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Dynamic changes in innate immune responses during direct‐acting antiviral therapy for HCV infection
Author(s) -
Holmes Jacinta A.,
CarltonSmith Charles,
Kim Arthur Y.,
Dumas Emily O.,
Brown Joelle,
Gustafson Jenna L.,
Lauer Georg M.,
Silva Sakuni T.,
Robidoux Maxwell,
Kvistad Daniel,
Alatrakchi Nadia,
Tonnerre Pierre,
Cohen Daniel E.,
Zhang Hongtao,
Shulman Nancy S.,
Chung Raymond T.
Publication year - 2019
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.13041
Subject(s) - ombitasvir , medicine , ribavirin , chemokine , dasabuvir , interferon , paritaprevir , immunology , innate immune system , immune system , hepatitis c virus , ritonavir , alpha interferon , peripheral blood mononuclear cell , hepatitis c , viral load , virus , biology , antiretroviral therapy , biochemistry , in vitro
Summary 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 ( DAA s). In this phase 3b open‐label study, we assessed changes in IFN ‐stimulated genes ( ISG s) in non‐cirrhotic treatment‐naïve or peg IFN / RBV ‐experienced HCV ‐ GT 1a‐infected patients receiving paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin (Pr OD + R) for 12 weeks. ISG expression was quantified from peripheral blood mononuclear cells at baseline, treatment weeks ( TW )2, TW 4, TW 8, 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 ISG s were downregulated at TW 2‐ TW 4 (nadir TW 4); however, a relative increase was observed at TW 8‐ EOT , although levels were lower than baseline. This downregulation was accompanied by increases in IFN ‐α/ IFN ‐related chemokines, a finding not observed with T H 1/2‐related cytokines. Following SVR , ISG expression returned to TW 2 levels. In conclusion, Pr OD + 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 ISG s 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.