Group: 4
Assignment: 2
Group members: Registration Numbers:
Kashmala Khan (MPhil 1st) 02272313004
Laveeza Khan (MPhil 1st) 02272313003
Uzair Khan (MPhil 1st) 02272313002
Muhammad Jawad (MPhil 1st) 02272313011
Literature Review
Hepatitis C is caused by the hepatitis C virus (HCV), which is an RNA virus of the family
Flaviviridae. There are six major types of HCV namely genotype 1, 2, 3, 4, 5 and 6, each one
has its own subtypes. HCV infection can cause acute hepatitis C; following acute infection,
50–80% of patients develop chronic hepatitis C. Chronic HCV infection triggers a chronic
inflammatory disease process, which might lead to liver fibrosis, cirrhosis, hepatocellular
carcinoma and death (Stanaway, Flaxman et al. 2016).
The first treatment for hepatitis C was developed in 1980s known as recombinant interferon-
alfa (IFNa) which was based on a series of protein injections. Interferon (IFN) has been used
for more than 20 years for chronic HCV treatment, due to its antiviral and immune
stimulatory properties (Hoofnagle, Mullen et al. 1986). Unfortunately, treatment with IFN
alone did not result in effective response and the success rate was about 16-20% in a course
of 6 months. The association of a broad-spectrum antiviral agent, Ribavirin (RBV), made it
possible to significantly increase the effectiveness of these treatments and the response rate
was increased to 35-40% (Manns, McHutchison et al. 2001). This treatment was further
improved by pegylation of interferon where a polyethylene glycol molecule is covalently
bound to recombinant IFN. This resulted in a response rate of 54-56%. The limitations of this
combination were the poor clinical tolerance (acute dysimmune pathologies, flu-like
syndrome, neurocognitive disorders) and biological (neutropenia and thrombocytopenia for
IFN, hemolytic anemia for RBV). Also, the response rate was 54-56% which mean that 40-
50% of patients were still suffering from the infection thus, more effective therapies were
needed (Feld and Hoofnagle 2005).
Following an era dominated by interferon (IFN)-based therapies, targeted drugs known as
direct-acting antiviral agent (DAA)-based regimens have been developed that cure chronic
HCV infection in the majority of patients (Manns, Pockros et al. 2013). DAA medicines are
the most effective and safest against hepatitis C. They are known to treat the infection in
more than 90% of patients. Multiple steps in the HCV life cycle provide the targets for DAAs
(Pawlotsky 2016). Replication of the virus can be directly inhibited by NS5B inhibitors.
NS5A inhibitors alter the regulatory role of NS5A and seem to disorganize the replication
complex, thereby inhibiting HCV replication in a potent manner, enhanced by their ability to
also inhibit viral assembly and release (Janssen, Reesink et al. 2013). Hepatitis C medicines
approved by NSH include; sofosbuvir, ribavirin, a combination of sofosbuvir and ledipasvir,
a combination of grazoprevir and elbasvir, combination of sofosbuvir and velpatasvir,
combination of ritonavir, ombitasvir and paritaprevir, combination of pibrentasvir and
glecaprevir. There are little side effects associated with DAA but some people may
experience severe complications such as skin irritation, insomnia, anemia, hair loss,
depression and anxiety.
The effectiveness of DAA therapy can be enhanced by conjugating it with an antibody. The
identification of monoclonal neutralizing antibodies (mnAbs) that target conserved and
functionally important regions of the E1 and E2 glycoproteins on the viral surface (Cashman,
Marsden et al. 2014) could be the best antibodies to conjugate with DAA for targeted
treatment of HCV infection. This treatment procedure would enable us to selectively deliver
the specified drug to the target site which could improve the drug’s biodistribution and
efficacy while reducing its systematic toxicity.
References;
Alley, S. C., et al. (2010). "Antibody–drug conjugates: targeted drug delivery for cancer." Current
opinion in chemical biology 14(4): 529-537.
Dietz, C. and B. Maasoumy (2022). "Direct-acting antiviral agents for hepatitis C virus infection—
From drug discovery to successful implementation in clinical practice." Viruses 14(6): 1325.
Cashman, S. B., et al. (2014). "The humoral immune response to HCV: understanding is key to
vaccine development." Frontiers in immunology 5: 550.
Feld, J. J. and J. H. Hoofnagle (2005). "Mechanism of action of interferon and ribavirin in treatment
of hepatitis C." Nature 436(7053): 967-972.
Hoofnagle, J. H., et al. (1986). "Treatment of chronic non-A, non-B hepatitis with recombinant
human alpha interferon." New England Journal of Medicine 315(25): 1575-1578.
Janssen, H. L., et al. (2013). "Treatment of HCV infection by targeting microRNA." New England
Journal of Medicine 368(18): 1685-1694.
Manns, M., et al. (2013). "Long‐term clearance of hepatitis C virus following interferon α‐2b or
peginterferon α‐2b, alone or in combination with ribavirin." Journal of viral hepatitis 20(8): 524-529.
Manns, M. P., et al. (2001). "Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b
plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial." The Lancet 358(9286):
958-965.
Pawlotsky, J.-M. (2016). "Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free
regimens." Gastroenterology 151(1): 70-86.
Stanaway, J. D., et al. (2016). "The global burden of viral hepatitis from 1990 to 2013: findings from
the Global Burden of Disease Study 2013." The Lancet 388(10049): 1081-1088.
Tsuchikama, K. and Z. An (2018). "Antibody-drug conjugates: recent advances in conjugation and
linker chemistries." Protein & cell 9(1): 33-46.
