Antiviral combinations for severe influenza

Abstract

Observational data suggest that the treatment of influenza infection with neuraminidase inhibitors decreases progression to more severe illness, especially when treatment is started soon after symptom onset. However, even early treatment might fail to prevent complications in some patients, particularly those infected with novel viruses such as the 2009 pandemic influenza A H1N1, avian influenza A H5N1 virus subtype, or the avian influenza A H7N9 virus subtype. Furthermore, treatment with one antiviral drug might promote the development of antiviral resistance, especially in immunocompromised hosts and critically ill patients. An obvious strategy to optimise antiviral therapy is to combine drugs with different modes of action. Because host immune responses to infection might also contribute to illness pathogenesis, improved outcomes might be gained from the combination of antiviral therapy with drugs that modulate the immune response in an infected individual. We review available data from preclinical and clinical studies of combination antiviral therapy and of combined antiviral-immunomodulator therapy for influenza. Early-stage data draw attention to several promising antiviral combinations with therapeutic potential in severe infections, but there remains a need to substantiate clinical benefit. Combination therapies with favourable experimental data need to be tested in carefully designed aclinical trials to assess their efficacy.

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

“…Each year, influenza epidemics can be responsible for an average of 3e5 millions of severe cases and up to 500,000 deaths in the world (Dunning et al, 2014). The immunocompromised population is at particularly high risk of developing severe complications from influenza infections.…”

Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection

“…Although an annual vaccination for specific IAV variants is the current primary choice for seasonal influenza control, there are limitations to this strategy, such as production problems and low efficacies, and vaccines are unlikely to be available in time to manage new antigenic variants (4). Antiviral drugs, such as neuraminidase inhibitors, reduce progression to more severe complications, especially when treatment is within 2 to 3 days of infection (5). However, new variants that are resistant to existing antiviral drugs are emerging and might limit the effectiveness of antiviral drugs in the future (6).…”

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

“…Combinations of NA inhibitors with adamantanes, favipiravir, or the nucleoside analogue ribavirin have already been demonstrated to cause additive to synergistic inhibition of influenza virus infection in vitro and to enhance survival of infected mice more efficiently than either drug used alone, even in the case of amantadine-or oseltamivir-resistant viruses [149][150][151][152]. However, the clinical benefits of such combinatorial treatments have to be demonstrated in controlled trials in man; a number of studies are ongoing [36].…”

“…AVI-7100 inhibits also the translation of the matrix protein and is a phosphorodiamidate morpholino oligomer with enhanced resistance to enzymatic degradation [36]. Based on results from phase 1 studies reported in September 2014, AVI-7100 is well tolerated in human (see NCT01747148).…”

“…However, the toxicity of polyacrylamide and acrylamide limits the application of such conjugates. Moreover, two trivalent SA conjugates based on a trityl core have been described, whereby the SA-containing arms have been coupled via a phenol ether (35) or amide bond (36) (Fig. 10).…”