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Page 8 of 14 Irshad et al. Hepatoma Res 2018;4:23 I http://dx.doi.org/10.20517/2394-5079.2018.25

some studies have demonstrated that IFN-α based treatment of HCV infection is influenced by several
factors including viral as well as host factors. Viral load and HCV genotypes were found to be important
factors influencing IFN-therapy. HCV genotype-1 responded poorly to IFN therapy achieving SVR to near
[104]
about 50% in comparison to HCV genotype-2 and -3 where SVR reached up to 85% . It has been found that
many HCV proteins interfere in the antiviral action of IFN-α . Subsequently, it was noted that various HCV
[105]
proteins including Core, E2, NS3/4A, NS5A/5B, antagonize antiviral effect of IFN-α. It may be illustrated
more specifically in reference to individual HCV viral proteins. For example, HCV core induces expression of
Suppressor of cytokine signaling-3 and -1 (SOCS-3 and SOCS-1), which antagonize IFN-α action by blocking
JAK/STAT-pathway and ISGs expression [106,107] . HCV core also inhibits IFN induced phosphorylation and
nuclear translocation of STAT-1. Binding of HCV core to STAT-1 decreases its phosphorylation and ISGs
transcription [108,109] . Another important structural protein HCV E2 was also found inactivating IFN-α through
inhibition of PKR . This effect of E2 was detected prominently in patients infected with HCV-1 isolate. HCV
[110]
genotype-2 and -3 could not show the same effect . Of the nonstructural proteins, HCV NS3/4A was found to
[110]
disrupt the IFN induction pathway. HCV NS3/4A protease cleaves various proteins including antiviral signaling
proteins (MAVs) [111,112] , TIR domain containing adaptor inducing IFN-α (TRIF) and adapter protein of RIG-1
[113]
TLR-3 signaling pathways etc. This cleavage disrupts not only innate immune response but also IFN-induction
pathway, ultimately resulting in down regulation of the transcription of IFN-alpha inducible genes [114,115] . In
addition, HCV NS4B and NS5A were also found to inhibit protective action of IFN-α. NS4B reduces IFN-α
induced phosphorylation of STAT-1 and expression of IFN receptors. On the other hand NS5A binds and
inactivates PKR [116-118] . Several studies have shown inhibitory effect of NS5A on IFN induced JAK-STAT
signaling pathway [119-121] . NS5A usually blocks IFN-1 induced STAT-1 phosphorylation and its nuclear
translocation resulting in downregulation of ISGs induced expression.

IL28B polymorphism
Single nucleotide polymorphism (SNP) in IL28B gene present on chromosome 9 has an impact on HCV
treatment response. The SVR rate of SOC in HCV patients carrying CC genotypes was 2-3 times higher
as compared to the one with its clearance. There is high frequency of CC genotypes in comparison to
[122]
European and African. IL28B polymorphism is the best predictor of treatment response, better even than
viral load, liver fibrosis, glucose level etc. EASL guidelines showed that IL28B polymorphism can be used
to give a predictive value. Thus IL28B gene has a better predictive value in comparison to SOC and DAAs.

Hepatic steatosis
Patients with hepatic steatosis usually do not respond well to HCV infection treatment. The presence
of steatosis does not allow the EVR or SVR to attain in genotype-1 infected patients when treated with
SOC. Similarly, steatosis affects negatively in patients infected with other genotypes. It causes relapse after
discontinuation of treatment in patients with genotype-3. This all indicates that pathogenesis of steatosis
differs in different genotypes and influences the treatment. In addition to all above factors influencing the
treatment response, other conditions like age, insulin resistance, and metabolic syndrome etc. also have
negative impacts on treatment.

Virological response to therapy
The therapy of HCV infection is basically aimed to eradicate the virus and prevent the ensuing disease
complications. The success of therapy is monitored by SVR rate which is defined as the absence of the HCV
RNA in serum post 24 weeks of stoppage of treatment . The value of SVR indicated not only eradication of
[123]
virion from circulation but also correlates with symptoms [124-127] . The combination of PegIFN and ribavirin
has been the SOC for all patients infected with HCV irrespective of viral genotypes . This regimen
[123]
produces SVR to 70%-80% in patients with HCV genotype-2 or -3 infection. However, SVR reached only
45%-70% in patients infected with other genotypes . In recent trials of boceprevir and telaprevir in patients
[123]
with cirrhosis it was noted that SVR was low in comparison to that in non-cirrhotic patients.