Recombinant human activated protein C for the postexposure treatment of Ebola hemorrhagic fever.
BACKGROUND
Infection of primates with Zaire ebolavirus (ZEBOV) leads to hypotension, coagulation disorders, and an impaired immune response and, in many ways, resembles severe sepsis. Rapid decreases in plasma levels of protein C are a prominent feature of severe sepsis and ZEBOV hemorrhagic fever (ZHF). Currently, recombinant human activated protein C (rhAPC [Xigris; Eli Lilly]) is licensed for treating human patients with severe sepsis who are at high risk of death. The aim of this study was to test the efficacy of rhAPC as a potential treatment for ZHF.


METHODS
Fourteen rhesus macaques were challenged with a uniformly lethal dose of ZEBOV; 11 of these monkeys were treated by intravenous infusion with rhAPC beginning 30-60 min after challenge and continuing for 7 days. Three control monkeys received sterile saline in parallel.


RESULTS
All 3 control monkeys died on day 8, whereas 2 of the 11 rhAPC-treated monkeys survived. The mean time to death for the rhAPC-treated monkeys that did not survive ZEBOV challenge was 12.6 days. The difference in survival was significant when the rhAPC-treated monkeys were compared with historical controls.


CONCLUSIONS
The experimental findings provide evidence that ZHF and severe sepsis share underlying mechanisms and may respond to the same therapies.
Hensley
Lisa E
LE
Virology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA.
Stevens
Edward L
EL
Yan
S Betty
SB
Geisbert
Joan B
JB
Macias
William L
WL
Larsen
Tom
T
Daddario-DiCaprio
Kathleen M
KM
Cassell
Gail H
GH
Jahrling
Peter B
PB
Geisbert
Thomas W
TW
D000818:Animals; D002405:Catheterization, Central Venous; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000302:isolation & purification*; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy*; D008253:Macaca mulatta; D009842:Oligopeptides / Q000627:therapeutic use; D011323:Primates; D011486:Protein C / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D009842:Oligopeptides; D011486:Protein C; D011994:Recombinant Proteins; C047135:protein C activator peptide