Table 5.

Comparison of clinical trials examining ribavirin in hantavirus disease

Characteristics	Huggins et al. [252]	Malinin et al. [254]	Mertz et al. [258]
Disease entity	HFRS	HFRS	HCPS
Study period	1985–1987	2004–2005	1996—2001
Trial design	Prospective, double-blind, placebo-controlled trial	Prospective, open-label, phase II study	Prospective, double-blind, placebo-controlled trial
Number of patients	293	73	36
Dose of ribavirin	Loading dose of 33 mg/kg, followed by a dose of 16 mg/kg every 6 h for the first 4 days and 8 mg/kg every 8 h for the subsequent 3 days	Loading dose of 33 mg/kg, followed by a dose of 16 mg/kg every 6 h for the first 4 days and 8 mg/kg every 8 h for the subsequent 3 days	Loading dose of 33 mg/kg, followed by a dose of 16 mg/kg every 6 h for the first 4 days and 8 mg/kg every 8 h for the subsequent 3 days
Timing of ribavirin with respect to onset of infection	4 days (lengthened to 6 days in 1986) after onset of symptoms	4 days after onset of symptoms	Not specified; however, patients had to be in the prodromal or cardiopulmonary stage
Hantaviruses involved	HTNV (confirmed in 82.6% by ELISA)	PUUV	SNV (confirmed in 63.9% by ELISA)
Primary endpoint	Reduction in mortality, occurrence of oliguria and hemorrhages	Change in viral load	Survival at day 28 after study entry
Results for primary endpoint	7-fold reduction of mortality in the ribavirin group (P = .01)3.7 reduction of oliguria in the ribavirin group (P = .01)	Insufficient efficacy of ribavirin	No difference in survival between the ribavirin and placebo group
Adverse events	Drug-related anemia in all male study subjects (males accounted for 75% of study subjects). Females showed similar trends that were less dramatic due to sex-related differences in hematocrit	Low hemoglobin levels in 95%, hyperbilirubinemia in 81%, sinus bradycardia in 43% and rash in 19% of the ribavirin-treated patients	No significant differences in the frequency of adverse events; however, there was trend toward a higher rate in anemia in the ribavirin group
Inclusion criteria	Age ≥14 years Fever duration ≤4 days (lengthened to 6 days in 1986) Clinical diagnosis of HFRS including fever and proteinuria History making exposure to infection likelyOR Findings consistent with early HFRS Hantaviral IgM antibodies No other evidence for an alternative diagnosis	Age 18–65 years Suspected diagnosis of HFRS within 4 days of onset of disease SOFA score = 1	Age ≥12 years Suspected or serologically confirmed acute hantavirus disease in the prodromal of cardiopulmonary stage
Exclusion criteria	Advanced renal failure manifested by oliguria or uremia Pregnancy or breast feeding Known intolerance to ribavirin Moribund on presentation or life expectancy <48 h Pre-existing non-HFRS life-threatening condition	Known intolerance to ribavirin Pregnancy or breast feeding NYHA cardiac function ≥2 History of severe chronic pulmonary or kidney disease History of autoimmune hepatitis Serum aminotransferase levels greater than two times the upper limit of normal Hemoglobin level <12 g/dL	Pregnancy or breast-feeding A likely diagnosis other than HCPS Immunocompromised status Receipt of systemic corticosteroids within 30 days prior to enrolment A mean arterial pressure of <60 mmHg for 2 h despite optimal medical management A cardiac index <2.1 L/min/m2 Arterial oxygen pressure <65 mmHg in intubated subjects receiving 100% oxygen The presence of unilateral pulmonary infiltrates that did not become bilateral within 24 h
Comments	Study showed efficacy in reducing case fatality and oliguria in HTNV-infected patients	Study revealed insufficient efficacy and safety of intravenous ribavirin in PUUV-infected patients. Severity of PUUV-caused HFRS is not associated with viral load, in contrast to HTNV, explaining the different outcomes observed [255–257]	Premature termination of the study due to the slow rate of accrual of subjects and the findings of futility analysis

NYHA: New York Hearth Association; SOFA: Sepsis-related Organ Failure Assessment score.