Oseltamivir-treated Patients Research Articles

Household Influenza Transmission and Healthcare Resource Utilization Among Patients Treated with Baloxavir vs Oseltamivir: A United States Outpatient Prospective Survey.

Influenza is a common, seasonal infectious disease with broad medical, economic, and social consequences. Real-world evidence on the effect of influenza treatment on household transmission and healthcare resource utilization is limited in outpatient settings in the USA. This study examined the real-world effectiveness of baloxavir vs oseltamivir in reducing influenza household transmission and healthcare resource utilization. This prospective electronic survey on patient-reported outcomes was conducted between October 2022 and May2023 via CVS Pharmacy in the USA. Adult participants (≥ 18years old) were eligible if they filled a prescription for baloxavir or oseltamivir at a CVS Pharmacy within 2days of influenza symptom onset. Participant demographics, household transmission, and all-cause healthcare resource utilization were collected. Transmission and utilization outcomes were assessed using χ2 and Fisher exact tests. Of 87,871 unique patients contacted, 1346 (1.5%) consented. Of 374 eligible patients, 286 (90 baloxavir- and 196 oseltamivir-treated patients) completed the survey and were included in the analysis. Mean age of participants was 45.4years, 65.6% were female, and 86.7% were White. Lower household transmission was observed with baloxavir compared with oseltamivir therapy (17.8% vs 26.5%; relative risk = 0.67; 95%CI 0.41-1.11). Healthcare resource utilization, particularly emergency department visits (0.0% vs 4.6%), was also numerically lower in the baloxavir-treated group; no hospitalizations were reported in either cohort. The findings from this real-world study suggest that antiviral treatment of influenza with baloxavir may decrease household transmission and reduce healthcare resource utilization compared with oseltamivir.

Baloxavir vs oseltamivir: reduced utilization and costs in influenza.

To determine whether baloxavir use is associated with lower health care resource utilization (HCRU) and costs for secondary influenza complications post treatment compared with oseltamivir. Retrospective cohort study. Patients filling a prescription for baloxavir or oseltamivir within 48 hours following an influenza-related outpatient visit were identified in the 2018-2019 influenza season from the US Truven MarketScan Research Databases and propensity matched 1:2 (baloxavir:oseltamivir). Outcomes were assessed 15 and 30 days after antiviral treatment and included all-cause, all respiratory-related, and select respiratory-related (influenza, asthma, chronic obstructive pulmonary disease, or infection) HCRU and costs. The study included 5080 baloxavir-treated and 10,160 matched oseltamivir-treated patients. All-cause emergency department (ED) visits and inpatient hospitalizations were lower in baloxavir-treated patients, with a statistically significant difference in the percentage hospitalized at 30 days (0.3% vs 0.5%; P = .04). ED visits for all or select respiratory-related conditions were significantly reduced with baloxavir (P < .01 for all comparisons). Mean per-patient cost savings at day 30 for all-cause, all respiratory-related, and select respiratory-related conditions were $79, $50, and $51, respectively, despite slightly higher prescription costs for baloxavir. In high-risk patients (baloxavir: n = 1958; oseltamivir: n = 3949), the incidence of ED visits was significantly lower for all respiratory-related and select respiratory-related conditions (P < .01); cost savings with baloxavir in the high-risk cohort were substantially greater than in the overall cohort. Treatment of patients with influenza with single-dose baloxavir was generally associated with lower HCRU and costs post treatment compared with oseltamivir, particularly in high-risk patients.

Costs of influenza-like illness lower in oseltamivir-treated patients in Europe

Costs of influenza-like illness lower in oseltamivir-treated patients in Europe

1518. Real-World Comparative Effectiveness of Baloxavir Marboxil versus Oseltamivir on Influenza-Related Complication and Resource Utilization

BackgroundIn the 2018-19 season, there were an estimated 490,500 hospitalizations and 24,000 deaths from influenza in the US. Understanding how antiviral use affects rates and severity of complications is crucial to inform clinical practice. The objective of this study was to compare the frequency and costs of complications in influenza patients treated with baloxavir compared with oseltamivir-treated patients. This is one of the first analyses to examine comparative effectiveness of baloxavir in a real-world setting.MethodsThis retrospective cohort study used IBM MarketScan US administrative claims data from the 2018–19 influenza season. Patients were required to have an outpatient visit for influenza followed by a prescription for baloxavir or oseltamivir within 2 days. Baloxavir- and oseltamivir-treated patients were propensity score matched based on key baseline clinical and demographic characteristics. All-cause, all respiratory-related, and select respiratory-related (infection, asthma, and COPD) HRU in the 15 and 30 days following prescription fill were assessed using chi-square and Fisher’s exact tests for categorical measures and Wilcoxon signed-rank tests for counts and costs.ResultsWe included 5,080 baloxavir-treated patients and 10,160 matched oseltamivir-treated patients in the analysis. Statistically significantly lower HRU was associated with baloxavir compared with oseltamivir therapy (15-day: respiratory-related ED visits, select respiratory-related ED visits and outpatient visits; 30-day: all-cause hospitalization, respiratory-related ED visits, select respiratory-related ED visits and outpatient visits (Table 1). Similarly, associated costs were generally lower in the baloxavir-treated group. Baloxavir-treated patients had lower mean per-patient all-cause 15-day costs (ED visits: $30 [95% CI: $21–$39] vs $42 [95% CI: $32–$51]; hospitalizations: $31 [95% CI: $6–$55] vs $74 [95% CI: $43–$104]) and 30-day costs (ED visits: $46 [95% CI: $35–$57] vs $67 [95% CI: $55–$79]; hospitalizations: $47 [95% CI: $15–$80] vs $119 [95% CI: $78–$161]).Table 1. Proportion of patients with at least one event ConclusionThese findings suggest that treatment of influenza with baloxavir may improve outcomes and lower HRU costs compared with oseltamivir treatment.DisclosuresEddie Neuberger, PharmD, Genentech, Inc. (Employee) Chris Wallick, PharmD, MS, Genentech, Inc. (Employee) Devika Chawla, PhD MSPH, Genentech, Inc. (Employee) Rita de Cassia Castro, MD, Genentech, Inc. (Employee)

Comparison of Hospitalization Incidence in Influenza Outpatients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study

BackgroundBaloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors.MethodsIn this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2–14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use.ResultsCompared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00–2.00]; risk difference [RD] and 95% CI, 0.06 [.01–.12]) and zanamivir group (RR, 1.85 [1.23–2.78]; RD, 0.11 [.02–.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82–.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21–2.38]) or antibacterial injection (RR, 1.67 [1.17–2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05–2.18], 2.84 [2.04–3.96], and 1.68 [1.35–2.10], respectively).ConclusionsBaloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir.Clinical Trials RegistrationUniversity hospital Medical Information Network Clinical Trials Registry (UMIN000038159).

Oseltamivir Resistance in Severe Influenza A(H1N1)pdm09 Pneumonia and Acute Respiratory Distress Syndrome: A French Multicenter Observational Cohort Study.

In a multicenter cohort study including 22 oseltamivir-treated patients with influenza A(H1N1)pdm09 acute respiratory distress syndrome, prevalence of the H275Y substitution in the neuraminidase, responsible for highly reduced sensitivity to oseltamivir, was 23%. Patients infected with the H275Y mutant virus had higher day 28 mortality than others (80% vs 12%; P = .011).

Effects of antiviral treatment on influenza-related complications over four influenza seasons: 2006–2010

Purpose: The objective of the study is to evaluate the effect of antiviral treatment, pre-existing diseases, and sociodemographic factors on the risk of influenza-related complications and healthcare utilization.Methods: Case data was obtained from U.S. MarketScan Research Databases. Cases had a clinical diagnosis of influenza between 2006 and 2010 and continuous healthcare insurance from 90 days before to 30 days after diagnosis. Logistic regression models were applied to explore the impact of antiviral treatment on complications and healthcare utilization. Modified generalized estimating equation regression models in propensity score matched samples were used to address the robustness of the study.Results: Analyses included 1,557,437 cases from four influenza seasons. In each season, 34.82%–43.42% of patients received antiviral treatment, mostly oseltamivir. On average, 1.86% of patients were hospitalized, 9.56% visited the emergency room and 41.14% made ≥2 outpatient visits. The incidence of complications ranged from 17.62 to 19.67 per 100 patient-months. The relative risk of complications was increased in patients aged 0–4 years and those with pre-existing diseases, including asthma, Parkinson’s disease, and cystic fibrosis. Overall, patients receiving antiviral treatment had an 11% reduction in the risk of complications. Among oseltamivir-treated patients, the risk of complications was significantly reduced by 81% in those treated ≤2 days after diagnosis compared with later. Antiviral treatment significantly reduced the risk of hospitalization, emergency room visits and need for ≥2 outpatient visits by 29%, 24% and 11%, respectively. The propensity score matching method improved the strength of the study.Conclusions: Early treatment with antivirals, and specifically oseltamivir, significantly reduced the risk of influenza-related complications and healthcare utilization. However, lacking information about disease severity and the time from onset of symptoms to fulfillment of a prescription may bias the outcomes.

Oseltamivir use and outcomes during the 2009 influenza A H1N1 pandemic in Taiwan

BackgroundThe Taiwan CDC provided free oseltamivir to all patients with influenza infections confirmed by rapid testing or who had clinical warning symptoms during the 2009 H1N1 influenza pandemic in Taiwan. However, oseltamivir utilization patterns, cost, and outcomes among oseltamivir-treated patients remained unclear.MethodA population-level, observational cohort study was conducted using the Taiwan National Health Insurance Database from January to December 2009 to describe the use of oseltamivir.ResultPrescription trend over weeks increased after a change in government policy and responded to the influenza virus activity. The overall prescription rate was 22.33 per 1000 persons, with the highest prescription rate of 116.5 for those aged 7–12 years, followed by 69.0 for those aged 13–18 years, while the lowest rate was 1.7 for those aged ≥ 65 years. As influenza virus activity increased, the number of prescriptions for those aged ≤18 years rose significantly, whereas no substantial change was observed for those aged ≥65 years. There were also regional variations in terms of oseltamivir utilization and influenza complication rates.ConclusionsOseltamivir was widely used in the 2009 H1N1 influenza pandemic in Taiwan, particularly in those aged 7–18 years. The number of prescriptions for oseltamivir increased with a change in government policy and with increasing cases of pandemic influenza. Further study is needed to examine whether there is an over- or under-use of anti-influenza drugs in different age groups or regions and to examine the current policy of public use of anti-influenza drugs to reduce influenza-associated morbidity and mortality.

Benign Clinical Course in H1N1 2009 Influenza Infection in Young Oseltamivir-treated Immunocompromised Patients With Kidney Disease in Singapore

This report describes the clinical features of H1N1 2009 influenza infection in 10 young renal patients receiving chronic dialysis or immunosuppressants, and to compare their durations of viral shedding with 20 healthy controls. Although patients shed the virus for longer periods compared with controls, all had a self-limited clinical course. Studies on indications, dosages and durations of antiviral therapy in renal and immunocompromised patients are warranted.

Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project, 2007–2010

An association between the influenza antiviral medication oseltamivir and neuropsychiatric events has been suggested by post-marketing case reports in Japan. This possible association was not supported by cohort studies in the U.S. conducted prior to the 2009 influenza A (H1N1) pandemic, when usage rates were comparatively low. We assessed oseltamivir safety before and during the pandemic using biologically plausible risk intervals, particularly focusing on psychiatric events. Outpatients with influenza episodes from January 2007 through June 2010 were identified using diagnosis codes and positive tests at eight health care systems (sites) in the Vaccine Safety Datalink Project. Oseltamivir-treated and untreated patients were matched according to calendar week, age, sex, site, and propensity for treatment. Within this matched cohort, conditional logistic regression models were used to estimate the risk of four neuropsychiatric and five other adverse events (AEs) during pre-specified risk intervals. Among 27,684 matched pairs, no associations were identified between oseltamivir treatment and any pre-defined AE. The absolute risks of incident psychiatric events in the 1-7 day risk interval were 0.126% for oseltamivir-treated and 0.105% for untreated patients (odds ratio = 1.21, 95% confidence interval [CI]: 0.74, 1.97; risk difference = 0.022%, 95% CI: -0.035%, 0.078%); the most common diagnosis was unspecified anxiety state. Results were similar for 1-14 and 1-2 day risk intervals and for pediatric/adolescent subgroups. Consistent with prior U.S. cohort studies, no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment. Safety should be prospectively monitored to inform antiviral medication usage recommendations.

Post-Marketing Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir: An Updated Review

A 2008 review by our group concluded that the risk of neuropsychiatric adverse events (NPAEs) in influenza patients was not increased by oseltamivir exposure, and did not identify any mechanism by which oseltamivir or its metabolites could cause or worsen such events. The current article reviews new information on this topic. Between September 16, 2007 and May 15, 2010, 1,805 spontaneously-reported NPAEs were identified in 1,330 patients receiving oseltamivir: 767 (42.5%) from Japan, 296 (16.4%) from the USA, and 742 (41.1%) from other countries. NPAEs were more common in children: 1,072 (59.4%) events were in those aged ≤16 years. NPAEs often occurred within 48 h of treatment initiation (953 events; 52.8%). Nearly half of the events were serious in nature (838; 46.4%). The three largest categories of events were abnormal behavior (457 events, 25.3%), miscellaneous psychiatric events (370; 20.5%), and delusions/perceptual disturbances (316 events, 17.5%). A total of 1,545 events (85.6%) in eight different categories were considered to be delirium or delirium-like. Twenty-eight suicide-related events were reported. A US healthcare claims database analysis showed that the risk of NPAEs in 7,798 oseltamivir-treated patients was no higher than that in 10,411 patients not on antivirals, but a study on oseltamivir and abnormal behavior in Japan was less conclusive. NPAE frequency in oseltamivir-exposed Japanese and Taiwanese children with influenza was the same as in unexposed children. New analysis of the UK General Practice Research Database showed that the relative adjusted risk of NPAEs in influenza patients was 2.18-times higher than in the general population. Other epidemiology studies report frequent occurrence of encephalitis and similar disorders in influenza patients independently of oseltamivir exposure. The new data support the findings of the original assessment. Evidence suggests that influenza-related encephalopathies are caused by influenza-induced inflammatory responses, but more work is needed to confirm the underlying mechanisms.

Oseltamivir Shortens Hospital Stays of Critically Ill Children Hospitalized With Seasonal Influenza

Antiviral therapy reduces symptom duration and hospitalization risk among previously healthy and chronically ill children infected with seasonal influenza. The effect of oseltamivir on outcomes of hospitalized children is unknown. The primary objective of this study was to determine whether oseltamivir improves outcomes of critically ill children hospitalized with influenza. We performed a retrospective cohort study of children with influenza infection admitted to a pediatric intensive care unit during 6 consecutive winter seasons (2001-2007). We used the Pediatric Health Information System database, which contains resource utilization data from 41 children's hospitals. We matched oseltamivir-treated patients with oseltamivir-nontreated patients by the probability of oseltamivir exposure using a propensity score we derived from patient and hospital characteristics. We subsequently compared the outcomes of critically ill children treated with oseltamivir within 24 hours of admission with propensity score matched children who were not treated with oseltamivir. We identified 1257 children with influenza infection, 264 of whom were treated with oseltamivir within 24 hours of hospital admission. Multivariable analysis of 252 oseltamivir-treated patients and 252 propensity score-matched untreated patients demonstrated that patients treated with oseltamivir experienced an 18% reduction in total hospital days (time ratio: 0.82, P = 0.02), whereas intensive care unit stay, in-hospital mortality, and readmission rates did not differ. For critically ill children infected with seasonal influenza, treatment with oseltamivir within 24 hours of hospitalization was associated with a shorter duration of hospital stay. Additional study is needed to determine the effect of delayed initiation of oseltamivir on clinical outcomes.

Frequency of Drug-resistant Viruses and Virus Shedding in Pediatric Influenza Patients Treated With Neuraminidase Inhibitors

Although influenza virus resistance to the neuraminidase inhibitor zanamivir is reported less frequently than is resistance to the neuraminidase inhibitor oseltamivir in clinical settings, it is unknown whether this difference is due to the limited use of zanamivir or to an inherent property of the drug. We therefore compared the prevalence of drug-resistant viruses and virus shedding in seasonal influenza virus-infected children treated with either oseltamivir or zanamivir. Clinical specimens (throat or nasal swab) were collected from a total of 144 pediatric influenza patients during the 2005-2006, 2006-2007, 2007-2008, and 2008-2009 influenza seasons. Neuraminidase inhibitor-resistant mutants were detected among the isolated viruses by sequencing the viral hemagglutinin and neuraminidase genes. Sensitivity of the viruses to neuraminidase inhibitors was tested by neuraminidase inhibition assay. In oseltamivir- or zanamivir-treated influenza patients who were statistically comparable in their age distribution, vaccination history, and type or subtype of virus isolates, the virus-shedding period in zanamivir-treated patients was significantly shorter than that in oseltamivir-treated patients. Furthermore, the frequency of zanamivir-resistant viruses was significantly lower than that of oseltamivir-resistant viruses. In comparison with treatment with oseltamivir, treatment of pediatric patients with zanamivir resulted in the emergence of fewer drug-resistant influenza viruses and a shorter virus-shedding period. We conclude that zanamivir shows promise as a better therapy for pediatric influenza patients.

Longitudinal clearance of seasonal influenza A viral RNA measured by real-time polymerase chain reaction in patients identified at a hospital emergency department

To study influenza virus shedding during acute infection, viral load was longitudinally measured by quantitative PCR in nasal flocked swabs from patients with seasonal H3N2 influenza at a Swedish emergency department, including both hospitalized patients and outpatients. Influenza A was detected in 65/184 patients. Sampling was repeated every 3-4 days in 45 patients, with the aim of continuing sampling until day 12 after disease onset. Home visits were offered. Antibodies were measured on paired sera in 95/184 patients. Fifty percent of the patients remained polymerase chain reaction (PCR)-positive 8 days after disease onset in a Kaplan-Meier survival curve. The longest observed duration of viral shedding was 12 days. The average viral load was initially low, peaked on days 2-3 of disease and then declined. Viral decline results remained similar when all 15 (25%) oseltamivir-treated patients were excluded. Significant antibody titre changes were seen in all the 35 PCR verified cases with available paired sera and in 8 of the 58 patients with negative PCR tests on acute phase nasal samples. In conclusion, quantitative PCR testing indicated the presence of influenza virus for up to 12 days, which could have implications for disease transmission and infection control.

Detection of the rapid emergence of the H275Y mutation associated with oseltamivir resistance in severe pandemic influenza virus A/H1N1 09 infections

In 2009 a new swine-origin influenza virus A/H1N1 (A/H1N1 09) emerged, causing the century's first pandemic. Most isolates of the new A/H1N1 09 virus are susceptible to neuraminidase inhibitors, but the H275Y mutation in the neuraminidase gene region associated with high-level oseltamivir resistance has been detected. Using rolling circle amplification (RCA) technology, 96 A/H1N1 09-specific RT-PCR positive clinical samples collected from 80 oseltamivir-treated and untreated patients were screened for the presence of the H275Y mutation. Samples positive for 275Y mutation by RCA were cloned and sequenced for confirmation. From 25 patients who had been treated with oseltamivir and remained A/H1N1 09 RT-PCR positive, we identified three (12%) individuals with the H275Y mutation: one immuno-suppressed adult, one immuno-competent adult and one child. Samples collected at multiple time points from the two adults showed a switch from wild-type oseltamivir-sensitive 275H to oseltamivir-resistant 275Y population after 9 days of treatment. The child had the 275Y mutation detected after being persistently A/H1N1 09 RT-PCR positive while receiving oseltamivir treatment. Resistance was not detected in 17 pre-treatment samples and 54 A/H1N1 09 RT-PCR positive outpatients. RCA demonstrates the rapid emergence of the H275Y resistance mutation in individuals with severe A/H1N1 09 infection receiving neuraminidase inhibitors. Rapid detection of oseltamivir resistance in severe infection is essential for patients to receive maximum therapeutic benefit. In the light of emerging resistance, close monitoring and understanding of the nature and dynamics of resistance mutations in newly emerging strains should be a priority.

The Natural Viral Load Profile of Patients With Pandemic 2009 Influenza A(H1N1) and the Effect of Oseltamivir Treatment

BackgroundThe natural history of viral shedding from the upper respiratory tract of the new pandemic 2009 influenza A(H1N1) and the effect of oseltamivir treatment were uncertain.MethodsA retrospective cohort study involving 145 consecutive patients with specimens positive by reverse transcriptase-polymerase chain reaction for the matrix and new H1 genes was conducted.ResultsThe nontreated and oseltamivir-treated patients were comparable in their viral load at presentation, demography, and the presenting symptoms. No correlation was observed between viral load with age and number of symptoms. Viral load of nasopharyngeal aspirate (NPA) was significantly lower in treated than in nontreated patients at day 5 after symptom onset. When oseltamivir was initiated ≤ 2 days after symptom onset, a greater rate of viral load reduction in NPA of treated patients than that of nontreated patients was observed (−0.638 [95% CI, −0.809 to −0.466] vs −0.409 [95% CI, −0.663 to −0.185] log10 copies/mL/d post-symptom onset), and the viral load was undetectable at day 6 after oseltamivir initiation, which was 1 day earlier than that of those whose treatment was initiated > 2 days of symptom onset. The viral load was inversely correlated with concomitant absolute lymphocyte count in nontreated patients (Pearson correlation coefficient [r] = −0.687, P = .001) and treated patients (Pearson r = −0.365, P < .001). Resolution of fever was 1.4 days later in nontreated than treated patients (P = .012)ConclusionsThe natural viral load profile was described. Oral oseltamivir suppresses viral load more effectively when given early in mild cases of pandemic 2009 influenza A(H1N1) infections.

Oseltamivir in seasonal influenza: cumulative experience in low- and high-risk patients.

Seasonal influenza viruses cause annual disease epidemics that affect individuals at low and high risk for secondary illnesses. Influenza vaccines are widely used in high-risk patients to prevent infection, but the protection afforded varies by population; uptake is also limited in some groups. Antiviral drugs for influenza are now readily available. Oseltamivir is the most widely used antiviral for the treatment and prophylaxis of seasonal influenza, and its efficacy and safety are now well established in a variety of populations. In addition to decreasing the severity and duration of the symptoms of influenza, clinical and epidemiological studies demonstrate that oseltamivir significantly reduces the frequency of secondary illnesses and exacerbation of underlying conditions; survival is also significantly improved in seriously ill patients who are hospitalized with severe influenza. Resistant viruses are isolated with a low frequency during oseltamivir treatment (0.33% in adults and 4.0% in children among almost 2000 oseltamivir-treated patients enrolled onto Roche-sponsored clinical trials of oseltamivir treatment during the oseltamivir development programme). However, an oseltamivir-resistant influenza A (H1N1) virus emerged in Europe during the 2007–08 season and circulated in the southern and northern hemispheres in 2008–09. No link with oseltamivir usage could be detected, and the clinical impact of these viruses was limited. Oseltamivir-susceptible pandemic (H1N1) 2009 viruses now predominate in many countries. Oseltamivir is generally well tolerated, with a similar adverse event profile to placebo.

Detection of E119V and E119I Mutations in Influenza A (H3N2) Viruses Isolated from an Immunocompromised Patient: Challenges in Diagnosis of Oseltamivir Resistance

The clinical use of the neuraminidase inhibitor (NAI) oseltamivir is associated with the emergence of drug resistance resulting from subtype-specific neuraminidase (NA) mutations. The influenza A/Texas/12/2007 (H3N2) virus isolated from an oseltamivir-treated immunocompromised patient exhibited reduced susceptibility to oseltamivir in the chemiluminescent neuraminidase inhibition (NI) assay (approximately 60-fold increase in its 50% inhibitory concentration [IC(50)] compared to that for a control virus). When further propagated in cell culture, the isolate maintained reduced susceptibility to oseltamivir in both chemiluminescent and fluorescent NI assays (approximately 50- and 350-fold increases in IC(50), respectively). Sequencing analysis of the isolate revealed a mix of nucleotides coding for amino acids at position 119 of the NA [E119(V/I)]. Plaque purification of the isolate yielded E119V and E119I variants, both exhibiting reduced susceptibility to oseltamivir. The E119I variant also showed decreased susceptibility to zanamivir and the investigational NAIs peramivir and A-315675. The emergence of E119V variants in oseltamivir-treated patients has been previously reported; however, the E119I mutation detected here is a novel one which reduces susceptibility to several NAIs. Both mutations were not detected in unpropagated original clinical specimens using either conventional sequencing or pyrosequencing, suggesting that these variants were present in very low proportions (<10%) in clinical specimens and gained dominance after virus propagation in MDCK cells. All virus isolates recovered from the patient were resistant to adamantanes. Our findings highlight the potential for emergence and persistence of multidrug-resistant influenza viruses in oseltamivir-treated immunocompromised subjects and also highlight challenges for drug resistance diagnosis due to the genetic instability of the virus population upon propagation in cell culture.

T-705 (favipiravir) activity against lethal H5N1 influenza A viruses

The neuraminidase inhibitors oseltamivir and zanamivi are used to treat H5N1 influenza. However, oseltamivir-resistant H5N1 viruses have been isolated from oseltamivir-treated patients. Moreover, reassortment between H5N1 viruses and oseltamvir-resistant human H1N1 viruses currently circulating could create oseltamivir-resistant H5N1 viruses, rendering the oseltamivir stockpile obsolete. Therefore, there is a need for unique and effective antivirals to combat H5N1 influenza viruses. The investigational drug T-705 (favipiravir; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has antiviral activity against seasonal influenza viruses and a mouse-adapted H5N1 influenza virus derived from a benign duck virus. However, its efficacy against highly pathogenic H5N1 viruses, which are substantially more virulent, remains unclear. Here, we demonstrate that T-705 effectively protects mice from lethal infection with oseltamivir-sensitive or -resistant highly pathogenic H5N1 viruses. Furthermore, our biochemical analysis suggests that T-705 ribofuranosyl triphosphate, an active form of T-705, acts like purines or purine nucleosides in human cells and does not inhibit human DNA synthesis. We conclude that T-705 shows promise as a therapeutic agent for the treatment of highly pathogenic H5N1 influenza patients.

Surveillance for neuraminidase-inhibitor-resistant influenza viruses in Japan, 1996–2007

High usage of the neuraminidase inhibitor (NAI) oseltamivir in Japan since 2003 led the Neuraminidase Inhibitor Susceptibility Network to assess the susceptibility of community isolates of influenza viruses to oseltamivir and zanamivir. Isolates were tested by the enzyme inhibition assay and by neuraminidase (NA) sequence analysis. Among 1,141 A(H3N2) viruses and 171 type B viruses collected in Japan during the 2003-2004 season, 3 (0.3%) A(H3N2) isolates showed high 50% inhibitory concentrations (IC(50)) to oseltamivir. Each possessed a known resistance NA mutation at R292K or E119V. During the 2004-2005 season, no resistance was found among 567 influenza A(H3N2) or 60 A(H1N1) isolates, but 1 of 58 influenza B isolates had an NAI resistance mutation (D197N). Sequence analysis found that 4 (3%) of 132 A(H1N1) viruses from 2005-2006 had known NA resistance mutations (all H274Y), but no additional resistant isolates were detected from that or the subsequent 2006-2007 season. Concurrent testing of a selection of 500 influenza B viruses from 2000 to 2006 showed significant variations between seasons in both oseltamivir and zanamivir IC(50) values, but no persistent increases over this period. Our findings suggested possible low-level transmission of resistant variants from oseltamivir-treated patients in several seasons in Japan but no sustained reductions in NAI susceptibility or consistently increased frequency of detecting resistant variants for any strain or subtype, despite high levels of drug use. In particular, although oseltamivir-resistant A(H1N1) viruses with the H274Y mutation spread globally in 2007-2008, we found little evidence for increasing levels of resistant A(H1N1) variants in Japan in preceding years.