HEPATITIS C VIRUS

Maruf Aberra(MD)

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

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

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

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%

Transmission Sources of Infection

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

Posttransfusion Hepatitis C

30 25

All volunteer donors HBsAg

20 15 10 5

Donor Screening for HIV Risk Factors Anti-HIV ALT/Anti-HBc Anti-HCV Improved HCV Tests

0 1965 1970 1975 1980 1985 1990 1995 Year

Adapted from HJ Alter and Tobler and Busch, Clin Chem 1997

2000

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

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

Sexual Transmission of HCV

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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

Natural History of HCV Infection

Incubation period Acute illness (jaundice) Case fatality rate Chronic infection Chronic hepatitis Cirrhosis Mortality from CLD Age related Average 6-7 weeks Range 2-26 weeks Mild (<20%) Low 60%-85% 10%-70% <5%-20% 1%-5%

Serologic Pattern of Acute HCV Infection with Recovery

anti HCV Symptoms +/ HCV RNA ALT 0 1 Normal 2 3 Months 4 5 Time after Exposure 6 1 2 3 Years 4

Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection

anti HCV Symptoms +/ HCV RNA ALT 0 1 Normal 2 3 Months 4 5 Time after Exposure 6 1 2 3 Years 4

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

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

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

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

Diagnosis

 Indirect assay (EIAs)  Anti-HCV Direct Assays

Qualitative-

HCV RNA Quantitative- HCV RNA levels

HCV Core Antigen Assay- EIA HCV genotyping

Histopathology

  Considered as the gold standard for establishing the severity of the disease.

Two components-

Necroinflammatory changes Stage of structural alterations

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Exclusion of coexisting Disease

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Determination of Rate of Progression

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Guidance in Treatment decision-making

 Scoring systems

Histology Activity Index(HAI) METAVIR scoring system