Placebo-Controlled, Double-Blind Trial of Intravenous Ribavirin for the Treatment of Hantavirus Cardiopulmonary Syndrome in North America

University of Alabama at Birmingham, Birmingham, Alabama, United States
Clinical Infectious Diseases (Impact Factor: 8.89). 12/2004; 39(9):1307-13. DOI: 10.1086/425007
Source: PubMed


BACKGROUND. Ribavirin is active in vitro against hantaviruses, but the findings of an open trial of the use of 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 [<or=2 g], followed by 16 mg/kg [<or=1 g] given every 6 h for 4 days and by 8 mg/kg [<or=.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. The proportion 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.

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Available from: Gregory J Mertz, Jan 04, 2016
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    • "Currently, no vaccines or antiviral drugs are approved to prevent or to treat HPS. Attempts to treat HPS with intravenous ribavirin have been ineffective after hospitalization [10], indicating that the final clinical stages of HPS progress too rapidly for ribavirin to exert an antiviral effect. However, no firm conclusions can be drawn from these studies given the low number of patients enrolled. "
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    ABSTRACT: Andes virus (ANDV) is the most common causative agent of hantavirus pulmonary syndrome (HPS) in the Americas, and is the only hantavirus associated with human-to-human transmission. Case fatality rates of ANDV-induced HPS are approximately 40%. There are currently no effective vaccines or antivirals against ANDV. Since HPS severity correlates with viral load, we tested small interfering RNA (siRNA) directed against ANDV genes as a potential antiviral strategy. We designed pools of 4 siRNAs targeting each of the ANDV genome segments (S, M, and L), and tested their efficacy in reducing viral replication in vitro. The siRNA pool targeting the S segment reduced viral transcription and replication in Vero-E6 cells more efficiently than those targeting the M and L segments. In contrast, siRNAs targeting the S, M, or L segment were similar in their ability to reduce viral replication in human lung microvascular endothelial cells. Importantly, these siRNAs inhibit ANDV replication even if given after infection. Taken together, our findings indicate that siRNAs targeting the ANDV genome efficiently inhibit ANDV replication, and show promise as a strategy for developing therapeutics against ANDV infection.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "At this time, no safe and effective vaccines have been approved . In clinical trials, the antiviral drug ribavirin was somewhat effective against HFRS if used early after onset; however, ribavirin was not effective against HPS probably because the duration from first symptoms to lethal disease is less for HPS (Huggins et al., 1991; Mertz et al., 2004). Therefore, early diagnosis and support are currently the most effective means of treating these diseases (reviewed in (Maes et al., 2009)). "
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    ABSTRACT: Puumala (PUUV) and Hantaan (HTNV) viruses are hantaviruses within the family Bunyaviridae and associated with Hemorrhagic Fever with Renal Syndrome (HFRS) in humans. Little is known about how these viruses interact with host cells, though pathogenic hantaviruses interact with α(v)β(3) integrin. To study host cell interactions and rapidly test the ability of antibodies to prevent infection, we produced HTNV and PUUV pseudovirions on a vesicular stomatitis virus (VSV) core. Similar to replication-competent hantaviruses, infection was low-pH-dependent. Despite broad cell tropism, several human T cell lines were poorly permissive to hantavirus pseudovirions, compared to VSV, indicating a relative block to infection at the level of entry. Stable expression of α(v)β(3) integrin in SupT1 cells did not restore infectivity. Finally, the pseudovirion system provided a rapid, quantitative, and specific method to screen for neutralizing antibodies in immune sera.
    Full-text · Article · Dec 2011 · Virology
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    • "Medina and colleagues showed that ribavirin inhibited Sin Nombre virus (SNV) infection in vitro and demonstrated that pre-treatment of deer mice, followed by daily therapy with 100 mg ribavirin kg−1 reduced SNV infection as measured by seroconversion, viral RNA synthesis and immunohistochemistry (IHC), while treatment with 50 mg kg−1 or less had a reduced inhibitory effect [16]. Two attempts have been made to assess the value of ribavirin therapy in patients with HPS in North America and although hampered by low enrollment rates, the results of these studies showed no effect of ribavirin therapy when treatment was initiated during the symptomatic phase of infection [17], [18]. The purpose of this study was to evaluate the antiviral activity of ribavirin against ANDV, both in vitro and in vivo using a lethal hamster model of HPS [19], [20]. "
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    ABSTRACT: Pathogenic hantaviruses are a closely related group of rodent-borne viruses which are responsible for two distinct diseases in humans, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (HPS, otherwise known as hantavirus cardiopulmonary syndrome, HCPS). The antiviral effect of ribavirin against Old World hantaviruses, most notably Hantaan virus, is well documented; however, only a few studies have addressed its inhibitory effect on New World hantaviruses. In the present study, we demonstrate that ribavirin is highly active against Andes virus (ANDV), an important etiological agent of HPS, both in vitro and in vivo using a lethal hamster model of HPS. Treatment of ANDV infected Vero E6 cells with ribavirin resulted in dose-dependent reductions in viral RNA and protein as well as virus yields with a half maximal inhibitory concentration between 5 and 12.5 µg ml(-1). In hamsters, treatment with as little as 5 mg kg(-1) day(-1) was 100% effective at preventing lethal HPS disease when therapy was administered by intraperitoneal injection from day 1 through day 10 post-infection. Significant reductions were observed in ANDV RNA and antigen positive cells in lung and liver tissues. Ribavirin remained completely protective when administered by intraperitoneal injections up to three days post-infection. In addition, we show that daily oral ribavirin therapy initiated 1 day post-infection and continuing for ten days is also protective against lethal ANDV disease, even at doses of 5 mg kg(-1) day(-1). Our results suggest ribavirin treatment is beneficial for postexposure prophylaxis against HPS-causing hantaviruses and should be considered in scenarios where exposure to the virus is probable. The similarities between the results obtained in this study and those from previous clinical evaluations of ribavirin against HPS, further validate the hamster model of lethal HPS and demonstrate its usefulness in screening antiviral agents against this disease.
    Full-text · Article · Aug 2011 · PLoS ONE
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