Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via Toll-like receptor 7.
BACKGROUND
ANA773, an oral prodrug of a small-molecule Toll-like receptor (TLR)7 agonist, induces a dose-related decrease in serum HCV RNA levels in chronic hepatitis C patients.


METHODS
The prodrug ANA773 was administered to healthy individuals and chronic hepatitis C patients. At different time points during the course of treatment, modulation of the phenotype and function of peripheral leukocytes were evaluated to determine the role of distinct immune cells on the clinical outcome of therapy.


RESULTS
Early after administration of the TLR7 agonist, a mild transient reduction of the number of lymphocytes was observed in both healthy individuals and chronic hepatitis C patients. Moreover, repeated administration of ANA773 resulted in transiently reduced numbers of myeloid and plasmacytoid dendritic cells (DC) in blood. Interestingly, reduced plasmacytoid DC numbers as well as increased serum interferon (IFN)-α and IFN-γ inducible protein (IP)-10 levels were observed only in virological responders (≥1 log(10) IU/ml reduction of HCV RNA levels upon ANA773 treatment), but were absent in virological non-responders. In vitro stimulation of peripheral blood mononuclear cells from virological responders showed a high frequency of IFN-α-producing plasmacytoid DC upon stimulation in vitro with ANA773, whereas no IFN-α was induced in non-responders.


CONCLUSIONS
These findings indicate that the viral load decline in chronic hepatitis C patients treated with the TLR7 agonist ANA773 is likely due to intrinsic differences in the induction of endogenous IFNs and IFN-stimulated gene products (IFN-α and IP-10) upon TLR7 ligation.
Department of Gastroenterology and Hepatology, Erasmus Medical Center University Hospital, Rotterdam, the Netherlands. p.a.boonstra@erasmusmc.nl
Andre
A
Boonstra
Bi-Sheng
BS
Liu
Zwier M A
ZM
Groothuismink
Jilling F
JF
Bergmann
Joep
J
de Bruijne
Daphne M
DM
Hotho
Bettina E
BE
Hansen
Andre A
AA
van Vliet
Jeroen
J
van de Wetering de Rooij
Simon P
SP
Fletcher
Lisa A
LA
Bauman
Mohamad
M
Rahimy
James R
JR
Appleman
James L
JL
Freddo
Hendrik W
HW
Reesink
Robert J
RJ
de Knegt
Harry L A
HL
Janssen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007369:Interferon Inducers / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D055815:Young Adult
D000998:Antiviral Agents; D007369:Interferon Inducers; D011355:Prodrugs; D012367:RNA, Viral; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7