Page 29 - Read Online

Page 2 of 14 Irshad et al. Hepatoma Res 2018;4:23 I http://dx.doi.org/10.20517/2394-5079.2018.25

awareness. HCV infection causes both acute as well as chronic liver diseases including cirrhosis of liver and
hepatocellular carcinoma. Globally, HCV infection affects nearly 180 million people which account for 3%
[1]
population of the world. Approximately 3 million new cases are added to this population every year . A
[2,3]
high proportion of HCV infected patients develop chronic liver diseases and nearly 20% of them progress
to cirrhosis and about 10% to liver cancer in later stage. The presence of HCV infection, though varies
[4,5]
from region to region, has been noted throughout the world. Hepatitis B virus (HBV)-based prevention and
control measures for viral hepatitis have achieved remarkable results, and hepatitis C has relatively little
awareness. Efforts have been made to develop effective prophylactic and therapeutic measures for treatment
of chronic HCV infection. There is a common belief now that HCV infection needs more attention even than
human immunodeficiency virus (HIV) infection in terms of its early detection and timely remedies since
both of them do not have any vaccine for prevention. Moreover, the disease burden caused by HCV is also
more serious even than HIV. A high genomic variability in HCV has led to development of at least seven
genotypes and many isotypes.

HCV is an RNA virus with about 9.6 kb genome. This is a single stranded, enveloped virus with positive
polarity and has been categorized under flaviviridae family. Its genome has a single ORF encoding for
polypeptides of 3011 amino acids. The 5’UTR region has an internal ribosomal entry site (IRES) which is involved
in HCV replication. Using host and viral proteases, HCV polyprotein is cleaved into three structural proteins
(Core, E1 and E2) and seven non-structural proteins (P7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) . HCV-core
[6]
forms viral nucleotide that has significant role in viral pathogenesis and E1 and E2 proteins are involved
[7]
in viral entry into the cell . The P7, a 63-amino acid protein, helps in translocation of NS2 into endoplasmic
[8]
reticulum and also in viral assembly and release of HCV virions [9,10] . The NS2 peptide is a transmembrane
protein which plays role in viral replication. The NS3, on the contrary, is a protease and acts as ATPase/
helicase [11,12] . Usually, HCV protease disrupts interferon (IFN) and toll-like receptor-3 (TLR-3) signaling
pathways. The NS4A acts as a cofactor for NS3 protease, the NS4B is needed to recruit other viral proteins [13,14]
and NS5A, a phosphoprotein, plays role in viral replication [15,16] . The last non-structural protein i.e. NS5B is
an HCV RNA dependent RNA polymerase (RdRp) which also participates in RNA replication .
[17]

The studies available in last few decades have elucidated the virus specific events in infected cells. In order
to use these events as targets for chemotherapy, some antiviral agents were developed and used to treat HCV
infection on a line similar to the one used for other viral infections. This targeting is aimed to suppress virus
reproduction without an adverse effect on the host-cell. There are a number of virus specific processes within
virus replicative cycle in an infected cell that may be targeted for chemotherapeutic intervention. The major
target steps include virus entry into the cell, reverse transcription, viral DNA/RNA polymerization and the
reactions involved in viral DNA/RNA synthesis etc. At present, a variety of agents including nucleosides and
non-nucleosides entities have been developed which interact with virus targets and inhibit virus replication.
In case of treating HCV infection, today a variety of agents are available for use. In addition to the virus-
specific events, there are several host enzymes and processes that are closely associated with viral DNA,
RNA or protein synthesis. These processes may also be the targets for antiviral agents.

The recommended treatment for HCV infection includes a combination therapy with PegIFN and
ribavirin . However, recently several new regimens have been evolved for treatment of HCV infection.
[18]
The drugs including direct-acting antiviral agents (DAAs) like boceprevir or telaprevir as protease
inhibitors have provided a new promise to aim the HCV treatment. This therapy improves sustained
virological response (SVR) in patients infected with HCV genotype-1 by more than 70%. Moreover, it has
an additional significance of little chances of development of drugs resistant variants [19-21] . Several other
DAAs are in clinical trials today and have been evaluated for combination therapy . The emerging new
[22]
antivirals need a new trial for serious liver diseases, particularly, in those cases with poor response to
current regimens [23,24] .