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Antimicrob Agents Chemother 2020 Jun 23;64(7):e00301-20

Laninamivir-interferon-lambda1 combination treatment promotes resistance by influenza A virus more rapidly than laninamivir alone.

Adams SE, Lugovtsev VY, Kan A, Bovin NV, Donnelly RP, Ilyushina NA

Abstract

Each year, 5-20% of the population of the United States becomes infected with influenza A virus. Combination therapy with two or more antiviral agents has been considered as a potential treatment option for influenza virus infection. However, the clinical results derived from combination treatment with two or more antiviral drugs have been variable. We examined the effectiveness of co-treatment with two distinct classes of anti-influenza drugs, i.e., neuraminidase (NA) inhibitor, laninamivir, and interferon (IFN)-lambda1, against the emergence of drug-resistant virus variants in vitro We serially passaged pandemic A/California/04/09 (A(H1N1)pdm09) influenza virus in a human lung epithelial cell line (Calu-3) in the presence or absence of increasing concentrations of laninamivir or laninamivir plus IFN-lambda1. Surprisingly, laninamivir used in combination with IFN-lambda1 promoted the emergence of the E119G NA mutation five passages earlier than laninamivir alone (passage 2 vs passage 7, respectively). Acquisition of this mutation resulted in significantly reduced sensitivity to NA inhibitors, laninamivir ( approximately 284-fold downward arrow) and zanamivir ( approximately 1024-fold downward arrow), and decreased NA enzyme catalytic activity ( approximately 5-fold downward arrow) compared to the parental virus. Moreover, the E119G NA mutation emerged together with concomitant hemagglutinin (HA) mutations (T197A and D222G), which were selected more rapidly by combination treatment with laninamivir plus IFN-lambda1 (passage 2 and 3, respectively) than by laninamivir alone (passage 10). Our results show that treatment with laninamivir alone or in combination with IFN-lambda1 can lead to the emergence of drug-resistant influenza virus variants. Addition of IFN-lambda1 in combination with laninamivir may promote acquisition of drug resistance more rapidly than treatment with laninamivir alone.


Category: Journal Article
PubMed ID: #32393488 DOI: 10.1128/AAC.00301-20
Includes FDA Authors from Scientific Area(s): Drugs Biologics
Entry Created: 2020-05-17 Entry Last Modified: 2020-07-26
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