Ribavirin does not potentiate favipiravir antiviral activity against Ebola virus in non-human primates.

BACKGROUND: In spite of recurrent and dramatic outbreaks, there are no therapeutics approved against Ebola virus disease. Favipiravir, a RNA polymerase inhibitor active against several RNA viruses, recently demonstrated significant but not complete protection in a non-human primate model of Ebola virus disease. In this study, we assessed the benefit of the combination of favipiravir and ribavirin, another broad spectrum antiviral agent, in the same model. METHODS: 15 female cynomolgus macaques were challenged intramuscularly with 1,000 FFU of Ebola virus Gabon 2001 strain and followed for 21 days. All animals received favipiravir 180 mg/kg twice a day (BID), either as monotherapy (n = 5) or in combination with ribavirin (n = 10). Ribavirin was given either at the dose 10 mg/kg BID (n = 5) or 5 mg/kg BID (n = 5). Favipiravir and ribavirin were initiated two and one days before viral challenge respectively and treatment were continued for 14 days. Treatment effects on viral and hematological markers were assessed using a mathematical model. Survival rate of 0% and 20% were obtained in macaques receiving favipiravir plus ribavirin 10 and 5 mg/kg BID, respectively, compared to 40% in the favipiravir monotherapy group (P = 0.061 when comparing monotherapy and bitherapy, log rank). Viral dynamic modeling analysis did not identify an association between plasma concentrations of ribavirin and viral load levels. Using a model of erythropoiesis, plasma concentrations of ribavirin were strongly associated with a hemoglobin drop (p = 0.0015). CONCLUSION: Ribavirin plus favipiravir did not extend survival rates and did not lower viral replication rate compared to favipiravir monotherapy in this animal model. Patients receiving this combination in other indications, such as Lassa fever, should be closely monitored to prevent potential toxicity associated with anemia.

Lassa fever in Benin: description of the 2014 and 2016 epidemics and genetic characterization of a new Lassa virus.

We report two outbreaks of Lassa fever that occurred in Benin in 2014 and 2016 with 20 confirmed cases and 50% (10/20) mortality. Benin was not previously considered to be an endemic country for Lassa fever, resulting in a delay to diagnose the disease and its human transmission. Molecular investigations showed the viral genomes to be similar to that of the Togo strain, which is genetically very different from other known strains and confirms the existence of a new lineage. Endemic circulation of Lassa virus in a new territory and the genetic diversity thus confirm that this virus represents a growing threat for West African people. Given the divergence of the Benin strain from the prototypic Josiah Sierra Leone strain frequently used to generate vaccine candidates, the efficacy of vaccine candidates should also be demonstrated with this strain.

Differential susceptibility of adenovirus clinical isolates to cidofovir and ribavirin is not related to species alone.

BACKGROUND: We have previously reported that human adenovirus (HAdV) reference strains clearly show species-dependent resistance to ribavirin, whereas different species of HAdV are equally sensitive to cidofovir. All the serotypes tested were susceptible to cidofovir, whereas only serotypes from species C were sensitive to ribavirin. Here, we aimed to extend these investigations to clinical isolates. METHODS: In vitro, we tested 126 isolates obtained from 65 patients included in a European survey of HAdV infection. RESULTS: Among the 126 isolates tested, all presented cidofovir 50% inhibitory concentration (IC50) in the same range as the HAdV 5 reference strain. Regarding ribavirin, all isolates from species C (79 tested) showed an IC50 comparable with previously reported results for reference strains; however, 24/32, 2/6 and 3/3 tested isolates from species A, B and D, respectively, were shown to have a ribavirin IC50 comparable with the HAdV 5 reference strain (species C), contrary to previous observations for reference strains of the same species. Among patients who were treated with cidofovir for disseminated HAdV infection, > or = 4 sequential isolates could be obtained from 9 patients; no variation in cidofovir susceptibility could be detected. CONCLUSIONS: Cidofovir is active in vitro in all HAdV clinical isolates. Ribavirin was revealed to be active on most HAdV isolates from species A, B and D, and in all isolates from species C. Finally, no resistance to cidofovir became apparent in sequential isolates obtained from treated patients.

In vitro susceptibility of adenovirus to antiviral drugs is species-dependent.

Adenovirus infections are a frequent and serious complication following allogeneic haematopoietic stem cell transplantation (HSCT). The antiviral drugs cidofovir and ribavirin have been used as first-line therapy for disseminated infections with variable results. In the present study, in vitro susceptibility to these two drugs was evaluated on HEp-2 cells in adenovirus reference strains representing serotypes of each of the six species and in clinical isolates. Susceptibility to cidofovir was comparable between species with inhibition of replication of all tested serotypes in a narrow dose range (IC50=17-81 microM). However, susceptibility to ribavirin was highly dependent on the species. Serotypes from species A, B, D, E and F were all resistant to ribavirin (IC50=396 to >500 microM). Only replication of serotypes from species C was inhibited by ribavirin (IC50=48-108 microM). This species-dependent susceptibility of adenovirus to ribavirin was confirmed in clinical isolates. When tested on other cell lines (PLC, A549 and 293), all species were revealed to be resistant to ribavirin. If our in vitro findings are predictive of virological responses in vivo, these results suggest that ribavirin would not be effective for management of non-C species adenovirus infections after HSCT.