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Background The Centers for Disease Control and Prevention (CDC) recommends oseltamivir phosphate for children <2 years old with confirmed or suspected influenza as they are at high risk for complications. We analyzed infant characteristics associated with nonprescription of oseltamivir over 9 years. Methods We conducted a retrospective electronic health record (EHR) review of infants <12 months old born between January 1, 2012 and December 31, 2019 within the University of Pittsburgh Medical Center health system in Southwestern Pennsylvania who had >2 well-child visits during their first year. Infants with a confirmed positive test for influenza were included in the analysis. Factors associated with infant oseltamivir nonprescription were assessed using multivariable logistic regression. Results Of 457 infants with confirmed influenza, 86% were prescribed oseltamivir. The proportion of infants prescribed oseltamivir increased from an average of 64.6% during the 2012–2016 influenza seasons to 90.4% during the 2016–2020 influenza seasons. Infants were more likely to not be prescribed oseltamivir if they experienced >2 days of influenza symptoms (odds ratio (OR): 9.4, 95% CI: 4.8, 18.7, P <.001), were diagnosed during the 2012–2016 influenza seasons (OR: 4.2, 95% CI: 1.8, 9.5, P <.001), tested positive for influenza via a multiplex/reverse transcriptase polymerase chain reaction test (OR: 6.7, 95% CI: 2.7, 16.3, P <.001; OR: 2.7, 95% CI: 1.1, 7.1; P =.04), or did not have a fever at point-of-care (OR: 2.3, 95% CI: 1.2, 4.6, P =.01). Conclusion Adherence to CDC influenza antiviral treatment guidelines for infants is high and improved over time. However, the provision of targeted education to providers may further improve oseltamivir prescribing practices for high-risk children <12 months of age. [ABSTRACT FROM AUTHOR]

To gain insight into interactions among respiratory viruses, we modeled influenza A virus (IAV)-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coinfections using differentiated human airway epithelial cultures. Replicating IAV induced a more robust interferon response than SARS-CoV-2 and suppressed SARS-CoV-2 replication in both sequential and simultaneous infections, whereas SARS-CoV-2 did not enhance host cell defense during influenza infection or suppress IAV replication. Oseltamivir, an antiviral targeting influenza, reduced IAV replication during coinfection but also reduced the host antiviral response and restored SARS-CoV-2 replication. These results demonstrate how perturbations in one viral infection can impact its effect on a coinfecting virus. [ABSTRACT FROM AUTHOR]

Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA. [ABSTRACT FROM AUTHOR]

Background National guidelines recommend antiviral treatment for children with influenza at high risk for complications regardless of symptom duration. Little is known about concordance of clinical practice with this recommendation. Methods We performed a cross-sectional study of outpatient children (aged 1–18 years) at high risk for complications who were diagnosed with influenza during the 2016–2019 influenza seasons. High-risk status was determined using an existing definition that includes age, comorbidities, and residence in a long-term care facility. The primary outcome was influenza antiviral dispensing within 2 days of influenza diagnosis. We determined patient- and provider-level factors associated with guideline-concordant treatment using multivariable logistic regression. Results Of the 274 213 children with influenza at high risk for influenza complications, 159 350 (58.1%) received antiviral treatment. Antiviral treatment was associated with the presence of asthma (aOR, 1.13; 95% confidence interval [CI], 1.11–1.16), immunosuppression (aOR, 1.10; 95% CI, 1.05–1.16), complex chronic conditions (aOR, 1.04; 95% CI, 1.01–1.07), and index encounter in the urgent care setting (aOR, 1.3; 95% CI, 1.26–1.34). Factors associated with decreased odds of antiviral treatment include age 2–5 years compared with 6–17 years (aOR, 0.95; 95% CI,.93–.97), residing in a chronic care facility (aOR,.61; 95% CI,.46–.81), and index encounter in an emergency department (aOR, 0.66; 95% CI,.63–.71). Conclusions Among children with influenza at high risk for complications, 42% did not receive guideline-concordant antiviral treatment. Further study is needed to elucidate barriers to appropriate use of antivirals in this vulnerable population. [ABSTRACT FROM AUTHOR]

From surveillance data of patients hospitalized with laboratory-confirmed influenza in the United States during the 2015–2016 through 2018–2019 seasons, initiation of antiviral treatment increased from 86% to 94%, with increases seen across all age groups. However, 62% started therapy ≥3 days after illness onset, driven by late presentation to care. [ABSTRACT FROM AUTHOR]

Background Meta-analyses of individual patient data from randomized, controlled trials show that early oseltamivir treatment for influenza cut the risk of pneumonia and hospitalization by 44% and 63%, respectively. However, data on the effectiveness of inhaled zanamivir in preventing hospitalization and death are lacking. Methods This nationwide, population-based, cohort study included all outpatients treated with inhaled zanamivir or oral oseltamivir within 48 hours after a clinical diagnosis of influenza before and after the rollout of inhaled zanamivir as the first-line antiviral in Taiwan. The main outcome was influenza-related hospitalization or death within 14 days. Those who developed the outcome within 2 days were excluded from analyses. Propensity score stratification was used to control confounding from covariates. Results A total of 865 032 eligible influenza outpatients were included in the analysis. The risk of developing the main outcome (adjusted hazard ratio [aHR], 1.01; 95% confidence interval [CI],.96 to 1.06) did not differ between the inhaled zanamivir group (n = 595 897, 68.9%, the reference) and the oral oseltamivir group (n = 269 135, 31.1%). Prespecified analysis on high-risk subgroups further showed that inhaled zanamivir is not inferior to oral oseltamivir in either patients aged ≥65 years (aHR, 1.14; 95% CI: 1.05 to 1.25) or patients with chronic lung diseases (aHR, 1.23; 95% CI: 1.08 to 1.41). Conclusions Inhaled zanamivir is not inferior to oral oseltamivir as outpatient treatment in preventing influenza-related hospitalization or death for patients whose conditions do not require hospitalization within 2 days. [ABSTRACT FROM AUTHOR]

Background Influenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. Methods Using the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018–19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. Results The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th–97.5th percentiles, 1.68–1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs' age category, virus type, and month of onset revealed similar trends favoring BXM. Conclusions BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment. [ABSTRACT FROM AUTHOR]

Background Baloxavir marboxil is an anti-influenza medication that was newly introduced into clinical practice in 2018. Baloxavir might be more beneficial than neuraminidase inhibitors (NAIs), as suggested by a subgroup analysis of a clinical trial. Although the association between baloxavir prescription and healthcare use pertains mainly to influenza A, few studies have investigated the association in influenza B. Methods We evaluated the healthcare utilization of children (0–15 years old) treated with either baloxavir or NAIs between December 2018 and May 2019 using claims records in Japan. The primary endpoint was the composite of medical resource utilization, including hospitalization, antibiotic use, laboratory tests, radiological images, and fluid replacement therapy, over 1–9 days after antiviral prescription. Secondary outcomes representing each single outcome in the composite were examined. Subgroup analyses comparing baloxavir with each NAI were also performed. Results Of 4490 patients with influenza B who received antiviral treatment, 51.6% were male, and the median age was 8 years old. Baloxavir was prescribed for 29.4% of the population, and NAIs were prescribed for 70.6%. In the total cohort, 49.3% of patients had any comorbidity related to complicated influenza infection. Concerning the composite endpoint, baloxavir prescription was not associated with a risk of subsequent medical resource use (adjusted odds ratio 1.11; 95% confidence interval 0.90–1.38; P = 0.34). Secondary outcomes and subgroup analyses showed similar results to the primary outcome. Conclusions In a single-year comparative study in Japan, baloxavir prescription for influenza B was not associated with less healthcare consumption than NAIs within 9 days of treatment. [ABSTRACT FROM AUTHOR]

Background: Both the elderly and individuals with comorbidities are at increased risk of developing influenza-related complications. Novel influenza antivirals are required, given limitations of current drugs (eg, resistance emergence and poor efficacy). Pimodivir is a first-in-class antiviral for influenza A under development for these patients.Methods: Hospitalized patients with influenza A infection were randomized 2:1 to receive pimodivir 600 mg plus oseltamivir 75 mg or placebo plus oseltamivir 75 mg twice daily for 7 days in this phase 2b study. The primary objective was to compare pimodivir pharmacokinetics in elderly (aged 65-85 years) versus nonelderly adults (aged 18-64 years). Secondary end points included time to patient-reported symptom resolution.Results: Pimodivir pharmacokinetic parameters in nonelderly and elderly patients were similar. Time to influenza symptom resolution was numerically shorter with pimodivir (72.45 hours) than placebo (94.15 hours). There was a lower incidence of influenza-related complications in the pimodivir group (7.9%) versus placebo group (15.6%). Treatment was generally well tolerated.Conclusions: No apparent relationship was observed between pimodivir pharmacokinetics and age. Our data demonstrate the need for a larger study of pimodivir in addition to oseltamivir to test whether it results in a clinically significant decrease in time-to-influenza-symptom alleviation and/or the frequency of influenza complications.Clinical Trials Registration: NCT02532283. [ABSTRACT FROM AUTHOR]

Observational studies of oseltamivir use and influenza complications could suffer from residual confounding. Using negative control risk periods and a negative control outcome, we examined confounding control in a health-insurance-claims–based study of oseltamivir and influenza complications (pneumonia, all-cause hospitalization, and dispensing of an antibiotic). Within the Food and Drug Administration's Sentinel System, we identified individuals aged ≥18 years who initiated oseltamivir use on the influenza diagnosis date versus those who did not, during 3 influenza seasons (2014–2017). We evaluated primary outcomes within the following 1–30 days (the primary risk period) and 61–90 days (the negative control period) and nonvertebral fractures (the negative control outcome) within days 1–30. We estimated propensity-score–matched risk ratios (RRs) per season. During the 2014–2015 influenza season, oseltamivir use was associated with a reduction in the risk of pneumonia (RR = 0.72, 95% confidence interval (CI): 0.70, 0.75) and all-cause hospitalization (RR = 0.54, 95% CI: 0.53, 0.55) in days 1–30. During days 61–90, estimates were near-null for pneumonia (RR = 1.04, 95% CI: 0.95, 1.15) and hospitalization (RR = 0.94, 95% CI: 0.91, 0.98) but slightly increased for antibiotic dispensing (RR = 1.14, 95% CI: 1.08, 1.21). The RR for fractures was near-null (RR = 1.09, 95% CI: 0.99, 1.20). Estimates for the 2016–2017 influenza season were comparable, while the 2015–2016 season had conflicting results. Our study suggests minimal residual confounding for specific outcomes, but results differed by season. [ABSTRACT FROM AUTHOR]

Prompt antiviral treatment has the potential to reduce influenza virus transmission to close contacts, but rigorous data on the magnitude of treatment effects on transmission are limited. Animal model data indicate that rapid reductions in viral replication after antiviral treatment reduce the risk of transmission. Observational and clinical trial data with oseltamivir and other neuraminidase inhibitors indicate that prompt treatment of household index patients seems to reduce the risk of illness in contacts, although the magnitude of the reported effects has varied widely across studies. In addition, the potential risk of transmitting drug-resistant variants exists with all approved classes of influenza antivirals. A controlled trial examining baloxavir treatment efficacy to reduce transmission, including the risk of transmitting virus with reduced baloxavir susceptibility, is currently in progress. If reduced transmission risk is confirmed, modeling studies indicate that early treatment could have major epidemiologic benefits in seasonal and pandemic influenza. [ABSTRACT FROM AUTHOR]

Background: We aimed to detect influenza variants with reduced susceptibility to baloxavir marboxil (baloxavir) and oseltamivir and identify differences in the clinical course between children with and without these variants after antiviral treatment.Methods: During the 2019-2020 influenza season, we enrolled children with confirmed influenza A (20 treated with baloxavir and 16 with oseltamivir). We analyzed patients' sequential viral RNA loads and infectious virus titers, the drug susceptibilities of clinical isolates, and amino acid substitutions in the viral polymerase acidic protein subunits or neuraminidase. We assessed patients' clinical information using questionnaires.Results: All viral RNA loads and virus titers were significantly decreased after treatment, but we detected baloxavir-resistant and oseltamivir-resistant variants in 5 of 20 and 3 of 16 patients, respectively. The duration of fever was similar between patients with and without the variants, but infectious viral shedding lasted 3 days longer in patients with baloxavir-resistant variants. In addition, the duration to improvement of clinical symptoms was longer in these patients (75.0 vs 29.5 hours; P = .106).Conclusions: After antiviral treatment, the emergence of baloxavir-resistant variants may affect the patients' clinical course, but oseltamivir-resistant variants had no clinical impact. [ABSTRACT FROM AUTHOR]

The article presents the professional policies approved by the American Society of Health System Pharmacists (ASHS) House of Delegates including the policies 2101-2112, 2113-2120, and 2121-2143 that were respectively approved in March, May, and June 2021. Policy topics covered include direct-to-consumer clinical genetic tests, pharmacogenomics, and universal influenza vaccination. Also noted is planned posting of the House of Delegates complete proceedings in the ASHA website.

Background Baloxavir marboxil (baloxavir) is expected to reduce influenza transmission by rapid reduction of viral load. The incidence of household transmission was compared between index patients (IPs) treated with baloxavir and those treated with neuraminidase inhibitors. Methods Using a Japanese claims database, the first family members with influenza diagnosis during the 2018–2019 influenza season were identified as IPs, and the diagnosis date was designated day 1. According to the anti-influenza drug dispensed to the IP, their families were classified into the oral baloxavir group and 3 controls: oral oseltamivir group (a primary control), inhaled zanamivir group, and inhaled laninamivir group. A household transmission was defined as influenza diagnosed for any non-IP family members during days 3−8. The incidence of household transmission was compared between groups using a logistic regression model adjusting backgrounds of IPs. Results The proportion of families with household transmission was 17.98% (15 226 of 84 672) in the baloxavir group and 24.16% (14 983 of 62 004) in the oseltamivir group. The covariate-adjusted odds ratio (oseltamivir/baloxavir) was 1.09 (95% confidence interval [95% CI], 1.05–1.12), which indicated significantly lower incidence in the baloxavir group. The adjusted odds ratios (controls/baloxavir) against zanamivir and laninamivir were 0.93 (95% CI,.89–.97) and 0.99 (95% CI,.96–1.02), respectively. Conclusions Baloxavir may contribute to reduction in household transmission compared with oseltamivir. In comparison between baloxavir and inhalants, a similar reduction was not shown and it might be due to unmeasured confounding by administration route differences. [ABSTRACT FROM AUTHOR]

Background: Oseltamivir shows effectiveness in reducing influenza-related symptoms, morbidity and mortality. Its prescription remains suboptimal.Objectives: We aim to describe oseltamivir prescription in confirmed cases of influenza and to identify associated factors.Methods: A prospective monocentric observational study was conducted between 1 December 2018 and 30 April 2019. All patients with a virologically confirmed influenza diagnosis were included. Factors associated with oseltamivir prescription were studied.Results: Influenza was confirmed in 755 patients (483 children and 272 adults), of which 188 (25.1%) were hospitalized and 86 (11.4%) had signs of severity. Oseltamivir was prescribed for 452 patients (59.9%), more frequently in children than in adults [329/483 (68.1%) versus 123/272 (45.2%), P < 0.001]. Factors associated with oseltamivir prescription were evaluated in 729 patients (246 adults and 483 children). Patients with at least one risk factor for severe influenza received oseltamivir less frequently (50%, 137/274) than those without risk factors (70%, 315/452) (P < 0.001). Pregnant women received oseltamivir in 81% of cases (17/21). Severe influenza cases were treated with oseltamivir in only 45.3% (39/86). The median duration of symptoms was 24 h (IQR 12-48) in treated patients versus 72 h (IQR 48-120) in untreated patients (P < 0.01).Conclusions: Oseltamivir should be administered as early as possible, preferably within 24-48 h after illness onset, for the best benefits. It is, however, very important to promote the use of neuraminidase inhibitor ('NAI') treatment beyond 48 h in some specific patient populations. [ABSTRACT FROM AUTHOR]

Background High-quality evidence confirms that the clinical efficacy of peramivir in severe influenza patients with primary viral pneumonia is lacking. To optimize clinical medication, we evaluate the different efficacy between peramivir and oseltamivir in the treatment of severe influenza A with primary viral pneumonia. Methods A single-center, randomized, controlled trial was conducted during the Chinese influenza season from December 2018 to April 2019 in patients with severe influenza A with primary viral pneumonia. A total of 40 inpatients were enrolled and treated with either intravenous peramivir (300 mg, once daily for 5 days) or oral oseltamivir (75 mg, twice daily for 5 days). Results The duration of influenza virus nucleic acid positivity in the oseltamivir group and the peramivir group was 2.95 days and 2.80 days, respectively. The remission times of clinical symptoms in the oseltamivir group and the peramivir group were 3.90 days and 3.25 days, respectively. In addition, the remission time of cough symptoms in the peramivir group (63.89 hours) was shorter than that in the oseltamivir group (75.53 hours). There was no significant difference between these values (P  > .05). The remission time of fever symptoms in the oseltamivir group was 23.67 hours, which was significantly longer than that in the peramivir group (12.32 hours) (P  = .034). Conclusions Peramivir is no less effective than oseltamivir in the treatment of severe influenza A with primary viral pneumonia, and patients treated with peramivir had significantly shorter remission times of fever symptoms than those treated with oseltamivir. [ABSTRACT FROM AUTHOR]

Background Reports of serious neuropsychiatric events (NPEs), specifically suicide/suicide attempts, following the use of oseltamivir have led to public concerns. Our aim in this study was to determine whether an association exists between oseltamivir use and NPEs. Method This study was a population-based, retrospective, cohort study on a random sample of 50% of individuals in the Korean National Health Insurance Service (KNIS) database aged ≥8 years who were diagnosed with influenza between 2009 and 2017. The primary exposure was oseltamivir prescription at the time of influenza diagnosis, whereas the primary outcome was a diagnosis of an NPE within 30 days after the influenza diagnosis. Information on oseltamivir prescription, diagnoses of NPEs, demographic characteristics, comorbidities, drugs prescribed within the year before influenza diagnosis, and healthcare utilization were extracted from the KNIS database. Results Of 3 352 015 individuals included in the analysis, 1 266 780 (37.8%) were prescribed oseltamivir. The incidence of NPEs was 0.86% and 1.16% in patients who were and were not prescribed oseltamivir, respectively (hazard ratio [HR], 0.74; 95% confidence interval [CI],.73 to.75; P <.001). Oseltamivir use was not associated with a difference in the overall risk of NPEs in the adjusted model (HR, 0.98; 95% CI,.96 to 1.01; P =.16), but the incidence of moderate-to-severe NPEs was significantly lower in those prescribed oseltamivir (HR, 0.92; 95% CI,.88–.96; P <.001). Conclusion Treating influenza with oseltamivir does not increase the risk of NPEs. Thus, public concern regarding its use is unwarranted. [ABSTRACT FROM AUTHOR]

Background: Antibacterial agents are often prescribed for patients with suspected respiratory tract infections even though these are most often caused by viruses. In this study, we sought to evaluate the effect of Respiratory Pathogen Panel (RPP) PCR result availability and antimicrobial stewardship education on antibiotic prescription rates in the adult emergency department (ED). Methods: We compared rates of antibacterial and oseltamivir prescriptions between 2 nonconsecutive influenza seasons among ED visits, wherein the latter season followed the implementation of a comprehensive educational stewardship campaign. In addition, we sought to elucidate the effect of RPP-PCR on antibiotic prescriptions, with focus on result availability prior to the conclusion of emergency department encounters. Results: Antibiotic prescription rates globally decreased by 17.9% in the FS-17/18 cohort compared to FS-14/15 (P < 0.001), while oseltamivir prescription rates stayed the same overall (P = 0.42). Multivariate regression across both cohorts revealed that patients were less likely to receive antibiotics if RPP-PCR results were available before the end of the ED visit or if the RPP-PCR result was positive for influenza. Patients in the educational intervention cohort were also less likely to receive an antibiotic prescription. Conclusion: This study provides evidence that RPP-PCR results are most helpful if available prior to the end of the provider-patient interaction. Further, these data suggest that detection of influenza remains an influential result in the context of antimicrobial treatment decision making. In addition, these data contribute to the body of literature which supports comprehensive ASP interventions including leadership and patient engagement. [ABSTRACT FROM AUTHOR]

We assessed the impact of a rapid molecular assay for influenza detection whether outsourced or performed onsite 24/7 in a University Hospital in Paris, France. Shorter median time-to-results (16.8 vs 2.3 hours, P  < .05) and an increased rate of adequate prescription of oseltamivir (76.6% vs 95.3%, P  < .05) were observed. [ABSTRACT FROM AUTHOR]

Background The efficacy and optimal duration of postexposure influenza prophylaxis with oseltamivir are undetermined in hospital settings, where immediate separation from index cases is not feasible. Methods In an open-label noninferiority randomized clinical trial in a single-center university hospital, the efficacy of 5-day vs 10-day postexposure prophylaxis with oseltamivir was compared in adult patients exposed to influenza who could not be immediately separated from index influenza cases. Influenza incidence was assessed for 10 days after discontinuing prophylaxis. Results Among 222 exposed patients (median age, 75 years; male 119; median Charlson Comorbidity Index, 5), 110 patients were assigned to 5 days of postexposure prophylaxis with oseltamivir, and 112 patients were assigned to the 10-day group. The median duration of exposure to influenza (interquartile range) was 2 (1–3) days. In the intention-to-treat analysis, the incidence of influenza was 2/110 (1.8%) in the 5-day group and 0/112 (0%) in the 10-day group (difference, 1.8 percentage points; 1-sided 95% CI, –1 to 4.9 percentage points; P  = .77). Conclusions For patients exposed to influenza in a hospital setting and who were not immediately separated from index cases, postexposure prophylaxis with oseltamivir resulted in low incidence of nosocomial influenza transmission. Five-day postexposure prophylaxis was noninferior to 10-day regimen. ClinicalTrials.gov Registration NCT03899571. [ABSTRACT FROM AUTHOR]

During the 2018–2019 influenza seasons, we detected reduced baloxavir marboxil (baloxavir) susceptible variants with I38S or I38T amino acid substitutions on the PA subunit of influenza virus ribonucleic acid polymerase in 7 of 18 baloxavi-treated children and found that virus titer rebounded in some of these children with variants. We also found fever durations to be similar between patients with or without the variants, but the patients with variants shed the virus 3 days longer and took longer to improve clinical symptoms than those without variants. The emergence of these variants should be monitored during future influenza seasons. [ABSTRACT FROM AUTHOR]

Seasonal human influenza viruses continually change antigenically to escape from neutralizing antibodies. It remains unclear how genetic variation in the intrahost virus population and selection at the level of individual hosts translates to the fast-paced evolution observed at the global level because emerging intrahost antigenic variants are rarely detected. We tracked intrahost variants in the hemagglutinin and neuraminidase surface proteins using longitudinally collected samples from 52 patients infected by A/H3N2 influenza virus, mostly young children, who received oseltamivir treatment. We identified emerging putative antigenic variants and oseltamivir-resistant variants, most of which remained detectable in samples collected at subsequent days, and identified variants that emerged intrahost immediately prior to increases in global rates. In contrast to most putative antigenic variants, oseltamivir-resistant variants rapidly increased to high frequencies in the virus population. Importantly, the majority of putative antigenic variants and oseltamivir-resistant variants were first detectable four or more days after onset of symptoms or start of treatment, respectively. Our observations demonstrate that de novo variants emerge, and may be positively selected, during the course of infection. Additionally, based on the 4–7 days post-treatment delay in emergence of oseltamivir-resistant variants in six out of the eight individuals with such variants, we find that limiting sample collection for routine surveillance and diagnostic testing to early timepoints after onset of symptoms can potentially preclude detection of emerging, positively selected variants. [ABSTRACT FROM AUTHOR]

Background Duration of viral shedding is a determinant of infectivity and transmissibility, but few data exist about oseltamivir's ability to alter viral shedding. Methods From January 2012 through October 2017, a randomized, double-blinded multicenter clinical trial was conducted in adults aged 18–64 years at 42 sites in Thailand, the United States, and Argentina. Participants with influenza A or B and without risk factors for complications of influenza were screened for the study. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3. Results Of 716 adults screened for the study, 558 were randomized, and 501 were confirmed to have influenza. Forty-six participants in the pilot study were excluded, and 449 of the 455 participants in the population for the primary analysis had day 3 viral shedding results. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm (absolute difference of −12.2% [−21.4%, −3.0%], P =;.010). The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =;.34) in those with confirmed influenza infection. Conclusions Oseltamivir decreased viral shedding in this low-risk population. However, in the population enrolled in this study, it did not significantly decrease the time to resolution of clinical symptoms. Clinical Trials Registration NCT01314911. [ABSTRACT FROM AUTHOR]

Background: A synergistic effect of combination therapy with favipiravir and oseltamivir has been reported in preclinical models of influenza. However, no data are available on the clinical effectiveness of combination therapy in severe influenza.Methods: Data from 2 separate prospective studies of influenza adults were used to compare outcomes between combination and oseltamivir monotherapy. Outcomes included rate of clinical improvement (defined as a decrease of 2 categories on a 7-category ordinal scale) and viral RNA detectability over time. Subhazard ratios (sHRs) were estimated by the Fine and Gray model for competing risks.Results: In total, 40 patients were treated with combination therapy and 128 with oseltamivir alone. Clinical improvement on day 14 in the combination group was higher than in the monotherapy group (62.5% vs 42.2%; P = .0247). The adjusted sHR for combination therapy was 2.06 (95% confidence interval, 1.30-3.26). The proportion of undetectable viral RNA at day 10 was higher in the combination group than the oseltamivir group (67.5% vs 21.9%; P < .01). No significant differences were observed in mortality or other outcomes.Conclusions: Favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, and this strategy should be formally evaluated in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Background Since their emergence in Indonesia in 2005, 200 human infections with clade 2.1 highly pathogenic avian influenza A/H5N1 virus have been reported, associated with exceptionally high mortality (84%) compared to regions affected by other genetic clades of this virus. To provide potential clues towards understanding this high mortality, detailed clinical virological analyses were performed in specimens from 180 H5N1 patients, representing 90% of all Indonesian patients and 20% of reported H5N1-infected patients globally. Methods H5N1 RNA was quantified in available upper- and lower-respiratory tract specimens as well as fecal and blood samples from 180 patients with confirmed infection between 2005 and 2017. Mutations in the neuraminidase and M2 genes that confer resistance to oseltamivir and adamantanes were assessed. Fatal and nonfatal cases were compared. Results High viral RNA loads in nasal and pharyngeal specimens were associated with fatal outcome. Mortality increased over time during the study period, which correlated with increasing viral RNA loads on admission. Furthermore, the prevalence of amantadine resistance–conferring M2 mutations increased over time, and viral loads were higher in patients infected with viruses that harbored these mutations. Compared to observations from other regions, viral RNA was detected more frequently in feces (80%) and particularly in blood (85%), and antiviral responses to oseltamivir appeared less pronounced. Conclusions These observations confirm the association of viral load with outcome of human H5N1 infections and suggest potential differences in virulence and antiviral responses to oseltamivir that may explain the exceptionally high mortality related to clade 2.1 H5N1 infections in Indonesia. [ABSTRACT FROM AUTHOR]

Influenza is a significant cause of childhood morbidity and death; it contributes to up to 16% of hospitalizations for respiratory illnesses worldwide. Novel rapid viral diagnostic tests, including molecular diagnostic tests, have the potential to significantly affect both time to diagnosis and selection of optimal anti-infective therapy. However, little is known about current treatment algorithms used in US hospitals. In this study, for hospitalized children in the United States, we aimed to define the current approaches to influenza diagnosis and treatment and to explore reasons for their potential variation. In this study, we aimed to define the current approaches to pediatric influenza diagnosis and treatment in US hospitals, and to explore reasons for their potential variation. Our results suggest a rise in the availability and use of rapid molecular diagnostic testing in addition to continued variability in anti-infective management, particularly with regard to antiviral use. [ABSTRACT FROM AUTHOR]

Background: Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.Methods: We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.Results: Viruses containing PA/I38X substitutions were identified 3-9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.Conclusions: The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.Clinical Trial Registration: NCT02954354. [ABSTRACT FROM AUTHOR]

Background The available evidence on whether neuraminidase inhibitors reduce mortality in patients with influenza is inconclusive and focuses solely on influenza A/H1N1pdm09. We assessed whether early oseltamivir treatment (≤48 hours from symptom onset) decreases mortality compared to late treatment in a large cohort of critically ill patients with influenza of all types. Methods The study included all adults with laboratory-confirmed influenza hospitalized in intensive care units (ICUs) in Greece over 8 seasons (2010–2011 to 2017–2018) and treated with oseltamivir. The association of early oseltamivir with mortality was assessed with log-binomial models and a competing risks analysis estimating cause-specific and subdistribution hazards for death and discharge. Effect estimates were stratified by influenza type and adjusted for multiple covariates. Results A total of 1330 patients were studied, of whom 622 (46.8%) died in the ICU. Among patients with influenza A/H3N2, early treatment was associated with significantly lower mortality (relative risk, 0.69 [95% credible interval {CrI},.49–.94]; subdistribution hazard ratio, 0.58 [95% CrI,.37–.88]). This effect was purely due to an increased cause-specific hazard for discharge, whereas the cause-specific hazard for death was not increased. Among survivors, the median length of ICU stay was shorter with early treatment by 1.8 days (95% CrI,.5–3.5 days). No effect on mortality was observed for A/H1N1 and influenza B patients. Conclusions Severely ill patients with suspected influenza should be promptly treated with oseltamivir, particularly when A/H3N2 is circulating. The efficacy of oseltamivir should not be assumed to be equal against all types of influenza. [ABSTRACT FROM AUTHOR]

The article presents a study which assessed the patient-level factors associated with receipt of early neuraminidase inhibitors (NAI) therapy among hospitalized patients and the association of early NAI therapy with clinical outcomes over five years at an academic center. Topics discussed include categories of NAI therapy timing used in the study, patient characteristics on admission, and clinical outcomes.

Background Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. Methods In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. Results Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription–polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, −3.6 day*log10 copies/mL [95% confidence interval {CI}, −7.1 to −0.1]; 600 mg group, −4.5 [95%CI −8.0 to −1.0]; and combination group, −8.6 [95% CI, −12.0 to −5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. Conclusions Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. Clinical Trials Registration NCT02342249, 2014-004068-39, and CR107745. [ABSTRACT FROM AUTHOR]

Background In 2017, Australia experienced record influenza notifications. Two surveillance programs combined to summarize the epidemiology of hospitalized influenza in children and report on vaccine effectiveness (VE) in the context of a limited nationally funded vaccination program. Methods Subjects were prospectively recruited (April–October 2017). Case patients were children aged ≤16 years admitted to 11 hospitals with an acute respiratory illness and laboratory-confirmed influenza. Controls were hospitalized with acute respiratory illness and tested negative for influenza. VE estimates were calculated using the test-negative design. Results A total of 1268 children were hospitalized with influenza: 31.5% were <2 years old, 8.3% were indigenous, and 45.1% had comorbid conditions predisposing to severe influenza. Influenza B was detected in 34.1% with influenza A/H1N1 and A/H3N2 detected in 47.2% and 52.8% of subtyped influenza A specimens. The median length of stay was 3 days (interquartile range, 1–5), 14.5% were admitted to the intensive care unit, and 15.9% received oseltamivir. Four in-hospital deaths occurred (0.3%): one was considered influenza associated. Only 17.1% of test-negative-controls were vaccinated. The VE of inactivated quadrivalent influenza vaccine for preventing hospitalized influenza was estimated at 30.3% (95% confidence interval, 2.6%–50.2%). Conclusions Significant influenza-associated morbidity was observed in 2017 in Australia. Most hospitalized children had no comorbid conditions. Vaccine coverage and antiviral use was inadequate. Influenza vaccine was protective in 2017, yet VE was lower than previous seasons. Multiple Australian states have introduced funded preschool vaccination programs in 2018. Additional efforts to promote vaccination and monitor effectiveness are required. [ABSTRACT FROM AUTHOR]

Objectives: Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection.Methods: The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection.Results: Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung.Conclusions: Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial. [ABSTRACT FROM AUTHOR]

Background: Although the potential risk of neuropsychiatric adverse events (NPAEs) upon administration of oseltamivir has been raised in case reports, the association between the use of oseltamivir and the risk of NPAEs is unclear.Objectives: We aimed to evaluate whether the use of oseltamivir triggers NPAEs.Patients and methods: We conducted a population-based case-crossover study using the National Sample Cohort data from the National Health Insurance Service in South Korea. From a total of 236 348 incident patients with NPAEs as either a primary or secondary diagnosis, our final case series included 5322 patients with a prior prescription for oseltamivir between 2009 and 2013. Exposure to oseltamivir was assessed during 2, 7, 14, 28 and 56 day hazard periods prior to each patient's NPAE. Three pre-consecutive control periods were matched using the same time windows. Conditional logistic regression analysis was used to estimate adjusted ORs (aORs), adjusting for time-variant diagnosis of influenza and concomitant medications.Results: Matched analyses found a consistently increased risk of NPAEs associated with the use of oseltamivir in the 2 day (aOR 1.90, 95% CI 1.29-2.81), 7 day (aOR 1.32, 95% CI 1.00-1.74), 14 day (aOR 1.28, 95% CI 1.03-1.60), 28 day (aOR 1.25, 95% CI 1.06-1.47) and 56 day (aOR 1.13, 95% CI 0.99-1.29) hazard periods compared with use in the three control periods.Conclusions: This study found that the short-term use of oseltamivir triggers the incidence of NPAEs. Early monitoring of NPAEs may be required when prescribing oseltamivir with careful consideration of the risk-benefit balance of oseltamivir. [ABSTRACT FROM AUTHOR]

The article discusses respiratory syncytial virus has a major cause of morbidity and mortality for specific risk groups, including infants with or without comorbidities, older adults, and immunocompromised patients. Topics include challenges in drug delivery such as poor tolerability and potential toxicity of ribavirin have a major limitation; and respiratory syncytial virus antiviral agents that have being developed divided into different therapeutic classes.

The article discusses case study of a 63-year-old female suffering from brain lesion and influenza. Topics include regular acid–Schiff and Grocott methenamine silver staining in the brain-imaging test with narrow angle branching septate suggestive of Aspergillus infection, and magnetic resonance imaging scan being repeated because of increasing size of the abscesses as well as worsening surrounding edema.

Background Influenza-associated hospitalizations result in high morbidity and mortality. We sought to determine if early empiric anti-influenza therapy improves outcomes of hospitalized patients with influenza-associated lower respiratory tract infections (I-LRTIs). Methods This was a randomized, unblinded, trial of adult patients hospitalized with I-LRTIs in Kentucky during 2009–2012. Patients were randomized to group A (standard of care) or group B (standard of care plus oseltamivir as early as possible but within 24 hours of enrollment). The primary outcome was development of clinical failure (composite variable including failure to reach clinical improvement within 7 days, transfer to intensive care 24 hours after admission, or rehospitalization or death within 30 days). Intent-to-treat (ITT) (all LRTI) and per-protocol (PP) (I-LRTI) analyses were done. Results A total of 1107 patients were enrolled and included in the ITT analysis, 556 in group A and 551 in group B. The median time from symptom onset to hospital admission was 5 days (interquartile range, 5) for both groups; oseltamivir was initiated median day 6 in group B. There was no difference in the development of clinical failure (group A, 25%, and group B, 24%; P =.561). In the PP analysis, 11 of 45 (24%) patients in group A and 4 of 29 (14%) patients in group B had clinical failure (P =.414). Conclusions Initiation of oseltamivir more than 5 days after illness onset did not reduce clinical failures among hospitalized patients with I- LRTIs. However, we did not enroll our projected sample size of I-LRTI. Clinical Trials Registration NCT01248715. [ABSTRACT FROM AUTHOR]

Background Little is known about how pharmaceutical companies lobby authorities or experts regarding procurement or the use of vaccines and antivirals. This paper investigates how members of Denmark's pandemic planning committee experienced lobbying efforts by Roche, manufacturer of Tamiflu, the antiviral that was stockpiled before the 2009 A(H1N1) pandemic. Methods Analysis of interviews with six of seven members of the Danish core pandemic committee, supplemented with documentary analysis. We sought to identify (1) arguments and (2) tactics used in lobbying, and to characterize interviewees' views on the impact of (3) lobbying and (4) scientific evidence on the decision to stockpile Tamiflu. Results Roche lobbied directly (in its own name) and through a seemingly independent third party. Roche used two arguments: (1) the procurement agreement had to be signed quickly because the drug would be delivered on a first-come, first-served basis and (2) Denmark was especially vulnerable to an influenza crisis because it had smaller Tamiflu stocks than other countries. Most interviewees suspected that lobbying had an impact on Tamiflu procurement. Conclusions Our study highlights risks posed by pharmaceutical lobbying. Arguments and tactics deployed by Roche are likely to be repeated whenever many countries are negotiating drug procurements in a monopolistic market. [ABSTRACT FROM AUTHOR]

Background Statins are used to reduce cardiovascular disease risk. Recent studies suggest that statin use may be associated with an increased influenza risk among influenza vaccinees. We used Medicare data to evaluate associations between statins and risks of influenza-related encounters among vaccinees. Methods In this retrospective cohort study, we identified Medicare beneficiaries aged > 65 years who received high-dose (HD) or standard-dose (SD) influenza vaccines at pharmacies from 2010–2011 through 2014–2015. Statin users were matched to nonusers by vaccine type, demographics, prior medical encounters, and comorbidities. We used multivariable Poisson models to estimate associations between statin use around the time of vaccination and risk of influenza-related encounters. Study outcomes included influenza-related office visits with a rapid test followed by dispensing of oseltamivir and influenza-related hospitalizations (including emergency room visits) during high influenza circulation periods. Results The study included 1403651 statin users matched to nonusers. Cohorts were well balanced, with standardized mean differences ≤0.03 for all measured covariates. For statin users compared to nonusers, the adjusted relative risk was 1.086 (95% confidence interval [CI], 1.025–1.150) for influenza-related visits and 1.096 (95% CI, 1.013–1.185) for influenza-related hospitalizations. The risk difference ranged from ‒0.02 to 0.23 for influenza-related visits and from ‒0.04 to 0.13 for hospitalizations, depending on season severity. Results were similar for HD and SD vaccinees and for nonsynthetic and synthetic statin users. Conclusions Among 2.8 million Medicare beneficiaries, these results suggest that statin use around the time of vaccination does not substantially affect the risk of influenza-related medical encounters among older adults. [ABSTRACT FROM AUTHOR]

Background: Data are limited on the impact of neuraminidase inhibitor (NAI) treatment on avian influenza A(H7N9) virus RNA shedding.Methods: In this multicenter, retrospective study, data were collected from adults hospitalized with A(H7N9) infection during 2013-2017 in China. We compared clinical features and A(H7N9) shedding among patients with different NAI doses and combination therapies and evaluated factors associated with A(H7N9) shedding, using Cox proportional hazards regression.Results: Among 478 patients, the median age was 56 years, 71% were male, and 37% died. The median time from illness onset to NAI treatment initiation was 8 days (interquartile range [IQR], 6-10 days), and the median duration of A(H7N9) RNA detection from onset was 15.5 days (IQR, 12-20 days). A(H7N9) RNA shedding was shorter in survivors than in patients who died (P < .001). Corticosteroid administration (hazard ratio [HR], 0.62 [95% confidence interval {CI}, .50-.77]) and delayed NAI treatment (HR, 0.90 [95% CI, .91-.96]) were independent risk factors for prolonged A(H7N9) shedding. There was no significant difference in A(H7N9) shedding duration between NAI combination treatment and monotherapy (P = .65) or between standard-dose and double-dose oseltamivir treatment (P = .70).Conclusions: Corticosteroid therapy and delayed NAI treatment were associated with prolonged A(H7N9) RNA shedding. NAI combination therapy and double-dose oseltamivir treatment were not associated with a reduced A(H7N9) shedding duration as compared to standard-dose oseltamivir. [ABSTRACT FROM AUTHOR]

Background. Oseltamivir has been used to treat children with influenza for nearly 2 decades, with treatment currently approved for infants aged ≥2 weeks. However, efficacy and safety remain controversial. Newer randomized, placebo-controlled trials (RCTs), not included in previous meta-analyses, can add to the evidence base. Methods. We conducted a systematic review to identify RCTs of oseltamivir therapy in children. We obtained individual patient data and examined protocol-defined outcomes. We then conducted a 2-stage, random-effects meta-analysis to determine the efficacy of treatment in reducing the duration of illness, estimated using differences in restricted mean survival time (RMST) by treatment group. We also examined complications and safety. Results. We identified 5 trials that included 2561 patients in the intention-to-treat (ITT) and 1598 in the intention-to-treat infected (ITTI) populations. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population (RMST difference, -17.6 hours; 95% confidence interval [CI], -34.7 to -0.62 hours). In trials that enrolled patients without asthma, the difference was larger (-29.9 hours; 95% CI, -53.9 to -5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group. Conclusions. Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma. [ABSTRACT FROM AUTHOR]

A correction to the article "Response to 'Inhaled Zanamivir versus Oral Oseltamivir to Prevent Influenza-Related Hospitalization or Death: A Nationwide Population-Based Quasi-experimental Study'" in the November 1, 2022 issue discusses a correction in the corresponding author's name.

Background: Neuraminidase (NA) inhibitors are the recommended antiviral medications for influenza treatment. However, their therapeutic efficacy can be compromised by NA changes that emerge naturally and/or following antiviral treatment. Knowledge of which molecular changes confer drug resistance of influenza A(H7N9) viruses (group 2NA) remains sparse.Methods: Fourteen amino acid substitutions were introduced into the NA of A/Shanghai/2/2013(H7N9). Recombinant N9 (recN9) proteins were expressed in a baculovirus system in insect cells and tested using the Centers for Disease Control and Prevention standardized NA inhibition (NI) assay with oseltamivir, zanamivir, peramivir, and laninamivir. The wild-type N9 crystal structure was determined in complex with oseltamivir, zanamivir, or sialic acid, and structural analysis was performed.Results: All substitutions conferred either reduced or highly reduced inhibition by at least 1 NA inhibitor; half of them caused reduced inhibition or highly reduced inhibition by all NA inhibitors. R292K conferred the highest increase in oseltamivir half-maximal inhibitory concentration (IC50), and E119D conferred the highest zanamivir IC50. Unlike N2 (another group 2NA), H274Y conferred highly reduced inhibition by oseltamivir. Additionally, R152K, a naturally occurring variation at the NA catalytic residue of A(H7N9) viruses, conferred reduced inhibition by laninamivir.Conclusions: The recNA method is a valuable tool for assessing the effect of NA changes on drug susceptibility of emerging influenza viruses. [ABSTRACT FROM AUTHOR]

Antiviral compounds (eg, the neuraminidase inhibitor oseltamivir) are invaluable for the treatment of individuals infected with influenza A viruses of the H7N9 subtype (A[H7N9]), which have infected and killed hundreds of persons. However, oseltamivir treatment often leads to the emergence of resistant viruses in immunocompromised individuals. To better understand the emergence and properties of oseltamivir-resistant A(H7N9) viruses in immunosuppressed individuals, we infected immunosuppressed cynomolgus macaques with an A(H7N9) virus and treated them with oseltamivir. Disease severity and mortality were higher in immunosuppressed than in immunocompetent animals. Oseltamivir treatment at 2 different doses reduced A(H7N9) viral titers in infected animals, but even high-dose oseltamivir did not block viral replication sufficiently to suppress the emergence of resistant variants. Some resistant variants were not appreciably attenuated in cultured cells, but an oseltamivir-resistant A(H7N9) virus did not transmit among ferrets. These findings are useful for the control of A(H7N9) virus infections in clinical settings. [ABSTRACT FROM AUTHOR]

Background: MEDI8852 is a novel monoclonal antibody (mAb) that neutralizes both group I and group II influenza A viruses (IAVs) in vitro. We evaluated whether MEDI8852 was effective for prophylaxis and therapy against representative group I (H5N1) and group II (H7N9) pandemic IAVs in mice and ferrets and could be used to block transmission of influenza H1N1pdm09 in ferrets, compared to an irrelevant control mAb R347 and oseltamivir.Methods: MEDI8852 was administered to mice and ferrets by intraperitoneal injection at varying doses, 24 hours prior to intranasal infection with H5N1 and H7N9 viruses for prophylaxis, and 24, 48, and 72 hours post-infection for treatment. A comparison with oseltamivir alone and combination of MEDI8852 and oseltamivir was included in some studies. Survival, weight loss, and viral titers were assessed over a 14-day study period. For the transmission study, naive respiratory contact ferrets received MEDI8852 or R347 prior to exposure to ferrets infected with an H1N1pdm09 virus.Results: MEDI8852 was effective for prophylaxis and treatment of H7N9 and H5N1 infection in mice, with a clear dose-dependent response and treatment with MEDI8852 24, 48, or 72 hours postinfection was superior to oseltamivir for H5N1. MEDI8852 alone was effective treatment for lethal H5N1 infection in ferrets compared to oseltamivir and R347, and MEDI8852 plus oseltamivir was better than oseltamivir alone. MEDI8852 or oseltamivir alone early in infection was equally effective for H7N9 infection in ferrets while the combination yielded similar protection when treatment was delayed. MEDI8852 was able to protect naive ferrets from airborne transmission of H1N1pdm09.Conclusions: MEDI8852, alone or with oseltamivir, shows promise for prophylaxis or therapy of group I and II IAVs with pandemic potential. Additionally, MEDI8852 blocked influenza transmission in ferrets, a unique finding among influenza-specific mAbs. [ABSTRACT FROM AUTHOR]

Influenza virus inflicts a heavy death toll annually and resistance to existing antiviral drugs has generated interest in the development of agents with novel mechanisms of action. Favipiravir is an antiviral drug that acts by increasing the genome-wide mutation rate of influenza A virus (IAV). Potential synergistic benefits of combining oseltamivir and favipiravir have been demonstrated in animal models of influenza, but the population-level effects of combining the drugs are unknown. In order to elucidate the underlying evolutionary processes at play, we performed genome-wide sequencing of IAV experimental populations subjected to serial pass-aging in vitro under a combined protocol of oseltamivir and favipiravir. We describe the interplay between mutation, selection, and genetic drift that ultimately culminates in population extinction. In particular, selective sweeps around oseltamivir resistance mutations reduce genome-wide variation while deleterious mutations hitchhike to fixation given the increased mutational load generated by favipiravir. This latter effect reduces viral fitness and accelerates extinction compared with IAV populations treated with favipiravir alone, but risks spreading both established and newly emerging mutations, including possible drug resistance mutations, if transmission occurs before the viral populations are eradicated. [ABSTRACT FROM AUTHOR]

Background. Clinical studies comparing the different neuraminidase inhibitors for treatment of at-risk patients with influenza have not been performed. To optimize such treatments, we assessed the efficacy and safety of intravenous peramivir compared with oral oseltamivir in treating seasonal influenza A or B virus infection. Methods. A multicenter, randomized, controlled clinical trial was conducted from December 2012 to May 2014 in high-risk patients infected with seasonal influenza. A total of 92 adult inpatients and outpatients with high risk factors (HRFs) were treated by either a single intravenous infusion of peramivir (600 mg) or oral administration of oseltamivir (75 mg, twice per day for 5 days). Results. The median times to clinical stability (time to reach <37°C) were 40.0 hours (95% confidence interval [CI] = 23.3-64.5) and 37.8 hours (95% CI = 26.3-45.3) in the peramivir and oseltamivir groups, respectively; these values did not reveal a significant difference. The virus titer and change of mean total symptom scores decreased similarly with both treatments. Results of step-wise regression suggested that virus type was a significantly effective prognostic factor with respect to illness resolution. Adverse events (AEs) with peramivir and oseltamivir occurred in 2.2% (n = 1/46) and 13.0% (n = 6/46) of patients, respectively. The severity of AEs was mild in all cases except 2 patients who showed pneumonia or COPD aggravation; both were in the oseltamivir group. Conclusions. Intravenous peramivir was effective based on the result of direct comparison with oral oseltamivir. Thus our data show that peramivir is a useful option for the treatment of influenza-infected patients with HRFs. [ABSTRACT FROM AUTHOR]

Anti-influenza drugs play major roles in the management of severe influenza infections. Neuraminidase inhibitors (NAIs), which are active against all influenza A subtypes and the 2 major influenza B lineages, constitute the only class of antivirals recommended for the control of influenza epidemics and eventual pandemics. Thus, the emergence of NAI resistance could be a major clinical concern. Although most currently circulating influenza A and B strains are susceptible to NAIs, clinical cases of influenza viruses harboring single or multiple NA substitutions or deletions conferring a cross-resistance phenotype to the 2 main NAIs (oseltamivir and zanamivir) have been reported, mostly in immunocompromised individuals. Moreover, such events seem to be more frequent in A(H1N1)pdm09 viruses containing the H274Y substitution together with other NA changes (I222R, E119D/G). This review summarizes the therapeutic regimens leading to the emergence of NAI cross-resistant influenza A and B viruses as well as the virologic properties of such variants. [ABSTRACT FROM AUTHOR]