1. Maruf Aberra(MD) HEPATITIS C VIRUS

2. Virology RNA virus that belongs to the family flaviviruses; sole member of the genus hepacivirus. Enveloped, 55-65 nm in diameter. Circulates in various forms in the serum (1)Lipo - Viro-Particles, represent the infectious fraction (2)Bound to immunoglobulin (3)Free virions

3. Viral replication and Life Cycle  Hepatocytes are major sites of replication. Mononuclear cell, dendritic cells also support replication.  Viral binding  Entry  Inside hepatocytes  viral packaging and release  infect adjacent hepatocytes or enter circulation

4. Genotypes and quasispecies  Genetic heterogeneity Six distinct but related HCV genotypes and multiple subtypes have been identified. Genotype 1 is common (60 to 70 percent of isolates) in the United States and Europe followed by genotypes 2 and 3 Genotype 3 is most common in India, the Far East, and Australia Genotype 4 is most common in Africa and the Middle East Genotype 5 is most common in South Africa Genotype 6 is most common in Hong Kong, Vietnam and Australia Quasispecies-closely related yet heterogeneous sequences of HCV within a single infected person

5. Epidemiology Worldwide seroprevalence - 3% >170 million people infected chronically Prevalence of anti-HCV antibody in Ethiopians  Healthy Blood donors -1.4%.  urban/rural communities(1993) -2%  patients with chronic hepatitis -21%.  cirrhosis of liver -36%  HCC -46%

8. Transmission Sources of Infection

9. Injecting Drug Use and HCV Transmission  Highly efficient  Contamination of drug paraphernalia, not just needles and syringes  Rapidly acquired after initiation  30% prevalence after 3 years  >50% after 5 years  Four times more common than HIV

10. Posttransfusion Hepatitis C All volunteer donors HBsAg Donor Screening for HIV Risk Factors Anti-HIV ALT/Anti-HBc Anti-HCV Improved HCV Tests Adapted from HJ Alter and Tobler and Busch, Clin Chem 1997

11. Occupational Transmission of HCV  Inefficient by occupational exposures  Average incidence 1.8% following needle stick from HCV-positive source  Associated with hollow-bore needles  Case reports of transmission from blood splash to eye; one from exposure to non-intact skin  Prevalence 1-2% among health care workers  Lower than adults in the general population  10 times lower than for HBV infection

12. Perinatal Transmission of HCV  Transmission only from women HCV-RNA positive at delivery  Average rate of infection 6%  Higher (17%) if woman co-infected with HIV  Role of viral titer unclear  No association with  Delivery method  Breastfeeding  Infected infants do well  Severe hepatitis is rare

13. Sexual Transmission of HCV  Partner studies  Low prevalence (1.5%) among long-term partners  infections might be due to common percutaneous exposures (e.g., drug use), BUT  Male to female transmission more efficient more indicative of sexual transmission  Occurs, but efficiency is low  Factors that facilitate transmission between partners unknown (e.g., viral titer)  Accounts for 15-20% of acute and chronic infections in the United States

14. Natural History of HCV Infection Incubation periodAverage 6-7 weeks Range 2-26 weeks Acute illness (jaundice)Mild (<20%) Case fatality rateLow Chronic infection60%-85% Chronic hepatitis10%-70% Cirrhosis<5%-20% Mortality from CLD1%-5% Age- related

15. Serologic Pattern of Acute HCV Infection with Recovery Symptoms +/- Time after Exposure Titer anti- HCV ALT Normal 012345 61234 Years Months HCV RNA

16. Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection Symptoms +/- Time after Exposure Titer anti- HCV ALT Normal 012345 61234 Years Months HCV RNA

17. Chronic Hepatitis C Factors Promoting Progression or Severity  Increased alcohol intake  Age > 40 years at time of infection  HIV co-infection  Other  Male gender  Chronic HBV co-infection

18. Clinical Features  Acute Hepatitis (20%) Jaundice - 10-20% Non specific sx- 20-30%  Chronic hepatitis Most patients are asymptomatic mild nonspecific symptoms most frequent complaint is fatigue; other less common manifestations include nausea, anorexia, myalgia, arthralgia, weakness, and weight loss

19. Extrahepatic manifestation of HCV  HEMATOLOGIC DISORDERS Essential mixed cryoglobulinemia Monoclonal gammopathies Lymphoma  DIABETES MELLITUS  AUTOIMMUNE DISORDERS Autoantibodies Thyroid disease Sialadenitis Autoimmune idiopathic thrombocytopenic purpura Myasthenia gravis Sarcoidosis

20. Extrahepatic Manifestations of HCV  OCULAR DISEASE  RENAL DISEASE  DERMATOLOGIC DISEASE  Porphyria cutanea tarda  Leukocytoclastic vasculitis  Lichen planus  Necrolytic acral erythema  MUSCULOSKELETAL  MYOCARDITIS AND CARDIOMYOPATHY  NEUROCOGNITIVE DYSFUNCTION

22. Diagnosis  Indirect assay (EIAs) Anti-HCV  Direct Assays Qualitative- HCV RNA Quantitative- HCV RNA levels HCV Core Antigen Assay- EIA HCV genotyping

23. Histopathology  Considered as the gold standard for establishing the severity of the disease.  Two components- Necroinflammatory changes Stage of structural alterations  Exclusion of coexisting Disease  Determination of Rate of Progression  Guidance in Treatment decision-making  Scoring systems Histology Activity Index(HAI) METAVIR scoring system