Advances in HCV Therapy.ppt

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1、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 worldwidePrevalence is 0.8%of the CDN popul

2、ation1990-2015: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,SOUTHAMERICA10 M,AFRICA 32 M,EAST MEDITERRANEAN20M,SOUTH EAST ASIA30 M,AUSTRALIA0.2 M,SOURCE,WHO 1999,WEST EUR

3、OPE 9 M,FAR EAST ASIA60 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,South Africa,Middle EastNorth Africa,Asia,IVDU,

4、Acute Hepatitis C Clinical Presentation and Natural History,HCV RNA can be detected in blood within 1-3 weeks after exposureImplications for Healthcare WorkersAverage time from exposure to seroconversion is 8-9 weeksAverage time from exposure to symptoms period 6-7 weeksLiver injury(elevations in AL

5、T)with 4-12 weeksSymptoms develop in only of 20%of patientsNonspecific 10%-20%Jaundice in only 20%-30%,CDC.MMWR.1998;47(No.RR-19):1-39.Hoofnagle JH Hepatology.1997;26(suppl 1):15S-20SNIH Consensus Development Conference Panel Statement Management of Hepatitis C,2002,*Adapted from Brown RS.Epidemiolo

6、gy 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 testingof blood donors,Anti-HCV test(1st generation)licensed,Anti-HCV test(2nd generation)licensed,Decline amonginje

7、cting drug users,Decline amongtransfusion recipients,1983,1985,1987,1989,1991,1993,Year,AcuteHCV,Liver Diseasefrom HCV,Incidence of HCV:Infection vs Disease*,Epidemiology,Estimated number infected0.8%anti HCV positively,%male250,000-300,000Majority between 25 and 45 years of ageEstimated number diag

8、nosed(2001)100,000-120,0002nd most frequently reported disease8000 new infections per year2000 acute,1.Zou S et al.Canada Communicable Disease Report.Sept 2001;2753.3.Health Canada-About Hepatitis C;2003 05 01,Hepatitis C in Ontario,Hepatitis C in Ontario,Hepatitis C in Ontario,Chronic Hepatitis C,A

9、 leading cause of cirrhosis in the Canada1,000-2,000 deaths/yrThis number expected to triple in the next 10 to 20 years(without therapy)Associated with an increased risk of liver cancerMost common reason for liver transplantation in Canada,CDC.MMWR.1998;47(No.RR-19):1-39.NIH Consensus Development Co

10、nference Panel Statement Management of Hepatitis C,2002,Epidemiology of Hepatitis C,How many patients are there in Ontario?Remis estimate100,000-130,000 patientsWho are they(estimates)?Ex/current IDUImmigrants from endemic areasRecipients of blood/blood productsOthers?Sexual,?cocaine,?tattoos,etc,He

11、patitis C in Ontario,Risk Factors for HCV,Intravenous drug use(even one-time use)High risk country of originTransfusions of blood or blood products before 1992Current recipients of multiple blood transfusionsHemophiliacs given clotting factorsSexual partners of intravenous drug usersIntranasal cocai

12、ne useTattooing or body piercingMedical procedures in other countries,Long-term hemodialysisHistory of imprisonmentHigh risk sexual contact,patients with multiple sexual partnersOccupational exposure to blood or blood productsReceiving an organ,graft,or tissue transplant from an HCV-positive donorHe

13、alth-care workers exposed to needle-stick and sharp injuriesPatients with sexually transmitted diseases,HIV,HBV,Hadziyannis SJ.J Eur Acad Dermatol Venereol.1998;10:12-21.,HCV Infection:Extrahepatic Manifestations,HematologicMixed cryoglobulinemiaAplastic anemiaThrombocytopeniaNon-Hodgkins b-cell lym

14、phoma,DermatologicPorphyria cutanea tardaLichen planusCutaneous necrotizing vasculitis,RenalGlomerulonephritisNephrotic syndrome,EndocrineAnti-thyroid antibodiesDiabetes mellitus,SalivarySialadenitis,OcularCorneal ulcerUveitis,VascularNecrotizing vasculitisPolyarteritis nodosa,NeuromuscularWeakness/

15、myalgiaPeripheral neuropathyArthritis/arthralgia,AutoimmunePhenomenaCREST syndrome,HEPATITIS C AROUND THE WORLD,Who is At-Risk in Your Community?,Audience Poll,In your clinical practice,what percentage of your patients are Canadian immigrants?40%,HEPATITIS C IN IMMIGRANTS,Reprinted from Cohen J.Scie

16、nce.1999;285:26.,Worldwide Prevalence,Hepatitis C Virus Infection,HEPATITIS C TRANSMISSION IN ITALY,PREVALENCE OF HEPATITIS C IN A SOUTHERN ITALIAN TOWN488 SUBJECTS1.2%PREVALENCE IN UNDER 30S42.1%PREVALENCE IN 60SMULTIVARIATE ANALYSISASSOCIATION WITH USE OF NON-DISPOSABLE GLASS SYRINGES,Maio et al J

17、 Hepatol 2000,HEPATITIS C TRANSMISSION IN ITALY,RISK FACTORS FOR HEPATITIS C INFECTION IN THE ELDERLY11.1-11.8%PREVALENCEASSOCIATED WITH ANTI-HBs SUGGESTS PARENTERAL TRANSMISSIONSUGGESTS EPIDEMIC DURING AND AFTER WWII,Baldo et al Geront 2000,Saracco et al J Viral Hep 2000Vitale et al New Microbiol 1

18、998,HEPATITIS C TRANSMISSION IN ITALY,GENOTYPE DISTRIBUTION IN ITALYGENERAL POPULATIONGENOTYPE 1-74%IVDUSGENOTYPE 3-49%,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 IMMIGR

19、ANTS OF ALL AGES FROM HIGH ENDEMIC AREAS WILL DEVELOP CIRRHOSIS AND HCC OVER NEXT 20-30 YEARS,ACUTE INFECTION90%ASYMPTOMATIC(POST TRANSFUSION)20-30%“RECOVER”SPONTANEOUSLYMAY HAVE PERSISTENT HCV RNA IN LIVER70-80%DEVELOP CHRONIC INFECTION,NATURAL HISTORY OF HEPATITIS C INFECTION,HEPATITIS C SPECTRUMO

20、F DISEASE,Adapted from Hoofnagle JH.Hepatology.1997;26(suppl 1):16S.,Mild,Moderate,Severe,15%-30%,70%-85%,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 HEPA

21、TITIS C,DETERMINANTS OF PROGRESSION TO CIRRHOSISDisease durationComorbid conditionsMale,alcohol use,HIV/HBV coinfectionGrade of Inflammation,RELATIONSHIP BETWEEN CIRRHOSIS AND YEARS AFTER EXPOSURE,Wiley et al.Hepatology,1998,NATURAL HISTORY OF CHRONIC HEPATITIS C,Future HCV Disease Burdenin the Nort

22、h America,Davis et al.Hepatology,1998,Predictions for 2010-2019US Numbers,193,000 HCV deaths720,700 million years of advanced liver disease1.83 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 fo

23、r canadian equivalent,Wong Am J Pub Health 2000,Factors Which Might Influence The Outcome 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

24、 can only have one?,Hepatitis C Screening and Diagnosis,Diagnosis of Chronic Viral HepatitisSerologic Testing,ALT levels may be intermittently normal in a significant number of patients who have chronic hepatitis CPatients should be tested if they:Have known risk factors for viral hepatitisIndicate

25、possible risk factors for hepatitisHave elevated liver enzymes,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 usual

26、ly diagnostic in patients with elevated levels of liver enzymes and presence of risk factorsFalse 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 antibo

27、diesHelpful in difficult cases,when antibody tests 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 regardingDegre

28、e of inflammationDisease severityTissue damagePresence/absence of cirrhosisHelps determineDegree of disease progressionCause of liver diseaseNeed for treatment/Patient MotivationEstimate chance of response,Patient Management,When chronic hepatitis C is diagnosed:Immunize against hepatitis A and hepa

29、titis BAdvise patient to avoid alcohol consumptionReview all medications,including vitamins,OTC,and herbal medications,Treatment of Hepatitis C,Standard Therapy for HCV,SVR nave patients(%),No therapy,1989,1999,2002,Monotherapy24 weeks,Combination therapy48 weeks,16%,0%,41%,Combined data:Poynard et

30、al(1998),McHutchison et al(1998),Zeuzem et al(2000),Fried et al(2002),0,10,20,30,40,50,60,6%,Monotherapy48 weeks,1995,PEG-IF48 weeks,PEG-IF+RIBA48 weeksGenotype sp,39%,2000,54,56,61,76%,Keys,Spend time before,during and after Rx.Educate patient on Side effectsInclude caregiversStess the positiveTeam

31、 approachIndividualize therapy,Factors that Improve Adherence,Education and support of the patientEase of dosingManagement of side effectsPositive ReinforcementClose Follow Up:CONTACT,HCV Summary,300,000 Canadian with HCV and growing100,000 in OntarioDiagnosis and treatment vitalNeed a high index of suspicionTreatment effectiveHealth and Economic impact immenseOnly treat those you know!,