Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice

Abstract

We studied the effects of a neuraminidase inhibitor (oseltamivir) and an inhibitor of influenza virus polymerases (ribavirin) against two highly pathogenic H5N1 influenza viruses. In vitro, A/Vietnam/1203/04 virus (clade 1) was highly susceptible to oseltamivir carboxylate (50% inhibitory concentration [IC 50 ] ‫؍‬ 0.3 nM), whereas A/Turkey/15/06 virus (clade 2.2) had reduced susceptibility (IC 50 ‫؍‬ 5.5 nM). In vivo, BALB/c mice were treated with oseltamivir (1, 10, 50, or 100 mg/kg of body weight/day), ribavirin (37.5, 55, or 75 mg/kg/day), or the combination of both drugs for 8 days, starting 4 h before virus inoculation. Monotherapy produced a dose-dependent antiviral effect against the two H5N1 viruses in vivo. Three-dimensional analysis of the drug-drug interactions revealed that oseltamivir and ribavirin interacted principally in an additive manner, with several exceptions of marginal synergy or marginal antagonism at some concentrations. The combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 1 mg/kg/day and the combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 10 mg/kg/day were synergistic against A/Vietnam/1203/04 and A/Turkey/ 15/06 viruses, respectively. These optimal oseltamivir-ribavirin combinations significantly inhibited virus replication in mouse organs, prevented the spread of H5N1 viruses beyond the respiratory tract, and abrogated the cytokine response (P < 0.01). Importantly, we observed clear differences between the efficacies of the drug combinations against two H5N1 viruses: higher doses were required for the protection of mice against A/Turkey/15/06 virus than for the protection of mice against A/Vietnam/1203/04 virus. Our preliminary results suggest that oseltamivir-ribavirin combinations can have a greater or lesser antiviral effect than monotherapy, depending on the H5N1 virus and the concentrations used.

Combinations of Oseltamivir and T-705 Extend the Treatment Window for Highly Pathogenic Influenza A(H5N1) Virus Infection in Mice

“…Although various antiviral agents have been used in combination with NAIs (e.g., amantadine, rimantadine, ribavirin, human IFN-α, plant extracts, and others) for different subtypes of influenza viruses42, including the HPAI A(H5N1) viruses1743, the major drawback of these studies has been the use of non–FDA-approved drugs (ribavirin, human IFN-α, plant extracts) and the high frequency of resistance to other compounds (amantadine, rimantadine) among circulating human viruses1743. The development of T-705 presented an opportunity to use it in a combination therapy regimen.…”

Drugs in Development for Influenza

“…[97–100] An oseltamivir and ribavirin combination therapy was tested against H5N1 influenza virus in a mouse model and shown to be beneficial; however the results were dependent on the H5N1 influenza strain used. [101] More recent studies have shown a triple combination of amantadine, oseltamivir and ribavirin to be efficacious against multiple influenza virus strains in vitro including drug resistant strains. [102, 103] This triple combination was effective against amantadine- and oseltamivir- resistant viruses with synergy greater than any double combination tested.…”

Model-Based Simulation and Prediction of an Antiviral Strategy against Influenza A Infection

“…Although it is hard to directly compare the efficacy of the different drugs, the data indicates that model simulations might be useful for the investigation of the key biological parameters that affect the viral and host dynamics in populations infected with influenza A virus. Combinatorial treatments of various drugs have been widely studied to efficiently control an infection with influenza virus [42]–[45]. As we predicted, a combinatorial treatment of Oseltamivir with Ribavirin, which inhibits the viral replication, exhibited increased efficacy in MDCK cells infected with A/NewCaledonia/20/99 influenza virus [41].…”