Laninamivir-Interferon- λ1 Combination Treatment Promotes Resistance by Influenza A Virus More Rapidly Than Laninamivir Alone.

We examined the effectiveness of co-treatment with two distinct classes of anti-influenza drugs, i.e., neuraminidase (NA) inhibitor, laninamivir, and interferon (IFN)-λ1, 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-λ1. Surprisingly, laninamivir used in combination with IFN-λ1 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 (∼284-fold↓) and zanamivir (∼1024-fold↓), and decreased NA enzyme catalytic activity (∼5-fold↓) 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-λ1 (passage 2 and 3, respectively) than by laninamivir alone (passage 10). Our results show that treatment with laninamivir alone or in combination with IFN-λ1 can lead to the emergence of drug-resistant influenza virus variants. Addition of IFN-λ1 in combination with laninamivir may promote acquisition of drug resistance more rapidly than treatment with laninamivir alone. PMID: 32393488 [...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research