GASTROENTEROLOGY CURRENT HOT TOPICS Hepatitis C © 2006 TAP Pharmaceutical Products Inc.

CURRENT HOT TOPICS Hepatitis C Virus (HCV) Introduction Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, A major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) The most common indication for liver transplantation in the United States Most HCV-infected people are expected to first present for medical attention in the next decade –Result: a 4-fold increase in diagnosed cases by 2015 A projected $11 billion for direct medical costs will occur between 2010 and 2019 –$75 billion in indirect costs associated with premature disability and mortality A major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) The most common indication for liver transplantation in the United States Most HCV-infected people are expected to first present for medical attention in the next decade –Result: a 4-fold increase in diagnosed cases by 2015 A projected $11 billion for direct medical costs will occur between 2010 and 2019 –$75 billion in indirect costs associated with premature disability and mortality

CURRENT HOT TOPICS Hepatitis C Virus Introduction HCV is a single-stranded positive- sense RNA virus that belongs to the Flaviviridae family HCV does not integrate into the human genome and therefore allows for a possible cure HCV is a single-stranded positive- sense RNA virus that belongs to the Flaviviridae family HCV does not integrate into the human genome and therefore allows for a possible cure Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, 2006.

CURRENT HOT TOPICS Hepatitis C Virus Replication Pathogenesis Entry Uncoating Replication Translation Export E1-E2 NS4B + + Progeny genome Assembly E1 C C E1-E2 Golgi NS3/4A NS2 NS5B NS5A Chaperones Nucleus Lipoproteins E2 ERER ERER ERER ERER Chopra S, et al. AGA Gastroenterology Teaching Project Web site. Available at: Accessed August 14, Chopra S, et al. AGA Gastroenterology Teaching Project Web site. Available at: Accessed August 14, 2006.

CURRENT HOT TOPICS Chronic HCV Infection in the United States World Health Organization (WHO) estimates 3% (170 million) of the world’s population is infected –Four million Americans are hepatitis C antibody-positive Approximately 2.7 million (95% CI, ) people are chronically infected with the hepatitis C virus World Health Organization (WHO) estimates 3% (170 million) of the world’s population is infected –Four million Americans are hepatitis C antibody-positive Approximately 2.7 million (95% CI, ) people are chronically infected with the hepatitis C virus Annual 10,000-12,000 deaths from chronic Hepatitis C Annual 10,000-12,000 deaths from chronic Hepatitis C Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, 2006.

CURRENT HOT TOPICS Incidence of Acute HCV Infection in the United States New infections per year –Mid-1980s: 180,000 –1995: 28,000 New infections per year –Mid-1980s: 180,000 –1995: 28,000 Alter MJ. Hepatology. 1997;26:62S-65S. Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Alter MJ. Hepatology. 1997;26:62S-65S. Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Year New infections per 100,000 Decline in injection drug users Decline in transfusion recipients

GASTROENTEROLOGY CURRENT HOT TOPICS Chronic Hepatitis C

CURRENT HOT TOPICS Prevalence in Age and Race Increased prevalence between ages 30 and 49 years African Americans and Mexican Americans are more likely to have HCV than Caucasians Increased prevalence between ages 30 and 49 years African Americans and Mexican Americans are more likely to have HCV than Caucasians African American Mexican American Caucasian Anti-HCV positive (%) Age (years) Alter MJ. Hepatology. 1997;26:62S-65S. Armstrong GL, et al. Ann Intern Med. 2006;144: Adapted from Williams I. Am J Med. 1999;107(6B):2-9. Alter MJ. Hepatology. 1997;26:62S-65S. Armstrong GL, et al. Ann Intern Med. 2006;144: Adapted from Williams I. Am J Med. 1999;107(6B):2-9.

CURRENT HOT TOPICS Prevalence of HCV by Age and Gender, Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Percent anti-HCV positive ≥ 70 Age (years) Males Total Females Prevalence is higher in males than females (2.5% vs. 1.2%) Prevalence is higher in males than females (2.5% vs. 1.2%)

CURRENT HOT TOPICS VariableAdjusted odds ratio (95% CI)* Blood transfusion before 1992 NoYes ( ) Lifetime number of sexual partners ≥ ( ) 5.2 ( ) Adapted from Armstrong GL, et al. Ann Intern Med. 2006;144: * The model is adjusted for age (10-year categories), sex, and the interaction of age and sex. Two variables, history of blood transfusion and injection drug use, were forced into the model. VariableAdjusted odds ratio (95% CI)* Ethnicity Non-Hispanic white Non-Hispanic black Mexican American (0.9–3.8) 2.6 (1.2–5.8) Ratio of family income to poverty threshold ≥ (1.9–6.4) 9.1 ( ) Illicit drug use (ever) Never (or marijuana only) Noninjection drug use (except marijuana) Injection drug use ( ) ( ) Adjusted Relative Odds of the Presence of Antibody to HCV in the United States From 1999 to 2002 In a survey of 15,079 participants aged years:

CURRENT HOT TOPICS Evaluation of Potential Screening for HCV Infection *The analysis of persons aged years included only those for whom all 4 variables (drug use history, sexual history, transfusion history, and ALT level) were not missing. The analysis of persons > 60 years o f age included only those for whom both transfusion history and ALT level were not missing. For this reason, the estimates may vary slightly. † Includes drug use by injection or otherwise, except marijuana; ‡ ALT = alanine aminotransferase *The analysis of persons aged years included only those for whom all 4 variables (drug use history, sexual history, transfusion history, and ALT level) were not missing. The analysis of persons > 60 years o f age included only those for whom both transfusion history and ALT level were not missing. For this reason, the estimates may vary slightly. † Includes drug use by injection or otherwise, except marijuana; ‡ ALT = alanine aminotransferase Persons aged years * Participants with criteria (%) Risk factor historyGeneral populationHCV RNA+ population Injection drug use Injection drug use or transfusion before Injection drug use or transfusing before 1992 or ≥ 20 lifetime sex partners Any illicit drug use † or transfusion before 1992 or ≥ 20 lifetime sex partners Risk factor history and ALT ‡ level General populationHCV RNA+ population Abnormal ALT level Abnormal ALT level or injection drug use Abnormal ALT level or injection drug use or transfusion before Abnormal ALT level or injection drug use or transfusion before 1992 or ≥ 20 lifetime sex partners Abnormal ALT level or illicit drug use † or transfusion before 1992 or ≥ 20 lifetime sex partners Adapted from Armstrong GL, et al. Ann Intern Med. 2006;144:

CURRENT HOT TOPICS HCV Prevalence by Selected Groups in the United States Adapted from Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Adapted from Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Hemophilia Injecting drug users Hemodialysis STD clients General population (adults) Surgeons, PSWs Pregnant women Military personnel Percent

CURRENT HOT TOPICS Transmission Routes of HCV Berenguer M, et al. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7 th ed. 2002: Percutaneous Blood transfusion from unscreened donors* Needlestick inoculation Injection drug use Hemodialysis Nosocomial Patient-to-patient Patient-to-health care worker Nonpercutaneous Sexual contact by infected or multiple partners Perinatal contact from HCV- positive mothers to infants Other Routes Nonintravenous illicit drug use (intranasal cocaine use) Tattoos or body piercing Sharing of body jewelry *After 1991, transfusion-related HCV infection cases declined significantly due to introduction of donor screening and more sensitive second-generation assays

CURRENT HOT TOPICS HCV Testing Initial test for HCV is an enzyme-linked immunoassay (EIA) to detect antibody against HCV (anti-HCV) –Current EIA has a specificity of 99% In those with immunodeficiencies and those undergoing hemodialysis, RNA testing should be the initial test Anti-HCV is detectable within 4-10 weeks of infection –Anti-HCV cannot distinguish new, chronic, or previous infection Initial test for HCV is an enzyme-linked immunoassay (EIA) to detect antibody against HCV (anti-HCV) –Current EIA has a specificity of 99% In those with immunodeficiencies and those undergoing hemodialysis, RNA testing should be the initial test Anti-HCV is detectable within 4-10 weeks of infection –Anti-HCV cannot distinguish new, chronic, or previous infection Pawlotsky JM. Clin Liver Dis. 2003;7: Poynard T, et al. Lancet. 2003;362; Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Pawlotsky JM. Clin Liver Dis. 2003;7: Poynard T, et al. Lancet. 2003;362; Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, 2006.

CURRENT HOT TOPICS HCV RNA Assay as a Successful Test for Confirmation of HCV The confirmatory test of choice is HCV RNA assay –Detects the presence or absence of the virus –Two types of assays: Qualitative Quantitative HCV RNA is detectable 1-3 weeks after infection The confirmatory test of choice is HCV RNA assay –Detects the presence or absence of the virus –Two types of assays: Qualitative Quantitative HCV RNA is detectable 1-3 weeks after infection Pawlotsky JM. Clin Liver Dis. 2003;7: NIH Consensus Development Conference Statement: Management of Hepatitis C: 2002 – June 10-12, Hepatology. 2002;36(5 suppl 1):3-20. Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Pawlotsky JM. Clin Liver Dis. 2003;7: NIH Consensus Development Conference Statement: Management of Hepatitis C: 2002 – June 10-12, Hepatology. 2002;36(5 suppl 1):3-20. Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, 2006.

CURRENT HOT TOPICS Anti-HCV and HCV RNA Testing Anti-HCV/RNA Results Outcomes Negative anti-HCV + Negative HCV RNANo infection Positive anti-HCV + Positive HCV RNAAcute or chronic infection Negative anti-HCV + Positive HCV RNAEarly acute infection or chronic infection in an immunosuppressed state Positive anti-HCV + Negative HCV RNAResolved infection False-positive antibody Low-level or intermittent viremia Passively acquired antibody Using both anti-HCV and HCV RNA tests allows the establishment and diagnosis of HCV Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, 2006.

CURRENT HOT TOPICS HCV Genotypes There are at least 6 HCV genotypes and more than 50 subtypes –Genotypes differ from each other by 31%-34% –Subtypes differ by 20%-23% Genotype 1 is the most common genotype in the United States Genotype is the most significant determinant of treatment response There are at least 6 HCV genotypes and more than 50 subtypes –Genotypes differ from each other by 31%-34% –Subtypes differ by 20%-23% Genotype 1 is the most common genotype in the United States Genotype is the most significant determinant of treatment response NIH Consensus Development Conference Statement. Hepatology. 2002;36(5 suppl 1):3-20. Alter MJ, et al. N Engl J Med. 1999;341: Pawlotsky JM. Clin Liver Dis. 2003;7: NIH Consensus Development Conference Statement. Hepatology. 2002;36(5 suppl 1):3-20. Alter MJ, et al. N Engl J Med. 1999;341: Pawlotsky JM. Clin Liver Dis. 2003;7:45-66.

CURRENT HOT TOPICS Natural History Average incubation period: weeks (range, weeks) Asymptomatic acute infection in 60% - 70% of patients Chronic infection develops in 60% - 85% –20% can lead to cirrhosis –6% liver failure –4% hepatocellular carcinoma (HCC) Average incubation period: weeks (range, weeks) Asymptomatic acute infection in 60% - 70% of patients Chronic infection develops in 60% - 85% –20% can lead to cirrhosis –6% liver failure –4% hepatocellular carcinoma (HCC) Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Williams I. Am J Med. 1999;107(6B):2S-9S. NIH Consensus Development Conference Statement. Hepatology. 2002;36(5 suppl 1):3-20. Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Williams I. Am J Med. 1999;107(6B):2S-9S. NIH Consensus Development Conference Statement. Hepatology. 2002;36(5 suppl 1):3-20. Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, 2006.

CURRENT HOT TOPICS Serological Pattern of Acute HCV Infection With Progression to Chronic Infection Presence of antibody does not imply immunity Alter MJ, et al. N Engl J Med. 1999;341: Adapted from Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Alter MJ, et al. N Engl J Med. 1999;341: Adapted from Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Normal Titer Months Years Time after exposure HCV RNA anti-HCV ALT

CURRENT HOT TOPICS Serological Pattern of Acute HCV Infection With Recovery Adapted from Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Adapted from Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Normal Titer Months Years Time after exposure HCV RNA anti-HCV ALT

CURRENT HOT TOPICS Transaminase Levels: Impact on Diagnosis All patients with elevated ALT levels should also undergo testing Approximately 20% of patients with chronic hepatitis C have persistently normal alanine aminotransferase (ALT) levels Many patients with chronic hepatitis C will have waxing and waning ALT levels, including periods with normal levels Normal ALT levels should not prevent appropriate testing of patients at risk for hepatitis C All patients with elevated ALT levels should also undergo testing Approximately 20% of patients with chronic hepatitis C have persistently normal alanine aminotransferase (ALT) levels Many patients with chronic hepatitis C will have waxing and waning ALT levels, including periods with normal levels Normal ALT levels should not prevent appropriate testing of patients at risk for hepatitis C Frequently Asked Questions About Hepatitis C. Centers for Disease Control Website. Available at Accessed September 6, Chronic Hepatitis C: Current Disease Management. National Digestive Diseases Information Clearninghouse Web site. Available at Accessed September 20, Shakil AO, et al. Ann Intern Med. 1995;123: Frequently Asked Questions About Hepatitis C. Centers for Disease Control Website. Available at Accessed September 6, Chronic Hepatitis C: Current Disease Management. National Digestive Diseases Information Clearninghouse Web site. Available at Accessed September 20, Shakil AO, et al. Ann Intern Med. 1995;123:

CURRENT HOT TOPICS Transaminase Levels: Impact on Disease Course There is no direct correlation between ALT levels and level of histologic disease 20% of patients with persistently normal liver enzymes have advanced hepatic fibrosis Further evaluation should be considered for all patients who are HCV RNA-positive regardless of ALT levels There is no direct correlation between ALT levels and level of histologic disease 20% of patients with persistently normal liver enzymes have advanced hepatic fibrosis Further evaluation should be considered for all patients who are HCV RNA-positive regardless of ALT levels Persico M, et al. Gastroenterology. 2000;118: Stanley AJ, et al. Eur J Gastroenterol Hepatol. 1996;8: Shehab TM, et al. Am J Gastroenterol. 2003;98: Persico M, et al. Gastroenterology. 2000;118: Stanley AJ, et al. Eur J Gastroenterol Hepatol. 1996;8: Shehab TM, et al. Am J Gastroenterol. 2003;98:

CURRENT HOT TOPICS Factors Associated With Disease Progression Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Alcohol consumption > 30 g/d in men > 20 g/d in women Acquisition at age ≥ 40 years Male gender HIV or HBV coinfection Immuno- compromised state Steatosis FACTORS ASSOCIATED WITH HCV PROGRESSION

CURRENT HOT TOPICS Factors Not Associated With Disease Progression Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Alanine aminotransferase level (ALT) Alanine aminotransferase level (ALT) Genotype Mode of transmission Mode of transmission Viral load FACTORS NOT ASSOCIATED WITH HCV PROGRESSION

CURRENT HOT TOPICS Progression to Fibrosis, Cirrhosis, and Hepatocellular Carcinoma Fibrosis is the result of chronic inflammation and is characterized by the deposition of extracellular matrix, causing deformity of the liver architecture, which leads to hepatic cell dysfunction Infection leads to inflammation, which leads to fibrosis Fibrosis is the result of chronic inflammation and is characterized by the deposition of extracellular matrix, causing deformity of the liver architecture, which leads to hepatic cell dysfunction Infection leads to inflammation, which leads to fibrosis Hepatitis C infection © Dr. Peter Anderson, University of Alabama at Birmingham, Department of Pathology Hepatitis C infection © Dr. Peter Anderson, University of Alabama at Birmingham, Department of Pathology Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, 2006.

CURRENT HOT TOPICS Progression to Fibrosis, Cirrhosis, and HCC The degree of hepatocellular necrosis, inflammation, and fibrosis on initial liver biopsy is the best predictor of risk for progression to cirrhosis –Cirrhosis of any cause is a major risk factor for the development of HCC –An estimated rate of 3% per year of HCC occurs in HCV cirrhosis The degree of hepatocellular necrosis, inflammation, and fibrosis on initial liver biopsy is the best predictor of risk for progression to cirrhosis –Cirrhosis of any cause is a major risk factor for the development of HCC –An estimated rate of 3% per year of HCC occurs in HCV cirrhosis Baseline liver biopsy is considered the gold standard to determine the extent of disease in hepatitis C Hepatocellular carcinoma in a hepatitis C infected Liver © Dr. Peter Anderson, University of Alabama at Birmingham, Department of Pathology Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, 2006.

CURRENT HOT TOPICS Extrahepatic Manifestations of HCV Clinical extrahepatic manifestations of HCV include: –Arthralgias and arthritis (23%) –Paresthesia (17%) –Myalgia (15%) –Pruritus (15%) –Sicca syndrome (11%) –Arterial hypertension (10%) –Purpura (1.5%) –Lichen planus (1%) –Vasculitis (1%) –Porphyria cutanea tarda (0.2%) A study of 1614 patients found that 74% of patients have at least 1 clinical extrahepatic manifestation Clinical extrahepatic manifestations of HCV include: –Arthralgias and arthritis (23%) –Paresthesia (17%) –Myalgia (15%) –Pruritus (15%) –Sicca syndrome (11%) –Arterial hypertension (10%) –Purpura (1.5%) –Lichen planus (1%) –Vasculitis (1%) –Porphyria cutanea tarda (0.2%) A study of 1614 patients found that 74% of patients have at least 1 clinical extrahepatic manifestation Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, 2006.

CURRENT HOT TOPICS Benefits of Early Diagnosis Allows the patient an opportunity to change behaviors that may transmit infections to others (sharing razors, sharing toothbrushes, drug use, etc) Allows the patient to modify behaviors that may impact disease (decrease alcohol use, vaccination, etc) Allows access to antiviral therapy Allows the patient an opportunity to change behaviors that may transmit infections to others (sharing razors, sharing toothbrushes, drug use, etc) Allows the patient to modify behaviors that may impact disease (decrease alcohol use, vaccination, etc) Allows access to antiviral therapy Frequently Asked Questions About Hepatitis C. Centers for Disease Control Website. Available at Accessed September 6, 2006.

CURRENT HOT TOPICS Factors Impacting Diagnosis People are not aware of risk factors Those who are infected are often asymptomatic Liver panel testing is often ordered due to elevated ALTs Current research has shown primary care physicians practice suboptimal risk factor assessment and need specific educational initiatives and practice guidelines to ensure appropriate testing and referral People are not aware of risk factors Those who are infected are often asymptomatic Liver panel testing is often ordered due to elevated ALTs Current research has shown primary care physicians practice suboptimal risk factor assessment and need specific educational initiatives and practice guidelines to ensure appropriate testing and referral Hepatitis Fact Sheet. American Liver Foundation Web site. Available at: Accessed August 12, Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Shehab TM, et al. J Viral Hepat. 2001;8: Hepatitis Fact Sheet. American Liver Foundation Web site. Available at: Accessed August 12, Winston DH, et al. Management of Hepatitis C by the Primary Care Provider. HCV Advocate Web site. Available at: About_Hepatitis_pdf/1.1.2_Training_Resources/PCP_web.pdf. Accessed August 8, Shehab TM, et al. J Viral Hepat. 2001;8:

CURRENT HOT TOPICS Disease Prevention Prevention and control in the United States must focus on –Reducing transmission in high-risk groups –Early identification of persons with chronic infection Key to these efforts are –Counseling infected individuals to prevent transmission –Educating health care providers and the general public Prevention and control in the United States must focus on –Reducing transmission in high-risk groups –Early identification of persons with chronic infection Key to these efforts are –Counseling infected individuals to prevent transmission –Educating health care providers and the general public Williams I. Am J Med. 1999;107(6B):2S-9S.

CURRENT HOT TOPICS Counseling Patients With Chronic Hepatitis C Minimize alcohol use Do not donate blood, blood products, or body organs Do not share razors or toothbrushes Risk of vertical transmission (from infection mother to fetus) in 4%-6 % of pregnancies Minimize alcohol use Do not donate blood, blood products, or body organs Do not share razors or toothbrushes Risk of vertical transmission (from infection mother to fetus) in 4%-6 % of pregnancies Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Viral Hepatitis. Centers for Disease Control Web site. Available at: hepatitis/slideset/hep_c/hcv_epi_for_distrib_ ppt. Accessed August 9, Hepatitis C is not transmitted via: –Casual contact –Food or water –Sharing eating utensils or drinking glasses

CURRENT HOT TOPICS NIH Consensus Recommendations All patients with chronic hepatitis C are potential candidates for therapy Educate the American public on the transmission of HCV in order to better identify affected individuals and to institute preventive measures All patients with chronic hepatitis C are potential candidates for therapy Educate the American public on the transmission of HCV in order to better identify affected individuals and to institute preventive measures NIH Consensus Development Conference Statement. Hepatology. 2002;36(5 suppl 1):3-20.

CURRENT HOT TOPICS Goals of Therapy Hepatitis C. Hepatitis C Advocacy Web site. Available at: Accessed August 30, Yoshida H, et al. Ann Intern Med. 1999;131: Hepatitis C. Hepatitis C Advocacy Web site. Available at: Accessed August 30, Yoshida H, et al. Ann Intern Med. 1999;131: Eradicate HCV infection Improve health-related quality of life Slow disease progression Improve histology Reduce risk of hepatocellular carcinoma Eradicate HCV infection Improve health-related quality of life Slow disease progression Improve histology Reduce risk of hepatocellular carcinoma

CURRENT HOT TOPICS Progression of Therapeutic Advances in HCV Treatments and Their Associated Effectiveness Strader DB, et al. Hepatology. 2004;39: IFN: interferon; RBV: ribarivin; PEG: pegylated interferon Sustained virologic response (%) Sustained virologic response (%) 6 months 12 months TIME 12 months

CURRENT HOT TOPICS Summary Primary care providers are the “gate-keepers” to the US health care system It is imperative that PCPs are able to –Identify patients at risk for HCV –Institute proper diagnostic testing and referral while the disease is at its early stage Early diagnosis allows opportunities for patients to alter behaviors that may accelerate disease progression or transmit infection to others Primary care providers are the “gate-keepers” to the US health care system It is imperative that PCPs are able to –Identify patients at risk for HCV –Institute proper diagnostic testing and referral while the disease is at its early stage Early diagnosis allows opportunities for patients to alter behaviors that may accelerate disease progression or transmit infection to others Shehab TM, et al. J Viral Hepat. 2001;8: Shehab TM, et al. Am J Gastroenterol. 2003;98: Shehab TM, et al. J Viral Hepat. 2001;8: Shehab TM, et al. Am J Gastroenterol. 2003;98: