In vitro activity of favipiravir and neuraminidase inhibitor combinations against oseltamivir-sensitive and oseltamivir-resistant pandemic influenza A (H1N1) virus

Abstract

Few anti-influenza drugs are licensed in the United States for the prevention and therapy of influenza A and B virus infections. This shortage, coupled with continuously emerging drug resistance, as detected through a global surveillance network, seriously limits our anti-influenza armamentarium. Combination therapy appears to offer several advantages over traditional monotherapy in not only delaying development of resistance but also potentially enhancing single antiviral activity. In the present study, we evaluated the antiviral drug susceptibilities of fourteen pandemic influenza A (H1N1) virus isolates in MDCK cells. In addition, we evaluated favipiravir (T-705), an investigational drug with a broad antiviral spectrum and a unique mode of action, alone and in dual combination with the neuraminidase inhibitors (NAIs) oseltamivir, peramivir, or zanamivir, against oseltamivir-sensitive pandemic influenza A/California/07/2009 (H1N1) and oseltamivir-resistant A/Hong Kong/2369/2009 (H1N1) virus. Mean inhibitory values showed that the tested virus isolates remained sensitive to commonly used antiviral drugs, with the exception of the Hong Kong virus isolate. Drug dose-response curves confirmed complete drug resistance to oseltamivir, partial sensitivity to peramivir, and retained susceptibility to zanamivir and favipiravir against the A/Hong Kong/2369/2009 virus. Three-dimensional analysis of drug interactions using the MacSynergy(TM) II program indicated an overall synergistic interaction when favipiravir was combined with the NAIs against the oseltamivir-sensitive influenza virus, and an additive effect against the oseltamivir-resistant virus. Although the clinical relevance of these drug combinations remains to be evaluated, results obtained from this study support the use of combination therapy with favipiravir and NAIs for treatment of human influenza virus infections.

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

“…The development of T-705 presented an opportunity to use it in a combination therapy regimen. In murine lethal-infection models, T-705 showed strong efficacy against a variety of influenza viruses, including A(H5N1) viruses2123444546, with treatment being delayed by up to 72 hpi21, and the efficacy of combined oseltamivir and T-705 against several strains of seasonal influenza viruses as well as mouse-adapted low pathogenic A(H5N1) influenza virus was also investigated in mice2347. Extending the treatment window is important if patients admitted to hospital more than 48 h after the onset of symptoms are to be successfully treated, and administering suboptimal doses of drug combinations, as opposed to the optimal dose of a single drug, may not only inhibit virus replication but also reduce the possibility of drug side effects, e.g., by decreasing the mitochondrial toxicity associated with nucleoside analogs4849.…”

Japanese Surveillance Systems and Treatment for Influenza

“…Additionally, since it does not target the NA, it is effective against NAI-resistant influenza viruses [98]. A phase III clinical trial of favipiravir, a double-blind, randomized study comparing it against oseltamivir has been conducted in Japan since 2009 [99].…”

Peptidomimetic furin inhibitor MI-701 in combination with oseltamivir and ribavirin efficiently blocks propagation of highly pathogenic avian influenza viruses and delays high level oseltamivir resistance in MDCK cells

“…Moreover, also a transient 501 furin blockade appears to be well tolerated as indicated by studies 502 on conditional furin knock-out mice (Roebroek et al, 2004). 503 However, before any medication with furin inhibitors will be 504 considered for use as antivirals, pharmacokinetics and pharmacol-505 ogy studies in animals need to be performed to clarify the absorp- Dunning et al, 2014;Tarbet et al, 2012Tarbet et al, , 2014 534 Webster and Govorkova, 2014). 535 Other cellular proteins involved in influenza virus replication 536 can also be exploited as targets for a combination drug therapy 537 (Steinmetzer et al, 2015).…”