sirs,
We thank Dr Galmozzi and Dr Lampertico for their comment on our recently published paper on the effect of the dinucleotide frameshift variant in ss469415590 in the interferon (IFN)‐λ4 gene on interferon/ribavirin treatment and its relationship with the two commonly used single nucleotide polymorphisms (SNP) in IL28B (rs12979860, rs8099917).1, 2
We agree that our study does not provide insights on the causal relationship between IFNL4 and treatment response in patients with chronic hepatitis C virus (HCV) infection. Nevertheless, our study was designed to investigate the clinical usefulness of the different SNPs in IL28B and IFNL4 in a large cohort of Caucasian patients infected with chronic HCV.
Hamming et al. demonstrated that IFNL4 encodes an active type III interferon with potent anti‐viral activity against both HCV and coronaviruses.3 Galmozzi and Lampertico therefore conclude that this strong anti‐viral activity works against the assumption of an inhibition of the IFNL4 protein of treatment‐induced HCV clearance. We would like to remind them that up‐regulation of intrahepatic interferon‐stimulated genes (ISG) is associated with treatment failure in patients with chronic HCV, and levels of ISG are differently distributed according to different IL28B genotypes.4 Furthermore, Prokunina‐Olsson and her collaborators demonstrated that IFNL4 induces ISG expression in HepG2 hepatoma cells.5 Thus, high baseline ISG levels might be associated with poor response to exogenous IFN, by exhausting the IFN response pathways.6
Finally, we agree that the causal role of IFNL4 genotypes for viral clearance is conflicting, and further studies need to be performed to elucidate the molecular mechanistic relationship.
Acknowledgement
The authors' declarations of personal and financial interests are unchanged from those in the original article.2
References
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