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Favipiravir is currently approved for the treatment of the influenza virus and has shown encouraging results in terms of antiviral capacity in clinical studies against severe acute respiratory syndrome coronavirus 2. Favipiravir is a prodrug, where its favipiravir-ribofuranosyl-5B-triphosphate metabolite is capable of blocking RNA replication of the virus. However, the antiviral efficiency of favipiravir is limited by two factors: (i) low accumulation in plasma and rapid excretion/elimination post-administration and (ii) low conversion rate into the active metabolite. To tackle these problems, herein, we have designed new favipiravir analogues focusing on the replacement of the fluorine atom at the 6-position by halogen or hydrogen atoms and 3-O-functionalization with labile groups. The first type of functionalization seeks to increase the antiviral activity because of the better ability of the keto-tautomer as a function of the halogen, and it is hypothesized that the keto-tautomer tends to promote the formation of the ribofuranosyl-5B-triphosphate (RTP) metabolite. Meanwhile, the second type of functionalization seeks to promote lipophilicity and increase accumulation in cells. From the in vitro antiviral activity against two coronavirus models (bovine and human 229E), it was identified that the replacement did not improve the antiviral activity against both the models, which seems to be attributable to the low water solubility of these new 6-functionalized analogues. Meanwhile, with 3-O-functionalization, acetylation provided the most active compounds with higher half-maximal inhibitory concentration and selectivity than favipiravir, whereas benzylation/methanosulfonation yielded the least active compounds. In summary, acetylation is found to be a convenient functionalization to enhance the antiviral profile of favipiravir.

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The emergence and spread of antiviral-resistant influenza viruses are of great concern. To minimize the public health risk, it is important to monitor antiviral susceptibilities of influenza viruses. Analyses of the antiviral susceptibilities of influenza A and B viruses have been conducted globally; however, those of influenza C and D viruses are limited. Here, we determined the susceptibilities of influenza C viruses representing all six lineages (C/Taylor, C/Yamagata, C/Sao Paulo, C/Aichi, C/Kanagawa, and C/Mississippi) and influenza D viruses representing four lineages (D/OK, D/660, D/Yama2016, and D/Yama2019) to RNA polymerase inhibitors (baloxavir and favipiravir) by using a focus reduction assay. All viruses tested were susceptible to both drugs. We then performed a genetic analysis to check for amino acid substitutions associated with baloxavir and favipiravir resistance and found that none of the viruses tested possessed these substitutions. Use of the focus reduction assay with the genotypic assay has proven valuable for monitoring the antiviral susceptibilities of influenza C and D viruses as well as influenza A and B viruses. Antiviral susceptibility monitoring of all influenza virus types should continue in order to assess the public health risks posed by these viruses.

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The structure and dynamics of membranes are crucial to ensure the proper functioning of cells. There are some compounds used in therapeutics that show nonspecific interactions with membranes in addition to their specific molecular target. Among them, two compounds recently used in therapeutics against COVID-19, remdesivir and favipiravir, were subjected to molecular dynamics simulation assays. In these, we demonstrated that the compounds can spontaneously bind to model lipid membranes in the presence or absence of cholesterol. These findings correlate with the corresponding experimental results recently reported by our group. In conclusion, insertion of the compounds into the membrane is observed, with a mean position close to the phospholipid head groups.

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BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

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ABSTRACT BACKGROUND: Favipiravir is generally used in treating coronavirus disease 2019 (COVID-19) pneumonia in Turkey. OBJECTIVE: To determine the side effects of favipiravir and whether it is a good treatment option. DESIGN AND SETTING: Retrospective study conducted in Atatürk Chest Diseases and Chest Surgery Training and Research Hospital, Ankara, Turkey. METHODS: 357 patients who completed favipiravir treatment at the recommended dose were included. 37 patients with drug side effects and 320 patients without drug side effects were examined in two groups. RESULTS: Side effects were observed in 37 (10.36%) out of 357 patients using favipiravir. The most common side effect was liver dysfunction, in 26 (7.28%) of the patients. The following other side effects were also observed: diarrhea (1.4%), nausea (0.84%), abdominal pain (0.28%) and thrombocytopenia (0.28%). One patient (0.28%) presented both increased transaminases and nausea. CONCLUSION: In this study, it was determined that favipiravir may constitute an alternative for treating COVID-19 pneumonia given that its side effects are generally well tolerated and not serious.

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OBJECTIVES: Comparative data on hydroxychloroquine and favipiravir, commonly used agents in the treatment of Coronavirus Disease-2019 (COVID-19), are still limited. In this study, it was aimed to compare treatment outcomes in healthcare workers with COVID-19 who were prospectively followed by the occupational health and safety unit. METHODS: A total of 237 healthcare-workers, diagnosed as mild or moderate COVID-19 between March 11, 2020 and January 1, 2021, were given hydroxychloroquine (n = 114) or favipiravir (n = 123). Clinical and laboratory findings were evaluated. RESULTS: The mean age of the patients was 33.4±11.5 years. The mean time to negative PCR was found to be significantly shorter in patients receiving favipiravir compared to the hydroxychloroquine group (10.9 vs. 13.9 days; p < 0.001). The rate of hospitalization in the hydroxychloroquine group was significantly higher than favipiravir group (15.8% vs. 3.3%). In terms of side effects; the frequency of diarrhea in patients receiving hydroxychloroquine was significantly higher than that in the favipiravir group (31.6% vs. 6.5%; p < 0.001). CONCLUSIONS: Favipiravir and hydroxychloroquine were similar in terms of improvement of clinical symptoms of healthcare workers with mild or moderate COVID-19 infection, but favipiravir was significantly more effective in reducing viral load and hospitalization rates. Furthermore, favipiravir caused significantly less side-effects than hydroxychloroquine.

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Abstract Objectives Comparative data on hydroxychloroquine and favipiravir, commonly used agents in the treatment of Coronavirus Disease-2019 (COVID-19), are still limited. In this study, it was aimed to compare treatment outcomes in healthcare workers with COVID-19 who were prospectively followed by the occupational health and safety unit. Methods A total of 237 healthcare-workers, diagnosed as mild or moderate COVID-19 between March 11, 2020 and January 1, 2021, were given hydroxychloroquine (n = 114) or favipiravir (n = 123). Clinical and laboratory findings were evaluated. Results The mean age of the patients was 33.4±11.5 years. The mean time to negative PCR was found to be significantly shorter in patients receiving favipiravir compared to the hydroxychloroquine group (10.9 vs. 13.9 days; p < 0.001). The rate of hospitalization in the hydroxychloroquine group was significantly higher than favipiravir group (15.8% vs. 3.3%). In terms of side effects; the frequency of diarrhea in patients receiving hydroxychloroquine was significantly higher than that in the favipiravir group (31.6% vs. 6.5%; p < 0.001). Conclusions Favipiravir and hydroxychloroquine were similar in terms of improvement of clinical symptoms of healthcare workers with mild or moderate COVID-19 infection, but favipiravir was significantly more effective in reducing viral load and hospitalization rates. Furthermore, favipiravir caused significantly less side-effects than hydroxychloroquine.

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Resumen En infección por SARS-CoV-2 (COVID-19), las manifestaciones más comunes son las de vías aéreas superiores; en casos complicados se presenta neumonía intersticial bilateral, insuficiencia respiratoria aguda grave y falla orgánica múltiple que ameritan tratamiento hospitalario y soporte ventilatorio por puntas nasales o mascarilla, así como oxígeno con flujo a presión alta o intubación orotraqueal y ventilación mecánica. No hay antivirales específicos por lo que el manejo es sintomático, así como con antiplaquetarios (ácido acetilsalicílico, dipiridamol), heparina de bajo peso molecular ante hipercoagulabilidad (dímero D aumentado), dexametasona ante indicadores altos de inflamación. Previo consentimiento informado, experimentalmente se emplean antibióticos según los resultados microbiológicos, interferón beta 1b, favipiravir, tocilizumab, ivermectina e inmunoglobulina G. Cuando se presenta gastroenteritis se puede indicar nitazoxanida.

Abstract In SARS-CoV-2 infection (COVID-19), the most common manifestations involve the upper airways; in complicated cases, bilateral interstitial pneumonia, severe acute respiratory failure and multiple organ failure occur, which require hospital treatment and ventilatory support with nasal cannula or mask and high flow oxygen, or orotracheal intubation and mechanical ventilation. There are no specific antivirals, and thus management is symptomatic, as well as with antiplatelet drugs (acetylsalicylic acid, dipyridamole), low molecular weight heparin when there is hypercoagulability (increased D-dimer), dexamethasone when inflammation indicators are elevated; experimentally, under informed consent, antibiotics are used according to microbiological results, as well as interferon beta 1b, favipiravir, tocilizumab, ivermectin and immunoglobulin G. When gastroenteritis occurs, nitazoxanide can be indicated.

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We report a case of Argentine hemorrhagic fever diagnosed in a woman in Belgium who traveled from a disease-endemic area. Patient management included supportive care and combination therapy with ribavirin and favipiravir. Of 137 potential contacts, including friends, relatives, and healthcare and laboratory workers, none showed development of clinical symptoms of this disease.

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In SARS-CoV-2 infection (COVID-19), the most common manifestations involve the upper airways; in complicated cases, bilateral interstitial pneumonia, severe acute respiratory failure and multiple organ failure occur, which require hospital treatment and ventilatory support with nasal cannula or mask and high flow oxygen, or orotracheal intubation and mechanical ventilation. There are no specific antivirals, and thus management is symptomatic, as well as with antiplatelet drugs (acetylsalicylic acid, dipyridamole), low molecular weight heparin when there is hypercoagulability (increased D-dimer), dexamethasone when inflammation indicators are elevated; experimentally, under informed consent, antibiotics are used according to microbiological results, as well as interferon beta 1b, favipiravir, tocilizumab, ivermectin and immunoglobulin G. When gastroenteritis occurs, nitazoxanide can be indicated.En infección por SARS-CoV-2 (COVID-19), las manifestaciones más comunes son las de vías aéreas superiores; en casos complicados se presenta neumonía intersticial bilateral, insuficiencia respiratoria aguda grave y falla orgánica múltiple que ameritan tratamiento hospitalario y soporte ventilatorio por puntas nasales o mascarilla, así como oxígeno con flujo a presión alta o intubación orotraqueal y ventilación mecánica. No hay antivirales específicos por lo que el manejo es sintomático, así como con antiplaquetarios (ácido acetilsalicílico, dipiridamol), heparina de bajo peso molecular ante hipercoagulabilidad (dímero D aumentado), dexametasona ante indicadores altos de inflamación. Previo consentimiento informado, experimentalmente se emplean antibióticos según los resultados microbiológicos, interferón beta 1b, favipiravir, tocilizumab, ivermectina e inmunoglobulina G. Cuando se presenta gastroenteritis se puede indicar nitazoxanida.

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SUMMARY INTRODUCTION This study aims to evaluate changes in hematological parameters after the follow-up of patients who received treatment with favipiravir due to COVID-19 infections. METHODS Sixty-two cases receiving favipiravir treatment for at least five days due to COVID-19 infection were evaluated retrospectively. Parameters including age, gender, nasopharyngeal swab positivity, and chronic diseases were analyzed. Hematologic parameters were analyzed before and after the treatment. RESULTS The mean age of the patients receiving treatment with favipiravir was 63.7±12.3 years. Nasopharyngeal swab positivity was detected in 67.7%. The most common comorbid conditions detected in patients were hypertension in 25 cases (40.3%) and diabetes in 16 cases (25.8%). In the statistical analysis of the hematological parameters before and after treatment with favipiravir, WBC, PT-PTT-INR levels were found to be unaffected; the mean RBC was found to have decreased from 4.33 ± 0.58 M/uL to 4.16 ± 0.54 M/uL (p:0.003); the median hemoglobin level was found to have decreased from 12.3 g/dl to 11.9 g/dl (p:0.041); the hematocrit level decreased from 38.1% ± 4.8 to 36.9% ± 4.2 (p:0.026); the median neutrophil count decreased from 4.57 K/uL to 3.85 K/uL (p:0.001); the mean lymphocyte count increased from 1.22 ± 0.53 K/uL to 1.84 ± 1.19 K/uL (p:0.000); and the mean platelet count increased from 244.1 ± 85.1 K/uL to 281.9 ± 103.3 K/uL (p:0.005). CONCLUSION We concluded that the pathological effect of treatment with favipiravir on the hematologic system was the suppression in the erythrocyte series, and there were no adverse effects in other hematologic parameters.

RESUMO INTRODUÇÃO Este estudo tem como objetivo avaliar as alterações nos parâmetros hematológicos após o acompanhamento de pacientes que receberam tratamento com favipiravir devido à infecção por Covid-19. MÉTODOS Sessenta e dois casos em tratamento com favipiravir por pelo menos cinco dias devido à infecção por Covid-19 foram avaliados retrospectivamente. Parâmetros como idade, sexo, positividade do swab nasofaríngeo e doenças crônicas foram analisados. Os parâmetros hematológicos foram analisados antes e após o tratamento. RESULTADOS A idade média dos pacientes que receberam tratamento com favipiravir foi de 63,7±12,3 anos. A positividade do swab nasofaríngeo foi detectada em 67,7%. As condições comórbidas mais comuns detectadas nos pacientes foram hipertensão em 25 casos (40,3%) e diabetes em 16 casos (25,8%). Na análise estatística dos parâmetros hematológicos antes e após o tratamento com favipiravir, os níveis de leucócitos, PT-PTT-INR não foram afetados. Verificou-se que o RBC médio diminuiu de 4,33±0,58 M/uL para 4,16±0,54 M/uL (p=0,003); o nível médio de hemoglobina foi reduzido de 12,3 g/dl para 11,9 g/dl (p=0,041); o nível de hematócrito diminuiu de 38,1%±4,8 para 36,9%±4,2 (p=0,026); a contagem mediana de neutrófilos diminuiu de 4,57 K/uL para 3,85 K/uL (p=0,001); a contagem média de linfócitos aumentou de 1,22±0,53 K/uL para 1,84±1,19 K/uL (p=0,000); a contagem média de plaquetas aumentou de 244,1±85,1 K/uL para 281,9±103,3 K/uL (p=0,005). CONCLUSÃO Concluiu-se que o efeito patológico do tratamento com favipiravir no sistema hematológico foi a supressão na série eritrocitária e que não houve efeitos adversos em outros parâmetros hematológicos.

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