Antiviral Therapy 4: 211219

Intravenous ribavirin for hantavirus pulmonary syndrome: safety and tolerance during 1 year of open-label experience
Louisa E Chapman1*, Gregory J Mertz2, Clarence J Peters1, Heidi M Jolson3, Ali S Khan1, Thomas G Ksiazek1, Frederick T Koster2, Kenneth F Baum4, Pierre E Rollin1, Andrew T Pavia5, Robert C Holman1, John C Christenson5, Phillip J Rubin6, Rachel E Behrman3, Linda J Wilson Bell1, Gary L Simpson7, Ramses F Sadek1 and the Ribavirin Study Group
1

Hantavirus Task Force, Division of Viral and Rickettsial Diseases (DVRD), National Center for Infectious Diseases (NCID), Centers for Disease Control and Prevention (CDC), Atlanta, Ga., USA 2 Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, N. Mex., USA 3 Food and Drug Administration, Rockville, Md., USA 4 University of Colorado School of Medicine, Denver, Col., USA 5 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA 6 Infectious Diseases Consultants Ltd, Phoenix, Ariz., USA 7 New Mexico Department of Health, Santa Fe, N. Mex., USA *Corresponding author: Tel: +1 404 639 1028; Fax: +1 404 639 0868; E-mail: LEC3@cdc.gov For authors current affiliations, see Acknowledgements.

Intravenous ribavirin was provided non-selectively for investigational open-label use among persons with suspected hantavirus pulmonary syndrome (HPS) in the United States between 4 June 1993 and 1 September 1994. Therapy was initiated prior to laboratory confirmation of hantavirus infection because most deaths from HPS occur within 48 h of hospitalization. Thirty patients with confirmed HPS, 105 patients without HPS and 5 patients without adequate diagnostic testing for HPS were enrolled. This observational study arguably provides the most complete information available on ribavirinassociated adverse effects. Although ribavirin was generally well tolerated, 71% of recipients became

anaemic and 19% underwent transfusion. An apparent excess of hyperamylasaemia/pancreatitis was either therapy-associated or due to enrolment bias. The 30 enrolled HPS patients had a casefatality rate of 47% (14/30). It is not possible to assess efficacy with this study design. However, comparison of survival curves for the 30 enrolled HPS patients and 34 patients who developed HPS during the same time period but were not enrolled did not suggest an appreciable drug effect. A randomized, placebo-controlled trial that enrols patients during the prodrome phase would be necessary to assess the efficacy and further define the safety of intravenous ribavirin for HPS.

Introduction
In June 1993, an investigation into a cluster of unexplained deaths of previously healthy adults in the Four Corners region of the United States led to the recognition of hantavirus pulmonary syndrome (HPS) and the identification of Sin Nombre virus (SNV) (genus Hantavirus, family Bunyaviridae) as the aetiological agent [17]. Sin Nombre virus, like other hantaviruses, causes chronic infections of rodents. Peromyscus maniculatus (deer mouse) is the primary reservoir of SNV in nature [810]. The recognized home range of P. maniculatus extends over most of continental United States and parts of Canada and Mexico [7,8]. Laboratory evidence first suggested a hantaviral aetiology for this syndrome on 4 June 1993, when the
1999 International Medical Press 1359-6535/99/$17.00

mortality rate of HPS appeared to be greater than 50% in the absence of therapeutic intervention [11]. Immediately following this serological link, the US Food and Drug Administration (FDA) authorized a protocol amendment to an ongoing Centers for Disease Control and Prevention (CDC)-sponsored Investigational New Drug Application (IND) to allow provision of intravenous ribavirin for open-label investigational use in patients with presumed HPS [12]. The primary objective of the open-label trial was to provide a potential therapeutic intervention for an often fatal disease. There were four reasons for selecting intravenous ribavirin. First, all previously isolated and tested hantaviruses had exhibited similar
211

LE Chapman et al.

Table 1. Demographic description of patients enrolled for ribavirin

All persons enrolled in ribavirin trial n (%) mean age (years) 72 (51) 38.2 68 (49) 42.4 140 (100) 40.3 Status unknown HPS-negative enrolled enrolled n (%) mean age (years) n (%) mean age (years) 3 (60) 40.7 51 (49) 39.3 2 (40) 21.0 54 (51) 44.6 5 (100) 32.8 105 (100) 41.6 HPS-positive enrolled n (%) mean age (years) 18 (60) 34.7 12 (40) 36.3 30 (100) 35.4 HPS-positive not enrolled n (%) mean age (years) 14 (41) 39.8 20 (59) 36.2 34 (100) 37.7

Female Male Total

in vitro sensitivity to ribavirin (J Huggins, US Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA, unpublished results); comparable in vitro sensitivity was anticipated and subsequently confirmed for SNV (S Ruyo, CDC, unpublished results). Second, results from a prospective, double-blind, placebo-controlled trial in China had suggested increased survival and decreased morbidity among patients infected with Hantaan virus (the prototype hantavirus) when treated with intravenous ribavirin within the first 4 days of symptomatic haemorrhagic fever with renal syndrome (HFRS) [13]. Third, experience with use of ribavirin for other human viral infections has established an acceptable safety profile [1419]. Fourth, no other pharmacological candidate (either licensed or investigational) could be identified for which there was an a priori reason to anticipate efficacy. Secondary goals included assessment of the safety of intravenous ribavirin for HPS, augmentation of public health surveillance for HPS, collection of prospective information on clinical, laboratory and virological parameters throughout the course of therapy and identification of discriminators between hantaviral and non-hantaviral illness. Although assessment of efficacy was not considered possible in the absence of a concurrent randomized control group, given the high casefatality rate, it was anticipated that a large drug effect, if present, could be suspected by comparison with untreated patients concurrently identified through surveillance.

We present the results of safety and tolerance during 1 year of open-label use of intravenous ribavirin for HPS. A companion paper will discuss the clinical experience during the open-label trial and discriminators between hantaviral and non-hantaviral illness among enrolled patients [Chapman LE, Koster FT, Ellis B, Peters CJ, Sortir M, Ksiazek TG et al., unpublished results].

Materials and Methods

Study population
Residents of the United States were eligible for enrolment between 4 June 1993 and 1 September 1994 if they had either (a) acute onset of respiratory failure requiring assisted ventilation or bilateral, diffuse infiltrates present on chest roentgenogram, absence of cardiac disease as the sole cause of pulmonary oedema, and/or severe hypoxaemia that responded poorly to supplemental oxygen therapy; or (b) an acute febrile illness of less than 10 days duration characterized by oxygen desaturation or bilateral interstitial chest roentgenogram infiltrates and myalgias, with some combination of the following: tachypnea, cough, nausea/vomiting, headache, malaise, thrombocytopenia or lymphocytosis. In addition, they must have had no other diagnosis strongly suggested by history, chest roentgenogram or laboratory studies, and HPS must have been reasonably likely in the clinical judgement of the enrolling co-investigator. If a clinical suspicion of immunosuppression existed, opportunistic infections must have been carefully sought out. Patients who were less than 12 years old or pregnant, had severe uncorrected anaemia, or were receiving other investigational drugs were excluded from enrolment. Such patients could be considered by the FDA for investigational use of the drug on a caseby-case basis. However, no such patients are discussed in this paper.

Table 2. Clinical adverse events reported in temporal association with ribavirin receipt and presumed to be aetiologically related
Events presumed HPS ribavirin positive related n=25 (%) Anaemia 18 (72) Transfusion 6 (24) Chills/rigors 1 (4) Elevated serum uric acid 1 (4) Hyperbilirubinaemia 1 (4) Unnecessary procedures (endoscopy & colonoscopy to evaluate anaemia) Biopsy of tattoo mistaken for drug rash
212

HPS negative n=99 (%) 78 (79) 18 (18) 5 (5) 3 (3) 1 (1) 1 (1)

HPS status unknown n=4 (%) 3 (75) 2 (50)

Enrolment
The treating physician contacted either a co-investigator at the CDC or one of the regional authorizing co-investigators in the original four outbreak states (Arizona, Colorado, New Mexico and Utah) to determine eligibility and secure approval for intravenous
1999 International Medical Press

1 (1)

Intravenous ribavirin for HPS

Table 3. Clinical adverse events reported in temporal association with ribavirin receipt, regardless of causality
Events HPS presumed positive unrelated n=25 (%) Cardiovascular: Myocarditis Myocardial infarction Renal: Renal failure: oliguric non-oliguric unspecified 1 (4) Acute tubular necrosis Transient creatinine elevation 1 (4) Hyperkalaemia Elevated serum phosphate Gastrointestinal: Right upper quadrant pain Peritonitis Ascites Nausea Duodenal ulcer Bleed Necrotic bowel Hepatic dysfunction: elevated transaminases 1 (4) encephalopathy 1 (4) failure Pancreatitis: Gallstone Vasculitis Not specified Central nervous system: General weakness Metabolic encephalopathy Hallucinosis Encephalitis 1 (4) Seizures Multiple cerebral infarcts Intracranial bleed Dermatological: Non-specific dermatitis Hair loss Haematological: Leukocytosis Thrombocytopaenia Disseminated intravascular Coagulation 1 (4) Retinal haemorrhages Miscellaneous: Gangrene 1 (4) Death 9 (36) HPS negative n=99 (%) 1 (1) 1 (1) HPS status unknown n=4 (%)

2 (2) 3 (3) 8 (8) 2 (2) 5 (5) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 3 (3) 1 (1) 4 (4) 3 (3) 1 (1) 1 (1) 2 (2) 1 (1) 2 (2) 1 (1) 1 (1) 2 (2) 3 (3) 3 (3) 1 (1) 1 (1) 2 (2) 8 (8) 1 (1) 33 (33)

1 (25) 1 (25)

Ribavirin has been shown to be teratogenic or embryocidal in rodents and may, therefore, cause foetal toxicity when administered to pregnant women. Ribavirin is also sequestered in red blood cells and therefore eliminated slowly, remaining present in the body (and breast milk of lactating women) for 36 months after discontinuation of the drug. In light of these features, the treating physician was responsible for verifying a negative serum pregnancy test (or, if unavailable, urine pregnancy test) prior to ribavirin receipt by menstruating females, and providing counselling about teratogenicity risks and pregnancy prevention in the 3 months following discontinuation of ribavirin. The treating physician was also responsible for counselling lactating women who receive intravenous ribavirin regarding the presence of ribavirin in breast milk, concerns with growth retardation and the risks of nursing during or for up to 1 month after ribavirin receipt.

Drug supply
CDC purchased ribavirin from ICN Pharmaceuticals.

Drug administration
From June to November 1993, intravenous ribavirin was made available through an amendment to a CDCsponsored IND allowing use of intravenous ribavirin for the treatment of Lassa fever in Sierra Leone, West Africa. The amendment initially used a dosing schedule identical to that for treatment of Lassa fever: a onetime loading dose of 30 mg/kg (up to a maximum of 2 g) followed by 15 mg/kg every 6 h for 4 days, and then 7.5 mg/kg every 8 h for 6 days. Beginning in November 1993, the dosing schedule was modified to conform to that used for Hantaan virus-associated illness in China: a one-time loading dose of 33 mg/kg (up to a maximum of 2 g) followed in 6 h by 16 mg/kg (up to a maximum of 1 g) every 6 h for 15 doses, followed by 8 mg/kg (up to a maximum of 500 mg) every 8 h for nine doses [13]. Each dose was administered diluted in either 5% dextrose water or normal saline by intravenous drip over 1530 min.

Criteria for discontinuing the drug

Ribavirin was discontinued in the presence of a blood haemoglobin of less than 8 gm/dl unless compelling reasons to correct anaemia with transfusion and continue therapy existed. Notification of new onset of creatinine of greater than 2 mg/100 ml in patients receiving ribavirin was requested, but discontinuation of the drug was not generally recommended because renal failure is not recognized to affect ribavirin clearance. Notification of the investigators was requested if serum transaminase levels increased greater than 10 times the baseline on admission, and discontinuation
213

ribavirin. Intravenous ribavirin and study protocol were available from the CDC (Atlanta), the US Quarantine Stations in Los Angeles, San Francisco, Miami, Chicago, New York, Honolulu and Seattle, and selected sites within the original four outbreak states. These drug and protocol depots allowed immediate shipment and receipt of ribavirin by treating physicians anywhere within the USA within hours of initial contact.
Antiviral Therapy 4:4

LE Chapman et al.

Figure 1. Geographical distribution of patients enrolled for open-label investigational ribavirin for suspicion of HPS as well as those not enrolled who had onset of HPS between 4 June 1993 and 1 September 1994
1 1 3 3 2 1 3 1 2 2 2 1 1 1 4 1 11 1 13 3 20 9 4 20 2 8 1 1 1 1 1 3 1 1 1 3 11 2 1 1 1 3 1 1 2 1 1 1 2 1 DC 1 1 1 1 1 1 1

() HPS-positive patients enrolled for ribavirin; () HPS-positive patients with onset between 4 June 1993 and 1 September 1994 who were not enrolled for ribavirin; () HPS-negative patients enrolled for ribavirin; () patients enrolled for ribavirin for whom adequate diagnostic specimens to determine HPS status were not available.

was recommended in the setting of progressive transaminase increases associated with hepatic encephalopathy. Treating physicians were requested to discuss adverse events that might represent toxicities of ribavirin on a case-by-case basis as they arose with an enrolling co-investigator.

Confirmation of hantavirus infection

Laboratory confirmation of hantavirus infection was defined as a positive result of serological testing for antihantavirus IgM by ELISA, positive PCR testing for SNV or positive immunohistochemistry results on a biopsy or autopsy specimen as previously described [3,5,20].

Laboratory monitoring
The following laboratory studies were requested at baseline: complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), creatinine, glucose, liver function tests, serum uric acid, creatine phosphokinase, total protein, albumin, amylase, urinanalysis, coagulation screen, arterial blood gas or oximetry reading, chest radiographs, serum or urine pregnancy test if appropriate and 10 ml of whole blood separated into serum and clot frozen separately at 70C and shipped on dry ice to CDC for viral studies. All of the above except amylase, coagulation studies, chest roentgenogram and the pregnancy test were requested daily on days 27. Results of convalescent studies, including convalescent phase serum for hantavirus testing, urinanalysis, CBC, BUN, creatinine, serum uric acid (if abnormal on day 7 of treatment) and liver function tests (if abnormal on day 7 of treatment) were obtained a minimum of 4 weeks after terminating ribavirin treatment to screen for long-term toxicity.
214

Statistics
Comparisons were made between patients with onset of HPS between 4 June 1993 and 1 September 1994 who were enrolled for ribavirin and patients with onset of HPS during the same period who were not enrolled. Survival curves for these two groups were estimated using the KaplanMeier method [21,22]. Most patients were enrolled for ribavirin therapy within hours of hospital admission. Therefore, survival time was measured in days from the date of hospitalization to the date of death, or 31 days after hospitalization, if the patient was still alive. The logrank test was used to compare survival curves for enrolled HPS patients and HPS patients who were not enrolled, using an intent-to-treat approach. Survival curves and group comparisons were also performed restricting patients to those who survived at least 24 h, and also for those who survived 48 h to control for differences in the severity of illness at presentation and to exclude from the analysis those least likely to benefit from ribavirin.
1999 International Medical Press

Intravenous ribavirin for HPS

Figure 2. Estimated survival curves from hospitalization for HPS patients enrolled for ribavirin and not enrolled HPS patients
100 90 80 Proportionate survival (%) 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Ribavirin No ribavirin

Days since hospitalization

No ribavirin, HPS-positive patients with onset between 4 June 1993 and 1 September 1994 who were not enrolled for ribavirin Ribavirin, HPS-positive patients who were enrolled for receipt of investigational intravenous ribavirin

Results
Enrolment
Between 8 June 1993 and 28 August 1994, 140 patients from 31 states were enrolled and adequate diagnostic specimens to confirm or refute the diagnosis were received from 135 (96%). Hantavirus infection was confirmed in 30/135 (22%) from seven states among whom the case-fatality rate was 14/30 (47%). Of the 140 patients enrolled in this study, 37 completed the 710 day course of therapy as planned. The following reasons were given for early termination of treatment among the remaining 103 patients: death, 36; alternate diagnosis established, 29; adverse clinical event, 24; negative HPS testing, five; clinical improvement, five; drug shortage, two. No reasons were given for withdrawal of treatment from two patients. The demographics of these patients are described in Table 1. The geographic distribution of these patients is shown in Figure 1.

Safety and tolerance

Among the 140 patients enrolled for suspicion of HPS, 37 (26%) completed the course as planned. One hundred and three (74%) withdrew prior to completion of the intended treatment course. Follow-up clinical information was unobtainable for 4/140 (3%) enrolled patients. No biological specimen was received from one of these four; the remaining three tested negative for HPS. At least limited clinical follow-up information was available for 136 patients, although biological specimens for HPS testing were unavailable for four of these. Eleven of these remaining 136 patients received
Antiviral Therapy 4:4

no drug owing to rapid death (five HPS-positive and three HPS-negative); establishment of an alternative diagnosis (two HPS-negative); or marked clinical improvement prior to drug arrival (one HPS-negative). A summary of clinical adverse events reported in temporal association with ribavirin receipt among the 125 subjects who received ribavirin and for whom at least limited clinical follow-up information was obtainable is presented in Tables 2, 3 and 4. The most common ribavirin-associated adverse event was anaemia. While this feature was a known side effect of ribavirin, the frequency and severity of anaemia among patients enrolled in our protocol exceeded expectations. Ninety-nine (79%) recipients became anaemic, of whom 26 (21% of total recipients) were transfused. Among the 86 subjects for whom haemoglobin values were reported, the mean low haemoglobin was 9.7 gm/dl (mode 8.3, range 4.814.8). Twenty-four patients were withdrawn from the protocol before completion of the planned treatment course because of adverse clinical events. Anaemia was also the most common adverse event that resulted in withdrawal from the protocol [19 withdrawals, seven (37%) of whom were transfused]. Three additional patients were withdrawn because of pancreatitis, and one each for nausea and hepatic failure. A summary of ascertained causes of death among enrolled patients is presented in Table 5. The treating physician attributed no deaths to ribavirin.

Analysis for suggestion of a drug effect

It was not possible to randomly assign treatment in this open-label protocol. Therefore it was not possible to assess the efficacy of intravenous ribavirin for HPS
215

LE Chapman et al.

Table 4. Clinical adverse events reported in temporal association with ribavirin receipt of unclear aetiology
Events of HPS unclear positive association n=25 (%) Hyperamylasaemia 3 (12) Pancreatitis Possible pancreatitis 1 (4) Jaundice with hyperbilirubinaemia HPS HPS status negative unknown n=99 (%) n=4 (%) 1 (1) 5 (5) 1 (1) 1 (1)

Table 5. Causes of deaths among patients enrolled for openlabel intravenous ribavirin
Cause of death Number of deaths HPS 14 Other pulmonary: Pneumonia/ARDS 10 Tension pneumothorax/cardiovascular arrest 1 Chronic pulmonary disease 2 Other infectious: Coccidioides immitis pneumonia 1 Meningococcemia 1 Enterobacter bacteremia 1 Septic shock 1 Autoimmune Disease: Culture-negative endocarditis/collagen-vascular disease 1 Thrombotic thrombocytopenia purpura 1 Goodpastures versus Wegeners granulomatosis 1 Neurological: Intracranial bleed 2 Brain death following shock/hypotension 1 Miscellaneous: Disseminated small cell carcinoma 1 Necrotic bowel 1 Myocardial infarction 2 Cardiac arrest 1 Pericarditis 1 Endstage diabetes mellitus with heart failure 1 Multisystem failure 2 Unknown 4

from these observations. However, as of 2 August 1995, surveillance had identified an additional 34 persons with HPS from 18 states who had onset during the enrolment period (4 June 1993 to 1 September 1994), but who were not enrolled in this protocol and did not receive ribavirin treatment. As a group, the patients who did not receive ribavirin differed from the recipients in important ways that could not be controlled for during analysis. Six (18%) of the 34 HPS patients who did not receive ribavirin were infected with variant hantaviruses outside of the known geographical range of P. maniculatus. Fourteen (41%) were each the first HPS patient recognized in states where the clinical suspicion for the diagnosis had been low pre-mortem. Co-investigators had rejected an additional two (6%) patients as candidates for enrolment because they had an atypical clinical course that did not fit the profile of the disease as it was understood at that time. Comparison of the clinical course and case-fatality rate of these contemporaneous untreated HPS patients [casefatality rate 17/34 (50%)] with the 30 HPS patients enrolled in the open-label study did not suggest a substantial drug effect. The highest casefatality rate for either the ribavirin-enrolled or the unenrolled group occurred within the first 2472 h following hospitalization, after which the survival curves level out (Figure 2). There were no differences in survival between the two groups. Similar findings are observed when analysis was restricted to patients surviving at least 24, then at least 48 h of hospitalization (casefatality rate for treated versus untreated: 9/25, 36% versus 11/28, 39% and 6/22, 27% versus 10/27, 37%, respectively).

Discussion
This open-label protocol of ribavirin for treatment of presumed HPS provides the most complete information on adverse events temporally associated with intravenous ribavirin available to date. In spite of the use of intravenous ribavirin for Lassa fever and HFRS patients abroad, this study of HPS patients represents by far the largest experience at this dosage under conditions permitting close observation of patients
216

with accompanying clinical laboratory support. Adverse clinical events previously associated with ribavirin (anaemia, chills/rigors, elevated serum uric acid and hyperbilirubinaemia) [1315,2326] occurred in temporal association with drug receipt at essentially equal rates among HPS and non-HPS patients (Table 3). The slightly increased frequency of transfusions, despite a slightly lower frequency of anaemia among HPS-confirmed patients, can be attributed to a tendency to transfuse and continue treatment among hantavirus-infected patients, contrasted to a propensity to discontinue drug treatment among patients who did not have HPS. Adverse clinical events that are presumed to be aetiologically unrelated to ribavirin are shown in Table 2. The presence of transient creatinine elevations, renal failure, hepatic dysfunction with elevated transaminases, and DIC are evenly distributed between HPS-confirmed and disproven cases. Hyperamylasaemia or overt pancreatitis occurred more frequently than anticipated among patients enrolled for ribavirin. Pancreatitis was present in 6% of enrolled patients (7/125), only two of whom had clearly identifiable aetiologies (gallstones and vasculitis). Possible pancreatitis was present in an additional two patients (total 9/125, 7%). By comparison, for the period 1989 through 1991, the US Vital Records Multiple Cause of Death Tapes record pancreatic diseases in only 2.9% of death certificates with
1999 International Medical Press

Intravenous ribavirin for HPS

mention of adult respiratory distress syndrome (CDC, unpublished data). In the absence of a control group, it is not possible to determine whether this apparent excess of cases is therapy-associated or due to an enrolment bias resulting in a higher number of patients with pancreatitis as an underlying contributor to the clinical syndrome of abdominal symptoms and unexplained pulmonary insufficiency. The rises in amylase did occur in temporal association with ribavirin administration, although this also corresponded to the height of clinical illness among a group of extremely ill patients who had multisystem diseases. Nucleoside analogues have been associated with the induction of pancreatitis [2729]. Although excessive pancreatitis has not been previously described in temporal association with ribavirin usage, it is prudent to consider that the association may be aetiological until this can be clarified through a placebo controlled trial. Patients were enrolled onto this protocol on the basis of a presumptive clinical diagnosis owing to the limited availability of diagnostic testing during the outbreak. Because the overall HPS confirmation rate was low (22%), many patients were exposed to the potential toxicities of ribavirin without the possibility of therapeutic gain. Furthermore, the red cell loading accomplished by the initial dose results in a long intracellular half-life of ribavirin, thus limiting the benefit of early discontinuation of treatment once an HPS diagnosis is excluded. HPS remains an uncommon disease generally acquired in widely geographically dispersed rural areas [30]. The accuracy of initial diagnosis can likely be improved, in the absence of rapidly available laboratory testing, if physicians take into account the seasonal patterns of the disease, the patients history of probable exposures, and the now better described clinical profile of HPS [2,5,9,3134, Chapman LE, Koster FT, Ellis B, Peters CJ, Sortir M, Ksiazek TG et al., unpublished results] when making a presumptive diagnosis. In addition, the current wide availability of diagnostic testing in most state health departments and several academic institutions in addition to CDC should offer the potential for earlier confirmation of the diagnosis, allowing discontinuation of ribavirin treatment of patients without HPS within 2448 h. Although the presence of untreated HPS cases with onset between 4 June 1993 and 1 September 1994 is useful as a comparison group, the lack of randomization prohibits analysis of efficacy under this study design. A prospective, randomized, double-blind, placebo-controlled trial would be necessary to evaluate the efficacy and more definitively assess the safety of intravenous ribavirin for HPS patients. In vitro efficacy values of ribavirin for Hantaan virus and SNV are comparable (Suyu Ruyo, CDC, unpublished data), and in vivo efficacy appears to exist
Antiviral Therapy 4:4

for HFRS [13]. However, the very different clinical profiles of HFRS and HPS may temper expectations for efficacy of antiviral drug intervention for HPS begun at the point of hospital admission. Intravenous ribavirin was generally begun for both HFRS and HPS within hours of hospital admission [3,Chapman LE, Koster FT, Ellis B, Peters CJ, Sortir M, Ksiazek TG et al., unpublished results]. However, mortality associated with HFRS generally began to occur about 1 week into hospital admission, whereas HPS-associated mortality was virtually complete by 72 h following hospitalization [2,32,Chapman LE, Koster FT, Ellis B, Peters CJ, Sortir M, Ksiazek TG et al., unpublished results]. The prodrome of HPS is minimally distinguishable from that of many other viral syndromes and rarely prompts serological testing before the onset of pulmonary oedema. While the syndrome does become clinically distinct at the point of pulmonary decline, the progression to mortality from this point is swift, limiting in vivo opportunity for pharmacological impact on disease progression [3,5,3134,Chapman LE, Koster FT, Ellis B, Peters CJ, Sortir M, Ksiazek TG et al., unpublished results]. Therefore, in the absence of an extremely rapid and powerful effect, the compact clinical course of HPS may allow inadequate time for any pharmacological intervention to have a significant effect when therapy is started coincident with pulmonary decline. The severity of the disease combined with the current absence of alternative therapeutic options other than careful fluid management and intensive cardiopulmonary support make consideration of a prospective, randomized, double-blind, placebocontrolled trial of intravenous ribavirin for HPS tenable. Our results provide ethical, scientific and medical justification for the use of placebo in such a trial.

Acknowledgements
The authors wish to acknowledge the remarkable teamwork among hundreds of physicians, public health professionals, healthcare and administrative workers and other citizens in the private sector, the academic community and many different government agencies from the local to the federal levels that made the rapid availability of a potential therapeutic intervention possible in the midst of a public health emergency. We particularly acknowledge the work of the Indian Health Service West, the Navajo Nation Division of Health, the University of New Mexico Medical Center, the public health professionals in Arizona, Colorado, New Mexico and Utah, and the officers of the US Quarantine stations. In addition, the authors recognize with gratitude the decades of system217

LE Chapman et al.

atic groundwork laid by investigations performed at or funded through the US Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland, USA. Lastly, we thank John OConnor for consistently excellent editorial advice. Portions of the information presented in this manuscript were presented at the International Society for Antiviral Research 7th International Conference on Antiviral Research, Charleston, South Carolina, March, 1994; the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Abstract H111, Orlando, Florida, 47 October 1994; the Collaborative Antiviral Study Group (CASG) meeting, National Institute of Allergy and Infectious Diseases (NIAID)/ National Institutes of Health (NIH), Bethesda, Maryland, USA, 1 December 1994; and the Public Health Service (PHS) Commissioned Officers Association (COA) service meeting, Orlando, Florida, USA, May 1995. Informed consent was obtained from patients or their next of kin, and human experimentation guidelines of the US Department of Health and Human Services and those of the authors institutions were followed in the conduct of clinical research. This study was supported by the CDC. The views expressed are the authors own and do not necessarily represent those of, nor imply endorsement from the Food and Drug Administration or the US Government.

Current affiliations of authors

LE Chapman: HIV and Retrovirology Branch, Division of AIDS, STD and TB Laboratory Research, NCID, CDC, USA; RC Holman: Office of the Director (OD), DVRD, NCID, CDC, USA; AS Khan, TG Ksiazek, CJ Peters, PE Rollin: Special Pathogens Branch, DVRD, NCID, CDC, USA; LJ Wilson Bell: South Carolina Department of Health and Environmental Control, Columbia, South Carolina, USA; RF Sadek: Mallinkrodt Medical Inc., 675 McDonnell Blvd., PO Box 5840, St Louis, MO 63134, USA.

California: Coronado: R Moncada; Covina: S Singh Bassi; Daly City: JS Rumack; Escondido: S Kuriyama; Long Beach: J McGovern; Oakdale: D Olson; Oakland: P Garst; San Diego: ML Butera; San Francisco: K Erlich; Santa Monica: M Dinolfo; Colorado: Colorado Department of Public Health and Environment: C Dalton, R Hoffman; University of Colorado Health Center: D Kuritzkes, N Madinger, R Schooley; Aspen: A Mass; Colorado Springs: JM Hofflin; Cortez: K Britton; Denver: R Blum, G Cott, B Golub, K Greenberg, K Lichtenstien, R OBrien; Montrose: RF Motley; Wheat Ridge: M Culliman, N Fujeta, S Mason; Connecticut: Stamford: GX McLeod; Florida: Merritt Island: M Mateos-Mora; Hawaii: Honolulu: D Demers; Idaho, Pocatello: C Jackson; Illinois: Evanston: B Zar; Palos Heights: B Ramakrishna; Indiana: Indianapolis: CL Jones; Kansas: Halstead: W Lucht; Louisiana: Shreveport: S Conrad, LR Grier, JW King; Maryland: Greenbelt: J Adelso; Lanham: M Kim-Karpe; Massachusetts: Milford: M Bergman; Minnesota: Minneapolis: R Schut; Mississippi: Biloxi: T Sterling; Missouri: Kansas City: JH Brewer; Montana: Great Falls: DE Anderson; Nebraska: Omaha: J Roehrs; Nevada: Reno: JE Dietrich, D Jones; Tonopah: C Ward; New Jersey: Long Branch: JF Stockfish; Orange: R Eng; New Mexico: University of New Mexico School of Medicine: S Allen, RE Crowell, A Cushing, D Goade, L Irizarry, S Jenison, H Levy, G Overturf, D Palmer, R Quenzer, W Reed, S Simpson, J Williams; New York: Brooklyn and Queens: BJ Berger, F Hussain; Elmhurst: B Berger; North Dakota: Fargo: F Sepe; Grand Forks: J Hargreaves; Tennessee: Knoxville: LM Baddour; Oak Ridge: R Parrish; Texas: Blanco: R Plemmons; Dallas: J Radolf; El Paso: G Szeyko; Fort Worth: K Elkind; Houston: V Knight; Washington: Spokane: MS Badger, J Furlan, M Gillum; Tacoma: AD Tice; Yakima: J Barany.

References
1. Ksiazek TG, Peters CJ, Rollin PE, Zaki S, Nichol S, Spiropoulou C, Morzunov S, Feldmann H, Sanchez A, Khan AS, Mahy BWJ, Wachsmuth K & Butler JC. Identification of a new North American hantavirus that causes acute pulmonary insufficiency. American Journal of Tropical Medicine & Hygiene 1995; 52:117123. Duchin JS, Koster FT, Peters CJ, Simpson GL, Tempest B, Zaki SR, Ksiazek TG, Rollin PE, Nichol S, Umland ET, Moolenaar RL, Reef SE, Nolte KB, Gallaher MM, Butler JC, Breiman RF & the Hantavirus Study Group. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. New England Journal of Medicine 1994; 330:949955. Nichol ST, Spiropoulou CF, Morzunov S, Rollin PE, Ksiazek TG, Feldman H, Sanchez A, Childs J, Zaki S & Peters CJ. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 1993; 262:914917. Spiropoulou CF, Morzunov S, Feldmann H, Sanchez A, Peters CJ & Nichol ST. Genome structure and variability

Ribavirin Study Group

Indian Health Service West: B Armstrong, BT Atterbury, G Baacke II, D Bellardi, M Carroll, J Cheek, A Craig, D Daniels, W Freeman, F Held, D Kessler, S Konicck, A Light, J McGee, J Savage, M Sloan, B Tempest, K Vaughan, D Waite; CDC: J Becher, R Brieman, J Bulter, MJ Schmidt-Dalton, DC Hart, J Hawk, R Khabbaz, E Lloyd, M Sortir, S Stokes, TJ Torok, C Vitek; Alabama: Birmingham: S Harding; Arizona: Arizona Department of Health Services: R England, C Kioski, D Mosley, L Sands; Flagstaff: T Johnson-Baach, KJ Ronnau; Phoenix: DD Mast, R Servi; Scottsdale: R Levinson, FS Yeager; Tucson: R Adam, B Friedman, L Lincoln, EA Petersen, E Wack;
218

2.

3.

4.

1999 International Medical Press

Intravenous ribavirin for HPS

5.

6.

7. 8.

9.

10.

11. 12.

13.

14.

15.

16.

17.

of a virus causing hantavirus pulmonary syndrome. Virology 1994; 200:715723. Zaki SR, Greer PW, Coffield LM, Goldsmith CS, Nolte KB, Foucar K, Feddersen RM, Zumwalt RE, Miller GL, Khan AS, Rollin PE, Ksiazek TG, Nichol ST, Mahy BWJ & Peters CJ. Hantavirus pulmonary syndrome. Pathogenesis of an emerging infectious disease. American Journal of Pathology 1995; 146:552579. Elliott L, Ksiazek TG, Rollin PE, Spiropoulou CF, Morzunov S, Monroe M, Goldsmith CS, Humphrey CD, Zaki SR, Krebs JW, Maupin G, Gage K, Childs JE, Nichol ST & Peters CJ. Isolation of the causative agent of hantavirus pulmonary syndrome. American Journal of Tropical Medicine & Hygiene 1994; 51:102108. Chapman LE & Khabbaz RF. Review. Etiology and epidemiology of the Four Corners hantavirus outbreak. Infectious Agents and Diseases 1994; 3:234244. Childs JE, Ksiazek TG, Spiropoulou CF, Krebs JW, Morzunov S, Maupin GO, Gage KL, Rollin PE, Sarisky J, Enscore RE, Frey JK, Peters CJ & Nichol ST. Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the southwestern United States. Journal of Infectious Diseases 1994; 169:12711280. Zeitz PS, Butler JC, Cheek JE, Samuel MC, Childs JE, Shands LA, Turner RE, Voorhees RE, Sarisky J, Rollin PE, Ksiazek TG, Chapman LE, Reef SE, Komatsu KK, Dalton C, Krebs JW, Maupin GO, Gage K, Sewell CM, Brieman RF & Peters CJ. A case-control study of hantavirus pulmonary syndrome during an outbreak in the southwestern United States. Journal of Infectious Diseases 1995; 171:864870. Mills JN, Johnson JM, Ksiazek TG, Ellis BA, Rollin PE, Yates TL, Mann MO, Johnson MR, Campbell ML, Miyashiro J, Patrick M, Zyzak M, Lavender D, Novak MG, Schmidt K, Peters CJ & Childs JE. A survey of hantavirus antibody in small-mammal populations in selected United States National Parks. American Journal of Tropical Medicine & Hygiene 1998; 58:525532. Centers for Disease Control and Prevention. Outbreak of acute illnessSouthwestern United States, 1993. Morbidity and Mortality Weekly Report 1993; 42:421424. Centers for Disease Control and Prevention. Update: Hantavirus pulmonary syndromeUnited States, 1993. Morbidity and Mortality Weekly Report 1993; 42:816820. Huggins JW, Hsiang CM, Cosgriff TM, Guang MY, Smith JI, Wu ZO, LeDuc JW, Zheng ZM, Meegan JM, Wang QN, Oland DD, Gui XE, Gibbs PH, Yuan GH & Zhang TM. Prospective, double-blind, concurrent, placebocontrolled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. Journal of Infectious Diseases 1991; 164:11191127. McCormick JB, King IJ, Webb PA, Scribner CL, Craven RB, Johnson KM, Elliott LH & Belmont-Williams R. Lassa fever: effective therapy with ribavirin. New England Journal of Medicine 1986; 314:2026. Huggins JW. Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad spectrum antiviral drug. Reviews of Infectious Diseases 1989; 11 (Suppl.):S750761. Magnussen CR, Douglas RG Jr, Betts RF, Roth FK & Meagher MP. Double-blind evaluation of oral ribavirin (Virazole) in experimental influenza A virus infection in volunteers. Antimicrobial Agents and Chemotherapy 1977; 12:498502. Uylangco CV, Beroy GJ, Santiago LT, Mercoleza VD & Mendoza SL. A double-blind, placebo-controlled evaluation of ribavirin in the treatment of acute measles. Clinical Therapeutics 1981; 3:389396.

18. Connor E, Morrison S, Lane J, Oleske J, Sonke RL & Connor J. Safety, tolerance, and pharmacokinetics of systematic ribavirin in children with human immunodeficiency virus infection. Antimicrobial Agents and Chemotherapy 1993; 37:532539. 19. The Ribavirin ARC Study Group. Multicenter clinical trial of oral ribavirin in symptomatic HIV-infected patients. Journal of Acquired Immune Deficiency Syndromes 1993; 6:3241. 20. Feldmann H, Sanchez A, Morzunov S, Spiropoulou CF, Rollin PE, Ksiazek TG, Peters CJ & Nichol ST. Utilization of autopsy RNA for the synthesis of the nucleocapsid antigen of a newly recognized virus associated with hantavirus pulmonary syndrome. Virus Research 1993; 30:351367. 21. Lee ET. Statistical Methods for Survival Data Analysis. 1980. Belmont, California: Lifetime Learning Publications. 22. Allison PD. Survival Analysis Using the SAS System: A Practical Guide. 1995. Cary, NC: SAS Institute Inc. 23. Fisher-Hoch SP, Gborie S, Parker L & Huggins J. Unexpected adverse reactions during a clinical trial in rural West Africa. Antiviral Research 1992; 19:139147. 24. Di Bisceglie AM, Bacon BR, Kleiner DE & Hoofnagle JH. Increase in hepatic iron stores following prolonged therapy with ribavirin in patients with chronic hepatitis C. Journal of Hepatology 1994; 21:11091112. 25. Janai HK, Marks MI, Zaleska M & Stutman HR. Ribavirin: adverse drug reactions, 1986 to 1988. Pediatric Infectious Disease Journal 1990; 9:209211. 26. Johnson EM. Developmental toxicity and safety evaluations of ribavirin. Pediatric Infectious Disease Journal 1990; 9:S8587. 27. Maxson CJ, Greenfield SM & Turner JL. Acute pancreatitis as a common complication of 2,3-dideoxyinosine therapy in the acquired immunodeficiency syndrome. American Journal of Gastroenterology 1992; 87:708713. 28. McKenzie R, Fried MW, Sallie R, Conjeevaram H, DiBisceglie AM, Park Y, Savarese B, Kleiner D, Tsokos M, Luciano C, Pruett T, Stotka JL, Straus SE & Hoofnagle JH. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. New England Journal of Medicine 1995; 333:10991105. 29. Swartz MN. Mitochondrial toxicity new adverse drug effects. New England Journal of Medicine 1995; 333:11461148. 30. Khan AS, Khabbaz RF, Armstrong LR, Holman RC, Bauer SP, Graber J, Strine T, Miller G, Reef S, Tappero J, Rollin PE, Nichol ST, Zaki SR, Bryan RT, Chapman LE, Peters CJ & Ksiazek TG. Hantavirus pulmonary syndrome: the first 100 US cases. Journal of Infectious Diseases 1996; 173:12971303. 31. Nichol ST, Rollin PE, Ksiazek TG & Peters CJ. Hantavirus pulmonary syndrome and newly described hantaviruses in the United States. In Bunyaviridae. Edited by RM Elliott. 1996; pp 269280. New York: Plenum Press. 32. Levy H & Simpson SQ. Hantavirus pulmonary syndrome. American Journal of Respiratory Critical Care Medicine 1994; 149:17101713. 33. Moolenaar RL, Dalton C, Lipman HB, Umland ET, Gallaher M, Duchin JS, Chapman LE, Zaki SR, Ksiazek TG, Rollin PE, Nichol ST, Cheek JE, Butler JC, Peters CJ & Breiman RF. Clinical features that differentiate hantavirus pulmonary syndrome from three other acute respiratory illnesses. Clinical Infectious Diseases 1995; 21:643649. 34. Ketai LH, Williamson MR, Telepak RJ, Levy H, Koster FT, Nolte KB & Allen SE. Hantavirus pulmonary syndrome radiographic findings in 16 patients. Radiology 1994; 191:665668.

Revised 30 June 1999; accepted 18 August 1999

Antiviral Therapy 4:4

219