favipiravir and Viremia

A 49-year-old Japanese male was managed by mechanical ventilation due to coronavirus disease 2019 (COVID-19) pneumonia. Favipiravir as an antiviral therapy, and anti-inflammatory treatment were administered. SARS-CoV-2 RNA was detected in serum by the loop-mediated isothermal amplification (LAMP) method on Day 9; favipiravir treatment was continued. On Day 13, negative serum RNA was confirmed, followed by mechanical ventilation was removed. On Day 23, LAMP negative was confirmed in nasopharynx, after that the patient discharged on Day 27. We could treat successfully for severe COVID-19 pneumonia based on the LAMP method. We consider this method will be useful in COVID-19 treatment.

Topics: Amides; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; COVID-19 Testing; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Nasopharynx; Nucleic Acid Amplification Techniques; Pneumonia, Viral; Pyrazines; Respiration, Artificial; RNA, Viral; SARS-CoV-2; Treatment Outcome; Viremia

Ebola virus has been responsible for two major epidemics over the last several years and there has been a strong effort to find potential treatments that can improve the disease outcome. Antiviral favipiravir was thus tested on non-human primates infected with Ebola virus. Half of the treated animals survived the Ebola virus challenge, whereas the infection was fully lethal for the untreated ones. Moreover, the treated animals that did not survive died later than the controls. We evaluated the hematological, virological, biochemical, and immunological parameters of the animals and performed proteomic analysis at various timepoints of the disease. The viral load strongly correlated with dysregulation of the biological functions involved in pathogenesis, notably the inflammatory response, hemostatic functions, and response to stress. Thus, the management of viral replication in Ebola virus disease is of crucial importance in preventing the immunopathogenic disorders and septic-like shock syndrome generally observed in Ebola virus-infected patients.

Topics: Amides; Animals; Antiviral Agents; Cytokine Release Syndrome; Cytokines; Disease Models, Animal; Ebolavirus; Hemorrhagic Fever, Ebola; Macaca fascicularis; Pyrazines; T-Lymphocytes; Viral Load; Viremia; Virus Replication

Crimean-Congo hemorrhagic fever virus (CCHFV) is a widely distributed hemorrhagic fever virus found throughout Eastern Europe, Africa, the Middle East and Asia. It is spread through bites from infected ticks, animal husbandry and can also be acquired in the healthcare setting during care of infected patients. In humans, CCHFV can cause a sudden onset of a non-specific febrile illness that can rapidly progress to severe hemorrhagic manifestations. Currently, there is no widely available vaccine and although ribavirin has been suggested for the treatment of CCHFV, clinical efficacy in both animal models and humans is inconsistent suggesting more potent antivirals are needed for CCHFV. Favipiravir is approved in Japan for the treatment of influenza virus infections and has shown promise against other highly pathogenic RNA viruses including CCHFV with demonstrated efficacy in the type I interferon deficient mouse model. In this report we utilized the cynomolgus macaque model to evaluate the efficacy of once- and twice-daily favipiravir treatment against CCHFV infection. We found that favipiravir treatment suppressed viremia and viral shedding when treatment was initiated 24 h post-infection and viral burdens in key tissues trended lower in favipiravir-treated animals. Our data indicate that favipiravir has efficacy against CCHFV in vivo in a non-human primate model of infection.

Topics: Amides; Animals; Antiviral Agents; Disease Models, Animal; Drug Administration Schedule; Female; Hemorrhagic Fever Virus, Crimean-Congo; Hemorrhagic Fever, Crimean; Macaca fascicularis; Male; Pyrazines; Viral Load; Viremia; Virus Shedding

Nucleoside analogues (NA) disrupt RNA viral RNA-dependent RNA polymerase (RdRP) function and fidelity for multiple viral families. The mechanism of action (MOA) of T-705 has been attributed alternatively or concurrently to chain termination and lethal mutagenesis depending on the viral species during in vitro studies. In this study, we evaluated the effect of T-705 on the viral population in non-human primates (NHPs) after challenge with Ebola virus (EBOV) or Marburg virus (MARV) to identify the predominant in vivo MOA. We used common virological assays in conjunction with deep sequencing to characterize T-705 effects. T-705 exhibited antiviral activity that was associated with a reduction in specific infectivity and an accumulation of low frequency nucleotide variants in plasma samples collected day 7 post infection. Stranded analysis of deep sequencing data to identify chain termination demonstrated no change in the transcriptional gradient in negative stranded viral reads and minimal changes in positive stranded viral reads in T-705 treated animals, questioning as a MOA in vivo. These findings indicate that lethal mutagenesis is a MOA of T-705 that may serve as an indication of therapeutic activity of NAs for evaluation in clinical settings. This study expands our understanding of MOAs of these compounds for the Filovirus family and provides further evidence that lethal mutagenesis could be a preponderant MOA for this class of therapeutic compounds.

Topics: Amides; Animals; Antiviral Agents; DNA, Viral; Ebolavirus; Female; Hemorrhagic Fever, Ebola; Macaca; Male; Marburg Virus Disease; Marburgvirus; Mutagenesis; Pyrazines; Viremia

A nurse who acquired Lassa virus infection in Togo in the spring of 2016 was repatriated to the United States for care at Emory University Hospital. Serial sampling from this patient permitted the characterization of several aspects of the innate and cellular immune responses to Lassa virus. Although most of the immune responses correlated with the kinetics of viremia resolution, the CD8 T-cell response was of surprisingly high magnitude and prolonged duration, implying prolonged presentation of viral antigens. Indeed, long after viremia resolution, there was persistent viral RNA detected in the semen of the patient, accompanied by epididymitis, suggesting the male reproductive tract as 1 site of antigen persistence. Consistent with the magnitude of acute T-cell responses, the patient ultimately developed long-term, polyfunctional memory T-cell responses to Lassa virus.

Topics: Adult; Amides; Antibodies, Viral; Antigens, Viral; Antiviral Agents; CD8-Positive T-Lymphocytes; Enzyme-Linked Immunosorbent Assay; Humans; Immunity, Cellular; Immunoglobulin Class Switching; Lassa Fever; Lassa virus; Lymphocyte Activation; Male; Pyrazines; Ribavirin; Viremia

Junín virus (JUNV), the etiologic agent of Argentine hemorrhagic fever (AHF), is classified by the NIAID and CDC as a Category A priority pathogen. Presently, antiviral therapy for AHF is limited to immune plasma, which is readily available only in the endemic regions of Argentina. T-705 (favipiravir) is a broadly active small molecule RNA-dependent RNA polymerase inhibitor presently in clinical evaluation for the treatment of influenza. We have previously reported on the in vitro activity of favipiravir against several strains of JUNV and other pathogenic New World arenaviruses.. To evaluate the efficacy of favipiravir in vivo, guinea pigs were challenged with the pathogenic Romero strain of JUNV, and then treated twice daily for two weeks with oral or intraperitoneal (i.p.) favipiravir (300 mg/kg/day) starting 1-2 days post-infection. Although only 20% of animals treated orally with favipiravir survived the lethal challenge dose, those that succumbed survived considerably longer than guinea pigs treated with placebo. Consistent with pharmacokinetic analysis that showed greater plasma levels of favipiravir in animals dosed by i.p. injection, i.p. treatment resulted in a substantially higher level of protection (78% survival). Survival in guinea pigs treated with ribavirin was in the range of 33-40%. Favipiravir treatment resulted in undetectable levels of serum and tissue viral titers and prevented the prominent thrombocytopenia and leucopenia observed in placebo-treated animals during the acute phase of infection.. The remarkable protection afforded by i.p. favipiravir intervention beginning 2 days after challenge is the highest ever reported for a small molecule antiviral in the difficult to treat guinea pig JUNV challenge model. These findings support the continued development of favipiravir as a promising antiviral against JUNV and other related arenaviruses.

Topics: Administration, Oral; Amides; Animals; Antiviral Agents; Disease Models, Animal; Guinea Pigs; Hemorrhagic Fever, American; Injections, Intraperitoneal; Junin virus; Male; Plasma; Pyrazines; Survival Analysis; Viremia