Dynamic changes in innate immune responses during direct-acting antiviral therapy for HCV infection.
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| Abstract |
The role of the endogenous interferon (IFN) system has been well characterized during IFN-based therapy for chronic hepatitis C virus (HCV) infection; less is known for direct-acting antivirals (DAAs). In this phase 3b open-label study, we assessed changes in IFN-stimulated genes (ISGs) in non-cirrhotic treatment-naïve or pegIFN/RBV-experienced HCV-GT1a-infected patients receiving paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin (PrOD + R) for 12 weeks. ISG expression was quantified from peripheral blood mononuclear cells at baseline, treatment weeks (TW)2, TW4, TW8, end of treatment (EOT) and at post-treatment week 12. Paired sera were used to assess IFN-α/IFN-related chemokines/cytokines. Twenty-five patients were enrolled. Overall sustained virologic response (SVR)12 was 92% (no virologic failure [VF]) and 100% for those completing the study protocol. Two patients were excluded from the ISG analysis due to lack of post-treatment samples. The majority of ISGs were downregulated at TW2-TW4 (nadir TW4); however, a relative increase was observed at TW8-EOT, although levels were lower than baseline. This downregulation was accompanied by increases in IFN-α/IFN-related chemokines, a finding not observed with TH 1/2-related cytokines. Following SVR, ISG expression returned to TW2 levels. In conclusion, PrOD + R for 12 weeks was well-tolerated with no VF. Our data demonstrate dynamic alterations in innate immune profiles during highly potent IFN-free DAA therapy. The downregulation of ISG post-therapy suggests reversal of the "exhausted" ISG phenotype following SVR, and the rise in ISGs and IFN-α/IFN-responsive chemokines late during therapy suggests resetting of IFN responsiveness that may be relevant in determining duration of or immunological sequelae from DAA therapy, including HBV reactivation.
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| Authors | Jacinta A Holmes, Charles Carlton-Smith, Arthur Y Kim, Emily O Dumas, Joelle Brown, Jenna L Gustafson, Georg M Lauer, Sakuni T Silva, Maxwell Robidoux, Daniel Kvistad, Nadia Alatrakchi, Pierre Tonnerre, Daniel E Cohen, Hongtao Zhang, Nancy S Shulman, Raymond T Chung |
| Journal | Journal of viral hepatitis (J Viral Hepat) Vol. 26 Issue 3 Pg. 362-372 (03 2019) ISSN: 1365-2893 [Electronic] England |
| PMID | 30450781 (Publication Type: Clinical Trial, Phase III, Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2018 John Wiley & Sons Ltd. |
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