Trends to treat HCV

HCV structure and life cycle

HCV is a spherical RNA virus. Its RNA is more prone to damage,
which is advantageous to HCV as it allows facile mutations.
Important steps involved in the life cycle of HCV include
attachment, entry and uncoating of the virus with the host cell
membrane, translation and poly-protein processing, replication,
assembly, egress and release of the viral RNA.
Pathophysiology of chronic Hepatitis C
Genotype 1 is the most common genotype and causes severe liver
damage.
Chronic hepatitis C is not the consequence of direct destruction of
hepatic cells by HCV. Rather, it results from an immune response that
causes hepatic cellular injury. Such immune response is inadequate to
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eradicate the virus from its reservoir and culminates in fibrosis and
hepatic cirrhosis.
The effectiveness of a combination of interferon and ribavirin
is probably explained by its antiviral activity and restoration of HCV
specific immune response.
Therapeutic targets for treatment
Entry of viral RNA in the liver cells can be blocked through entry
inhibitors which include neutralizing anti-receptor antibodies and
receptor antagonists
Immune modulators include interferon derivatives, TLR agonists,
cytokines, and therapeutic vaccines
Helicase inhibitors block the subgenomic replication of virus
Anti-HIV drugs such as protease inhibitors have also shown high

potential to treat chronic hepatitis C

The Molecular Biology behind the mechanism
of drug action
• NS3/4A protease inhibitors

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• NS5B polymerase inhibitors (Sofosbuvir)
The key enzyme inHCV RNA replication is NS5B, an RNA-dependent
RNA polymerase thatcatalyses the synthesis of a complementary
negative-strand RNA by usingthe positive-strand RNA genome as a
template

• NS5A inhibitors ( daclatasvir, ledipasvir )

The HCV NS5A protein seems to play a manifold role in
HCV replication,assembly and release

• Cyclophilin B inhibitors (alisporivir)

HCV depends on various host factors throughout its
life cycle.Cyclophilin B is expressed in many human tissues and
provides a cistransisomerase activity, which supports the folding and
Combination therapy
• Sofosbuvir
It is an oral, direct acting nucleotide analogue inhibitor of the
nonstructural HCV protein NS5B polymerase
It is administered with ribavirin for the assessment of safety and
efficacy in a patient with HCV genotype 2 and 3.
Other combination therapy
• Combination of sofosbuvir and ribavirin
The most effective treatment of HCV infection

• Combination of sofosbuvir and ledipasivir

• The combination of ledipasivir and sofosbuvir with or without
ribavirin exhibited highly sustained virologic response among the
patients with HCV genotype 1. A combination of ledipasivir and
sofosbuvir was found to be more effective in patients with HCV
genotype 1 than a combination of ledipasivir, sofosbuvir and ribavirin.
Conclusion
It can be concluded that the use of interferon in the treatment of chronic
hepatitis C exhibits a large number of adverse effects. Pegylation of
interferon increases the efficacy and ameliorates the adverse effects
of interferons. Interferon can be replaced with nonstructural polymerase
NS5A and NS5B inhibitors such
as sofosbuvir and daclatasvir respectively. Sofosbuvir used
as monotherapy or in combination
with ribavirin, daclatasvir and ledipasivir is highly effective in
interferon resistance