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Hepatitis C: Epidemiology, Diagnosis and Treatment Mitchell L. Shiffman, MD Professor of Medicine Chief, Hepatology Section Medical Director, Liver Transplant.

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Presentation on theme: "Hepatitis C: Epidemiology, Diagnosis and Treatment Mitchell L. Shiffman, MD Professor of Medicine Chief, Hepatology Section Medical Director, Liver Transplant."— Presentation transcript:

1 Hepatitis C: Epidemiology, Diagnosis and Treatment Mitchell L. Shiffman, MD Professor of Medicine Chief, Hepatology Section Medical Director, Liver Transplant Program Virginia Commonwealth University Health System Richmond, Virginia

2 Hepatitis C: Epidemiology

3 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Infection Magnitude of the Problem  Nearly 4 million persons in United States infected  Approximately 35,000 new cases yearly  85% of new cases become chronic  Leading cause of  Chronic liver disease  Cirrhosis  Liver cancer  Liver transplantation Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: Accessed February 1, 2006.

4 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Fate of Acute Infection 15% Chronic 85% Spontaneous resolution Alter MJ, et al. N Eng J Med. 1999;341:

5 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Month ALT (IU/l) Resolution Chronic HCV RNA +/-+- Hepatitis C Virus Response to Acute Infection Illustration by Mitchell L. Shiffman, MD.

6 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Infection Natural History Stable 80% (68%) HCC Liver failure 25% (4%) Slowly progressive 75% (13%) Resolved 15% (15%) Acute HCV Cirrhosis 20% (17%) Chronic HCV 85% (85%) HCC, hepatocellular carcinoma

7 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Infection Population at Risk  Transfusion of blood products before 1992  Intravenous drug use  Nasal inhalation of cocaine  Chronic renal failure on dialysis  Incarceration  Occupational exposure to blood products  Transplantation of an organ/tissue graft from an HCV- positive donor  Body piercing and potentially tattoo Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: Accessed February 1, 2006.

8 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Infection Prevalence Sex B, Blacks; F, female; H, Hispanic; M, male; W, Whites AllWBHMF Race Anti-HCV Positive (%) Alter MJ, et al. N Eng J Med. 1999;341: %

9 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Infection Prevalence by Age < ≥ 70 Age Group Anti-HCV Positive (%) Alter MJ, et al. N Eng J Med. 1999;341:

10 Hepatitis C: Diagnosis and Management

11 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Management of Chronic HCV Tests Utilized Disease SeverityResponse to Therapy AST/ALT Bilirubin Albumin Pro-time (INR) Platelet count Liver histology ALT HCV RNA HCV genotype Liver histology LFTs

12 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Viral Hepatitis Role of Diagnostic Testing  Identify patients with viral hepatitis infection –Previous exposure to hepatitis virus –Active infection –Inactive infection –Resolved infection  Assess response to therapy –Prior to onset of treatment –During and following treatment

13 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Diagnostic Testing Diagnostic Test Type SpecificationsSerologicVirologic Mode of detectionAntibodiesVirus Sensitivity> 95%> 98% SpecificityVariable> 98% Detection postexposure2-6 months2-6 weeks UseScreeningConfirmation

14 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Host Production of HCV Antibodies  HCV infects cell  HCV proteins expressed on surface of hepatocytes  Antibodies to HCV proteins produced by host  HCV antibodies DO NOT convey immunity Y Y Y Y Y YYY Illustration by Mitchell L. Shiffman, MD.

15 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Testing for Hepatitis C Virus Anti-HCV Antibodies  ELISA screening test –Sensitivity: 97% –Detects circulating HCV antibodies  False positive reactions may occur –Cross-reacting circulating antibodies –Nonspecific binding of anti-HCV antibodies  Positive predictive value –95% with risk factors and elevated ALT –50% without risk factors and normal ALT Illustration by Mitchell L. Shiffman, MD.

16 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment  False positives –Autoimmune disorders –Spontaneous resolution of viral infection  False negatives –Chronically immune suppressed –Transplant recipients –Chronic renal failure on dialysis –HIV positive HCV Antibody Testing Limitations

17 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Testing for Hepatitis C Virus Recombinant Immunoblot Assay  Supplemental assay  Detects circulating antibodies to 4 HCV proteins  Antigen-antibody reaction  More specific than anti-HCV enzyme immunoassay  False positive reaction can still occur  Largely replaced by HCV RNA testing Positive ≥ 2 bands Indeterminate 1 band Control Illustration by Mitchell L. Shiffman, MD.

18 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Testing for Hepatitis C Virus Indications for HCV RNA  Confirm HCV infection –Persistently normal serum ALT –No risk factors –HCV antibody positive –Antinuclear antibodies –Prior to initiating therapy  Assess effectiveness of treatment –Predict likelihood of response before and during therapy –Confirm response after therapy completed

19 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Testing for Hepatitis C Virus Virologic Assays PCRTMAb-DNA Polymerase chain reaction Transcription mediated amplification Branched chain DNA Amplifies target Amplifies probe Qualitative Quantitative QualitativeQuantitative

20 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Quantitative HCV RNA Assays Inherent Variability  Normal variation of 1 log unit in HCV RNA assays  Differences of < 1 log between samples of probably NOT significant  HCV RNA titer best reported in log units , ,000 1,000,000 10,000, ,000,000 IIIIIIIVV Sample HCV RNA (IU/mL) Nolte FS, et al. J Clin Microbiol. 2001;39:

21 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Serum HCV RNA Level Stability Over Time Patient Limit of detection Baseline1234 Time (Years) Log HCV RNA (IU/mL) Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

22 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment HCV RNA and Liver Histology Fibrosis Genotype No Fibrosis Portal Fibrosis Bridging Fibrosis Cirrhosis  Serum HCV RNA does not correlate with level of fibrosis Log HCV RNA (copies/mL) Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

23 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment HCV RNA and Liver Histology Inflammation Genotype  Serum HCV RNA does not correlate with level of inflammation Inflammation Score Log HCV RNA (copies/mL) Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

24 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Genotypes in the USA All others 1% Type 3 10% Type 2 17% Type 1 72% McHutchinson JG, et al. N Engl J Med. 1998;339:

25 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Determination of HCV Genotype INNOLiPA Assay  HCV genotype –Best pretreatment predictor of response –Determines duration of therapy  All patients should have genotype determined prior to initiating therapy Illustration by Mitchell L. Shiffman, MD.

26 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Infection Liver Biopsy  Only test that can accurately assess –Severity of inflammation –Degree of fibrosis  Determines the following –Risk for developing cirrhosis in future –Need for therapy –Need for ongoing therapy when initial treatment has failed

27 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Management of Chronic HCV Is Liver Biopsy Necessary? NO  Patient wants treatment even if no fibrosis  Patient does not want treatment or treatment contraindicated even if advanced fibrosis  Labs and radiographic studies do not suggest cirrhosis  Patient achieves SVR YES  Patient would only accept treatment if advanced fibrosis  Labs or radiographic studies suggest cirrhosis may be present  Patient fails to achieve SVR and no recent biopsy available

28 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Assessment of Liver Histology Noninvasive Serum Tests Fibrosis Stage FIBROTEST Activity Grade ACTITEST Poynard T, et al. Hepatology. 2003;38:

29 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Chronic HCV With Normal Serum ALT ALT Patterns and Flares ULN Month ALT (IU/l) Single elevations Periodic elevations Always normal Illustration by Mitchell L. Shiffman, MD.

30 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Chronic HCV Infection Normal Serum ALT Normal ALTElevated ALT n = 37n = 58 Race  White, %  Black, % Serum ALT, IU/L46.6 ± ± 6.0 Log HCV RNA, copies/mL5.42 ± ± 0.07 Histology score  Inflammation  Fibrosis 4.2 ± ± ± ± 0.2 Shiffman ML, et al. J Infect Dis. 2000;182:

31 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Chronic HCV Infection Normal vs Elevated Serum ALT Normal ALTElevated ALT Portal 26% No fibrosis 23% Mild 39% Cirrhosis 6% Bridging 6% Portal 20% No fibrosis 16% Mild 33% Cirrhosis 18% Bridging 13% Shiffman ML, et al. J Infect Dis. 2000;182:

32 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Chronic HCV Infection Symptoms Asymptomatic Symptomatic Cirrhosis Fatigue Percentage of Patients 37% 7% 56% Unpublished data from MCV Hepatitis Program, 1995.

33 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Chronic HCV Infection Progression to Cirrhosis Time (Years) Bridging Portal None Approximate Percentage of Patients With Cirrhosis Yano M, et al. Hepatology. 1996;23: Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis

34 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Fibrosis Progression of HCV Effect of Inflammation Change in Fibrosis Score According to Necrosis Score at Baseline Piecemeal Necrosis Score at Baseline > 4 Number of patients Mean change in fibrosis score per year Ghany MG, et al. Gastroenterol. 2003;124:

35 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Poynard T, et al. Lancet. 1997;349: HCV Fibrosis Progression Effect of Alcohol Alcohol intake > 50 g/day* < 50 g/day *50 g is equal to approximately 3.5 drinks < > 40 Duration of Infection (Years) Fibrosis Score

36 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment < > 40 Duration of Infection (Years) Fibrosis Score Poynard T, et al. Lancet. 1997;349: HCV Fibrosis Progression Effect of Age Age at time of infection > 40 years < 40 years

37 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Poynard T, et al. Lancet. 1997;349: HCV Fibrosis Progression Effect of Histology < > 40 Duration of Infection (Years) Fibrosis Inflammation Grade or Stage

38 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment HCV and Alcohol Risk of Cirrhosis Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men Years Following Exposure Cirrhosis (%) HCV HCV + alcohol Wiley TE, et al. Hepatology. 1998:28:

39 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Fibrosis Progression in HCV Effect of Steatosis 2% 4% 7% 18% 6% 18% 30% 33% < 5%5%-10%11%-30%> 30% Percentage of Steatosis at Initial Biopsy Cumulative Probability of Fibrosis Progression (%) Year 4 Year 6 Fartoux L, et al. Hepatology. 2005;41: Cumulative Probability of Fibrosis According to Level of Steatosis

40 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Fattovich G, et al. Gastroenterology. 1997;112: HCV in Patients With Cirrhosis Survival and Rate of Decompensation Survival (%) Stable Decompensation 10-Year Cumulative Survival Years Percentage of Patients Decompensation HCC Cumulative Probability

41 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatocellular Carcinoma Incidence in the United States Cases/100,000 Black male White male Black female White female El-Serag HB, et al. N Engl J Med. 1999;340:

42 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Chronic Hepatitis C Infection Progression to Cirrhosis 20%-33%15%-33% HCC Cirrhosis C Cirrhosis A Severe Moderate Mild Years Shiffman ML. Viral Hepatitis Rev. 1999;5:27-43.

43 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Armstrong GL, et al. Hepatology. 2000;31: Hepatitis C Virus Infection The Burden of Disease Year All patients Infection for > 20 years Anti-HCV Positive (%)

44 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Hepatitis C Virus Infection Identification of Patients  Found to have elevated serum ALT during –Routine physical examination –Routine blood testing after starting certain medications  Test positive for anti-HCV during –Volunteer blood donation –Health or life insurance applications  Physician –Inquires about previous risk behaviors

45 Hepatitis C: Extrahepatic Manifestations

46 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Chronic Hepatitis C Virus Extrahepatic Manifestations  Nonspecific antibodies  Essential mixed cryoglobulinemia  Glomerulonephritis  Porphyria cutanea tarda  Leukocytoclastic vasculitis  Mooren’s corneal ulcer  Non-Hodgkin’s lymphoma  Autoimmune thyroiditis  Diabetes mellitus  Sjögren’s syndrome

47 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Pawlotsky JM, et al. Hepatology. 1994;19: Chronic Hepatitis C Virus Autoantibodies HCV, %Control, % Rheumatoid factor708 Cryoglobulins36< 1 ANA  > 1:40  > 1: Antismooth muscle  > 1:40  > 1: < 1 Anti–liver-kidney microsome5< 1 Antithyroid72

48 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Chronic Hepatitis C Virus Autoantibodies (cont’d)  No relationship between presence of autoantibodies and –Severity of chronic HCV –HCV genotype  Correlation between rheumatoid factor titer and –Cryoglobulinemia –But not symptomatic cryoglobulinemia  Circulating autoantibodies from autoimmune disorders may result in –False positive anti-HCV

49 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Cacoub P, et al. Curr Opin Rheumatol. 2002;14: Cryoglobulinemia Classification ImmunoglobulinClassification I Monoclonal No rheumatoid factor Primary II Polyclonal IgG Monoclonal IgM Rheumatoid factor Secondary mixed HCV infection III Polyclonal IgG Polyclonal IgM Secondary mixed Infections Autoimmune disorders Lymphoproliferative diseases

50 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Immune Manifestations of HCV Pathogenesis Illustration by Mitchell L. Shiffman, MD

51 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment HCV and Cryoglobulinemia Dermatitis  Occurs in dependent areas  Deposition of cryoglobulins in small capillaries  Ulcerations may develop  Pruritic

52 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Extrahepatic Effects of HCV Cryoglobulinemia CryoglobulinemiaControls Percentage of Patients Elevated ALT Anti-HCV HCV RNA Misiani R, et al. Ann Int Med. 1992;117:

53 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment HCV and Cryoglobulinemia Manifestations  Dermatitis (dependent areas)  Vasculitis  Myalgias (fibromyalgia?)  Arthralgias (RA and/or ANA positive)  Membranoproliferative glomerulonephritis  Neuropathy  Chronic fatigue syndrome (?)

54 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Characteristic HCV Sialadenitis Primary Sjögren’s Syndrome SS-A, SS-BNegativePositive Lymphocytic capillaritis Mild Pericapillary Mostly CD8 cells Severe Periductal Mostly CD4 cells Sicca syndrome:  Xerophthalmia  Xerostomia Absent 8%-36% Present Extrahepatic Effects of HCV Lymphocytic Sialadenitis

55 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Extrahepatic Effects of HCV B-Cell Lymphoma 8 case series 1754 pts evaluated Ferri (1994) Mazzaro (1996) Silvestri (1996) Izumi (1996) McColl (1996) Zignego (1997) DeRosa (1997) Zuckerman (1997) B Cell Lymphoma Controls

56 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Zein CO, et al. Am J Gastroenterol. 2005;100: Chronic HCV and Diabetes Mellitus Case Prevalence  N = 179 with chronic HCV  Prevalence of diabetes mellitus and insulin resistance noted  Compared with expected rate based on NHANES III study after adjusting for –Age –Sex –Race  Prevalence of DM or insulin resistance higher in those with chronic HCV FemalesMales Number of Cases Observed Expected

57 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Zein CO, et al. Am J Gastroenterol. 2005;100: Chronic HCV and Diabetes Mellitus Relationship to Fibrosis Stage Histologic Stage Percentage of Patients

58 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Extrahepatic Effects of HCV Porphyria Cutanea Tarda 2 case series 3 uncontrolled series 280 patients Alcohol: 36%-77% Fargion (1992) De Castro (1993) Criber (1995) Stolzel (1995) Kondo (1997) PCT Control

59 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Nagao Y, et al. J Gastroenterol Hepatol. 2004;19: Extrahepatic Effects of HCV Lichen Planus  Occurs in < 1% of the general population  10%-30% of patients with chronic HCV  Appearance –Flat topped, violaceous, pruritic papules –Throughout body –Oral mucosa  Histology –Dense infiltration of dermis with T lymphocytes

60 Hepatitis C: Treatment

61 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Treatment of Chronic HCV Peginterferon and Ribavirin Genotype Sustained Virologic Response (%) PegIFN-2a/RBV PegIFN-2b/RBV Fried MW, et al. N Eng J Med. 2002;347: Manns MP, et al. Lancet 2001;358:

62 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Treatment of Chronic HCV Effect on Survival  Interferon treatment reduces risk of death, transplantation, and complications of cirrhosis Risk Factors for Survival (Multivariate Cox Regression Analysis) Survival OutcomeRisk Ratio95% Confidence Interval Interferon therapy vs no therapy  Death and liver transplantation0.5*  Death, liver transplantation, and complications 0.5*  Development of HCC Niederau C, et al. Hepatology. 1998;28: *P <.05.

63 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment Nishiguchi S, et al. Lancet. 1995;346: Treatment of Chronic HCV Effect on Development of HCC  Interferon treatment reduces the risk of developing hepatocellular carcinoma among patients with chronic HCV (P =.002)  Hepatocellular carcinoma incidence –Untreated controls: 38% (24%-58%) –Interferon-treated patients: 4% (1%-15%)  HCC risk ratio: ( ; P =.01)

64 clinicaloptions.com/hep Hepatitis C: Epidemiology, Diagnosis, and Treatment The Many Faces of HCV Infection Summary  Chronic HCV infection leads to cirrhosis and liver failure in a large number of persons  Primary care physicians must recognize that chronic HCV is common in specific nonliver disorders  Effective treatment of chronic HCV can prevent fibrosis progression and reduce complications of HCV

65 Go Online to View More CCO Programs! Conference Coverage of all the key data presented at major hepatitis meetings News and Capsule Summaries covering the latest findings in the field of hepatitis Downloadable Slides, and much more! clinicaloptions.com/hep


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