Combinatorial Ribavirin and Interferon Alfacon-1 Therapy of Acute Arenaviral Disease in Hamsters

Abstract

Several arenaviruses endemic to South America (Junin, Machupo, and Guanarito) and Africa (Lassa) are known to cause frequently fatal haemorrhagic fever. With the exception of ribavirin, which has demonstrated efficacy in cases of Lassa fever, there is no other effective therapeutic for the treatment of arenaviral haemorrhagic fever. We have recently reported that consensus interferon-α α (IFN alfacon-1) can protect hamsters from lethal Pichinde virus (PCV) infection, which serves as a model for acute arenaviral disease in humans. Here we demonstrate highly effective therapy through the combined use of ribavirin with IFN alfacon-1 for the treatment of PCV infection in hamsters. Ribavirin was given orally, twice per day for 7 days, and IFN alfacon-1 was administered intraperitoneally once per day for 10 days. Treatments were initiated 1-5 days post-virus challenge using various dose combinations, many of which were less than optimal when the drugs were given independently. Combining suboptimal doses of ribavirin (5-10 mg/kg/day) with IFN alfacon-1 (5-10 µ g/kg/day), we were able to demonstrate increased protection from mortality, reduced viral burden and liver disease, and greatly extended survival times as compared to treatments where drugs were administered alone. Our data indicate that combination therapy results in synergistic activity that may slow down the progression of the disease and decrease fatality rates associated with severe arenaviral infections in humans. Further, combination therapy reduces the effective dosage of ribavirin, which would serve to limit its toxicity.

In Vitro and In Vivo Activities of T-705 against Arenavirus and Bunyavirus Infections

“…Interestingly, our data showed that lower doses of ribavirin were more effective than T-705 for the treatment of PICV infection. We previously showed that 20 mg/kg/day oral ribavirin is the lower limit for optimal protection against PICV infection when treatment is initiated 24 h post-infectious challenge (11). Here, we have verified that finding and reported that 50 mg/kg/day was the lowest tested dose of T-705 that provided complete protection in the PICV infection model.…”

Genomic Profiling of Host Responses to Lassa Virus: Therapeutic Potential from Primate to Man

“…A combination of ribavirin plus immune serum increased survival in LASV-infected monkeys, suggesting that this combination might be useful for treating human beings with LF [89]. The combination of IFN-alfacon-1 ( Escherichia coli -expressed human IFN-α) plus ribavirin had synergistic activity that slowed disease and reduced fatality rates in hamsters inoculated with the arenavirus, Pichindé [90], which serves as a small animal model for LF.…”

Development of a New Tacaribe Arenavirus Infection Model and Its Use to Explore Antiviral Activity of a Novel Aristeromycin Analog

“…Although Lassa fever is thought to be resistant to the effects of type I IFN [20], a recent study demonstrated sensitivity of several strains Lassa virus to IFN-α and -γ in cell culture [21]. Moreover, treatment with consensus IFN-α, alone or in combination with ribavirin has proven effective in the hamster PICV infection model [22], [23]. A novel therapy based on the targeting of anionic phospholipids exposed on infected cells and virions has shown promise in studies employing a guinea pig model based on infection with an adapted PICV [24].…”