Advances in HCV Therapy.ppt

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1、Advances in HCV Therapy,Hepatitis C Virus (HCV),Discovered in 1989 as a small RNA blood-borne virus with a large reservoir of chronic carriers worldwideMajor cause of posttransfusion hepatitis prior to 1992Major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwidePrevale

2、nce is 0.8% of the CDN population1990-2015: estimated 4-fold increase in the number of patients diagnosed with HCV in Canada,NIH Consensus Development Conference Panel Statement Management of Hepatitis C, 2002,U.S.A. 4 M,SOUTH AMERICA 10 M,AFRICA 32 M,EAST MEDITERRANEAN 20M,SOUTH EAST ASIA 30 M,AUST

3、RALIA 0.2 M,SOURCE, WHO 1999,WEST EUROPE 9 M,FAR EAST ASIA 60 M,170 Million Carriers Worldwide, 3 - 4 MM new cases/year 3% of World Population,HCV: A Global Health Problem,CANADA 300,000,HCV Genotypes and Subtypes,Simmonds P, Journal of Hepatology, 1999,Americas + Western Europe,Developed countries,

4、South Africa,Middle East North Africa,Asia,IVDU,Acute Hepatitis C Clinical Presentation and Natural History,HCV RNA can be detected in blood within 1-3 weeks after exposure Implications for Healthcare WorkersAverage time from exposure to seroconversion is 8-9 weeksAverage time from exposure to sympt

5、oms period 6-7 weeksLiver injury (elevations in ALT) with 4-12 weeksSymptoms develop in only of 20% of patients Nonspecific 10%-20% Jaundice in only 20%-30%,CDC. MMWR. 1998; 47(No. RR-19):1-39. Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S NIH Consensus Development Conference Panel Statement M

6、anagement of Hepatitis C, 2002,*Adapted from Brown RS. Epidemiology and Natural History of Hepatitis C. Presented at an ACG Clinical Implications meeting April 6, 2000 in Dallas, TX. Source: CDC Sentinel Counties Study of Acute Viral Hepatitis,Surrogate testing of blood donors,Anti-HCV test (1st gen

7、eration) licensed,Anti-HCV test (2nd generation) licensed,Decline among injecting drug users,Decline among transfusion recipients,1983,1985,1987,1989,1991,1993,Year,Acute HCV,Liver Disease from HCV,Incidence of HCV: Infection vs Disease*,Epidemiology,Estimated number infected0.8% anti HCV positively

8、, % male 250,000-300,000 Majority between 25 and 45 years of ageEstimated number diagnosed (2001)100,000-120,000 2nd most frequently reported disease 8000 new infections per year 2000 acute,1. Zou S et al. Canada Communicable Disease Report. Sept 2001; 2753. 3. Health Canada - About Hepatitis C; 200

9、3 05 01,Hepatitis C in Ontario,Hepatitis C in Ontario,Hepatitis C in Ontario,Chronic Hepatitis C,A leading cause of cirrhosis in the Canada1,000-2,000 deaths/yr This number expected to triple in the next 10 to 20 years (without therapy)Associated with an increased risk of liver cancerMost common rea

10、son for liver transplantation in Canada,CDC. MMWR. 1998; 47(No. RR-19):1-39. NIH Consensus Development Conference Panel Statement Management of Hepatitis C, 2002,Epidemiology of Hepatitis C,How many patients are there in Ontario? Remis estimate 100,000-130,000 patients Who are they (estimates)? Ex/c

11、urrent IDU Immigrants from endemic areas Recipients of blood/blood products Others ? Sexual, ? cocaine, ? tattoos, etc,Hepatitis C in Ontario,Risk Factors for HCV,Intravenous drug use (even one-time use) High risk country of origin Transfusions of blood or blood products before 1992 Current recipien

12、ts of multiple blood transfusions Hemophiliacs given clotting factors Sexual partners of intravenous drug users Intranasal cocaine use Tattooing or body piercing Medical procedures in other countries,Long-term hemodialysis History of imprisonment High risk sexual contact, patients with multiple sexu

13、al partners Occupational exposure to blood or blood products Receiving an organ, graft, or tissue transplant from an HCV-positive donor Health-care workers exposed to needle-stick and sharp injuries Patients with sexually transmitted diseases, HIV, HBV,Hadziyannis SJ. J Eur Acad Dermatol Venereol. 1

14、998;10:12-21.,HCV Infection: Extrahepatic Manifestations,Hematologic Mixed cryoglobulinemia Aplastic anemia Thrombocytopenia Non-Hodgkins b-cell lymphoma,Dermatologic Porphyria cutanea tarda Lichen planus Cutaneous necrotizing vasculitis,Renal Glomerulonephritis Nephrotic syndrome,Endocrine Anti-thy

15、roid antibodies Diabetes mellitus,Salivary Sialadenitis,Ocular Corneal ulcer Uveitis,Vascular Necrotizing vasculitis Polyarteritis nodosa,Neuromuscular Weakness/myalgia Peripheral neuropathy Arthritis/arthralgia,Autoimmune Phenomena CREST syndrome,HEPATITIS C AROUND THE WORLD,Who is At-Risk in Your

16、Community?,Audience Poll,In your clinical practice, what percentage of your patients are Canadian immigrants? 40%,HEPATITIS C IN IMMIGRANTS,Reprinted from Cohen J. Science. 1999;285:26.,Worldwide Prevalence,Hepatitis C Virus Infection,HEPATITIS C TRANSMISSION IN ITALY,PREVALENCE OF HEPATITIS C IN A

17、SOUTHERN ITALIAN TOWN 488 SUBJECTS 1.2% PREVALENCE IN UNDER 30S 42.1% PREVALENCE IN 60SMULTIVARIATE ANALYSIS ASSOCIATION WITH USE OF NON-DISPOSABLE GLASS SYRINGES,Maio et al J Hepatol 2000,HEPATITIS C TRANSMISSION IN ITALY,RISK FACTORS FOR HEPATITIS C INFECTION IN THE ELDERLY 11.1-11.8% PREVALENCE A

18、SSOCIATED WITH ANTI-HBs SUGGESTS PARENTERAL TRANSMISSION SUGGESTS EPIDEMIC DURING AND AFTER WWII,Baldo et al Geront 2000,Saracco et al J Viral Hep 2000 Vitale et al New Microbiol 1998,HEPATITIS C TRANSMISSION IN ITALY,GENOTYPE DISTRIBUTION IN ITALYGENERAL POPULATION GENOTYPE 1 - 74%IVDUS GENOTYPE 3

19、- 49%,HEPATITIS C IN CANADA,IMPLICATIONS OF HEPATITIS C IN THE IMMIGRANT POPULATIONGENERATION OF MIDDLE-AGED/ELDERLY MEDITERRANEANS AT RISK FOR CIRRHOSIS AND LIVER CANCERINFLUX OF IMMIGRANTS OF ALL AGES FROM HIGH ENDEMIC AREAS WILL DEVELOP CIRRHOSIS AND HCC OVER NEXT 20-30 YEARS,ACUTE INFECTION90 %

20、ASYMPTOMATIC (POST TRANSFUSION)20-30% “RECOVER” SPONTANEOUSLY MAY HAVE PERSISTENT HCV RNA IN LIVER70-80% DEVELOP CHRONIC INFECTION,NATURAL HISTORY OF HEPATITIS C INFECTION,HEPATITIS C SPECTRUM OF DISEASE,Adapted from Hoofnagle JH. Hepatology. 1997;26(suppl 1):16S.,Mild,Moderate,Severe,15%-30%,70%-85

21、%,Acute HCV Infection,Recovery,Chronic HCV Infection,Chronic Hepatitis C,Cirrhosis 15-20%,Hepatocellular Carcinoma 4%,End-Stage Liver Disease,Liver Transplantation,Death 4%,NATURAL HISTORY OF HEPATITIS C,DETERMINANTS OF PROGRESSION TO CIRRHOSIS Disease duration Comorbid conditions Male, alcohol use,

22、 HIV/HBV coinfection Grade of Inflammation,RELATIONSHIP BETWEEN CIRRHOSIS AND YEARS AFTER EXPOSURE,Wiley et al. Hepatology, 1998,NATURAL HISTORY OF CHRONIC HEPATITIS C,Future HCV Disease Burden in the North America,Davis et al. Hepatology, 1998,Predictions for 2010-2019 US Numbers,193,000 HCV deaths

23、 720,700 million years of advanced liver disease 1.83 million years of life lost$11 billion in direct medical care costs$21.3 and $54 billion societal costs from premature disability and mortalityDivide by 10 for canadian equivalent,Wong Am J Pub Health 2000,Factors Which Might Influence The Outcome

24、 Of Hepatitis C,Virus - Load - Genotype - Quasispecies,Host - Sex - Age - Race - Genetics - Immune response,Environment- Alcohol- HBV- HIV- Drugs- Steatosis- Iron- TREATMENT,Alberti, J of Hepatology, 1999,Alcohol,Are you sure he said we can only have one?,Hepatitis C Screening and Diagnosis,Diagnosi

25、s of Chronic Viral Hepatitis Serologic Testing,ALT levels may be intermittently normal in a significant number of patients who have chronic hepatitis C Patients should be tested if they: Have known risk factors for viral hepatitis Indicate possible risk factors for hepatitis Have elevated liver enzy

26、mes,Management of Hepatitis C. NIH Consensus Statement, 1997.,Hepatitis C Antibody (Anti-HCV) Test,EIA test for detection of hepatitis C antibodiesSensitivity over 99%Detection of anti-HCV following infection averages 12 weeksPositive test usually diagnostic in patients with elevated levels of liver

27、 enzymes and presence of risk factors False negatives in Immunosuppressed and Chronic Dialysis Patients,Management of Hepatitis C. NIH Consensus Statement, 2002.,Hepatitis C Virus RNA Tests,Determine the presence of actual virus, not anti-HCV antibodiesHelpful in difficult cases, when antibody tests

28、 inconclusiveGenotype and viral load necessary pre-Rx.Sensitivity may vary between labs; depends on type of assay,Management of Hepatitis C. NIH Consensus Statement, 2002.,Liver Biopsy,May be guided by CT or ultrasoundProvides information regarding Degree of inflammation Disease severity Tissue dama

29、ge Presence/absence of cirrhosisHelps determine Degree of disease progression Cause of liver disease Need for treatment / Patient Motivation Estimate chance of response,Patient Management,When chronic hepatitis C is diagnosed: Immunize against hepatitis A and hepatitis B Advise patient to avoid alco

30、hol consumption Review all medications, including vitamins, OTC, and herbal medications,Treatment of Hepatitis C,Standard Therapy for HCV,SVR navepatients (%),No therapy,1989,1999,2002,Monotherapy 24 weeks,Combination therapy 48 weeks,16%,0%,41%,Combined data :Poynard et al (1998), McHutchison et al

31、 (1998), Zeuzem et al (2000), Fried et al (2002),0,10,20,30,40,50,60,6%,Monotherapy 48 weeks,1995,PEG-IF 48 weeks,PEG-IF + RIBA 48 weeks Genotype sp,39%,2000,54,56,61,76%,Keys,Spend time before, during and after Rx. Educate patient on Side effects Include caregivers Stess the positive Team approach

32、Individualize therapy,Factors that Improve Adherence,Education and support of the patient Ease of dosing Management of side effects Positive Reinforcement Close Follow Up: CONTACT,HCV Summary,300,000 Canadian with HCV and growing 100,000 in Ontario Diagnosis and treatment vital Need a high index of suspicion Treatment effective Health and Economic impact immenseOnly treat those you know!,