A Cluster of Patients Infected with I221V Influenza B Virus Variants with Reduced Oseltamivir Susceptibility--North Carolina and South Carolina, 2010-2011.
ABSTRACT Background. During 2010-2011, influenza B viruses with a novel neuraminidase substitution, denoted I221V, (B/I221V) associated with reduced in vitro oseltamivir susceptibility were detected in North Carolina (NC).Methods. We determined the prevalence of I221V among B viruses submitted to CDC for antiviral resistance surveillance, including all B viruses submitted to NC and South Carolina (SC) state laboratories, during October 2010-September 2011.We conducted chart reviews and phone interviews to characterize NC and SC patients with B/I221V versus wild-type B virus infection (B/WT).Results. We detected I221V in 45 (22%) of 209 B viruses from NC and 8 (10%) of 82 B viruses from SC. We detected I221V in three (0.3%) of 881 B viruses tested from 45 other states. B/I221V infection was not associated with differences in underlying conditions or illness severity compared with B/WT infection. No patients with B/I221V infection received oseltamivir prior to specimen collection. Among patients who completed oseltamivir, those with B/I221V infection reported a longer duration until illness resolution (5 versus 3 days); P=0.02.Conclusions. B/I221V co-circulated with B/WT in NC and SC during 2010-2011. I221V did not alter illness severity but may have reduced oseltamivir effectiveness. Thus, global surveillance for I221V is important.
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ABSTRACT: Patients with severe viral infections are often hospitalized in intensive care units (ICUs) and recent studies underline the frequency of viral detection in ICU patients. Viral infections in the ICU often involve the respiratory or the central nervous system and can cause significant morbidity and mortality especially in immunocompromised patients. The mainstay of therapy of viral infections is supportive care and antiviral therapy when available. Increased understanding of the molecular mechanisms of viral infection has provided great potential for the discovery of new antiviral agents that target viral proteins or host proteins that regulate immunity and are involved in the viral life cycle. These novel treatments need to be further validated in animal and human randomized controlled studies.BMC Infectious Diseases 01/2014; 14(1):321. DOI:10.1186/1471-2334-14-321 · 2.56 Impact Factor
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ABSTRACT: Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 10,641 viruses collected by WHO-recognized National Influenza Centres between May 2013 and May 2014 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. In addition, neuraminidase (NA) sequence data, available from the WHO CCs and from sequence databases (n=3206), were screened for amino acid substitutions associated with reduced NAI susceptibility. Ninety-five per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 2% (n=172) showed highly reduced inhibition (HRI) against at least one of the four NAIs, commonly oseltamivir, while 0.3% (n=32) showed reduced inhibition (RI). Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=169), A(H3N2) with NA E119V (n=1), B/Victoria-lineage with NA E117G (n=1) and B/Yamagata-lineage with NA H273Y (n=1); amino acid position numbering is A subtype and B type specific. Although approximately 98% of circulating viruses tested during the 2013-2014 period were sensitive to all four NAIs, a large community cluster of A(H1N1)pdm09 viruses with the NA H275Y substitution from patients with no previous exposure to antivirals was detected in Hokkaido, Japan. Significant numbers of A(H1N1)pdm09 NA H275Y viruses were also detected in China and the United States: phylogenetic analyses showed that the Chinese viruses were similar to those from Japan, while the United States viruses clustered separately from those of the Hokkaido outbreak, indicative of multiple resistance-emergence events. Consequently, global surveillance of influenza antiviral susceptibility should be continued from a public health perspective. Copyright © 2015. Published by Elsevier B.V.Antiviral research 07/2014; DOI:10.1016/j.antiviral.2014.07.001 · 3.61 Impact Factor
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ABSTRACT: Introduction. Influenza B viruses with a novel I221 L substitution in neuraminidase (NA) conferring high level resistance to oseltamivir were isolated from an immunocompromised patient after prolonged oseltamivir treatment.Methods. Enzymatic characterization of the NAs (Km, Ki) and the in vitro fitness of viruses carrying wild-type (wt) or mutated (I221 L) NA genes were evaluated. Proportions of wt and mutated NA genes were directly quantified in the patient samples. Structural characterizations by X-ray crystallography of a wt and I221 L variant NA were performed.Results. The Km and Ki revealed that the I221 L variant NA had approximately 84 and 51 times lower affinity for oseltamivir carboxylate and zanamivir respectively compared to wt NA.Viruses with a wt or I221 L variant NA had similar growth kinetics in MDCK cells and five passages in MDCK cells revealed no reversion of the I221 L substitution. The crystal structure of the I221 L NA and oseltamivir complex showed that the leucine side-chain protrudes into the hydrophobic pocket of the active site that accommodates the pentyloxy substituent of oseltamivir.Conclusions. Enzyme kinetic and NA structural analyses provide an explanation for the high resistance to oseltamivir, while retaining good virus fitness of viruses carrying I221 L variant NA.The Journal of Infectious Diseases 05/2014; 210(8). DOI:10.1093/infdis/jiu244 · 5.85 Impact Factor