Oseltamivir-zanamivir combination therapy suppresses drug-resistant H1N1 influenza A viruses in the hollow fiber infection model (HFIM) system

Abstract

Drug-resistant influenza is a significant threat to global public health. Until new antiviral agents with novel mechanisms of action become available, there is a pressing need for alternative treatment strategies with available influenza antivirals. Our aims were to evaluate the antiviral activity of two neuraminidase inhibitors (oseltamivir and zanamivir) as combination therapy against H1N1 influenza A viruses, as these agents bind to the neuraminidase active site differently: oseltamivir requires a conformational change for binding whereas zanamivir does not. We performed pharmacodynamic studies in the hollow fiber infection model (HFIM) system with oseltamivir (75mg Q12h, t1/2: 8h) and zanamivir (600mg Q12h, t1/2: 2.5h), given as mono- or combination therapy, against viruses with varying susceptibilities to oseltamivir and zanamivir. Each antiviral suppressed the replication of influenza strains which were resistant to the other neuraminidase inhibitor, showing each drug does not engender cross-resistance to the other compound. Oseltamivir/zanamivir combination therapy was as effective at suppressing oseltamivir- and zanamivir-resistant influenza viruses and the combination regimen inhibited viral replication at a level that was similar to the most effective monotherapy arm. However, combination therapy offered a clear benefit by preventing the emergence and spread of drug-resistant viruses. These findings demonstrate that combination therapy with two agents that target the same viral protein through distinctly different binding interactions is a feasible strategy to combat resistance emergence. This is a novel finding that may be applicable to other viral and non-viral diseases for which different classes of agents do not exist.

High density Huh7.5 cell hollow fiber bioreactor culture for high-yield production of hepatitis C virus and studies of antivirals

“…Three-dimensional cell culture systems are used for various applications, and especially for studies of drug pharmaceuticals including antivirals. Thus, the hollow fiber bioreactor used in this study has previously been used for studies of antivirals 22 , 49 . While three-dimensional cell cultures have been developed for various cell types, liver cell systems are of special interest given the important role of the liver in drug metabolism and different three-dimensional liver cell models have been developed 20 , 21 , 47 , 50 – 52 .…”

Influenza and Viral Pneumonia

“…Ongoing research on antiviral treatment is promising. Just as for bacterial infection, combination therapy has been studied in influenza infection with different goals, such as preventing pathogen resistance, 119,120 mitigating the inflammatory response, 121 or achieving synergy. 122,123 There has been development of new compounds for the treatment of respiratory syncytial virus.…”

Virucidal and Synergistic Activity of Polyphenol-Rich Extracts of Seaweeds against Measles Virus

“…The strategy of simultaneously attacking multiple targets is a studied approach in the control of viral diseases [ 11 ]. Combining targeted therapies have demonstrated multiples advantages in this field, such the reduction of individual drug doses, the decrease in the side effects of antiviral agents, and the prevention of the emergence of drug-resistant viruses [ 12 ].…”