Impact of Interferon Lambda 4 Genotype on Interferon‐Stimulated Gene Expression During Direct‐Acting Antiviral Therapy for Hepatitis C

Abstract

New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat, including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, patients with cirrhosis receiving a 16‐week course of sofosbuvir and ribavirin had a sustained virological response (SVR) rate of around 50%. In patients with cirrhosis, interferon lambda 4 (IFNL4) CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon‐stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, whereas the reverse was true for non‐CC patients. Conclusion: These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection. (Hepatology 2018; 00:000‐000).

Dynamic changes in innate immune responses during direct‐acting antiviral therapy for HCV infection

“…Furthermore, there was a relative increase in ISG/IEG mRNA expression at TW8 and EOT relative to TW4, although levels were still lower than those observed at baseline, with the peak fold change reduction in ISG/IEG expression observed at TW4 for most ISG/IEGs (Figure , Table ). We did not observe a difference in ISG/IEG mRNA expression or fold change from baseline during treatment according to IL28B genotype in our HCV‐GT1a cohort (Figure ), in contrast to a recent report in HCV‐GT3 patients . The majority of the remaining ISG/EGs were still downregulated but again did not meet the 1.5‐fold differential expression threshold or P < 0.0007.…”

“…Therefore, direct comparison between results from the two studies is difficult, and differences in patterns of IFN‐related chemokines/cytokines may be due a combination of factors, including study design, DAA regimen, timing of mRNA/protein level evaluation, HCV genotype and the interactions between virus and host (HCV genotype and IFNL3 genotype). The latter is particularly relevant given the aforementioned study by Ramamurthy et al, where they observed dynamic changes in CXCL10 gene expression, with upregulation at treatment week 16 (end of treatment), but only in patients with the “good” responder IFNL3 genotype.…”

“…Although it would be highly interesting to perform a similar study of the intrahepatic compartment, such frequent liver sampling with liver biopsy is neither feasible nor ethical due to the risk of complications with frequent repeated liver biopsies. In addition, changes in the peripheral compartment have been shown to be important during both IFN‐based and DAA‐based therapy . Fourth, as the objective of this study to specifically study the type I antiviral response in relation to HCV antigen removal during DAA therapy, we designed a custom panel of ISG/IEGs based on published data that were shown to be highly relevant in CHC, including ISGs relevant to DAA therapy, rather than using an unbiased whole transcriptome sequencing approach.…”

“…Furthermore, baseline intrahepatic ISG expression strongly correlates with IL28B genotype, the strongest pre‐treatment predictor of outcome during IFN‐based therapy . These associations have not been consistently associated with baseline peripheral ISG expression …”

“…DAAs target HCV‐specific replication cycle proteins and, in contrast to IFN, are not recognized to be directly immunomodulatory. However, emerging data suggest that intrahepatic type I IFN responses may be restored in the context of IFN‐free DAA therapy for HCV‐GT1 and there is dynamic peripheral enrichment of genes in the type I IFN signalling pathways during DAA therapy in cirrhotic patients with HCV‐GT3 who carry the “good‐responder” IL28B genotype, although these data were generated using a suboptimal IFN‐free DAA regimen that has since been discontinued. Furthermore, DAAs have also been reported to normalize NK cell function and partially restore T‐cell function …”