Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus
The prolonged treatment of immunosuppressed (IS) individuals with anti-influenza monotherapies may lead to the emergence of drug-resistant variants. Herein, we evaluated oseltamivir and polymerase inhibitors combinations against influenza A/H3N2 infections in an IS mouse model. Mice were IS with cyc...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/8/12/1968 |
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| author | Zeineb Mhamdi Hugues Fausther-Bovendo Olus Uyar Julie Carbonneau Marie-Christine Venable Yacine Abed Gary Kobinger Guy Boivin Mariana Baz |
| author_facet | Zeineb Mhamdi Hugues Fausther-Bovendo Olus Uyar Julie Carbonneau Marie-Christine Venable Yacine Abed Gary Kobinger Guy Boivin Mariana Baz |
| author_sort | Zeineb Mhamdi |
| collection | DOAJ |
| description | The prolonged treatment of immunosuppressed (IS) individuals with anti-influenza monotherapies may lead to the emergence of drug-resistant variants. Herein, we evaluated oseltamivir and polymerase inhibitors combinations against influenza A/H3N2 infections in an IS mouse model. Mice were IS with cyclophosphamide and infected with 3 × 10<sup>3</sup> PFU of a mouse-adapted A/Switzerland/9715293/2013 (H3N2) virus. Forty-eight hours post-infection, the animals started oseltamivir, favipiravir or baloxavir marboxil (BXM) as single or combined therapies for 10 days. Weight losses, survival rates and lung viral titers (LVTs) were determined. The neuraminidase (NA) and polymerase genes from lung viral samples were sequenced. All untreated animals died. Oseltamivir and favipiravir monotherapies only delayed mortality (the mean day to death (MDD) of 21.4 and 24 compared to 11.4 days for those untreated) while a synergistic improvement in survival (80%) and LVT reduction was observed in the oseltamivir/favipiravir group compared to the oseltamivir group. BXM alone or in double/triple combination provided a complete protection and significantly reduced LVTs. Oseltamivir and BXM monotherapies induced the E119V (NA) and I38T (PA) substitutions, respectively, while no resistance mutation was detected with combinations. We found that the multiple dose regimen of BXM alone provided superior benefits compared to oseltamivir and favipiravir monotherapies. Moreover, we suggest the potential for drug combinations to reduce the incidence of resistance. |
| first_indexed | 2024-03-10T14:09:29Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-10T14:09:29Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-27c13394f1e448708c48dc0bc1f050aa2023-11-21T00:20:24ZengMDPI AGMicroorganisms2076-26072020-12-01812196810.3390/microorganisms8121968Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 VirusZeineb Mhamdi0Hugues Fausther-Bovendo1Olus Uyar2Julie Carbonneau3Marie-Christine Venable4Yacine Abed5Gary Kobinger6Guy Boivin7Mariana Baz8Research Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaResearch Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaResearch Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaResearch Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaResearch Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaResearch Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaResearch Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaResearch Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaResearch Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, CanadaThe prolonged treatment of immunosuppressed (IS) individuals with anti-influenza monotherapies may lead to the emergence of drug-resistant variants. Herein, we evaluated oseltamivir and polymerase inhibitors combinations against influenza A/H3N2 infections in an IS mouse model. Mice were IS with cyclophosphamide and infected with 3 × 10<sup>3</sup> PFU of a mouse-adapted A/Switzerland/9715293/2013 (H3N2) virus. Forty-eight hours post-infection, the animals started oseltamivir, favipiravir or baloxavir marboxil (BXM) as single or combined therapies for 10 days. Weight losses, survival rates and lung viral titers (LVTs) were determined. The neuraminidase (NA) and polymerase genes from lung viral samples were sequenced. All untreated animals died. Oseltamivir and favipiravir monotherapies only delayed mortality (the mean day to death (MDD) of 21.4 and 24 compared to 11.4 days for those untreated) while a synergistic improvement in survival (80%) and LVT reduction was observed in the oseltamivir/favipiravir group compared to the oseltamivir group. BXM alone or in double/triple combination provided a complete protection and significantly reduced LVTs. Oseltamivir and BXM monotherapies induced the E119V (NA) and I38T (PA) substitutions, respectively, while no resistance mutation was detected with combinations. We found that the multiple dose regimen of BXM alone provided superior benefits compared to oseltamivir and favipiravir monotherapies. Moreover, we suggest the potential for drug combinations to reduce the incidence of resistance.https://www.mdpi.com/2076-2607/8/12/1968influenzaH3N2immunosuppressioncombination therapyoseltamivirfavipiravir |
| spellingShingle | Zeineb Mhamdi Hugues Fausther-Bovendo Olus Uyar Julie Carbonneau Marie-Christine Venable Yacine Abed Gary Kobinger Guy Boivin Mariana Baz Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus Microorganisms influenza H3N2 immunosuppression combination therapy oseltamivir favipiravir |
| title | Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus |
| title_full | Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus |
| title_fullStr | Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus |
| title_full_unstemmed | Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus |
| title_short | Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus |
| title_sort | effects of different drug combinations in immunodeficient mice infected with an influenza a h3n2 virus |
| topic | influenza H3N2 immunosuppression combination therapy oseltamivir favipiravir |
| url | https://www.mdpi.com/2076-2607/8/12/1968 |
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