Antiviral resistance: influenza B

Currently circulating influenza viruses are resistant to adamantanes and except for a low number of sporadic cases most are sensitive to neuraminidase inhibitors (NI). Adamantanes are ineffective against influenza B viruses and although NI-resistant influenza B viruses have been rarely reported, recently in the United States was identified one cluster of influenza B viruses with reduced susceptibility to NI and with the I221V substitution in the active site of the neuraminidase. Despite the low prevalence of oseltamivir-resistant influenza viruses, the constant evolution of influenza requires the monitoring of antiviral resistance among these viruses in the community. This is very important for the clinical management of severe influenza cases as to the detection of novel genetic markers associated with antiviral resistance. This study reports the antiviral susceptibility to neuraminidase inhibitors of influenza B viruses isolated in Portugal during the 2010/2011, 2011/2011 and 2012/2013 seasons. Over the period of 3 influenza seasons, 146 influenza B viral strains were selected for phenotypic fluorescent assays in order to assess their susceptibility to NI, oseltamivir and zanamivir. For this purpose, was determined the NI concentration required to inhibit 50% of each influenza virus neuraminidase activity (IC50). The IC50 baseline of influenza B viruses was calculated for both oseltamivir and zanamivir using the Robust Excel programme. The neuraminidase gene segments were also monitored for the presence of the main molecular markers, associated with the resistance to neuraminidase inhibitors in influenza B viruses. All analysed influenza B strains proved to be susceptible to oseltamivir and zanamivir. In the 2010/2011 season the determined IC50 values ranged from 0 to 70 nM for oseltamivir and from 0 to 11nM to zanamivir. The zanamivir IC50 median value was about 8-fold lower than oseltamivir IC50 median value. Statistical analysis revealed the presence of one outlier (B/Lisboa/13/2010, 71.08nM) for oseltamivir (2-fold reduction in susceptibility) and four minor outliers (B/Lisboa/15/2010: 9.52 nM; B/Lisboa/19/2010: 9.25 nM; B/Lisboa/51/2010: 10.94 nM and B/Lisboa/53/2010: 9.62 nM) for zanamivir (3-fold reduction in susceptibility) comparing to the median IC50 value. During the 2011/2012 season IC50 values ranged from 23.0 to 38.38 nM (oseltamivir) and from 2.97 to 9.07nM (zanamivir). This season were not found minor or major outliers. The IC50 values obtained in 2012/2013 ranged from 7.91 to 84.84 nM (oseltamivir) and from 1.48 to 5.88 nM (zanamivir). During this last season were found 6 minor and 3 major outliers for oseltamivir and 13 minor outliers for zanamivir. Along the three seasons, the median IC50 values for both NI were higher among the B/Victoria than B/Yamagata viruses. None of the actually known mutations associated with resistance of influenza B viruses to NI was found in the neuraminidase gene (R150K, D197E/N/Y, I221T/V, N294S, R374K and G407S). Influenza B viruses isolated in Portugal during the last three seasons were susceptible to the neuraminidase inhibitors. Portuguese influenza B strains revealed higher susceptibility to zanamivir than to oseltamivir, as observed in other countries. The oseltamivir IC50 values were also different between viruses from the B/Victoria and B/Yamagata lineages, however this was not statistically demonstrated due to the small number of analysed viruses. Among B/Yamagata strains the oseltamivir and zanamivir IC50 values were higher in 2011/2012 than in 2010/2011 and 2012/2013 seasons

Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents

Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs

Emergence and Fixing of Antiviral Resistance in Influenza A Via Recombination and Hitch Hiking

The dramatic rise of oseltamivir resistance in the H1N1 serotype in the 2007/2008 season and the fixing of H274Y in the 2008/2009 season has raised concerns regarding individuals at risk for seasonal influenza, as well as development of similar resistance in the H5N1 serotype. Previously, oseltamivir resistance produced changes in H1N1 and H3N2 at multiple positions in treated patients. In contrast, the recently reported resistance involved patients who had not recently taken oseltamivir. Moreover, the resistance was limited to the H1N1 which had acquired H274Y. Using phylogenetic analysis I show that the fixing of H274Y was due to hitch hiking on a genetic background that acquired key changes from another circulating sub-clade. H274Y jumped from clade 2C (Hong Kong/2562/2006-like) to clade 1 (New Caledonia/20/1999-like) to clade 2B (Brisbane/59/2007-like) which included multiple introductions. Sub-clades that had acquired key changes on the neuramindase and hemagglutinin genes expanded and fixed of H274Y on H1N1. These changes led to the spread of adamantane resistance on clade 2C outside of Asia, followed by the spread of oseltamivir resistance in 2007/2008 and the fixing of H274Y in 2008/2009. The hemagglutinin change, A193T, was a key component and the coincident polymorphism, S193F, was linked to the fixing of adamantane resistance in H3N2. The aggregation of key polymorphisms onto different genetic backgrounds supports a mechanism of homologous recombination between co-circulating influenza sub-clades, and provides a rationale for the prediction of vaccine targets and emergence of antiviral resistance

Oseltamivir-Resistant Pandemic (H1N1) 2009 Virus Infection in England and Scotland, 2009–2010

Monitoring of antiviral resistance is strongly recommended for immunocompromised patients

Systematic review of influenza resistance to the neuraminidase inhibitors

<p>Abstract</p> <p>Background</p> <p>Antivirals play a critical role in the prevention and the management of influenza. One class of antivirals, neuraminidase inhibitors (NAIs), is effective against all human influenza viruses. Currently there are two NAI drugs which are licensed worldwide: oseltamivir (Tamiflu^®) and zanamivir (Relenza^®); and two drugs which have received recent approval in Japan: peramivir and laninamivir. Until recently, the prevalence of antiviral resistance has been relatively low. However, almost all seasonal H1N1 strains that circulated in 2008-09 were resistant to oseltamivir whereas about 1% of tested 2009 pandemic H1N1 viruses were found to be resistant to oseltamivir. To date, no studies have demonstrated widespread resistance to zanamivir. It seems likely that the literature on antiviral resistance associated with oseltamivir as well as zanamivir is now sufficiently comprehensive to warrant a systematic review.</p> <p>The primary objectives were to systematically review the literature to determine the incidence of resistance to oseltamivir, zanamivir, and peramivir in different population groups as well as assess the clinical consequences of antiviral resistance.</p> <p>Methods</p> <p>We searched MEDLINE and EMBASE without language restrictions in September 2010 to identify studies reporting incidence of resistance to oseltamivir, zanamivir, and peramivir. We used forest plots and meta-analysis of incidence of antiviral resistance associated with the three NAIs. Subgroup analyses were done across a number of population groups. Meta-analysis was also performed to evaluate associations between antiviral resistance and clinical complications and symptoms.</p> <p>Results</p> <p>We identified 19 studies reporting incidence of antiviral resistance. Meta-analysis of 15 studies yielded a pooled incidence rate for oseltamivir resistance of 2.6% (95%CI 0.7% to 5.5%). The incidence rate for all zanamivir resistance studies was 0%. Only one study measured incidence of antiviral resistance among subjects given peramivir and was reported to be 0%. Subgroup analyses detected higher incidence rates among influenza A patients, especially for H1N1 subtype influenza. Considerable heterogeneity between studies precluded definite inferences about subgroup results for immunocompromised patients, in-patients, and children. A meta-analysis of 4 studies reporting association between oseltamivir-resistance and pneumonia yielded a statistically significant risk ratio of 4.2 (95% CI 1.3 to 13.1, p = 0.02). Oseltamivir-resistance was not statistically significantly associated with other clinical complications and symptoms.</p> <p>Conclusion</p> <p>Our results demonstrate that that a substantial number of patients may become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance may be significantly associated with pneumonia. In contrast, zanamivir resistance has been rarely reported to date.</p

Optimal Treatment Rate During an Influenza Pandemic in the Presence of Drug-Resistance Emergence

The problem was posed by Seyed Moghadas, from the National Research Council Institute for Biodiagnostics in Winnipeg, Manitoba. It concerns the optimization of the rate of treatment with antivirals during a pandemic of influenza, to achieve the following objectives: 1. Minimize the total number of deaths due to influenza. 2. Minimize the total number of infections with influenza. 3. Reduce the spread of resistance to antivirals. It is understood that not all the objectives above might be satisfied at the same time, and the purpose of the work is to consider the outcome in the different scenarios. The aim of the present project is to see if optimal control theory can contribute to a better formulation of the treatment intensity, in order to bring the epidemic under control while avoiding wide-spread resistance in the population

Influenza and Other Respiratory Virus Weekly Activity Report, March 28, 2009, Week 12

Weekly report of the Iowa Influenza Surveillance Network produced by the Iowa Department of Public Health

Modeling viral infectious diseases and development of antiviral therapies using human induced pluripotent stem cell-derived systems

The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs), which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host-pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance