Article

Prolonged Shedding of Multidrug-Resistant Influenza A Virus in an Immunocompromised Patient

New England Journal of Medicine (Impact Factor: 54.42). 03/2003; 348(9):867-8. DOI: 10.1056/NEJM200302273480923
Source: PubMed
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    • "In N1 subtype especially, natural variation in the absence of any drug selective pressure may result in less pronounced but significant variations in the sensitivity of influenza viruses to anti-NA drugs (Le et al., 2008; Rameix-Welti et al., 2006). An example are the oseltamivir-resistant H274Y viruses, whose genesis remain unknown, but have previously been isolated from drug-treated patients (Gubareva et al., 2001; Ward et al., 2005; Weinstock et al., 2003; Whitley et al., 2001) and more recently from untreated patients (Sheu et al., 2008; Dharan et al., 2009; Lackenby et al., 2008a; Besselaar et al., 2008 "
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    ABSTRACT: The neuraminidase inhibitors (NAIs), oseltamivir and zanamivir, are essential for treatment and prevention of influenza A and B infections. Oseltamivir resistance among influenza A (H1N1) viruses rapidly emerged and spread globally during the 2007-2008 and 2008-2009 influenza seasons. Approximately 20% and 90% of viruses tested for NAI susceptibility at CDC during these seasons, respectively, were resistant to oseltamivir (IC(50) approximately 100-3000 time>those of sensitive viruses), based on the chemiluminescent NA inhibition assay. Pyrosequencing analysis confirmed H274Y mutation (H275Y in N1 numbering) in the neuraminidase (NA) gene of oseltamivir-resistant viruses. Full NA sequence analysis of a subset of oseltamivir-resistant and sensitive virus isolates from both seasons (n=725) showed that 53 (7.3%) had mutations at residue D151 (D-->E/G/N), while 9 (1.2%) had mutations at Q136 (Q-->K) and 2 (0.3%) had mutations at both residues. Viruses with very high IC(50) for oseltamivir and peramivir, and elevated IC(50) for zanamivir, had H274Y in addition to mutations at D151 and/or Q136, residues which can potentially confer NAI resistance based on recent N1 NA crystal structure data. Mutations at D151 without H274Y, did not elevate IC(50) for any tested NAI, however, Q136K alone significantly reduced susceptibility to zanamivir (36-fold), peramivir (80-fold) and A-315675 (114-fold) but not oseltamivir. Mutations at D151 and Q136 were present only in MDCK grown viruses but not in matching original clinical specimens (n=33) which were available for testing, suggesting that these variants were the result of cell culture selection or they were present in very low proportions. Our findings provide evidence that propagation of influenza virus outside its natural host may lead to selection of virus variants with mutations in the NA that affect sensitivity to NAIs and thus poses implications for drug resistance monitoring and diagnostics.
    Antiviral research 11/2009; 85(2):381-8. DOI:10.1016/j.antiviral.2009.11.005 · 3.94 Impact Factor
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    • "The animals survived and fully regenerated the epithelial tissue within a few weeks. On the other hand, reports from immunocompromised humans who shed influenza virus for prolonged periods suggest that the IR plays an important role in clearing the infection, or at least in preventing it from becoming chronic and potentially lethal (Rocha et al. 1991; Klimov et al. 1995; Boivin et al. 2002; Weinstock et al. 2003). The IR is likely to be especially important in more severe influenza infections of the lower respiratory tract (LRT). "
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    ABSTRACT: Although the influenza A virus has been extensively studied, a quantitative understanding of the infection dynamics is still lacking. To make progress in this direction, we designed several mathematical models and compared them with data from influenza A infections of mice. We find that the immune response (IR) plays an important part in the infection dynamics. Both an innate and an adaptive IR are required to provide adequate explanation of the data. In contrast, regrowth of epithelial cells did not seem to be an important mechanism on the time scale of the infection. We also find that different model variants for both innate and adaptive responses fit the data well, indicating the need for additional data to allow further model discrimination.
    Journal of The Royal Society Interface 06/2009; 7(42):35-47. DOI:10.1098/rsif.2009.0067 · 3.86 Impact Factor
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    • "The H275Y mutation was seen for N1 in both cell culture passaged viruses and in clinical isolates from immunocompetent or immunocompromised patients treated with Tamiflu ® (Ives et al., 2002; Weinstock et al., 2003; Gubareva, 2004) and was also found in H5N1 isolates from patients treated with Tamiflu ® (De Jong et al., 2005; Le et al., 2005). "
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    ABSTRACT: Neuraminidase inhibitors (NAIs) have been used since 2005 in France. Influenza viruses isolated in hospital and community cases in winter 2005-2006 were evaluated for their sensitivity to NAIs. Isolates were tested in duplicate with a fluorescence-based neuraminidase assay. The IC50 for oseltamivir or zanamivir was calculated for each strain. Mean IC50 (+/-S.D.) are expressed in nM. Viruses with IC50 superior or very superior to the upper limit (mean IC50+2.5 S.D.) were considered as outliers or resistant viruses, respectively. HA and NA genes for outliers, resistant strains and for a few sensitive strains were sequenced. Out of 225 B isolates, one was found resistant to both oseltamivir and zanamivir with a D197Y mutation in NA and eight isolates were outliers for oseltamivir and/or zanamivir. Out of 151 A (H1N1) isolates, one was found resistant to oseltamivir but sensitive to zanamivir with a H275Y mutation in NA, two isolates were resistant to zanamivir and three isolates were outliers for oseltamivir and/or zanamivir. New mutations were detected in outliers compared to sensitive viruses. Resistant influenza strains to NAIs are circulating at a stable and low level of 1% since the introduction of NAIs in clinical practice.
    Journal of Clinical Virology 02/2008; 41(1):25-8. DOI:10.1016/j.jcv.2007.10.019 · 3.47 Impact Factor
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