Ribavirin for the Treatment of HCPS • CID 2004:39 (1 November) • 1307
M A J O R A R T I C L E
Placebo-Controlled, Double-Blind Trial
of Intravenous Ribavirin for the Treatment
of Hantavirus Cardiopulmonary Syndrome
in North America
Gregory J. Mertz,1Lil Miedzinski,6Diane Goade,1Andrew T. Pavia,2Brian Hjelle,1Christine O. Hansbarger,1
Howard Levy,1,aFrederick T. Koster,1Kenneth Baum,3Adeline Lindemulder,6Wenquan Wang,4Laura Riser,4
Humberto Fernandez,5and Richard J. Whitley,4for the Collaborative Antiviral Study Group
1University of New Mexico, Albuquerque;
at Birmingham;5ICN Pharmaceuticals, Costa Mesa, California; and
2University of Utah, Salt Lake City;
3University of Colorado, Denver;
6University of Alberta, Edmonton, Alberta, Canada
4University of Alabama
intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome (HCPS) were inconclusive.
Subjects with suspected HCPS in the prodrome or cardiopulmonary phase but without shock were
eligible for randomization to receive either intravenous ribavirin (33 mg/kg [?2 g], followed by 16 mg/kg [?1
g] given every 6 h for 4 days and by 8 mg/kg [?.5 g] given every 8 h for 3 days) or placebo (administered for
7 days or until the initial Sin Nombre virus antibody test result was confirmed to be negative). The primary
outcome was survival at day 28 of the study without the need for extracorporeal membrane oxygenation(ECMO).
Thirty-six subjects were enrolled in the trial from March 1996 through July 2001, at which point the
study was terminated prematurely because of both the slow rate of accrual of subjects and the findings of a futility
analysis. Of the 36 subjects enrolled, 23 (all of whom were enrolled during the cardiopulmonary stage of HCPS)
had HCPS confirmed by serologic testing. The severity of illness at entry into the study was similar among the
10 subjects with HCPS who received ribavirin and the 13 subjects with HCPS who received placebo. Theproportion
of subjects who survived and who did not require ECMO was similar among ribavirin recipients and placebo
recipients (70% vs. 62%, respectively); 2 ribavirin recipients and 2 placebo recipients died, including 3 of 7 subjects
treated with ECMO. The frequency of adverse events, including anemia, was similar between treatment groups.
The rate of accrual of subjects in the present study was inadequate to clearly assess the safety
or efficacy of ribavirin in the treatment of HCPS. However, ribavirin was well tolerated, and the lack of trends
supporting the use of intravenous ribavirin suggests that it is probably ineffective in the treatment of HCPS in
the cardiopulmonary stage.
Ribavirin is active in vitro against hantaviruses, but the findings of an open trial of the use of
Since the recognition of hantavirus cardiopulmonary
syndrome (HCPS) in 1993, HCPS has been identified
throughout most of North and South America and in
Panama. Known also as “hantavirus pulmonary syn-
Received 23 April 2004; accepted 16 June 2004; electronically published 11
aPresent affiliation: Now also affiliated with Acute Care–US Medical Division,
Eli Lilly, Indianapolis, Indiana.
Investigators and institutions who participated in the study are listed at the
end of the text.
Reprints or correspondence: Dr. Gregory J. Mertz, Internal Medicine, MSC10
5550, 1 University of New Mexico, Albuquerque, New Mexico 87131-0001
Clinical Infectious Diseases 2004;39:1307–13
? 2004 by the Infectious Diseases Society of America. All rights reserved.
drome” (HPS), we prefer the term “hantavirus cardio-
pulmonary syndrome” because almost all fatalities as-
sociated with this syndrome are caused by cardiogenic
shock [1, 2]. In the United States, 379 cases of HCPS
have been reported through 1 September 2004, for a
case-fatality rate of 36% (http://www.cdc.gov/ncidod/
Canada, 47 cases of HCPS were reported through 31
December 2003, for a case-fatality rate of 36% (H. Art-
sorb, unpublished data). Sin Nombre virus (SNV) is
the etiologic agent of all cases of HCPS in Canada and
of all but a handful of cases of HCPS in the United
States, including all of the cases that occurred among
subjects enrolled in the present study.
Ribavirin is active in vitro against all hantaviruses
by guest on October 18, 2015
Ribavirin for the Treatment of HCPS • CID 2004:39 (1 November) • 1313
MEMBERS OF THE COLLABORATIVE
ANTIVIRAL STUDY GROUP RIBAVIRIN
CONTROLLED TRIAL FOR HCPS
Participating centers (locations) and members of the Collab-
orative Antiviral Study Group are as follows: University of New
Mexico (Albuquerque, NM): G.J.M., D.G., B.H., C.O.H., H.L.,
F.T.K., Suzanne Popejoy, Joseph Hubbard, and Karl Johnson;
University of Alberta (Edmonton, Alberta, Canada): L.M. and
A.L.; University of Utah (Salt Lake City): A.T.P. and John C.
Christenson; University of Alabama at Birmingham: R.J.W.,
L.R., Lynette Sherrill, W.W., and Mark Carpenter; ICN Phar-
maceuticals (Costa Mesa, CA): H.F.; University of Colorado
(Denver): K.B.; Gallup Indian Medical Center (Gallup, NM):
Bruce Tempest; Johns Hopkins University (Baltimore, MD):
Ray Reid; Division of Microbiology and Infectious Diseases,
National Institute of Allergy and Infectious Diseases, National
Institutes of Health (Bethesda, MD): Catherine Laughlin,Walla
Dempsey, and Thelma Gaither.
We thank Ms. Cindy Wootton, for help in preparation of themanuscript;
Suzanne Popejoy, for assistancewithextracorporealmembraneoxygenation
data; and Dr. Jonathan Iralu and the physicians working with participating
centers, for referring patients with suspected hantavirus cardiopulmonary
National Institute of Allergy and Infectious Dis-
eases, National Institutes of Health (contract NO-1-AI-30025; Bethesda,
Potential conflict of interest.
H.F. is an employee of ICN Pharmaceu-
ticals (Costa Mesa, CA). All other authors: No conflict.
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by guest on October 18, 2015