Chronic hepatitis C virus affects an around 14 million in Europe and 185 million individuals worldwide. On average, 2-3% of the world’s population is infected with hepatitis C virus (HCV) (Shiffman et al., 2017). Hepatitis C accounted for the greatest number of deaths and the highest mortality rate of 5.0 deaths/100,000 population in 2013 from three types of viral hepatitis (hepatitis A, B, and C). HCV transmission requires that infectious virions contact susceptible cells that allow replication. Most patients (80-85%) who become acutely infected cannot clear the virus and progress to chronic infection (Tyagi, Koirala, 2017). Persistent HCV infection is associated with the development of liver cirrhosis, hepatocellular carcinoma (HCC), liver failure, and death, and a significant portion of liver transplantation in Europe is attributable to disorders related to chronic hepatitis C (CHC) (Petruzziello et al., 2016 ). Chronic HCV infection causes approximately 500,000 deaths each year (Maasoumy et al., 2016 ).

Chronic hepatitis C

Infected population

185 million individuals worldwide


50 deaths/1,000,000 population in 2013

Chronic infection

80-85% of patients cannot clear the virus

Understanding the structure of HCV is important because newer therapies target specific viral proteins (Burstow et al., 2017). The Hepatitis C virus is a spherical, enveloped, positive strand RNA virus. It is a member of the family Flaviviridae, yet distinct to be classified as a separate genus, Hepacivirus. The genome is approximately 9.6 kb in length. It encodes a polyprotein that is then posttranslationally modified by proteolytic enzymes into four structural and six nonstructural (NS) proteins. Of particular importance are the NS3/4A, NS5A, and NS5B proteins. The NS3/4A serine protease mediates cleavage of the polyprotein into its respective structural and NS proteins. NS5B is responsible for RNA-dependent RNA polymerase activity, while NS5A is thought to have a number of roles including mediating interferon resistance. Viral proteins work together to drive viral replication and persistence (Burstow et al., 2017 Tyagi, Koirala, 2017).

Hepatitis C virus polyprotein structure (Burstow et al., 2017)

Hepatitis C virus polyprotein structure (adapted from Burstow et al., 2017)

The most updated classification identified 7 genotypes of Hepatitis C based on their nucleotide variability in HCV sequences recovered from multiple geographic regions (Tyagi, Koirala, 2017).

Genotype distribution in Central Europe (Petruzziello et al., 2016).

Genotype distribution in Central Europe (adapted from Petruzziello et al., 2016).

The Hepatitis C RNA virus enters the hepatocyte via endocytosis mediated by at least 4 co-receptor molecules. Following internalization in the cytoplasm its positive stranded RNA is uncoated and translated into 10 mature peptides. These are then cleaved by both host proteases and virally encoded proteases known as NS3-4a serine proteases. Mature peptides subsequently go on to reside on the endoplasmic reticulum forming a replication complex, which contains an important enzyme, the NS5B RNA dependent RNA polymerase. This enzyme catalyzes the positive RNA strand into its negative strand intermediate which in turn serves as the template for new positive strand synthesis. These are packaged with core and envelop glycoprotein into mature virions which then exit the cell via exocytosis. Hepatitis C virus has no ability to integrate in the host's genome. The virus can be detected in plasma within days of exposure, often 1 to 4 weeks, viremia peaks in the first 8 to 12 weeks of infection and then plateaus or drops to undetectable levels (viral clearance);in the majority 50-85% it persists. When chronic infection is established, HCV does not appear to be cytopathic; it is the local inflammatory response that triggers fibrogenesis (Tyagi, Koirala, 2017).

deaths each year by Hepatitis C
1 - 4 weeks
Virus detectable in plasma
genotypes of Hepatitis C

HCV infection risk factors include blood transfusion prior to 1992; born to HCV+ mother; current or past intravenous drug use; hemodialysis; high-risk sexual behaviors (particularly unprotected anal intercourse); incarceration; intranasal illicit drug use; unregulated tattoos (Shaffer, Ahuja, 2017). HCV RNA can be detected in blood (including serum and plasma), saliva, tears, seminal fluid, ascitic fluid, and cerebrospinal fluid. Perinatal transmission frequency range from 0% to 4% in larger studies (Tyagi, Koirala,2017). All people with risk factors for hepatitis C should have a serological screening test for antihepatitis C antibodies. These cannot differentiate between past or current HCV infection. A positive screening test should be followed by a test for hepatitis C RNA to confirm the diagnosis. The hepatitis C genotype and viral load should then be determined (Strasser, 2017). Direct testing for HCV RNA is necessary to distinguish between ongoing or prior infection in persons with HCV antibodies (Tyagi, Koirala, 2017).

Following the discovery of HCV in the late 1980s, development of molecular methods for the detection of nucleic acids was a milestone towards successful treatment of HCV infection (Maasoumy et al., 2016).

The only therapeutic option for the treatment of HCV infection before 2011 was pegylated interferon alfa (PegIFNa) and ribavirin (RBV) resulting in a sustained virologic response rate in 40%-70% depending on the genotype and the population (Flisiak et al., 2017). At the present time there are three classes of direct acting antivirals - second generation protease inhibitors that inhibit the NS3/4 serine proteases, the NS5A inhibitors which interferes with the structural protein NS5A which is a crucial element in the formation of the replication complex and the NS5B polymerase inhibitor which inhibits the enzyme responsible for transcription of a negative strand intermediate for future viral progeny. These three classes are used in different combinations to make a robust treatment regimen against the various genotypes of hepatitis C (Tyagi, Koirala, 2017). All oral, direct-acting antiviral treatments for chronic hepatitis C are highly effective and well tolerated. Approximately 95% of patients will be cured with a short course of treatment (Strasser, 2017).

Hepatitis C Virus

The Hepatitis C virus is a spherical, enveloped, positive strand RNA virus.


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2. Flisiak, R., Pogorzelska, J., Flisiak-Jackiewicz, M. Hepatitis C: efficacy and safety in real life, In: Liver international : official journal of the International Association for the Study of the Liver, 2017, 37 Suppl 1, p.26-32.

3. Maasoumy,B., Vermehren, J., Diagnostics in hepatitis C: The end of response-guided therapy?, In: Journal of Hepatology, 2016 vol. 65, p. S67–S81

4. Petruzziello, A., Marigliano, S., Loquercio, G., Cacciapuoti, C. Hepatitis C virus (HCV) genotypes distribution: an epidemiological up-date in Europe, In: Infectiou Agents and Cancer, 2016 ,11(53). eCollection 2016

5. Shaffer, M., Ahuja, D. Hepatitis C: Screening changes, treatment advances, In: Jornal of Family Practice, 2017,66(3), p. 136-144.

6. Shiffman, M.L., Gunn, N.T. Impact of hepatitis C virus therapy on metabolism and public health, In: Liver international : official journal of the International Association for the Study of the Liver , 2017, 37 Suppl 1, p.13-18.

7. Strasser, S.I. Managing hepatitis C in general practice, In: Australian Prescriber, 2017, 40(2), p. 64-69.

8. Tyagi,I., Koirala, J. Hepatitis C, e-book StatPearls, Last Update: February 8, 2017. https://www.ncbi.nlm.nih.gov/books/NBK430897/

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