc abuse, organ transplant, fatty liver • 20% risk of HCC if cirrhosis is present • All patients who are RNA positive should presented with the option of a liver biopsy • ~3% transmission: vertical, needlestick, sexual transmission

  45. 1600 1400 1200 1000 Annual Medical Care Costs ($ Million) 800 600 400 200 0 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020 Predicted Future HCV Costs Year

  46. 30000 25000 20000 Annual Deaths 15000 10000 5000 0 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020 Predicted Future HCV Mortality Year

  47. Spectrum of HCV infection 0 Acute HCV Infection 15%-30% 55%-85% Chronic HCV Infection Recovery ~ 30% Chronic Hepatitis C “Normal” ALT Mild Moderate Severe Cirrhosis 20% End-Stage Liver Disease Hepatocellular Carcinoma Liver Transplantation Death

  48. Number of Patients on the Waiting List Active at Year End, 1995-2004 16, 000 14, 000 12, 000 10,000 Number of Patients on Waiting List 8,000 6,000 4,000 2,000 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 -Current Year Source: 2005 OPTN/SRTR Annual Report, Table 9.1a

  49. Natural History of HCV Cirrhosis Clinical complications thatled to decompensation(N=355) Appearance of HCC(N=384) Fattovich G et al. Gastroenterology. 1997;112:466.

  50. Compensated Survival after OLT Survival probability After 1st complication Deaths Liver-related (70%) Other causes (30%) Years after diagnosis Natural History of HCV Cirrhosis 100% 80% 60% 40% 20% 0 0 1 2 3 4 5 6 7 8 9 10 Adapted from Fattovich G et al. Gastroenterology. 1997;112:466-467 and Forman LM et al. Gastroenterology 2002;122:889-896 .

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