The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus.
Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.6 log(10) after a 14-day oral treatment with 1200 mg twice daily (P < 0.0001) with an effect against the 3 genotypes (1, 3, and 4) represented in the study. In addition, the absence of viral rebound during treatment indicates that Debio-025 has a high barrier for the selection of resistance. In Debio-025-treated patients, cyclophilin B (CypB) levels in peripheral blood mononuclear cells decreased from 67 +/- 6 (standard error) ng/mg protein (baseline) to 5 +/- 1 ng/mg protein at day 15 (P < 0.01).


CONCLUSIONS
Debio-025 induced a strong drop in CypB levels, coinciding with the decrease in hepatitis C viral load. These are the first preliminary human data supporting the hypothesis that CypB may play an important role in hepatitis C virus replication and that Cyp inhibition is a valid target for the development of anti-hepatitis C drugs.
Flisiak
Robert
R
Department of Infectious Diseases, Medical University of Bialystok, Bialystok, Poland.
Horban
Andrzej
A
Gallay
Philippe
P
Bobardt
Michael
M
Selvarajah
Suganya
S
Wiercinska-Drapalo
Alicja
A
Siwak
Ewa
E
Cielniak
Iwona
I
Higersberger
Jozef
J
Kierkus
Jarek
J
Aeschlimann
Christian
C
Grosgurin
Pierre
P
Nicolas-Métral
Valérie
V
Dumont
Jean-Maurice
JM
Porchet
Hervé
H
Crabbé
Raf
R
Scalfaro
Pietro
P
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D021984:Cyclophilin A / Q000032:analysis / Q000037:antagonists & inhibitors*; D021983:Cyclophilins / Q000032:analysis / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000276:immunology; D015497:HIV-1; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019696:Peptidylprolyl Isomerase / Q000032:analysis / Q000037:antagonists & inhibitors*; D010919:Placebos; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D010919:Placebos; C081786:cyclophilin B; D016572:Cyclosporine; D021984:Cyclophilin A; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase; C499715:alisporivir