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Current Opinion in Infectious Diseases Apr 2023The heavily suppressed global influenza activity during the coronavirus disease 2019 (COVID-19) pandemic is expected to return upon relaxation of travel restriction and... (Review)
Review
PURPOSE OF REVIEW
The heavily suppressed global influenza activity during the coronavirus disease 2019 (COVID-19) pandemic is expected to return upon relaxation of travel restriction and nonpharmaceutical interventions (NPI). We reviewed the four marketed neuraminidase inhibitors (NAI e.g., oseltamivir, zanamivir, peramivir, laninamivir) and the only endonuclease inhibitor (baloxavir) on their clinical therapeutic effects and the ability of viral suppression in various groups of patients of different clinical settings based on the latest evidence.
RECENT FINDINGS
Early initiation, preferably within 48 h of symptom onsets, of antiviral treatments with NAI and baloxavir, is crucial to produce favourable outcomes in patients with influenza infection. Updated evidence does not suggest routine use of combined antiviral agents in patients with influenza infection. Treatment-emergent resistant influenza variants may occur during NAI and baloxavir use, but it has no major impact on subsequent recovery. Early treatment of index patients with influenza infection and post-exposure prophylaxis in specific populations is crucial in preventing influenza transmission.
SUMMARY
Antiviral therapy is the major defence therapeutically in the community and hospital settings to expedite early recovery and reduce influenza-related complications. Early treatment of index patients and post-exposure prophylaxis in susceptible close contacts may mitigate the spread of infection.
Topics: Humans; Influenza, Human; Neuraminidase; COVID-19; Zanamivir; Antiviral Agents; Oseltamivir; Enzyme Inhibitors
PubMed: 36752709
DOI: 10.1097/QCO.0000000000000910 -
Antiviral Research Feb 2023Effective antivirals provide crucial benefits during the early phase of an influenza pandemic, when vaccines are still being developed and manufactured. Currently, two... (Review)
Review
Effective antivirals provide crucial benefits during the early phase of an influenza pandemic, when vaccines are still being developed and manufactured. Currently, two classes of viral protein-targeting drugs, neuraminidase inhibitors and polymerase inhibitors, are approved for influenza treatment and post-exposure prophylaxis. Resistance to both classes has been documented, highlighting the need to develop novel antiviral options that may include both viral and host-targeted inhibitors. Such efforts will form the basis of management of seasonal influenza infections and of strategic planning for future influenza pandemics. This review focuses on the two classes of approved antivirals, their drawbacks, and ongoing work to characterize novel agents or combination therapy approaches to address these shortcomings. The importance of these topics in the ongoing process of influenza pandemic planning is also discussed.
Topics: Humans; Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Influenza, Human; Neuraminidase; Oseltamivir; Pandemics
PubMed: 36567025
DOI: 10.1016/j.antiviral.2022.105499 -
JAMA Internal Medicine Jan 2024Despite widespread use, summary evidence from prior meta-analyses has contradictory conclusions regarding whether oseltamivir decreases the risk of hospitalization when... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Despite widespread use, summary evidence from prior meta-analyses has contradictory conclusions regarding whether oseltamivir decreases the risk of hospitalization when given to outpatients. Several large investigator-initiated randomized clinical trials have not yet been meta-analyzed.
OBJECTIVE
To assess the efficacy and safety of oseltamivir in preventing hospitalization among influenza-infected adult and adolescent outpatients.
DATA SOURCES
PubMed, Ovid MEDLINE, Embase, Europe PubMed Central, Web of Science, Cochrane Central, ClinicalTrials.gov, and WHO International Clinical Trials Registry were searched from inception to January 4, 2022.
STUDY SELECTION
Included studies were randomized clinical trials comparing oseltamivir vs placebo or nonactive controls in outpatients with confirmed influenza infection.
DATA EXTRACTION AND SYNTHESIS
In this systematic review and meta-analysis, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two independent reviewers (R.H. and É.B.C.) extracted data and assessed risk of bias using the Cochrane Risk of Bias Tool 2.0. Each effect size was pooled using a restricted maximum likelihood random effects model. The quality of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework.
MAIN OUTCOMES AND MEASURES
Hospitalization was pooled as risk ratio (RR) and risk difference (RD) estimates with 95% CIs.
RESULTS
Of 2352 studies identified, 15 were included. The intention-to-treat infected (ITTi) population was comprised of 6166 individuals with 54.7% prescribed oseltamivir. Across study populations, 53.9% (5610 of 10 471) were female and the mean age was 45.3 (14.5) years. Overall, oseltamivir was not associated with reduced risk of hospitalization within the ITTi population (RR, 0.79; 95% CI, 0.48 to 1.29; RD, -0.17%; 95% CI, -0.23% to 0.48%). Oseltamivir was also not associated with reduced hospitalization in older populations (mean age ≥65 years: RR, 1.01; 95% CI, 0.21 to 4.90) or in patients considered at greater risk of hospitalization (RR, 0.65; 0.33 to 1.28). Within the safety population, oseltamivir was associated with increased nausea (RR, 1.43; 95% CI, 1.13 to 1.82) and vomiting (RR, 1.83; 95% CI, 1.28 to 2.63) but not serious adverse events (RR, 0.71; 95% CI, 0.46 to1.08).
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis among influenza-infected outpatients, oseltamivir was not associated with a reduced risk of hospitalization but was associated with increased gastrointestinal adverse events. To justify continued use for this purpose, an adequately powered trial in a suitably high-risk population is justified.
Topics: Adult; Adolescent; Humans; Female; Aged; Middle Aged; Male; Oseltamivir; Influenza, Human; Outpatients; Hospitalization; Europe
PubMed: 37306992
DOI: 10.1001/jamainternmed.2023.0699 -
The Lancet. Infectious Diseases Oct 2020Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of... (Randomized Controlled Trial)
Randomized Controlled Trial
Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial.
BACKGROUND
Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.
METHODS
We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.
FINDINGS
2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (-7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.
INTERPRETATION
Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.
FUNDING
Shionogi.
Topics: Adolescent; Adult; Aged; Antiviral Agents; Child; Dibenzothiepins; Double-Blind Method; Female; Humans; Influenza, Human; Male; Middle Aged; Morpholines; Oseltamivir; Oxazines; Pyridines; Pyridones; Thiepins; Triazines; Young Adult
PubMed: 32526195
DOI: 10.1016/S1473-3099(20)30004-9 -
JAMA Pediatrics Nov 2022Oseltamivir is recommended for all children hospitalized with influenza, despite limited evidence supporting its use in the inpatient setting.
IMPORTANCE
Oseltamivir is recommended for all children hospitalized with influenza, despite limited evidence supporting its use in the inpatient setting.
OBJECTIVE
To determine whether early oseltamivir use is associated with improved outcomes in children hospitalized with influenza.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter retrospective study included 55 799 children younger than 18 years who were hospitalized with influenza from October 1, 2007, to March 31, 2020, in 36 tertiary care pediatric hospitals who participate in the Pediatric Health Information System database. Data were analyzed from January 2021 to March 2022.
EXPOSURES
Early oseltamivir treatment, defined as use of oseltamivir on hospital day 0 or 1.
MAIN OUTCOMES AND MEASURES
The primary outcome was hospital length of stay (LOS) in calendar days. Secondary outcomes included 7-day hospital readmission, late (hospital day 2 or later) intensive care unit (ICU) transfer, and a composite outcome of in-hospital death or use of extracorporeal membrane oxygenation (ECMO). Inverse probability treatment weighting (IPTW) based on propensity scoring was used to address confounding by indication. Mixed-effects models were used to compare outcomes between children who did and did not receive early oseltamivir treatment. Outcomes were also compared within high-risk subgroups based on age, presence of a complex chronic condition, early critical illness, and history of asthma.
RESULTS
The analysis included 55 799 encounters from 36 hospitals. The median (IQR) age of the cohort was 3.61 years (1.03-8.27); 56% were male, and 44% were female. A total of 33 207 patients (59.5%) received early oseltamivir. In propensity score-weighted models, we found that children treated with early oseltamivir had shorter LOS (median 3 vs 4 days; IPTW model ratio, 0.52; 95% CI, 0.52-0.53) and lower odds of all-cause 7-day hospital readmission (3.5% vs 4.8%; adjusted odds ratio [aOR], 0.72; 95% CI, 0.66-0.77), late ICU transfer (2.4% vs 5.5%; aOR, 0.41; 95% CI, 0.37-0.46), and the composite outcome of death or ECMO use (0.9% vs 1.4%; aOR, 0.63; 95% CI, 0.54-0.73).
CONCLUSIONS AND RELEVANCE
Early use of oseltamivir in hospitalized children was associated with shorter hospital stay and lower odds of 7-day readmission, ICU transfer, ECMO use, and death. These findings support the current recommendations for oseltamivir use in children hospitalized with influenza.
Topics: Humans; Male; Female; Child; Child, Preschool; Oseltamivir; Influenza, Human; Child, Hospitalized; Retrospective Studies; Hospital Mortality; Antiviral Agents; Length of Stay; Hospitalization
PubMed: 36121673
DOI: 10.1001/jamapediatrics.2022.3261 -
Lancet (London, England) Jan 2020Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups.
METHODS
We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921.
FINDINGS
Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group.
INTERPRETATION
Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner.
FUNDING
European Commission's Seventh Framework Programme.
Topics: Adolescent; Adult; Aged; Antiviral Agents; Child; Child, Preschool; Combined Modality Therapy; Europe; Female; Humans; Infant; Influenza, Human; Male; Middle Aged; Oseltamivir; Primary Health Care; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult
PubMed: 31839279
DOI: 10.1016/S0140-6736(19)32982-4 -
MBio Oct 2023Influenza viruses (IVs) threaten global human health due to the high morbidity, infection, and mortality rates. Currently, the influenza drugs recommended by the FDA are... (Review)
Review
Influenza viruses (IVs) threaten global human health due to the high morbidity, infection, and mortality rates. Currently, the influenza drugs recommended by the FDA are oseltamivir, zanamivir, peramivir, and baloxavir marboxil. Notably, owing to the high variability of IVs, no drug exists that can effectively treat all types and subtypes of IVs. Moreover, the current trend of drug resistance is likely to continue as the viral genome is constantly mutating. Therefore, there is an urgent need to develop drugs related to the treatment of influenza to deal with the next pandemic. Here, we summarized the cutting-edge research in mechanism of action, inhibitory activity, and clinical efficacy of drugs that have been approved and drugs that are still in clinical trials for influenza treatment. We hope this review will provide up-to-date and comprehensive information on influenza antivirals and generate hypotheses for screens and development of new broad-spectrum influenza drugs in the near future.
Topics: Humans; Influenza, Human; Antiviral Agents; Oseltamivir; Zanamivir; Orthomyxoviridae; Drug Resistance, Viral; Neuraminidase; Enzyme Inhibitors
PubMed: 37610204
DOI: 10.1128/mbio.01273-23 -
Journal of Infection and Chemotherapy :... Mar 2024Baloxavir marboxil (BXM), a newly developed cap-dependent endonuclease inhibitor, is widely used to treat influenza virus infections in inpatients and outpatients. A... (Meta-Analysis)
Meta-Analysis
Comparison of clinical efficacy and safety of baloxavir marboxil versus oseltamivir as the treatment for influenza virus infections: A systematic review and meta-analysis.
INTRODUCTION
Baloxavir marboxil (BXM), a newly developed cap-dependent endonuclease inhibitor, is widely used to treat influenza virus infections in inpatients and outpatients. A previous meta-analysis included only outpatients and patients suspected of having an influenza virus infection based on clinical symptoms. However, whether BXM or oseltamivir is safer and more effective for inpatients remains controversial. Therefore, we conducted a systematic review and meta-analysis validating the effectiveness and safety of BXM versus oseltamivir in inpatients with influenza virus.
METHODS
The Scopus, EMBASE, PubMed, Ichushi, and CINAHL databases were systematically searched for articles published until January 2023. The outcomes were mortality, hospitalization period, incidence of BXM- or oseltamivir-related adverse events, illness duration, and changes of virus titers and viral RNA load in patients with influenza virus infections.
RESULTS
Two randomized controlled trials with 1624 outpatients and two retrospective studies with 874 inpatients were enrolled. No deaths occurred in outpatients treated with BXM or oseltamivir. Among inpatients, BXM reduced mortality (p = 0.06) and significantly shortened hospitalization period (p = 0.01) compared to oseltamivir. In outpatients, BXM had a significantly lower incidence of adverse events (p = 0.03), reductions in influenza virus titers (p < 0.001) and viral RNA loads (p < 0.001), and a tendency to be a shorter illness duration compared with that of oseltamivir (p = 0.27).
CONCLUSIONS
Our meta-analysis showed that BXM was safer and more effective in patients than oseltamivir; thus, supporting the use of BXM for the initial treatment of patients with proven influenza virus infection.
Topics: Humans; Oseltamivir; Influenza, Human; Retrospective Studies; Antiviral Agents; Oxazines; Pyridines; Thiepins; Orthomyxoviridae Infections; Treatment Outcome; RNA, Viral; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 37866622
DOI: 10.1016/j.jiac.2023.10.017 -
Cold Spring Harbor Perspectives in... Jan 2022The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic)... (Review)
Review
The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections. NA changes, naturally occurring or acquired under selective pressure, have been shown to reduce drug binding, thereby affecting the effectiveness of NA inhibitors. Drug resistance and other drawbacks have prompted the search for the next-generation NA-targeting therapeutics. One of the promising approaches is the identification of monoclonal antibodies (mAbs) targeting the conserved NA epitopes. Anti-NA mAbs demonstrate Fab-based antiviral activity supplemented with Fc-mediated immune effector functions. Antiviral Fc-conjugates offer another cutting-edge strategy that is based on a multimodal mechanism of action. These novel antiviral agents are composed of a small-molecule NA inhibitor and an Fc-region that simultaneously engages the immune system. The significant advancements made in recent years further support the value of NA as an attractive target for the antiviral development.
Topics: Antibodies, Monoclonal; Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Zanamivir
PubMed: 32152244
DOI: 10.1101/cshperspect.a038455