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WHO estimated that in 2015, 71 million persons were living with chronic HCV infection worldwide (global prevalence: 1%) and that 399 000 had died from cirrhosis or hepatocellular carcinoma. Aside from the burden of HCV infection secondary to liver-related sequelae, HCV causes an additional burden through comorbidities among persons with HCV infection, including depression(1), diabetes mellitus(2) and chronic renal disease(3). A proportion of these morbidities is directly attributable to HCV and is therefore referred to as extrahepatis manifestations. These manifestations are likely to be affected by treatment(4).
Mechanism of infection
HCV, which is transmitted parenterally, enters the liver via the bloodstream. In the liver sinusoids, the virus can pass the fenestrated endothelium and contact the basolateral surface of hepatocytes. HCV host cell entry is a complex multistep process that requires numerous host cell proteins like scavenger receptor class B type I (SCARB1), claudin-1, occludin and tetraspanin CD81. All four entry factors needs to be expressed on HCV-susceptible cells(6). SCARB1 and CD81 binds to glycoprotein E2 on the surface of virion. However, exact function of all four host cell receptors is not clear and its experimental evidence is lacking. After cell surface binding and coordinated interaction with entry factors, HCV is taken up by clathrin mediated endocytosis.
Despite 20 years of intensive research, a vaccine to prevent infection with the HCV remains elusive. HCV diversity is classified into seven genetically distinct genotypes (HCV 1–7) that differ by more than 30 % at nucleotide level, and into more than 50 subtypes that differ between 15 % and 25 % at nucleotide level within genotypes. A major barrier for the development of vaccines, broadly active antivirals, and assays, is the high genetic diversity of HCV and its potential to quickly adapt to different environments. HCV is under constant immunological pressure. Neutralizing antibody response of the host is targeting mainly the viral envelope proteins E1 and E2, but the virus manages to escape due to the large plasticity in the highly variable regions in these proteins. Effective targeting of conserved regions (Figure 1) in the genome may improve vaccine design. While vaccine design is still under experimental stage, development of DAADs has progressed into clinical practice.
HCV – basics, that helped to improve the therapy
Understanding of all aspects of HCV lifecycle helps to find therapy strategies targeted straightly to virus. An example of this approach is discovery of miRNA-122 (miR-122) involvement in HCV infection and subsequent development of drug called miravirsen. HCV relies on the host miR-122 in a unique way as miR-122 binds to the 5 ′-non-translated region of the HCV genome, which results in increased stability of the latter and thus increased replication. Miravirsen represents the first RNA-interference-based drug currently undergoing phase II of clinical trials(7). Silencing of expression miR-122 by Miravirsen leading to HCV genome degradation may be a solution for HC patients resistant to current pangenotypic regimens.
The story of increasing effectiveness
15 years ago the standard of care of adolescents and children infected with HCV was dual therapy with pegylated-interferon and ribavirin for 24 weeks for genotypes 2 and 3, and 48 weeks for genotypes 1 and 4. This combination resulted in an SVR rate of around 52% in children infected with HCV genotypes 1 and 4, and 89% in those infected with HCV genotypes 2 and 3, but was associated with significant side- effects(8). In 2011, two inhibitors against NS3 and NS4A viral proteases have been included in standard therapy in some regions, including Slovakia, which are mainly focused on the treatment of genotype 1. The triple combination of PEG-interferon, ribavirin and protease inhibitors improved virological response in several cohorts of patients from 50 % to 70 %(9,10). However, this approach has limited efficacy for a particular group of patients (with liver cirrhosis, liver transplant patients, patients who are primarily unresponsive to this type of treatment, and hemodialysis patients). An important aspect of the development of the NS3 inhibitor is resolution of the crystalline structure of this protein alone and in conjunction with the cofactor, which facilitated the design of the drug. There are currently several drugs that inhibit NS3 protease (Table 1).
All DAADs against NS3 target the active site of the protease, but it has been identified substitutions at this site that cause resistance(11). NS5A is another virus protein candidate to inhibit. This multifunctional protein is an essential component of the viral replication complex, involved in the regulation of replication and the composition of the viral particle.
These drugs (Table 1) have become a central part of the current combined DAAD therapy but have a relatively low barrier to the development of viral resistance(11). NS5B is an HCV protein that functions as a RNA-dependent RNA-polymerase and is therefore a target for the inhibition of viral replication. The basic research of the NS5B polymerase has enabled the generation of efficient nucleoside analogues against HCV virions with various pangenomes. The great advantage is that it is targeting a highly conserved enzyme, and therefore, in this case, the barrier to the development of resistance is high. This category includes the drug sofosbuvir, which is used in the treatment of all genotypes of HCV. The combination of sofosbuvirus with the NS5A inhibitor velpatasvirus is effective against all six genotypes of HCV(12,13). As of May 2018, the FDA or the EMA had approved 13 direct-acting antivirals from four classes (Table 1). Therefore, nowadays HCV therapy, including Slovak medical practice, combines DAAs according to a specific genotype at the highest efficacy level according to the recommendation table.
Acknowledgments: This publication is the result of project implementation: Development of the center of excellence for utilization of information on bio-macromolecules in disease prevention and in improvement of quality of life (ITMS 26240120027) supported by the R & D Operational Program funded by the ERDF.
Poďakovanie: Táto publikácia je výsledkom implementácie projektu: Rozvoj centra excelentnosti pre využitie informácií o biomakromolekulách pri predchádzaní ochorení a zlepšení kvality života (ITMS 26240120027) podporeného OPVaV z ERDF.
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- Serfaty L. Metabolic Manifestations of Hepatitis C Virus: Diabetes Mellitus, Dyslipidemia. Clin Liver Dis 2017; 21(3): 475-486. doi:10.1016/j. cld.2017. 03. 004
- Long JD, Rutledge SM, Sise ME. Autoimmune Kidney Diseases Associated with Chronic Viral Infections. Rheum Dis Clin N Am 2018; 44(4): 675-698. doi:10.1016/j.rdc.2018.06.006
- World Health Organization. WHO | Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. WHO. http://www.who.int/hepatitis/publications/hepatitis-c-guidelines-2018/ en/. Published 2018. Accessed December 3, 2018.
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