Page 30 - Read Online

Irshad et al. Hepatoma Res 2018;4:23 I http://dx.doi.org/10.20517/2394-5079.2018.25 Page 3 of 14

Present study gives an update on the availability and action of therapeutic agents targeting various steps of
HCV viral life cycle and infected host cell processes that may be disrupted to check viral reproduction and
underlying pathological reaction cascade. It also describes the comparative efficacies of different agents and
the future of HCV- treatment under the use of these agents.

TYPES OF DRUGS
In a common practice, the combination of pegylated interferon-α (PegIFN-α) and ribavirin, is used for the
treatment of HCV infection . The addition of DAAs, like boceprevir, ortelaprevir, in the drug regimen, has
[18]
brought a new change in the status of HCV treatment. This regimen improves the SVR to a significant level
even in genotype-1 infected patients . IFN and ribavirin can cause patients with flu-like symptoms, cognitive
[19]
dysfunction, thyroid dysfunction and other adverse reactions, leading to premature termination of treatment
in some patients. However DAAs were found to develop drug resistant variants [20,21] . Subsequent studies
introduced the next generation DAAs like simprevir and sofosbuvir, that were approved by FDA for treatment
of HCV infection [21,25] . An interferon free drug regimen comprising ombitasvir, paritaprevir, ritonavir and
dasabuvir has been approved for HCV genotype-1 infected patients. Now it is believed that the new drug
combination may consist of interferon free regimen with high viral killing efficiency, short therapy time and
less adverse effect. The development of drugs and their different combinations for an effective therapy against
HCV is under investigation for last several years. Some new drugs developed and used in recent past are
described in Table 1. These drugs are used both alone as well as in combination to other drugs. Based on their
nature, action and host response, these drugs have been classified under different categories:

Interferon
PegIFN-α, a commonly used drug increases the SVR rate by causing a delay in renal clearance. Human albumin-
IFN-α (Albinterferon) is a fusion protein. This protein is used for the treatment of HCV infection. Different
reports have shown that the SVR rate arising from the use of Albinterferon and Ribavirin was nearly the same
as noted with use of the SOC treatments [26,27] . Similarly, IFN-λ which is a class-III interferon, is also used for the
treatment of HCV infection. The receptors of IFN-λ are mainly present in the liver and therefore very minimal
extrahepatic adverse effects were recorded with the use of IFN-λ in comparison to IFN-α .
[28]
Direct acting antiviral agents
This is the class of drugs acting against viral and host proteins involved in HCV life cycle. The major
inhibitors of NS3 viral protein are telaprevir and boceprevir. Telaprevir was approved and recommended for
use with PegIFN-α and ribavirin in genotype-1 patients. This was classified as triple therapy. Since telaprevir
treatment is reported to be effective against the resistant mutants in the short term duration, it was decided
to use it for long-term and subsequently approved for the treatment . It is important to note here that the
[29]
long term use of these drugs often leads to drug resistance including T54A/S, R155K/T, V36A/M, V55A,
and A156/S/T/V, etc. Simeprevir is another NS3 protease inhibitor classified as second generation drug. This
drug is a reversible inhibitor of NS3/4A protease . Danoprevir and faldaprevir are also second-generation
[30]
HCV NS3/4A protease inhibitors and used in patients infected HCV genotype-1. In addition to these drugs,
there are various other NS3 protease inhibitors like Vaniprevir (MK-7009), Narlaprevir (SCH 900518),
Asunaprevir (BMS 650032), VX 985, and MK-5172 which are used for treatment of HCV infection. There is
every possibility that these drugs may be approved for therapeutic use against HCV infection .
[29]

Daclatasvir (BMS) 790052 was found to inhibit NS5A, a protein involved in HCV replication and therefore
used as a drug for control of HCV infection. This particular drug has a broad genotype antiviral activity. In
addition, other NS5A inhibitors include Ledipasvir (GS-5885), ABT 267, IDX791, and ACH-2928 etc. NS5B
is a RNA-dependent RNA polymerase (RdRp) involved in HCV replication. This NS5B enzyme activity is
inhibited by two categories of inhibitors that are nucleoside/nucleotide derivative inhibitors (NIs) and non-