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Transplant Infectious Disease : An... Apr 2024Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir...
BACKGROUND
Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir in outpatients with influenza. Baloxavir was equally effective as oseltamivir in a retrospective study of hospitalized patients with influenza at our institution. However, the efficacy of baloxavir in immunocompromised patients is unclear.
METHODS
We conducted a retrospective cohort study of immunocompromised adult patients hospitalized with influenza A who received baloxavir from January 2019 to April 2019 or oseltamivir from January 2018 to April 2018. Demographic and clinical outcomes were assessed. Primary outcomes were time from antiviral initiation to resolution of hypoxia and fever. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) care, ICU LOS, and 30-day mortality.
RESULTS
Of 95 total patients, 52 received baloxavir and 43 received oseltamivir. Other than younger age (57.5 vs. 65; p = .035) and longer duration between vaccination and symptom onset (114 vs. 86 days; p = .001) in the baloxavir group, baseline characteristics did not differ. H1 was the predominant subtype in the baloxavir group (65.3%) versus H3 in the oseltamivir group (85.7%). When comparing baloxavir to oseltamivir, there was no significant difference in median time from antiviral initiation to resolution of hypoxia (59.9 vs. 42.5 h) and to resolution of fever (21.6 vs. 26.6 h). There were no differences in secondary outcomes.
CONCLUSION
Baloxavir was not associated with longer time to resolution of hypoxia or fever in comparison to oseltamivir. Results must be taken in context of variations in seasonal influenza subtype and resistance rates.
Topics: Adult; Humans; Oseltamivir; Influenza, Human; Retrospective Studies; Oxazines; Pyridines; Thiepins; Antiviral Agents; Immunocompromised Host; Hypoxia; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 38319665
DOI: 10.1111/tid.14249 -
Journal of Medical Virology Aug 2023The aim of this study is to investigate the effectiveness of prolonged versus standard course oseltamivir treatment among critically ill patients with severe influenza....
The aim of this study is to investigate the effectiveness of prolonged versus standard course oseltamivir treatment among critically ill patients with severe influenza. A retrospective study of a prospectively collected database including adults with influenza infection admitted to 184 intensive care units (ICUs) in Spain from 2009 to 2018. Prolonged oseltamivir was defined if patients received the treatment beyond 5 days, whereas the standard-course group received oseltamivir for 5 days. The primary outcome was all-cause ICU mortality. Propensity score matching (PSM) was constructed, and the outcome was investigated through Cox regression and RCSs. Two thousand three hundred and ninety-seven subjects were included, of whom 1943 (81.1%) received prolonged oseltamivir and 454 (18.9%) received standard treatment. An optimal full matching algorithm was performed by matching 2171 patients, 1750 treated in the prolonged oseltamivir group and 421 controls in the standard oseltamivir group. After PSM, 387 (22.1%) patients in the prolonged oseltamivir and 119 (28.3%) patients in the standard group died (p = 0.009). After adjusting confounding factors, prolonged oseltamivir significantly reduced ICU mortality (odds ratio [OR]: 0.53, 95% confidence interval [CI]: 0.40-0.69). Prolonged oseltamivir may have protective effects on survival at Day 10 compared with a standard treatment course. Sensitivity analysis confirmed these findings. Compared with standard treatment, prolonged oseltamivir was associated with reduced ICU mortality in critically ill patients with severe influenza. Clinicians should consider extending the oseltamivir treatment duration to 10 days, particularly in higher-risk groups of prolonged viral shedding. Further randomized controlled trials are warranted to confirm these findings.
Topics: Adult; Humans; Oseltamivir; Influenza, Human; Antiviral Agents; Retrospective Studies; Critical Illness
PubMed: 37537755
DOI: 10.1002/jmv.29010 -
The Pediatric Infectious Disease Journal Nov 2023miniSTONE-2 (NCT03629184) was a global, phase 3, randomized, controlled study that investigated the safety and efficacy of single-dose baloxavir marboxil in otherwise...
BACKGROUND
miniSTONE-2 (NCT03629184) was a global, phase 3, randomized, controlled study that investigated the safety and efficacy of single-dose baloxavir marboxil in otherwise healthy children 1-<12 years of age and showed a positive risk-benefit profile. This post hoc analysis evaluated the safety and efficacy of baloxavir versus oseltamivir in children 5-11 years old with influenza.
METHODS
Children received single-dose baloxavir or twice-daily oseltamivir for 5 days. Safety was the primary objective. Efficacy and virological outcomes included time to alleviation of symptoms, duration of fever and time to cessation of viral shedding by titer. Data were summarized descriptively.
RESULTS
Ninety-four children 5-11 years old were included (61 baloxavir and 33 oseltamivir). Baseline characteristics were similar between the groups. The incidence of adverse events was balanced and low in both treatment groups, with the most common being vomiting (baloxavir 5% vs. oseltamivir 18%), diarrhea (5% vs. 0%) and otitis media (0% vs. 5%). No serious adverse events or deaths occurred. Median (95% CI) time to alleviation of symptoms with baloxavir was 138.4 hours (116.7-163.4) versus 126.1 hours (95.9-165.7) for oseltamivir; duration of fever was comparable between groups [41.2 hours (23.5-51.4) vs. 51.3 hours (30.7-56.8), respectively]. Median time to cessation of viral shedding was shorter in the baloxavir group versus oseltamivir (1 vs. ≈3 days).
CONCLUSIONS
Safety, efficacy and virological results in children 5-11 years were similar to those from the overall study population 1-<12 years of age. Single-dose baloxavir provides an additional treatment option for pediatric patients 5-11 years old with influenza.
PubMed: 37595103
DOI: 10.1097/INF.0000000000004062 -
The Journal of Antimicrobial... Jul 2023Widespread resistance of influenza viruses to neuraminidase (NA) inhibitor or polymerase inhibitor, baloxavir, is a major public health concern. The amino acid mutations...
OBJECTIVES
Widespread resistance of influenza viruses to neuraminidase (NA) inhibitor or polymerase inhibitor, baloxavir, is a major public health concern. The amino acid mutations R152K in NA and I38T in polymerase acidic (PA) are responsible for resistance to NA inhibitors and baloxavir, respectively.
METHODS
We generated recombinant A(H1N1)pdm09 viruses possessing NA-R152K, PA-I38T or both mutations by using a plasmid-based reverse genetics system, characterized their virological properties in vitro and in vivo, and examined whether oseltamivir, baloxavir and favipiravir are effective against these mutant viruses.
RESULTS
The three mutant viruses showed similar or superior growth kinetics and virulence to those of wild-type virus. Although oseltamivir and baloxavir blocked the replication of the wild-type virus in vitro, oseltamivir and baloxavir failed to suppress the replication of the NA-R152K and PA-I38T viruses in vitro, respectively. Mutant virus possessing both mutations grew in the presence of oseltamivir or baloxavir in vitro. Baloxavir treatment protected mice from lethal infection with wild-type or NA-R152K virus, but failed to protect mice from lethal infection with PA-I38T or PA-I38T/NA-R152K virus. Favipiravir treatment protected mice from lethal infection with all viruses tested, whereas oseltamivir treatment did not protect at all.
CONCLUSIONS
Our findings indicate that favipiravir should be used to treat patients with suspected baloxavir-resistant virus infection.
Topics: Animals; Mice; Humans; Oseltamivir; Neuraminidase; Influenza A Virus, H1N1 Subtype; Antiviral Agents; Pyridones; Enzyme Inhibitors; Triazines; Guanidines; Influenza, Human; Drug Resistance, Viral
PubMed: 37209424
DOI: 10.1093/jac/dkad145 -
Antiviral Research Apr 2024While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant... (Observational Study)
Observational Study
While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively. Cultured viruses were amplified using RT-PCR and sequenced to detect mutations. Fever and other symptoms were tracked via self-reporting diaries. In the baloxavir cohort, viral detection was 11.1% (4/36) and 0% (0/36) on day 5 and day 10, respectively. Two isolates from day 5 (5.6%, 2/36) manifested I38T/M-substitutions in the polymerase acidic protein (PA). For oseltamivir and other NAIs, viral detection rates were 60.0% (12/20) and 52.9% (9/17) on day 5, and 16.7% (3/18) and 6.3% (1/16) on day 10, respectively. No oseltamivir-resistant neuraminidase mutations were identified after treatment. Median fever durations for the baloxavir, oseltamivir, and other NAI cohorts were 27.0, 38.0, and 36.0 h, respectively, with no significant difference. Two patients harboring PA I38T/M-substitutions did not exhibit prolonged fever or other symptoms. These findings affirm baloxavir's virological and clinical effectiveness against A(H3N2) in the 2022-2023 season and suggest limited clinical influence of post-treatment resistance emergence.
Topics: Humans; Influenza, Human; Oseltamivir; Neuraminidase; Influenza A Virus, H3N2 Subtype; Outpatients; Seasons; Prospective Studies; Antiviral Agents; Pyridones; Enzyme Inhibitors; Guanidines; Fever; Dibenzothiepins; Morpholines; Triazines
PubMed: 38430970
DOI: 10.1016/j.antiviral.2024.105853 -
Biochimica Et Biophysica Acta.... Mar 2024Oseltamivir belongs to the neuraminidase inhibitors, developed against the influenza virus, and registered under the trademark Tamiflu. Despite its long-term...
Oseltamivir belongs to the neuraminidase inhibitors, developed against the influenza virus, and registered under the trademark Tamiflu. Despite its long-term acquaintance, there is limited information in the literature about its physicochemical and structural properties in a lipid-water system. We present an experimentally determined partition coefficient with structural information on the interaction of oseltamivir with the model membrane, its possible location, and its effect on the membrane thermodynamics. The hydrophobic part of the lipid bilayer is affected to a moderate extent, which was proved by slight changes in thermal and structural properties. Hereby, interaction of oseltamivir with the phospholipid bilayer induces concentration dependent decrease of lateral pressure in the bilayer acyl chain region. Oseltamivir charges the bilayer surface positively, which results in the zeta potential increase and changes in anisotropic properties studied by the polarised light microscopy. At the highest oseltamivir concentrations studied, the multilamellar structure is extensively disturbed, likely due to electrostatic repulsion between the adjacent bilayers.
Topics: Oseltamivir; Antiviral Agents; Lipid Bilayers; Phospholipids; Phosphates
PubMed: 38211646
DOI: 10.1016/j.bbamem.2024.184273 -
Journal of Medical Virology Jul 2023Influenza A(H3N8) viruses first emerged in humans in 2022, but their public health risk has not been evaluated. Here, we systematically investigated the biological...
Influenza A(H3N8) viruses first emerged in humans in 2022, but their public health risk has not been evaluated. Here, we systematically investigated the biological features of avian and human isolated H3N8 viruses. The human-origin H3N8 viruses exhibited dual receptor binding profiles but avian-origin H3N8 viruses bound to avian type (sialic acid α2, 3) receptors only. All H3N8 viruses were sensitive to the antiviral drug oseltamivir. Although H3N8 viruses showed lower virulence than the 2009 pandemic H1N1 (09pdmH1N1) viruses, they induced comparable infectivity in mice. More importantly, the human population is naïve to H3N8 virus infection and current seasonal vaccination is not protective. Therefore, the threat of influenza A(H3N8) viruses should not be underestimated. Any variations should be monitored closely and their effect should be studied in time for the pandemic potential preparedness purpose.
Topics: Humans; Animals; Mice; Influenza, Human; Influenza A Virus, H3N8 Subtype; Orthomyxoviridae Infections; Influenza A Virus, H1N1 Subtype; Antiviral Agents; Birds; China
PubMed: 37403888
DOI: 10.1002/jmv.28912 -
European Journal of Medicinal Chemistry Jul 2023The influenza virus remains a major health concern for mankind because it tends to mutate frequently and cause high morbidity. Influenza prevention and treatment are... (Review)
Review
The influenza virus remains a major health concern for mankind because it tends to mutate frequently and cause high morbidity. Influenza prevention and treatment are greatly aided by the use of antivirals. One such class of antivirals is neuraminidase inhibitors (NAIs), effective against influenza viruses. A neuraminidase on the virus's surface serves a vital function in viral propogation by assisting in the release of viruses from infected host cells. Neuraminidase inhibitors are the backbone in stoping such virus propagation thus helps in the treatment of influenza viruses infections. Two NAI medicines are licensed globally: Oseltamivir (Tamiflu™) and Zanamivir (Relanza™). There are two molecules that have acquired Japanese approval recently: Peramivir and Laninamivir, whereas Laninamivir octanoate is in Phase III clinical trials. The need for novel NAIs is due to frequent mutations in viruses and the rise in resistance against existing medication. The NA inhibitors (NAIs) are designed to have (oxa)cyclohexene scaffolds (a sugar scaffold) to mimic the oxonium transition state in the enzymatic cleavage of sialic acid. This review discusses in details and comprises all such conformationally locked (oxa)cyclohexene scaffolds and their analogues which have been recently designed and synthesized as potential neuraminidase inhibitors, thus as antiviral molecules. The structure-activity relationship of such diverese molecules has also been discussed in this review.
Topics: Humans; Neuraminidase; Antiviral Agents; Zanamivir; Enzyme Inhibitors; Oseltamivir; Influenza, Human; Guanidines; Orthomyxoviridae; Cyclohexenes; Drug Resistance, Viral
PubMed: 37120995
DOI: 10.1016/j.ejmech.2023.115410 -
BioRxiv : the Preprint Server For... May 2024Hearing loss affects up to 10% of all people worldwide, but currently there is only one FDA-approved drug for its prevention in a subgroup of cisplatin-treated pediatric...
Hearing loss affects up to 10% of all people worldwide, but currently there is only one FDA-approved drug for its prevention in a subgroup of cisplatin-treated pediatric patients. Here, we performed an unbiased screen of 1,300 FDA-approved drugs for protection against cisplatin-induced cell death in an inner ear cell line, and identified oseltamivir phosphate (brand name Tamiflu), a common influenza antiviral drug, as a top candidate. Oseltamivir phosphate was found to be otoprotective by oral delivery in multiple established cisplatin and noise exposure mouse models. The drug conferred permanent hearing protection of 15-25 dB SPL for both female and male mice. Oseltamivir treatment reduced in mice outer hair cells death after cisplatin treatment and mitigated cochlear synaptopathy after noise exposure. A potential binding protein, ERK1/2, associated with inflammation, was shown to be activated with cisplatin treatment and reduced by oseltamivir cotreatment in cochlear explants. Importantly, the number of infiltrating immune cells to the cochleae in mice post noise exposure, were significantly reduced with oseltamivir treatment, suggesting an anti-inflammatory mechanism of action. Our results support oseltamivir, a widespread drug for influenza with low side effects, as a promising otoprotective therapeutic candidate in both cisplatin chemotherapy and traumatic noise exposure.
PubMed: 38765999
DOI: 10.1101/2024.05.06.592815 -
The Pediatric Infectious Disease Journal Aug 2023Advances in multiplex polymerase chain reaction (PCR) methods have enabled the simultaneous detection of multiple respiratory viruses. We aimed to estimate the clinical...
BACKGROUND
Advances in multiplex polymerase chain reaction (PCR) methods have enabled the simultaneous detection of multiple respiratory viruses. We aimed to estimate the clinical and virologic impacts of influenza and other respiratory virus co-infection in children.
METHODS
We enrolled 38 and 35 children diagnosed with influenza and treated with baloxavir marboxil (baloxavir) and oseltamivir, respectively. We performed quantitative reverse transcription-PCR to detect and measure the levels of noninfluenza viruses from 3 nasopharyngeal swab samples collected before and on days 3 and 5 after the initial antiviral dose. We assessed patients' clinical information using questionnaires.
RESULTS
One or more respiratory viruses other than influenza virus were detected in 26 (35.6%) of 73 children before antiviral treatment. The influenza virus load and clinical characteristics on the day of influenza onset were similar between children with and without virus co-infections. Of the 26 and 32 children without the emergence of the reduced baloxavir and oseltamivir susceptible variants after treatment, 8 (30.8%) and 7 (21.9%) children were dually co-infected with human rhinovirus only, respectively. The level of human rhinovirus RNA on day 0 in these children was less than -3 log 10 that of influenza virus RNA, and the human rhinovirus co-infection had no impact on the disease course either clinically or virologically.
CONCLUSIONS
When multiple respiratory viruses are detected in the same patient, it is necessary to assess clinical symptoms as well as the levels of detected viruses to determine which virus contributes to the development of illness.
Topics: Humans; Child; Influenza, Human; Oseltamivir; Coinfection; Antiviral Agents; Viruses; Virus Diseases
PubMed: 37079571
DOI: 10.1097/INF.0000000000003940