Novel modelling approaches to predict the role of antivirals in reducing influenza transmission.

To aid understanding of the effect of antiviral treatment on population-level influenza transmission, we used a novel pharmacokinetic-viral kinetic transmission model to test the correlation between nasal viral load and infectiousness, and to evaluate the impact that timing of treatment with the antivirals oseltamivir or baloxavir has on influenza transmission. The model was run under three candidate profiles whereby infectiousness was assumed to be proportional to viral titer on a natural-scale, log-scale, or dose-response model. Viral kinetic profiles in the presence and absence of antiviral treatment were compared for each individual (N = 1000 simulated individuals); subsequently, viral transmission mitigation was calculated. The predicted transmission mitigation was greater with earlier administration of antiviral treatment, and with baloxavir versus oseltamivir. When treatment was initiated 12-24 hours post symptom onset, the predicted transmission mitigation was 39.9-56.4% for baloxavir and 26.6-38.3% for oseltamivir depending on the infectiousness profile. When treatment was initiated 36-48 hours post symptom onset, the predicted transmission mitigation decreased to 0.8-28.3% for baloxavir and 0.8-19.9% for oseltamivir. Model estimates were compared with clinical data from the BLOCKSTONE post-exposure prophylaxis study, which indicated the log-scale model for infectiousness best fit the observed data and that baloxavir affords greater reductions in secondary case rates compared with neuraminidase inhibitors. These findings suggest a role for baloxavir and oseltamivir in reducing influenza transmission when treatment is initiated within 48 hours of symptom onset in the index patient.

Evaluating the fitness of PA/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model.

Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses.

Understanding the Impact of Resistance to Influenza Antivirals.

Influenza poses a significant burden on society and health care systems. Although antivirals are an integral tool in effective influenza management, the potential for the emergence of antiviral-resistant viruses can lead to uncertainty and hesitation among front-line prescribers and policy makers. Here, we provide an overview of influenza antiviral resistance in context, exploring the key concepts underlying its development and clinical impact. Due to the acute nature of influenza in immunocompetent patients, resistant viruses that develop during antiviral treatment of a single patient ("treatment-emergent resistance") are usually cleared in a relatively short time, with no impact on future antiviral efficacy. In addition, although available data are limited by small numbers of patients, they show that antiviral treatment still provides clinical benefit to the patient within whom resistance emerges. In contrast, the sustained community transmission of resistant variants in the absence of treatment ("acquired resistance") is of greater concern and can potentially render front-line antivirals ineffective. Importantly, however, resistant viruses are usually associated with reduced fitness such that their widespread transmission is relatively rare. Influenza antivirals are an essential part of effective influenza management due to their ability to reduce the risk of complications and death in infected patients. Although antiviral resistance should be taken seriously and requires continuous careful monitoring, it is not comparable to antibiotic resistance in bacteria, which can become permanent and widespread, with far-reaching medical consequences. The benefits of antiviral treatment far outweigh concerns of potential resistance, which in the vast majority of cases does not have a significant clinical impact.

Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission.

Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community.

Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS).

BACKGROUND: We studied the effect of age, baseline viral load, vaccination status, antiviral therapy, and emergence of drug resistance on viral shedding in children infected with influenza A or B virus. METHODS: Samples from children (aged ≤13 years) enrolled during the 7 years of the prospective Influenza Resistance Information Study were analyzed using polymerase chain reaction to determine the influenza virus (sub-)type, viral load, and resistance mutations. Disease severity was assessed; clinical symptoms were recorded. The association of age with viral load and viral clearance was examined by determining the area under the curve for viral RNA shedding using logistic regression and Kaplan-Meier analyses. RESULTS: A total of 2131 children infected with influenza (683, A/H1N1pdm09; 825, A/H3N2; 623, influenza B) were investigated. Age did not affect the mean baseline viral load. Children aged 1-5 years had prolonged viral RNA shedding (±1-2 days) compared with older children and up to 1.2-fold higher total viral burden. Besides, in older age (odds ratio [OR], 1.08; confidence interval [CI], 1.05-1.12), prior vaccination status (OR, 1.72; CI, 1.22-2.43) and antiviral treatment (OR, 1.74; CI, 1.43-2.12) increased the rate of viral clearance. Resistance mutations were detected in 49 children infected with influenza A virus (34, A/H1N1pdm09; 15, A/H3N2) treated with oseltamivir, most of whom were aged <5 years (n = 39). CONCLUSIONS: Children aged 1-5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatment. CLINICAL TRIALS REGISTRATION: NCT00884117.

Oseltamivir in pregnancy and birth outcomes.

BACKGROUND: Prenatal exposure to influenza or fever is associated with risk of congenital malformations. Oseltamivir is used to treat influenza and to provide post-exposure prophylaxis. We examined the association between oseltamivir use during pregnancy and birth outcomes. METHODS: This was a nationwide registry-based prevalence study with individual level data linkage, in a setting of universal health care access. We included all recorded pregnancies in Denmark in 2002-2013, and used data from population registries to examine associations between dispensings for oseltamivir during pregnancy (first trimester, second/third trimester, none) and congenital malformations, foetal death, preterm birth, foetal growth, and low 5-min Apgar score. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using propensity score matching. RESULTS: The study included 946,176 pregnancies. Of these, 449 had first-trimester exposure and 1449 had second/third-trimester exposure to oseltamivir. Adjusted ORs following first-trimester exposure were 0.94 (95% CI 0.49 to 1.83) for any major congenital malformation and 1.75 (95% CI 0.51 to 5.98) for congenital heart defects, based on 7 exposed cases. The association with congenital heart defects was present for etiologically implausible exposure periods and for known safe exposures. There was no evidence of an association between prenatal exposure to oseltamivir and any of the other birth outcomes assessed. CONCLUSIONS: The study does not provide evidence of risk associated with oseltamivir treatment additional to that associated with influenza infection.

Investigating clinically adequate concentrations of oseltamivir carboxylate in end-stage renal disease patients undergoing hemodialysis using a population pharmacokinetic approach.

End-stage renal disease (ESRD) patients receiving hemodialysis (HD) are at heightened risk for influenza, but the optimal oseltamivir dosage regimen for treating or preventing influenza in this high-risk population is still uncertain. Pharmacokinetic data for 24 adults with ESRD were pooled from a single-dose and a multiple-dose study to develop a population pharmacokinetic model using nonlinear mixed-effects modeling. The final model comprised five compartments, two each to describe the systemic pharmacokinetics of oseltamivir phosphate and its metabolite, oseltamivir carboxylate (OC), and a delay compartment to describe oseltamivir metabolism. Estimated OC clearance in the model was markedly faster during HD sessions (7.43 liters/min) than at other times (0.19 liter/min). Model simulations showed that 30 mg oseltamivir given after every HD session is the most suitable regimen for influenza treatment, producing trough OC concentrations above the median value achieved with the 75-mg twice-daily regimen in patients with normal renal function and peak concentrations below the highest oseltamivir exposures known to be well tolerated (median exposures after twice-daily dosing of 450 mg). Administration of the first dose following diagnosis of influenza need not wait until after the next HD session: addition of a single 30-mg dose during the 12 h before the next HD session raises OC exposures quickly without posing any safety risk. Further simulation showed that 30 mg oseltamivir given after every other HD session is the most suitable regimen for influenza prophylaxis.

Pharmacokinetics and safety of intravenous oseltamivir in infants and children in open-label studies.

OBJECTIVE: Critically ill children with influenza may be unable to swallow or absorb oral drugs. An intravenous (IV) formulation of the antiviral oseltamivir was evaluated in two prospective open-label studies. METHODS: Hospitalized children aged <1 year (NCT01053663) or 1-12 years (NCT01033734) with clinical or laboratory-confirmed influenza, normal renal function, and who are unable to tolerate and/or absorb oral medication were enrolled. Patients received oseltamivir 2-3 mg/kg (age<1 year) or 2.5-3 mg/kg (max. 100 mg; age 1-12 years) by slow IV infusion twice daily for up to 6 days. Blood samples were taken for pharmacokinetics and nasal swabs taken to monitor viral shedding and resistance (by reverse transcriptase polymerase chain reaction (RTPCR) and culture). Adverse events (AEs) were monitored for 30 days from treatment initiation. RESULTS: 17 children were enrolled (9 aged<1 year; 8 aged 1-12 years). On day 1, 11 patients had laboratory-confirmed influenza. Seven patients switched from IV to oral dosing before the 10th dose. Individual plasma oseltamivir carboxylate exposures (AUClast) ranged from 1,700 to 11,500 h x ng/mL. 23 AEs were reported in 10 patients; 2 were considered treatment-related (rash, infusion site erythema). Eight serious AEs (SAEs) were reported in 7 patients, including 3 deaths in patients aged <1 year; none were considered treatment-related. Two SAEs caused treatment withdrawal. Six patients had influenza detected on or after day 11 of treatment. The oseltamivir resistance mutation H275Y was detected in three samples from 1 patient with H1N1pdm09 infection. CONCLUSIONS: IV oseltamivir was well tolerated in this sample of seriously ill children. The small patient numbers precluded any formal analysis by age group or dose.

Effect of bone-conduction harmonic distortions on hearing thresholds.

This study compares bone conduction (BC) thresholds obtained with two bone vibrators (BV): The Radioear B71 and an advanced BV, the Radioear B81. B81 has less distortion and is capable of higher output levels. Two tests with 20 normal hearing subjects were conducted to determine if the low distortion of B81 offers any advantages for audiometry. Hearing threshold differences between B71 and B81 are only significant at 250 Hz for levels between 20 dB hearing level (HL) and 30 dB HL. At other frequencies and higher levels, where B81 also performs with less distortion than B71, tactile responses interfere before B81 can be advantageous.

A Phase 2 Randomized Trial Evaluating the Antiviral Activity and Safety of the Direct-Acting Antiviral Bemnifosbuvir in Ambulatory Patients with Mild or Moderate COVID-19 (MOONSONG Study).

Bemnifosbuvir is an oral antiviral drug with a dual mechanism of action targeting viral RNA polymerase, with in vitro activity against SARS-CoV-2. We conducted a phase 2, double-blind study evaluating the antiviral activity, safety, efficacy, and pharmacokinetics of bemnifosbuvir in ambulatory patients with mild/moderate COVID-19. Patients were randomized 1:1 to bemnifosbuvir 550 mg or placebo (cohort A) and 3:1 to bemnifosbuvir 1,100 mg or placebo (cohort B); all doses were given twice daily for 5 days. The primary endpoint was a change from baseline in the amount of nasopharyngeal SARS-CoV-2 viral RNA by reverse transcription PCR (RT-PCR). The modified intent-to-treat infected population comprised 100 patients (bemnifosbuvir 550 mg, n = 30; bemnifosbuvir 1,100 mg, n = 30; cohort A placebo, n = 30; cohort B placebo, n = 10). The primary endpoint was not met: the difference in viral RNA adjusted means at day 7 was -0.25 log10 copies/mL between bemnifosbuvir 550 mg and cohort A placebo (80% confidence interval [CI], -0.66 to 0.16; P = 0.4260), and -0.08 log10 copies/mL between bemnifosbuvir 1,100 mg and pooled placebo (80% CI, -0.48 to 0.33; P = 0.8083). Bemnifosbuvir 550 mg was well tolerated. Incidence of nausea and vomiting was higher with bemnifosbuvir 1,100 mg (10.0% and 16.7% of patients, respectively) than pooled placebo (2.5% nausea, 2.5% vomiting). In the primary analysis, bemnifosbuvir did not show meaningful antiviral activity on nasopharyngeal viral load as measured by RT-PCR compared with placebo in patients with mild/moderate COVID-19. The trial is registered at ClinicalTrials.gov under registration number NCT04709835. IMPORTANCE COVID-19 continues to be a major global public health challenge, and there remains a need for effective and convenient direct-acting antivirals that can be administered outside health care settings. Bemnifosbuvir is an oral antiviral with a dual mechanism of action and potent in vitro activity against SARS-CoV-2. In this study, we evaluated the antiviral activity, safety, efficacy, and pharmacokinetics of bemnifosbuvir in ambulatory patients with mild/moderate COVID-19. In the primary analysis, bemnifosbuvir did not show meaningful antiviral activity compared with placebo as assessed by nasopharyngeal viral loads. The negative predictive value of nasopharyngeal viral load reduction for clinical outcomes in COVID-19 is currently unclear, and further evaluation of bemnifosbuvir for COVID-19 may be warranted despite the findings observed in this study.

Predictors of Seeking Care for Influenza-Like Illness in a Novel Digital Study.

Background: Previous research has estimated that >50% of individuals experiencing influenza-like illness (ILI) do not seek health care. Understanding factors influencing care-seeking behavior for viral respiratory infections may help inform policies to improve access to care and protect public health. We used person-generated health data (PGHD) to identify factors associated with seeking care for ILI. Methods: Two observational studies (FluStudy2020, ISP) were conducted during the United States 2019-2020 influenza season. Participants self-reported ILI symptoms using the online Evidation platform. A log-binomial regression model was used to identify factors associated with seeking care. Results: Of 1667 participants in FluStudy2020 and 47 480 participants in ISP eligible for analysis, 518 (31.1%) and 11 426 (24.1%), respectively, sought health care. Participants were mostly female (92.2% FluStudy2020, 80.6% ISP) and aged 18-49 years (89.6% FluStudy2020, 89.8% ISP). In FluStudy2020, factors associated with seeking care included having health insurance (risk ratio [RR], 2.14; 95% CI, 1.30-3.54), more severe respiratory symptoms (RR, 1.53; 95% CI, 1.37-1.71), and comorbidities (RR, 1.37; 95% CI, 1.20-1.58). In ISP, the strongest predictor of seeking care was high symptom number (RR for 6/7 symptoms, 2.14; 95% CI, 1.93-2.38). Conclusions: Using PGHD, we confirmed low rates of health care-seeking behavior for ILI and show that having health insurance, comorbidities, and a high symptom burden were associated with seeking health care. Reducing barriers in access to care for viral respiratory infections may lead to better disease management and contribute to protecting public health.

Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial.

BACKGROUND: Neuraminidase inhibitors (NAIs) are considered the standard of care for hospitalised patients with influenza. We aimed to test whether combining the cap-dependent endonuclease inhibitor baloxavir marboxil (hereafter baloxavir) with standard-of-care NAIs would result in improved clinical outcomes compared with NAI monotherapy in hospitalised patients with severe influenza. METHODS: We did a randomised, parallel-group, double-blind, placebo-controlled, superiority trial. Patients aged 12 years or older who were hospitalised with laboratory-confirmed influenza (by RT-PCR or a rapid test) and had a National Early Warning Score 2 (NEWS2) of 4 or greater were included. Recruitment took place in 124 centres across 25 countries. Using a permuted-block method and an interactive response system, patients were randomly assigned (2:1) to receive either baloxavir plus NAIs (hereafter the baloxavir group) or placebo plus NAIs (hereafter the control group). Participants, investigators, and those assessing outcomes were masked to group assignment. Baloxavir was administered orally on day 1 and day 4 (40 mg for bodyweight <80 kg, or 80 mg for ≥80 kg), and on day 7 if no clinical improvement had occurred by day 5. The NAIs included in this study were oseltamivir, zanamivir, and peramivir, which were selected and administered according to local standard practice. The primary endpoint was time to clinical improvement, defined as time to a NEWS2 of 2 or lower for 24 h or hospital discharge, whichever came first, based on daily assessments over the study duration of 35 days. Secondary endpoints included safety analyses. The modified intention-to-treat infected (mITTI) population (ie, all patients who were randomly assigned to treatment, received a dose of study drug, and were RT-PCR-positive for influenza at any timepoint according to the treatment assigned at randomisation) was used in all efficacy analyses. The safety population (ie, all patients who received at least one dose of study treatment, according to the treatment received) was used in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03684044. FINDINGS: Overall, 366 patients were enrolled between Jan 8, 2019, and March 16, 2020, of whom 241 were assigned to the baloxavir group and 125 to the control group. The mITTI population comprised 322 patients, 208 in the baloxivir group and 114 in the control group. In total, 280 (87%) of these patients had influenza A infections. Median time to clinical improvement was 97·5 h (95% CI 75·9 to 117·2) in the baloxavir group and 100·2 h (75·9 to 144·4) in the control group (median difference -2·7 h [95% CI -53·4 to 25·9], p=0·467). Baloxavir plus NAI was well tolerated, and no new safety signals were observed; serious adverse events occurred in 29 (12%) of 239 patients in the baloxavir group versus 19 (15%) of 124 patients in the control group, of which one was considered related to treatment (orthostatic hypotension in a patient in the control group). Overall, four deaths (2%) occurred in the baloxavir group and seven (6%) in the control group; none were considered related to treatment. INTERPRETATION: Combining baloxavir with NAIs did not result in superior clinical outcomes compared with NAIs alone. The combination of baloxavir plus NAI was well tolerated. The findings suggest that combination antivirals would not be routinely indicated in clinical practice for hospitalised patients with severe influenza. FUNDING: F Hoffmann-La Roche and the Biomedical Advanced Research and Development Authority.

Burden of influenza B virus infection and considerations for clinical management.

Influenza B viruses cause significant morbidity and mortality, particularly in children, but the awareness of their impact is often less than influenza A viruses partly due to their lack of pandemic potential. Here, we summarise the biology, epidemiology and disease burden of influenza B, and review existing data on available antivirals for its management. There has long been uncertainty surrounding the clinical efficacy of neuraminidase inhibitors (NAIs) for influenza B treatment. In this article, we bring together the existing data on NAIs and discuss these alongside recent large randomised controlled trial data for the new polymerase inhibitor baloxavir in high-risk influenza B patients. Finally, we offer considerations for the clinical management of influenza B, with a focus on children and high-risk patients where disease burden is highest.

Secondary substitutions in the hemagglutinin and neuraminidase genes associated with neuraminidase inhibitor resistance are rare in the Influenza Resistance Information Study (IRIS).

Amino acid substitutions in influenza virus neuraminidase (NA) that cause resistance to neuraminidase inhibitors (NAI) generally result in virus attenuation. However, influenza viruses may acquire secondary substitutions in the NA and hemagglutinin (HA) proteins that can restore viral fitness. To assess to which extent this happens, the emergence of NAI resistance substitutions and secondary - potentially compensatory - substitutions was quantified in influenza viruses of immunocompetent individuals included in the Influenza Resistance Information Study (IRIS; NCT00884117). Known resistance substitutions were detected by mutation specific RT-PCR in viruses of 57 of 1803 (3.2%) oseltamivir-treated individuals, including 39 individuals infected with A/H1N1pdm09 [H275Y] virus and 18 with A/H3N2 [R292K] virus. A total of fifteen and ten other amino acid substitutions were acquired in HA and NA respectively, of A/H1N1pdm09, A/H3N2 and influenza B viruses upon treatment with oseltamivir but none of these was associated with resistance to oseltamivir. All cultured viruses with the known resistance substitutions H275Y or R292K showed reduced susceptibility to oseltamivir in the NA-star assay. Upon next-generation sequencing, the vast majority of NAI resistant A/H1N1pdm09 and A/H3N2 viruses had no resistance-associated secondary substitutions at high frequency. Only in two A/H1N1pdm09 [H275Y] viruses, the potentially compensatory secondary substitutions HA-D52N and NA-R152K were detected. We conclude that the emergence of secondary substitutions that may restore viral fitness upon the emergence of known influenza virus NAI resistance substitutions was a rare event in this immunocompetent population.

Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2).

BACKGROUND: Baloxavir marboxil (baloxavir) is a novel, cap-dependent endonuclease inhibitor that has previously demonstrated efficacy in the treatment of influenza in adults and adolescents. We assessed the safety and efficacy of baloxavir in otherwise healthy children with acute influenza. METHODS: MiniSTONE-2 (Clinicaltrials.gov: NCT03629184) was a double-blind, randomized, active controlled trial enrolling children 1-<12 years old with a clinical diagnosis of influenza. Children were randomized 2:1 to receive either a single dose of oral baloxavir or oral oseltamivir twice daily for 5 days. The primary endpoint was incidence, severity and timing of adverse events (AEs); efficacy was a secondary endpoint. RESULTS: In total, 173 children were randomized and dosed, 115 to the baloxavir group and 58 to the oseltamivir group. Characteristics of participants were similar between treatment groups. Overall, 122 AEs were reported in 84 (48.6%) children. Incidence of AEs was similar between baloxavir and oseltamivir groups (46.1% vs. 53.4%, respectively). The most common AEs were gastrointestinal (vomiting/diarrhea) in both groups [baloxavir: 12 children (10.4%); oseltamivir: 10 children (17.2%)]. No deaths, serious AEs or hospitalizations were reported. Median time (95% confidence interval) to alleviation of signs and symptoms of influenza was similar between groups: 138.1 (116.6-163.2) hours with baloxavir versus 150.0 (115.0-165.7) hours with oseltamivir. CONCLUSIONS: Oral baloxavir is well tolerated and effective at alleviating symptoms in otherwise healthy children with acute influenza. Baloxavir provides a new therapeutic option with a simple oral dosing regimen.

Mechanistic Population Pharmacokinetic Model of Oseltamivir and Oseltamivir Carboxylate Accounting for Physiological Changes to Predict Exposures in Neonates and Infants.

A mechanistic population-pharmacokinetic model was developed to predict oseltamivir exposures in neonates and infants accounting for physiological changes during the first 2 years of life. The model included data from 13 studies, comprising 436 subjects with normal renal function (317 pediatric subjects (≥ 38 weeks postmenstrual age (PMA), ≥ 13 days old) and 119 adult subjects < 40 years). Concentration-time profiles of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were characterized by a four-compartment model, with absorption described by three additional compartments. Renal maturational changes were implemented by description of OC clearance with allometric function of weight and Hill function of PMA. Clearance of OC increased with weight up to 43 kg (allometric coefficient 0.75). Half the adult OC clearance was reached at a PMA of 45.6 weeks (95% confidence interval (CI) 41.6-49.6) with a Hill coefficient of 2.35 (95% CI 1.67-3.04). The model supports the European Union/United States-approved 3 mg/kg twice-daily oseltamivir dose for infants < 1 year (PMA ≥ 38 weeks) and allows prediction of exposures in preterm neonates.

Safety, Resistance, and Efficacy Results from a Phase IIIb Study of Conventional- and Double-Dose Oseltamivir Regimens for Treatment of Influenza in Immunocompromised Patients.

INTRODUCTION: Immunocompromised patients infected with influenza exhibit prolonged viral shedding and higher risk of resistance. Optimized treatment strategies are needed to reduce the risk of antiviral resistance. This phase IIIb, randomized, double-blind study (NCT00545532) evaluated conventional-dose or double-dose oseltamivir for the treatment of influenza in immunocompromised patients. METHODS: Patients with primary or secondary immunodeficiency and influenza infection were randomized 1:1 to receive conventional-dose oseltamivir (75 mg adolescents/adults [≥ 13 years]; 30-75 mg by body weight in children [1-12 years]) or double-dose oseltamivir (150 or 60-150 mg, respectively), twice daily for an extended period of 10 days. Nasal/throat swabs were taken for virology assessments at all study visits. Co-primary endpoints were safety/tolerability and viral resistance. Secondary endpoints included time to symptom alleviation (TTSA) and time to cessation of viral shedding (TTCVS). RESULTS: Of 228 patients enrolled between February 2008 and May 2017, 215 (199 adults) were evaluable for safety, 167 (151 adults) for efficacy, and 152 (138 adults) for resistance. Fewer patients experienced an adverse event (AE) in the conventional-dose group (50.5%) versus the double-dose group (59.1%). The most frequently reported AEs were nausea, diarrhea, vomiting, and headache. Fifteen patients had post-baseline resistance, more commonly in the conventional-dose group (n = 12) than in the double-dose group (n = 3). In adults, median TTSA was similar between arms, while median TTCVS was longer with conventional dosing. CONCLUSIONS: Oseltamivir was well tolerated, with a trend toward better safety/tolerability for conventional dosing versus double dosing. Resistance rates were higher with conventional dosing in this immunocompromised patient population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00545532. FUNDING: F. Hoffmann-La Roche Ltd.

Safety, virology and pharmacokinetics of oseltamivir in infants with laboratory-confirmed influenza: a Phase I/II, prospective, open-label, multicentre clinical trial.

BACKGROUND: The influenza antiviral oseltamivir is not licensed for infants aged <1 year in most countries outside the United States. More information is needed on oseltamivir safety at different dosing levels in this vulnerable age group. METHODS: In this prospective, observational, non-randomized study, infants aged <1 year with laboratory-confirmed influenza were treated with oral oseltamivir for 5 days. Cohorts 1, 2 and 3 (aged 91-364, 31-90 and 0-30 days, respectively), received twice-daily dosages of 3, 2.5 and 2 mg/kg, respectively. Assessments included pharmacokinetics, on-treatment adverse events, resistance testing and viral shedding. RESULTS: A total of 65 patients were enrolled: 40, 20 and 5 in cohorts 1, 2 and 3, respectively. Systemic exposure to oseltamivir carboxylate (active metabolite) reached therapeutic levels in all patients, with an adequate safety margin. On-treatment adverse events (n=48) were reported by 32 patients (49%). At least one adverse event was reported by 43%, 65% and 40% of infants in cohorts 1, 2 and 3, respectively; most frequently vomiting and diarrhoea. Eight serious adverse events were reported, all of which were considered unrelated to treatment by the investigator. No deaths occurred and no patient had treatment withdrawn. Oseltamivir resistance mutations were detected in eight patients. CONCLUSIONS: Oseltamivir dosages of 2-3 mg/kg were well tolerated in infants aged <1 year and achieved therapeutic exposure levels. The current study supports the adoption of a universal dosing recommendation for infants. Clinicaltrials.gov unique identifier NCT00988325.