By: Vicky Liu, PharmD Candidate c/o 2018

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Hepatitis is an inflammation of the liver commonly caused by viruses which can lead to self-limitation, fibrosis, cirrhosis, or liver cancer. Viral hepatitis is categorized into five types: A, B, C, D, and E. Of the five types, A, B, and C are the most prevalent in the United States. The Centers of Disease Control and Prevention (CDC) reported that there were 1,239 acute cases of hepatitis A virus (HAV), 2,953 acute cases of hepatitis B virus (HBV), and 2,194 acute cases of hepatitis C virus (HCV) in 2014. Out of the three, HCV is the most virulent. In 2014, 19,659 death certificates listed HCV as the primary cause of death compared to 76 and 1,843 for HAV and HBV, respectively.¹

Hepatitis C is further classified into genotypes based on the virus’s nucleotide sequence. There are six major genotypes of which genotypes 1, 2, and 3 are the most prevalent out of the six. The prevalence of each genotype may differ in each country. For example, genotype 1 is predominant in the United States and Europe, genotype 4 is seen in North Africa and the Middle East, and genotype 5 and 6 are only prevalent in Hong Kong and South Africa.² The mechanism behind HCV’s genotypic diversity is due to its RNA polymerase. Because HCV contains a RNA-dependent RNA polymerase, it does not have any means to correct errors in the new, complementary strand during replication, leading to rise of various genotypes.

Unfortunately, there are no vaccines available for HCV. However, there are four different classes of direct acting antivirals (DAAs) to treat and potentially cure hepatitis C. The DAAs are nonstructural protein 3/4A (NS3/4A) protease inhibitors, nucleoside nonstructural protein 5B (NS5B) polymerase inhibitors, non-nucleoside NS5B polymerase inhibitors, and nonstructural protein 5A (NS5A) inhibitors. These four classes target HCV’s lifecycle and affect essential proteins used for viral replication. For example, within HCV, there are structural and nonstructural proteins that help the virus in survival. Structural proteins are important in providing RNA binding, cell signaling, cell growth, and survival. Nonstructural proteins are utilized for replication, RNA transcription, post-translation, assembly, and attachment to hosts.³

NS3 is a nonstructural, multifunctional protease containing a helicase domain linked to a protease domain. NS3 with its cofactor NS4A cleaves polyproteins at four sites to produce proteins for replication and survival. NS3 also has a role in blocking host immune cell signaling. By targeting NS3/4A at its active site, these protease inhibitors prevent viral replication and promote antiviral signaling. Grazoprevir, paritaprevir, and simeprevir are examples of this class.⁴

NS5B is a polymerase which initiates RNA synthesis by forming a phosphodiester bond between the priming and initiating nucleotides. This early product is used as a primer to which additional nucleotides are added on. At this point, NS5B continues to add on nucleotides without dissociating from the chain. This inherent mechanism renders the polymerase vulnerable, which led to the development of three classes of NS5B polymerase inhibitors including nucleoside inhibitors (NIs), non-nucleoside inhibitors (NNIs), and pyrophosphate (PPi) analogs. PPi compounds are toxic, which limits their use for treatment and are employed as salvage therapy. NIs have been used to treat HBV, herpes viruses, and human immunodeficiency virus (HIV). NIs are prodrugs and are unionized, allowing them to penetrate the virus’s cell membrane. Next, they undergo phosphorylation to pose as nucleotides which NS5B collects and adds onto its chain of nucleotides. However, the incorporated NIs are non-functional, which causes the nucleotide chain to terminate—disabling viral replication. Sofosbuvir is the only nucleoside NS5B polymerase inhibitor available for treatment of HCV. On the other hand, NNIs work by binding allosterically to NS5B, causing a conformational change in the polymerase preventing further elongation of nucleotides. Dasabuvir is the only approved NNI.⁵

NS5A is a protease involved in RNA replication, RNA translation, and packaging. However, its exact mechanism for these processes is not well understood.  These inhibitors affect viral genome replication and the assembly and release of virions but it is unclear where they target within the NS5A. Examples of NS5A inhibitors are daclatasvir, ledipasvir, ombitasvir, elbasvir, and velpatasvir.⁶

Although treatment for hepatitis C has been improved, there are many individuals who are unable to access care. According to the World Health Organization (WHO), in 2015, 71 million people were infected with HCV but only 14 million (20%) knew of their diagnoses.  Of the 14 million, 1.1 million (7.4%) were treated.⁷ WHO implemented an annual World Hepatitis Day on July 28 to spread awareness and campaign to eliminate viral hepatitis.⁸

 

SOURCES:

1. 1. Viral hepatitis – statistics and surveillance. Centers for Disease Control and Prevention website https://www.cdc.gov/hepatitis/statistics/index.htm. Updated 05/11/2017. Accessed 06/29/2017.
2. Zein NN. Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev. 2000;13(2):223-35.
3. Kim CW, Chang KM. Hepatitis C virus: virology and life cycle. Clin Mol Hepatol. 2013;19(1):17-25.
4. McGivern DR, Masaki T, Lovell W, et al. Protease inhibitors block multiple functions of the NS3/4A protease-helicase during the Hepatitis C virus life cycle. J. Virol. 2015;89(10):5362–70.
5. Powdrill MH, Bernatchez JA, Götte M. Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B. Viruses. 2010;2(10):2169-2195.
6. Kohler JJ, Nettles JH, Amblard F, et al. Approaches to hepatitis C treatment and cure using NS5A inhibitors. Infect Drug Resist. 2014;7:41-56.
7. Hepatitis C. World Health Organization website http://www.who.int/mediacentre/factsheets/fs164/en/. Updated 04/2017. Accessed 06/29/2017.
8. WHO global health days. World Health Organization website http://www.who.int/campaigns/hepatitis-day/2017/what-you-can-do/en/. Accessed 06/29/2017.
9. Initial treatment of HCV infection. American Association for the Study of Liver Diseases website http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection. Updated 04/12/2017. Accessed 06/29/2017.
10. Zepatier® (elbasvir and grazoprevir) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2017.
11. Harvoni® (ledipasvir and sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2017.
12. Viekira Pak® (ombitasvir, paritaprevir, and ritonavir) [package insert]. North Chicago, IL: AbbVie Inc; 2017.
13. Viekira XR® (dasabuvir, ombitasvir, paritaprevir, and ritonavir) [package insert]. North Chicago, IL: AbbVie Inc; 2017.
14. Sovaldi® (sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2017.
15. Olysio® (simeprevir) [package insert]. Titusville, NJ: Janssen Therapeutics; 2017.
16. Epclusa® (sofosbuvir and velpatasvir) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2017.
17. Daklinza® (daclatasvir) [package insert]. Princeton, NJ: Bristol-Meyers; 2017.

Published by Rho Chi Post