peramivir and Influenza--Human

The study was to compare the efficacy between IV peramivir and oral oseltamivir treatments in patients with influenza.. The PubMed, EMBASE, Scopus, ClinicalTrials.gov, and Cochrane Library databases were searched for studies published before January 2020.. The meta-analysis was conducted to calculate the pooled effect size by using a random-effects model. Seven randomized controlled trials (RCTs) including 1,138 patients were reviewed. The incidence of total complications revealed no significant difference between 600 mg IV peramivir (P600) and 75 mg oral oseltamivir (O75) treatments (2.8% vs. 4.1%; risk ratio [RR] = 0.70; 95% confidence interval [CI]: 0.36-1.38). The incidence of pneumonia was not significantly different between the P600 and O75 treatment groups (2.2% vs. 2.7%; RR = 0.74; 95% CI: 0.37-1.51). Regarding the time to the alleviation of symptoms, no difference was found in P600 and O75 treatment (MD = -3.00; 95% CI: -11.07 to 5.06). The rate of fever clearance in 24 h and the time to fever resolution were not statistically different between the IV peramivir and oral oseltamivir treatments (at different dosages) groups.. The treatment of influenza with IV peramivir or oral oseltamivir had similar clinical efficacy.

Topics: Acids, Carbocyclic; Administration, Intravenous; Administration, Oral; Antiviral Agents; Guanidines; Humans; Influenza, Human; Oseltamivir; Pneumonia; Randomized Controlled Trials as Topic

This meta-analysis compared the efficacy and safety of peramivir compared to other neuraminidase inhibitors (NAIs).

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Enzyme Inhibitors; Guanidines; Humans; Influenza, Human; Neuraminidase; Observational Studies as Topic; Oseltamivir; Randomized Controlled Trials as Topic

Intravenous peramivir (Alpivab™; Rapivab

Topics: Acids, Carbocyclic; Administration, Intravenous; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Treatment Outcome

Peramivir is the first intravenously administered neuramidase inhibitor for immediate delivery of an effective single-dose treatment in patients with influenza. However, limited data are available on intravenous (IV) peramivir treatment compared to oral oseltamivir for these patients.. With a systematic review and meta-analysis, we compared the efficacy of IV peramivir with oral oseltamivir for treatment of patients with seasonal influenza. MEDLINE, EMBASE, and Cochrane Central Register were searched for relevant clinical trials.. A total of seven trials [two randomized controlled trials (RCTs) and five non-randomized observational trials] involving 1676 patients were finally analyzed. The total number of peramivir- and oseltamivir-treated patients was 956 and 720, respectively. Overall, the time to alleviation of fever was lower in the peramivir-treated group compared with the oseltamivir-treated group [mean difference (MD), -7.17 hours; 95% confidence interval (CI) -11.00 to -3.34]. Especially, pooled analysis of observational studies (n=4) and studies of outpatients (n=4) demonstrated the superiority of the peramivir-treated group (MD, -7.83 hours; 95% CI -11.81 to -3.84 and MD, -7.71 hours; 95% CI -11.61 to -3.80, respectively). Mortality, length of hospital stay, change in virus titer 48 hours after admission, and the incidence of adverse events in these patients were not significantly different between the two groups.. IV peramivir therapy might reduce the time to alleviation of fever in comparison with oral oseltamivir therapy in patients with influenza; however, we could not draw clear conclusions from a meta-analysis because of the few RCTs available and methodological limitations.

Topics: Acids, Carbocyclic; Administration, Intravenous; Administration, Oral; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Influenza, Human; Odds Ratio; Oseltamivir; Publication Bias; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, coronavirus, human metapneumovirus, and rhinovirus) represent the most common causes of respiratory viral infections in immunocompromised patients. Also, these infections may be more severe in immunocompromised patients than in the general population. Early diagnosis and treatment of viral infections continue to be of paramount importance in immunocompromised patients; because once viral replication and invasive infections are evident, prognosis can be grave. Areas covered: The purpose of this review is to provide an overview of the main antiviral agents used for the treatment of respiratory viral infections in immunocompromised patients and review of the new agents in the pipeline. Expert commentary: Over the past decade, important diagnostic advances, specifically, the use of rapid molecular testing has helped close the gap between clinical scenarios and pathogen identification and enhanced early diagnosis of viral infections and understanding of the role of prolonged shedding and viral loads. Advancements in novel antiviral therapeutics with high resistance thresholds and effective immunization for preventable infections in immunocompromised patients are needed.

Topics: Acids, Carbocyclic; Amantadine; Antiviral Agents; Coronavirus Infections; Cyclopentanes; Guanidines; Humans; Immunocompromised Host; Influenza, Human; Oseltamivir; Palivizumab; Paramyxoviridae Infections; Picornaviridae Infections; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Ribavirin; Zanamivir

Influenza viruses are a significant cause of morbidity and mortality in the United States. Given the wide range of symptoms, emergency physicians must maintain a broad differential diagnosis in the evaluation and treatment of patients presenting with influenza-like illnesses.. This review addresses objective and subjective symptoms commonly associated with influenza and discusses important mimics of influenza viruses, while offering a practical approach to their clinical evaluation and treatment.. Influenza-like symptoms are common in the emergency department (ED), and influenza accounts for > 200,000 hospitalizations annually. The three predominant types are A, B, and C, and these viruses are commonly transmitted through aerosolized viral particles with a wide range of symptoms. The most reliable means of identifying influenza in the ED is rapid antigen detection, although consideration of local prevalence is required. High-risk populations include children younger than 4 years, adults older than 50 years, adults with immunosuppression or chronic comorbidities, pregnancy, obesity, residents of long-term care facilities, and several others. The Centers for Disease Control and Prevention recommends treatment with neuraminidase inhibitors in these populations. However, up to 70% of patients with these symptoms may have a mimic. These mimics include infectious and noninfectious sources. The emergency physician must be aware of life-threatening mimics and assess for these conditions while beginning resuscitation and treatment.. The wide range of symptoms associated with influenza overlap with several life-threatening conditions. Emergency physicians must be able to rapidly identify patients at risk for complications and those who require immediate resuscitation.

Topics: Acids, Carbocyclic; Aged; Aged, 80 and over; Antiviral Agents; Child, Preschool; Cyclopentanes; Emergency Medicine; Guanidines; Humans; Infant; Influenza, Human; Middle Aged; Oseltamivir; Risk Factors; United States; Zanamivir

Current influenza treatment options include oral or inhaled antiviral agents. There is an unmet need for parenteral antiviral treatments.. Peramivir, a parenteral influenza neuraminidase inhibitor (NAI), was administered by single-dose intramuscular (IM) injection in two placebo-controlled studies in adult outpatients with acute, uncomplicated influenza during two consecutive influenza seasons.. In a Phase II study, peramivir treatment significantly shortened duration of fever and reduced viral load in nasopharyngeal secretions. A subsequent Phase III study was not fully enrolled; however, in both studies, the magnitude of the treatment effect favouring peramivir was consistent with that reported for other NAIs. A post-hoc analysis was conducted by integrating efficacy and safety results of 427 subjects from both studies. The median time to alleviation of symptoms (TTAS) in subjects receiving peramivir 300 mg (113.2 h) was shorter than for placebo (134.8 h; P=0.161 adjusted for smoking behaviour, influenza season and virus type; unadjusted P=0.047). The median time to resolution of fever was reduced by 24 h after treatment with peramivir 300 mg compared with placebo (P=0.004). The proportion of subjects shedding influenza virus was significantly decreased over 48 h following peramivir treatment (P=0.009). Detection of post-treatment viruses with decreased susceptibility to NAIs was uncommon. Peramivir was generally safe and well-tolerated with types and rates of adverse event similar to placebo.. The results of these studies are consistent with previous reports of peramivir administered by intravenous infusion, and demonstrate a positive risk-benefit profile for peramivir in patients with acute uncomplicated influenza.

Topics: Acids, Carbocyclic; Acute Disease; Adult; Antiviral Agents; Controlled Clinical Trials as Topic; Cyclopentanes; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Inhibitory Concentration 50; Male; Microbial Sensitivity Tests; Middle Aged; Multicenter Studies as Topic; Seasons; Treatment Outcome; Viral Load; Young Adult

Topics: Acids, Carbocyclic; Administration, Intravenous; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Enzyme Inhibitors; Guanidines; Humans; Influenza, Human; Neuraminidase; Treatment Outcome

Influenza is an important cause of annual epidemics of respiratory viral infection associated with significant morbidity and mortality. Three classes of drugs, the M2 ion channel, neuraminidase and RNA-dependent RNA polymerase inhibitors, are approved for the prevention and treatment of influenza. Due to widespread resistance to the class, the M2 ion channel inhibitors are not recommended currently for therapy. The only polymerase inhibitor, favipiravir, is approved only in Japan and its use is highly restricted. Despite significant data to support the early use of the neuraminidase inhibitors, their use in all patient populations is suboptimal. The data to support the early use of neuraminidase inhibitors will be reviewed, as will current data on the utilization rates in ambulatory and hospitalized populations.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A virus; Influenza, Human; Neuraminidase; Oseltamivir; Pyrans; RNA-Dependent RNA Polymerase; Sialic Acids; Viral Matrix Proteins; Viral Proteins; Zanamivir

Peramivir (BCX-1812, RWJ-270201) is a highly selective inhibitor of influenza A and B neuraminidase that has recently been approved in the USA by the FDA to treat acute, uncomplicated influenza in adults.. This review examines the discovery and development of peramavir as well as its role in the treatment of influenza. Peramivir is currently the only FDA-approved anti-influenza agent that can be given as an intravenous injection, granting it a unique role in therapy with the potential to improve adherence and outcomes in patients who are unable to tolerate oral agents. In vitro, animal, human and safety data are presented as well as information regarding special populations, resistance and drug approval.. Clinical trial data support the use of peramivir to relieve influenza symptoms in acute, uncomplicated influenza, with improvements over placebo similar to those of other approved anti-influenza treatments. The ability to give a one-time injectable dose offers improved adherence over currently available oral regimens. While not approved for hospitalized patients, available data suggest that multiple dose peramivir may also have a role in treatment of severally ill, hospitalized patients. Supportive data for the use of peramivir in special patient populations such as pediatrics and those especially at-risk to develop severe influenza symptoms are promising; however, they require further study.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza, Human; Injections, Intravenous; Neuraminidase

Influenza is a major cause of substantial morbidity and mortality in humans every year. Vaccination is the main strategy to prevent influenza infection, but antiviral agents also play an important role in the control of both seasonal and pandemic influenza. During the influenza A/H1N1 pandemic in 2009, early prompt antiviral therapy may have reduced the severity of the influenza outcomes including pneumonia, hospitalization and mortality in the Republic of Korea. Since the 2009 H1N1 pandemic, there have been increasing usages of antiviral agents for the treatment of patients with seasonal influenza. Although currently rare, antiviral resistance among influenza viruses may emerge and increase with increased use of neuraminidase inhibitors. New agents with different modes of action are under investigation, including favipiravir, DAS181, nitazoxanide and broad-spectrum neutralizing monoclonal antibodies. Data are limited with respect to high-dose and combination antiviral therapies. So, clinical trials are warranted to evaluate diverse antiviral combinations that may be synergistic and less likely to induce breakthrough resistance.

Topics: Acids, Carbocyclic; Amides; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Drug Resistance, Viral; Guanidines; Hospitalization; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oseltamivir; Pyrans; Pyrazines; Republic of Korea; Sialic Acids; Zanamivir

This report presents a review of the efficacy and safety of peramivir, a neuraminidase inhibitor that was granted Emergency Use Authorization by the US Food and Drug Administration (FDA) from October 23, 2009 to June 23, 2010 during the 2009 H1N1 pandemic.. Literature was accessed via PubMed (January 2000-April 2014) using several search terms: peramivir; BCX-1812; RWJ 270201; H1N1, influenza; antivirals; and neuraminidase inhibitors. The peramivir manufacturers, Shionogi and Co Ltd and BioCryst Pharmaceuticals, were contacted to obtain unpublished data and information presented at recent scientific meetings. Information was obtained from the Centers for Disease Control and Prevention (CDC) and from US FDA websites. English-language and Japanese-language reports in the literature were reviewed and selected based on relevance, along with information from the CDC, US FDA, and the drug manufacturers.. We obtained eleven clinical trial reports of intravenous peramivir, two of which described comparisons with oseltamivir. Seven of nine other recently reported published studies was a dose-response study. Clinical reports of critically ill patients and pediatric patients infected with pandemic H1N1 described that early treatment significantly decreased mortality. Peramivir administered at 300 mg once daily in adult patients with influenza significantly reduces the time to alleviation of symptoms or fever compared to placebo. It is likely to be as effective as other neuraminidase inhibitors.. Although peramivir shows efficacy for the treatment of seasonal and pH1N1 influenza, it has not received US FDA approval. Peramivir is used safely and efficiently in hospitalized adult and pediatric patients with suspected or laboratory-confirmed influenza. Peramivir might be a beneficial alternative antiviral treatment for many patients, including those unable to receive inhaled or oral neuraminidase inhibitors, or those requiring nonintravenous drug delivery.

Topics: Acids, Carbocyclic; Cyclopentanes; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Guanidines; Humans; Influenza, Human

Regulators must balance societal and medical requirements against the need for certainty about benefit and risk for new medicines. This is described in a case study of the expedited review and approval of peramivir, a novel neuraminidase inhibitor, in Japan in the context of the emergence of new strain of influenza in 2009. The case illustrates the importance of regulatory science and transparency in supporting such decision making.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Approval; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Japan; Needs Assessment

Many aspects of the biology and epidemiology of influenza B viruses are far less studied than for influenza A viruses, and one of these aspects is efficacy and resistance to the clinically available antiviral drugs, the neuraminidase (NA) inhibitors (NAIs). Acute respiratory infections are one of the leading causes of death in children and adults, and influenza is among the few respiratory infections that can be prevented and treated by vaccination and antiviral treatment. Recent data has suggested that influenza B virus infections are of specific concern to pediatric patients because of the increased risk of severe disease. Treatment of influenza B is a challenging task for the following reasons: This review presents current knowledge of the efficacy of NAIs for influenza B virus and antiviral resistance in clinical, surveillance, and experimental studies.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza B virus; Influenza, Human; Neuraminidase; Oseltamivir; Viral Proteins; Zanamivir

The recent emergence of the highly pathogenic H5N1 subtype of avian influenza virus (AIV) and of the new type of human influenza A (H1N1) have emphasized the need for the development of effective anti-influenza drugs. Presently, neuraminidase (NA) inhibitors are widely used in the treatment and prophylaxis of human influenza virus infection, and tremendous efforts have been made to develop more potent NA inhibitors to combat resistance and new influenza viruses. In this review, we discuss the structural characteristics of NA catalytic domains and the recent developments of new NA inhibitors using structure-based drug design strategies. These drugs include analogues of zanamivir, analogues of oseltamivir, analogues of peramivir, and analogues of aromatic carboxylic acid and present promising options for therapeutics or leads for further development of NA inhibitors that may be useful in the event of a future influenza pandemic.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Benzoic Acid; Cyclopentanes; Drug Design; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza, Human; Models, Molecular; Neuraminidase; Orthomyxoviridae; Orthomyxoviridae Infections; Oseltamivir; Zanamivir

In response to the 2009 H1N1 influenza pandemic, the governments of Japan and the United States for the first time authorized the emergency use of unapproved drugs. In this article, we comprehensively review the different regulatory approaches of Japan and the United States, countries with advanced regulatory and healthcare systems, to emergency authorization of the use of medical products as a countermeasure to public health emergencies. We outline the legal system, range of targeted products, requirements for the application dossier, legal stance for authorization, product availability, and termination of the Japanese Emergency Approval (EA), and we compare characteristics with those of the US Emergency Use Authorization (EUA). We also review the actual cases of these 2009 emergency authorizations. The Japanese EA importation of novel H1N1 influenza vaccines with adjuvant is presented, with lessons learned, and contrasted with the US EUA of peramivir.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Approval; Emergencies; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza Vaccines; Influenza, Human; Japan; Pandemics; United States

The emergence of the 2009 H1N1 pandemic influenza A virus, as well as constant antigenic drift of seasonal influenza, underscores the remarkable versatility of this virus in adapting to the human population. While vaccines are the principal public health defence against influenza, rapid vaccine development can be a daunting task. Antiviral drugs offer the promise of inhibiting influenza regardless of its genetic variations. However, the rapid rise of resistance to several antivirals has highlighted the need for developing novel therapeutics with reduced drug resistance potential. In this review, we will summarize the effects of the currently licensed anti-influenza drugs as well as the candidates in development against the seasonal and the 2009 H1N1 pandemic influenza A virus with an emphasis on drug resistance.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Disease Outbreaks; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Models, Biological; Oseltamivir; Recombinant Fusion Proteins; Zanamivir

A novel H1N1 influenza virus of swine origin has emerged, causing the first pandemic of the 21st century. Infections with 2009 pandemic influenza A (H1N1) are typically moderate. However, in rare cases, respiratory distress, neurological complications and death have been reported. To alleviate complications associated with 2009 H1N1 influenza infection, the neuraminidase (NA) inhibitors oseltamivir (oral) and zanamivir (inhaled) are recommended. Hospitalized patients with severe complications may not respond to these drugs or be able to receive oral antiviral therapy, and therefore, parenteral formulations that would allow rapid delivery at high concentrations are being pursued. Peramivir is a novel potent NA inhibitor currently in clinical trials for intravenous (i.v.) administration. In clinical trials, i.v. peramivir was shown to be safe and well tolerated, with a pharmacokinetic profile that supports once-daily dosing. Based on the safety and efficacy of i.v. peramivir in clinical trials and the need for a parenteral antiviral, the U.S. Food and Drug Administration issued an Emergency Use Authorization (EUA) for the use of peramivir for the treatment of hospitalized patients with known or suspected 2009 H1N1 influenza infection. In Japan, peramivir has been licensed under the name Rapiacta. The development of peramivir leading to the issuance of the EUA and approval in Japan will be discussed.

Topics: Acids, Carbocyclic; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Emergencies; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza, Human; Oseltamivir; United States; United States Food and Drug Administration

The environment surrounding influenza is changing in recent years. In the spring of 2009, pandemic (H1N1) 2009 occurred in Mexico, and became epidemic on a global scale thereafter. Therefore, control of influenza is very important all over the world. Now in Japan, four specific anti-influenza antiviral drugs are available: amantadine, oseltamivir, zanamivir and peramivir. Pandemic (H1N1) 2009 are amantadine-resistant viruses, thus is not recommended for use. Oseltamivir is most commonly used in Japan, however, we have to pay attention to oseltamivir-resistant influenza virus. Almost no zanamivir-resistant influenza virus has been so far reported. In Japan, peramivir is the first drip infusion medicine and is expected to be used in severe cases.

Topics: Acids, Carbocyclic; Amantadine; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Drug Utilization; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Infusions, Intravenous; Japan; Oseltamivir; Pandemics; Zanamivir

Human infections with avian influenza A (H5N1) are relatively rare but are associated with high mortality. As of July 5, 2010 there had been 500 cases and 296 fatalities. The influenza virus readily undergoes mutation and reassortment, and there are concerns that an H5N1 variant could be responsible for a future pandemic. The influenza neuraminidase inhibitors zanamivir and oseltamivir are approved for the treatment and prophylaxis of influenza. Oseltamivir is being used to treat H5N1 infections and the case has been made for a role for zanamivir; however, there are no case reports for the latter. Zanamivir is a potent inhibitor of H5N1, attains high lung concentrations immediately on administration, distributes into plasma at antiviral concentrations, has a low propensity for generating resistant virus, and retains activity against H275Y oseltamivir-resistant virus. There have been several reports of oseltamivir-resistant H5N1 arising during treatment with oseltamivir, and zanamivir retains effectiveness (in vitro or in vivo) against these isolates. Compassionate use of intravenous zanamivir for the treatment of seriously ill patients, including those with H275Y H1N1 infections, has also shown promising results. It is concluded that there is a role for zanamivir in treating H5N1 infections either as the approved, inhaled formulation in patients capable of using the Diskhaler, or as the intravenous formulation if compassionate use is warranted. The relatively small number of patients with these infections remains an obstacle to completion of clinical trials. Evidence is therefore likely to be based on carefully documented case reports, ideally in patients treated early in the course of the infection.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Disease Outbreaks; Drug Resistance, Viral; Guanidines; Humans; Immunocompromised Host; Influenza A Virus, H5N1 Subtype; Influenza, Human; Oseltamivir; Pneumonia, Viral; Pyrans; Severity of Illness Index; Sialic Acids; Zanamivir

Influenza is a major threat to millions of people worldwide. Vaccines and antiviral agents are two main options available to reduce the impact of the influenza virus, while anti-influenza agents are the most effective means to prevent the transmission of the highly contagious virus and to treat the epidemics of disease. At present, four anti-influenza agents have been approved by the FDA for the treatment of influenza, including two M2 protein ion channel inhibitors-amantadine and rimantadine and two neuraminidase inhibitors-zanamivir and oseltamivir. Arbidol hydrochloride, launched in Russia, is a potent inhibitor of influenza virus, too. Neuraminidase inhibitors could be classified generally by structure into six different kinds: sialic acid derivatives, benzoic acid derivatives, cyclohexene derivatives, cyclopentane derivatives, pyrrolidine derivatives and natural products. In this paper, recent progress in the research of the action mechanisms and structure-activity relationships of these anti-influenza virus agents were reviewed.

Topics: Acids, Carbocyclic; Amantadine; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Indoles; Influenza, Human; Neuraminidase; Orthomyxoviridae; Oseltamivir; Pyrrolidines; Rimantadine; Structure-Activity Relationship; Viral Matrix Proteins; Zanamivir

Antiviral agents for the treatment of influenza are urgently needed to circumvent the limitations of current drugs in several critical areas: high frequencies of resistance to M2 inhibitors among currently circulating strains and variable frequencies of resistance to oseltamivir among A(H1N1) strains, limited efficacy of treatment and treatment-emergent antiviral resistance in cases of avian influenza A(H5N1) illness in humans, and lack of parenteral agents for seriously ill patients. Two neuraminidase inhibitors (NAIs), zanamivir and peramivir, have undergone or are undergoing clinical trials for use by intravenous or intramuscular administration, and one long-acting NAI, designated CS-8958, is under study for use by inhalation. Advances in understanding the mechanisms involved in influenza virus replication have revealed a number of potential targets that might be exploited in the development of new agents. Among these agents are T-705, a polymerase inhibitor, and DAS181, an attachment inhibitor. Combination therapy with currently available agents is supported by data from animal models but has received limited clinical study to date.

Topics: Acids, Carbocyclic; Amides; Animals; Antiviral Agents; Cyclopentanes; Drug Discovery; Drug Resistance, Viral; Drug Therapy, Combination; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza, Human; Neuraminidase; Pyrazines; Recombinant Fusion Proteins; Zanamivir

Zanamivir and oseltamivir, the currently marketed influenza virus neuraminidase inhibitors (NAIs), are prescribed for the treatment and prophylaxis of influenza and are being stockpiled for pandemic influenza. Oseltamivir resistance has been reported in up to 2% of patients in clinical trials of oseltamivir and in up to 18% of treated children. There are also reports in at least three patients treated with oseltamivir for influenza A (H5N1) infections. At this stage, there are no reports of resistance occurring to zanamivir in immunocompetent patients. Zanamivir and oseltamivir bind differently at the neuraminidase catalytic site and this contributes to different drug resistance profiles. The magnitude and duration of NAI concentrations at the site of infection are also expected to be important factors and are determined by route and timing of drug administration, dose, and pharmacokinetic differences between patients. In addition, the type, strain, and virulence of the influenza strain and the nature of the immune response all appear to play a role in determining the likelihood of drug resistance arising. The clinical significance of a particular NAI-resistant isolate from a patient is often not clear but virus viability and transmissibility are clearly important characteristics. Early initiation of NAI treatment in suspected cases of influenza is important for maximizing efficacy and minimizing the risk of drug resistance. Higher NAI doses and longer periods of treatment may be required for patients with influenza A (H5N1) infections but further work is needed in this area.

Topics: Acids, Carbocyclic; Adult; Animals; Antiviral Agents; Catalytic Domain; Child; Clinical Trials as Topic; Cyclopentanes; Drug Administration Schedule; Enzyme Inhibitors; Guanidines; Humans; Immunocompromised Host; Influenza A Virus, H5N1 Subtype; Influenza, Human; Neuraminidase; Orthomyxoviridae; Orthomyxoviridae Infections; Oseltamivir; Seasons; Sentinel Surveillance; Viral Proteins; Virulence; Zanamivir

Topics: Acids, Carbocyclic; Amino Acid Substitution; Animals; Antiviral Agents; Binding Sites; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopentanes; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Guanidines; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Mice; Molecular Structure; Neuraminidase; Orthomyxoviridae; Oseltamivir; Point Mutation; Viral Proteins

The cyclopentane peramivir (BCX-1812, RWJ-270201) is a highly selective inhibitor of influenza A and B virus neuraminidases and a potent inhibitor of influenza A and B virus replication in cell culture. The in vitro potency appears to be greater than either zanamivir or oseltamivir carboxylate based on the generally lower EC(50) values seen using peramivir in studies run in parallel with each compound. In mice infected with influenza A or B viruses, oral treatment with peramivir was highly effective in preventing death, signs of the disease and in lowering lung virus titres. Similar effects were seen in influenza A virus-infected ferrets. Efficacy was seen in mice when therapy began after virus exposure. Peramivir is non-toxic in mice and rats at doses of 1000 mg/kg/day and ferrets tolerated doses of 100 mg/kg/day. Doses of 100 mg/kg/day do not appear to affect murine immune parameters. A pharmacokinetic study of this compound in influenza virus-infected mice indicates once-, twice- or thrice-daily oral dosing was equal in efficacy; once-daily dosing has been recommended in clinical trials of influenza therapy. Treatment of influenza virus infections in cyclophosphamide-immunosuppressed mice was effective in inhibiting the infection; an infection induced in severe combined immunodeficient mice was only weakly affected. Development of viral resistance to peramivir can occur by serial cell culture passage of the virus in the presence of the compound but the resistant virus was less virulent than the wild type virus. Viruses with neuraminidase mutations are not necessarily all cross-resistant to peramivir, zanamivir and oseltamivir carboxylate. In Phase I studies, peramivir was well-tolerated, with single or multiple oral doses up to 800 mg/kg/day evaluated. In clinical trials with patients experimentally infected with influenza A or B viruses, oral treatment with peramivir significantly reduced nasal wash virus titres with no adverse effects. Phase III clinical trials are underway.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Drug Design; Drug Resistance, Microbial; Guanidines; Humans; Influenza, Human; Neuraminidase; Orthomyxoviridae

The influenza virus neuraminidase (NA) is important in the pathogenesis of infection and, thus, is an attractive target for agents used in the treatment and prophylaxis of influenza. This article describes preclinical and early clinical data related to RWJ-270201 (BCX-1812), a novel, orally active NA inhibitor that was rationally designed for having potent and selective activity against influenza A and B viruses. RWJ-270201 is a unique NA inhibitor with a cyclopentane ring structure and high selectivity for the influenza NA. RWJ-270201 has efficacy comparable to or better than earlier NA inhibitors against a wide range of influenza A and B isolates, including recently emerged and avian strains, both in vitro and in a lethal murine model of influenza. Based on the high selectivity and efficacy of RWJ-270201 against both type A and B influenza strains in preclinical studies as well as murine pharmacodynamic studies supporting the potential for once-daily administration, clinical trials were initiated in order to determine the tolerability and antiviral activity of RWJ-270201 in humans. To date, clinical studies have indicated that RWJ-270201 is well tolerated and has antiviral activity in human experimental influenza models when administered orally once daily.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Guanidines; Humans; Influenza A virus; Influenza, Human; Neuraminidase

RWJ-270201, the lead compound in a series of influenza neuraminidase inhibitors, is under development by BioCryst for the potential treatment of influenza [214908], [337716]. Phase III trials commenced in North America and Europe in February 2000 [355053]. Phase II studies were performed to test the effectiveness of RWJ-270201 at reducing viral titers in infected patients. Data showed that the compound was well tolerated and produced statistically significant reductions in viral titers [337716]. Under a worldwide influenza collaboration formed in September 1998, two subsidiaries of Johnson & Johnson, the RW Johnson Pharmaceutical Research Institute and Ortho McNeil, have received exclusive worldwide rights to RWJ-270201 [298487].

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Drugs, Investigational; Enzyme Inhibitors; Guanidines; Humans; Influenza, Human; Neuraminidase; Structure-Activity Relationship

The efficacy of neuraminidase inhibitors on improvement of respiratory symptoms triggered by influenza in patients with pre-existing chronic respiratory diseases is unknown.. This 2-week, randomized, open-label study evaluated intravenous peramivir 600 mg on two consecutive days (peramivir-repeat), peramivir 300 mg single dose (peramivir-single), and oral oseltamivir 75 mg twice daily for 5 days in patients with confirmed influenza and chronic respiratory diseases. Patients recorded symptom scores daily. The primary endpoint of cumulative area of time vs symptoms (CATVS) was expressed as an index value of area under the curve vs time of the total score of cough, sore throat, and nasal congestion from baseline to 2 weeks.. Of 214 randomized patients, 209 (56% female, 77% aged <65 years, 94% outpatients, 91% bronchial asthma, 62% influenza A) received ≥1 dose of study drug. Mean (standard deviation) CATVS was similar for peramivir-repeat (782.78 [487.17]) vs peramivir-single (717.35 [347.55]; P = .4371), and for peramivir-repeat vs oseltamivir (856.34 [404.99]; P = 1.00). However, CATVS was significantly shorter for peramivir-single vs oseltamivir, with an estimated treatment difference (TD) of -145.07 (95% confidence interval: -284.57, -5.56; P = .0416). In subgroup analyses, CATVS was significantly shorter for peramivir-single vs oseltamivir among patients with influenza A (TD: -206.31 [-383.86, -28.76]; P = .0231), bronchial asthma (TD: -156.57 [-300.22, -12.92]; P = .0328), baseline respiratory severity score <5 (TD: -265.32 [-470.42, -60.21]; P = .0120), and age <65 (TD: -184.30 [-345.08, -23.52]; P = .0249).. In patients with chronic respiratory diseases, peramivir-single was not significantly different from peramivir-repeat and was more effective than oseltamivir at alleviating respiratory symptoms.

Topics: Acids, Carbocyclic; Antiviral Agents; Comorbidity; Cyclopentanes; Female; Guanidines; Humans; Influenza, Human; Male; Neuraminidase; Oseltamivir; Respiratory Tract Diseases; Treatment Outcome

Peramivir offers a single-dose intravenous (IV) treatment option for influenza (vs 5-day oral dosing for oseltamivir). We sought to compare outcomes of emergency department (ED) patients at high risk for influenza complications treated with IV peramivir vs oral oseltamivir.. During the 2015-16 and 2016-17 influenza seasons, adult patients in two US EDs were randomized to either oral oseltamivir or IV peramivir treatment group. Eligibility included positive molecular influenza test; met CDC criteria for antiviral treatment; able to provide informed consent and agree to follow-up assessment. Outcomes were measured by clinical end-point indicators, including FLU-PRO Score, Ordinal Scale, Patient Global Impression on Severity Score, and Karnofsky Performance Scale for 14 days. Non-inferior t test was performed to assess comparative outcomes between the two groups.. Five hundred and seventy-five (68%) of 847 influenza-positive patients were approached. Two hundred and eighty-four met enrollment criteria and 179 were enrolled; of these 95 (53%) were randomized to peramivir, and 84 to oseltamivir. Average FLU-PRO score at baseline was similar (peramivir: 2.67 vs oseltamivir: 2.52); the score decreased over time for both groups (day 5: peramivir: 1.71 vs oseltamivir: 1.62; day 10: peramivir: 1.48 vs oseltamivir: 1.37; day 14: peramivir: 1.40 vs oseltamivir: 1.33; all P < .05 for significantly non-inferior). Influenza-related complications were similar between two groups (All: peramivir: 31% vs oseltamivir: 21%, P > .05; pneumonia: peramivir: 11% vs oseltamivir: 14%, P > .05).. Clinical outcomes of influenza-infected patients treated with single-dose IV peramivir were comparable to those treated with oral oseltamivir, suggesting potential utility of peramivir for influenza-infected patients in the ED.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Emergency Service, Hospital; Guanidines; Humans; Influenza, Human; Oseltamivir; Pilot Projects; Treatment Outcome

To compare peramivir 300 mg single-dose, peramivir 600 mg repeat-dose, and oseltamivir effects on health-related quality of life, including respiratory symptoms and general conditions, time to symptom alleviation, time to fever resolution, incidence of exacerbations, and virus titer, in influenza patients with chronic respiratory disease.. We report additional outcomes from a 2-week, multicenter, randomized, open-label study in Japan (UMIN000030118). Influenza patients with chronic respiratory disease received intravenous peramivir (300 mg single-dose [n = 66], 600 mg repeat-dose [600 mg/d of 2 consecutive days; n = 70]) or oral oseltamivir (75 mg twice daily, 5 days; n = 72). The principal endpoint of this analysis was change from baseline to Day 14 at each time point in Chronic Obstructive Pulmonary Disease Assessment Test (CAT) scores.. Both peramivir regimens reduced total CAT score at Day 3 more than oseltamivir (peramivir 600 mg vs oseltamivir, P = .0032; peramivir 300 mg vs oseltamivir, P = .0203). Cough/phlegm CAT scores were most improved with peramivir 600 mg. Median time to alleviation of three respiratory symptoms was longer with peramivir 600 mg (68.9 hours) than with peramivir 300 mg (50.6 hours, hazard ratio [HR] 1.57; P = .0191) and shorter with peramivir 300 mg than oseltamivir (78.8 hours, HR 0.62; P = .0141). Alleviation of seven influenza symptoms and fever resolution was shortest with peramivir 300 mg.. Rapid improvement in CAT score, including cough, and shorter time to alleviation of respiratory symptoms associated with peramivir is of potential benefit to patients with chronic respiratory disease.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Influenza, Human; Oseltamivir; Quality of Life; Treatment Outcome

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Antiviral Agents; Cyclopentanes; Double-Blind Method; Guanidines; Humans; Influenza, Human; Middle Aged; Oseltamivir; Treatment Outcome; Young Adult

Neuraminidase inhibitors (NAIs) reduce influenza symptoms but clear evidence of relationships between viral titer reduction and symptom alleviation is lacking. This open-label, randomized study evaluated differences in viral dynamics between NAIs, and relationships between viral dynamics and influenza symptoms (trial registration number: UMIN000012670).. Patients (n = 123) aged 4-12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir. Patients received regular viral assessments of nasal discharge, at least until rapid antigen tests were negative. Time to virus clearance, based on influenza virus titer, was the primary endpoint.. Peramivir recipients had a significantly shorter time to virus clearance than oseltamivir recipients (adjusted p = 0.035). Comparisons between the peramivir group and other NAI groups were not significant. There were no significant inter-group differences in other clinical efficacy endpoints (time to resolution of fever, time to alleviation of symptoms). However, the peramivir group showed a smaller numerical proportion of relapses with fever or positive virus than the other groups.. The time to virus clearance was significantly shorter with peramivir than with oseltamivir. Although no clear relationship between virus dynamics and symptoms was observed, ongoing studies should clarify the situation.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Japan; Male; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Time Factors; Treatment Outcome; Zanamivir

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Female; Guanidines; Humans; Influenza, Human; Japan; Male; Middle Aged; Oseltamivir; Pyrans; Sialic Acids; Treatment Outcome; Zanamivir

Intravenous peramivir is a potent neuraminidase (NA) inhibitor with activity against influenza A and B viruses. The early use of NA inhibitors has been shown to reduce mortality in influenza patients.. To evaluate the pharmacokinetics of peramivir and confirm the safety and tolerability of multiple infusions of peramivir in healthy Japanese subjects, two Phase I, single-centre, randomized, double-blind and placebo-controlled studies consisting of a multiple-dose study and a high-dose study were conducted.. Multiple intravenous infusions of peramivir were well tolerated up to 800 mg once a day and 400 mg twice daily for 6 days. Dose proportionalities for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were established up to the 800 mg dose. Approximately 90% of unchanged peramivir was excreted into urine within 12 h after treatment with 800 mg of peramivir. The peramivir plasma and upper respiratory tract fluid levels were significantly higher than the 50% inhibition concentrations for NA enzyme activity (IC. The pharmacokinetic properties obtained here for intravenous peramivir are consistent with the previously reported clinical efficacy and safety of this antiviral.

Topics: Acids, Carbocyclic; Administration, Intravenous; Adult; Antiviral Agents; Area Under Curve; Cyclopentanes; Double-Blind Method; Drug Administration Schedule; Enzyme Inhibitors; Female; Gene Expression; Guanidines; Healthy Volunteers; Humans; Influenza A virus; Influenza, Human; Male; Neuraminidase; Patient Safety; Viral Proteins

Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S.. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.

Topics: Acids, Carbocyclic; Cyclopentanes; Guanidines; Healthy Volunteers; Humans; Influenza, Human; Japan; Models, Theoretical; Monte Carlo Method; United States

Influenza causes over 200,000 hospitalizations a year in the United States, but few antiviral treatment studies have focused on patients hospitalized with influenza. This open-label, randomized study was initiated during the 2009 H1N1 pandemic to help assess the antiviral activity, safety and tolerability of 5-10 days treatment with two different dosing regimens of the intravenous neuraminidase inhibitor, peramivir, in hospitalized subjects with influenza.. Quantitative virology was done on nasopharyngeal swab specimens from subjects ≥6 years of age to measure change from baseline in tissue culture infective dose (primary end point) and quantitative viral RNA levels by real-time PCR. Clinical end points included time to clinical resolution, a composite end point of four vital signs and oxygen saturation.. A total of 234 hospitalized patients were randomized to peramivir 300 mg twice daily or 600 mg once daily; 127 had laboratory confirmed influenza. In those with detectable virus at baseline, viral titres declined without differences between regimens. There were no significant differences in clinical or virological end points between treatment arms, and apparent differences were explained by baseline disease severity differences in the groups. Peramivir was generally safe and well tolerated for treated patients hospitalized with pandemic influenza with outcomes similar to those described in the literature.. This open-label trial of intravenous peramivir in subjects hospitalized predominantly with 2009 influenza A (H1N1) demonstrated that once- or twice-daily administration was associated with decreases in viral shedding and clinical improvement. ClinicalTrials.gov number NCT00957996.

Topics: Acids, Carbocyclic; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Female; Guanidines; Hospitalization; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Treatment Outcome; Viral Load; Virus Shedding; Young Adult

Seasonal influenza causes >200 000 annual hospitalizations in the United States. Current antiviral treatment options are limited to oral or inhaled agents. There is an urgent unmet need for intravenous antiviral treatments.. Patients hospitalized with suspected influenza were randomized to 5-day treatment with intravenous peramivir (600 mg once daily) or placebo; all received the institution's standard of care (SOC) treatment. Time to clinical resolution and change in viral shedding in nasopharyngeal specimens were the primary and key secondary end points.. Influenza infection was confirmed in 338 of 405 enrolled patients. At the time of a preplanned interim analysis, the primary efficacy analysis population comprised 121 patients who did not receive a concurrent neuraminidase inhibitor as part of the SOC. The median (95% confidence interval) time to clinical resolution was 42.5 (34.0-57.9) hours for peramivir versus 49.5 (40.0-61.9) hours for placebo (P = .97). A larger treatment effect was observed in patients with history of symptoms <48 hours or admitted to an intensive care unit. Greater reductions in viral shedding, based on median tissue culture infective dose, were observed in patients who received peramivir than in placebo recipients, although this difference was not statistically significant. The incidence and severity of adverse events and laboratory abnormalities were similar between the 2 treatment groups. The study was terminated for futility after a preplanned interim analysis.. A significant clinical benefit was not demonstrated for peramivir plus SOC compared with placebo plus SOC. Peramivir was generally safe and well tolerated. These findings highlight the challenges in designing studies to evaluate influenza antiviral agents in a hospitalized setting. Clinical Trials Registration. NCT00958776.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Female; Guanidines; Hospitalization; Humans; Influenza, Human; Male; Middle Aged; Young Adult

The neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, laninamivir and peramivir are available in Japan. However, the selective use of NAIs for treating outpatients with influenza has not been clearly defined.. We assigned 191 patients with influenza to 4 groups, each treated with a different NAI, and then compared how long it took to alleviate fever and other symptoms and to eliminate the virus.. Alleviation of fever occurred significantly sooner with peramivir than with either zanamivir (p = 0.0002) or oseltamivir (p = 0.0059), but was not significantly different from that with laninamivir (p = 0.0457; p < 0.0083). Other symptoms were also alleviated sooner by peramivir than by the other 3 NAIs.. The ability of each NAI to alleviate influenza symptoms and fever varied. The appropriate use of NAIs requires further study.

Topics: Acids, Carbocyclic; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Influenza, Human; Japan; Male; Middle Aged; Neuraminidase; Oseltamivir; Outpatients; Pyrans; Sialic Acids; Time Factors; Treatment Outcome; Young Adult; Zanamivir

Seasonal interpandemic influenza causes >200,000 annual hospitalizations in the United States. Optimal antiviral treatment in hospitalized patients is not established.. During three interpandemic influenza seasons, 137 patients hospitalized with suspected acute influenza were randomized to 5-day treatment with intravenous peramivir 400 mg or 200 mg once daily or oral oseltamivir 75 mg twice daily. Time to clinical stability and quantitative changes in viral titres from nasopharyngeal specimens were primary and key secondary end points, respectively.. Infection was confirmed in 122 patients with influenza A (H1N1), influenza A (H3N2) or influenza B. Median times (95% CI) to clinical stability were 37.0 h (22.0, 48.7) with peramivir 400 mg, 23.7 h (16.0, 38.9) with peramivir 200 mg and 28.1 h (22.0, 37.0) with oseltamivir (P=0.306). Patients (n=97) who were clinically unstable at enrolment had median times (95% CI) to clinical stability of 24.3 h (21.2, 47.5) with peramivir 400 mg, 31.0 h (17.2, 47.7) with peramivir 200 mg and 35.5 h (23.3, 37.9) with oseltamivir (P=0.541). Titres of influenza A viruses in nasopharyngeal specimens decreased similarly across treatments, but more rapid decreases in titres of influenza B occurred with peramivir treatment. There were no deaths among patients with confirmed influenza and the incidence of adverse events was low and generally similar among treatment groups.. Treatment of acute seasonal influenza in hospitalized adults with either peramivir or oseltamivir resulted in generally similar clinical outcomes. Treatment with peramivir was generally safe and well tolerated and could be of benefit in this population.

Topics: Acids, Carbocyclic; Administration, Intravenous; Administration, Oral; Adult; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Female; Guanidines; Hospitalization; Humans; Influenza A virus; Influenza, Human; Inhibitory Concentration 50; Male; Microbial Sensitivity Tests; Middle Aged; Oseltamivir; Risk Factors; Seasons; Treatment Outcome; Viral Load

Peramivir is a new neuraminidase inhibitor for intravenous administration that was first introduced in clinical practice in Japan. We conducted a multicenter, open-label, uncontrolled study in children with influenza virus infection ranging in age from ≥28 days to <16 years during the 2009 pandemic A (H1N1) influenza epidemic to evaluate the efficacy, safety, and pharmacokinetics of peramivir in children after intravenous infusion of 10 mg/kg (600 mg maximum) once daily. Among the 106 children (125 days to 15 years old) confirmed to have been infected with the pH1N1 virus by the PCR who were treated with peramivir, the median time to alleviation of symptoms was 29.1 h (95% confidence interval = 22.1 to 32.4), and the proportion of the 106 children who were virus positive was 78.2% on day 2 after the start of treatment and had decreased to 7.1% on day 6. The results of the safety evaluation among 117 patients enrolled in this study showed that adverse events and adverse drug reactions were reported in 62.4 and 29.1%, respectively, of the patients. All of the adverse events and adverse drug reactions resolved or improved rapidly. A population pharmacokinetic analysis was performed on the basis of 297 observed plasma concentration data obtained from 115 children with influenza virus infection. Peramivir exposure in children was within the range of levels within which the efficacy and safety was confirmed in adults, and it is considered that peramivir is clinically and virologically effective and safe in children with pH1N1 virus infection.

Topics: Acids, Carbocyclic; Adolescent; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza, Human; Japan; Male; Neuraminidase; Pandemics; Polymerase Chain Reaction; Treatment Outcome; Viral Proteins

The clinical effectiveness of the newly released neuraminidase inhibitors (NAIs) laninamivir and peramivir has not been sufficiently evaluated in influenza-infected patients in clinical and practical settings. In this study, we analyzed the clinical data of 211 patients infected with influenza A virus subtype H3N2 (A(H3N2)) and 45 patients infected with influenza A virus subtype H1N1pdm (A(H1N1)pdm09) who received the NAIs oseltamivir, zanamivir, laninamivir, or peramivir during the 2010-2011 influenza season. The duration of fever from the first dose of the NAI to fever alleviation to <37.5 °C was evaluated as an indicator of the clinical effectiveness of the NAIs in the influenza-infected patients. For the A(H3N2)-infected patients, Kaplan-Meier analysis showed the peramivir treatment group had the fastest time of fever alleviation to <37.5 °C (median 17.0 h, 95 % confidence interval [CI] 7.2-26.8 h) of the four treatment groups. No significant difference was found in the time to fever alleviation among the other antivirals, oseltamivir, zanamivir, and laninamivir. Results of multivariate analysis, using a Cox proportional-hazards model (hazard ratio 3.321) adjusted for the factors age, sex, body weight, vaccination status, time from onset to the clinic visit, and body temperature showed significantly faster fever alleviation in the peramivir treatment group compared with the oseltamivir treatment group. For the A(H1N1)pdm09-infected patients, only the oseltamivir and zanamivir treatment groups were compared, and no significant difference in time to alleviation of fever was observed between the two groups. Based on a cycling probe real-time polymerase chain reaction (PCR) assay, none of the A(H1N1)pdm09 strains in this study had the H275Y mutation conferring oseltamivir resistance. Further evaluation of the clinical effectiveness of the newly released NAIs for influenza-infected patients, including those infected with A(H1N1)pdm09, is needed.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Disease Outbreaks; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Japan; Male; Neuraminidase; Oseltamivir; Treatment Outcome; Zanamivir

Influenza virus infections are known to persist longer in patients with underlying diseases, including respiratory tract diseases, and tend to become complicated by secondary influenza-associated infections, such as pneumonia. To assess the efficacy and safety of the novel anti-influenza virus drug peramivir in high-risk patients, we conducted a clinical trial of patients with diabetes or chronic respiratory tract diseases and patients being treated with drugs that suppress immune function. In this multicenter, uncontrolled, randomized, double-blind study, peramivir was intravenously administered at 300 or 600 mg/day for 1 to 5 days, as needed. Efficacy was investigated in 37 patients (300 mg, n = 18 patients; 600 mg, n = 19 patients). The median durations of influenza illness were 68.6 h (90% confidence interval, 41.5 to 113.4 h) overall, 114.4 h (90% confidence interval, 40.2 to 235.3 h) in the 300-mg group, and 42.3 h (90% confidence interval, 30.0 to 82.7 h) in the 600-mg group. The hazard ratio for the 600-mg group compared to the 300-mg group was 0.497 (90% confidence interval, 0.251 to 0.984), and the duration of influenza illness was significantly shorter in the 600-mg group than in the 300-mg group. Among the 42 patients in the safety analysis set, adverse events occurred in 73.8% and adverse drug reactions in 33.3%. No adverse events were particularly problematic clinically, and all patients recovered quickly from all events. The measured blood drug concentrations showed no tendency toward accumulation. Drug accumulation with repeated doses was thus considered to be of little concern. Intravenous peramivir appears to offer a potentially useful treatment for high-risk patients in the future.

Topics: Acids, Carbocyclic; Adult; Aged; Antiviral Agents; Cyclopentanes; Double-Blind Method; Female; Guanidines; Humans; Influenza A virus; Influenza A Virus, H1N1 Subtype; Influenza B virus; Influenza, Human; Injections, Intravenous; Male; Middle Aged; Neuraminidase

Antiviral medications with activity against influenza viruses are important in controlling influenza. We compared intravenous peramivir, a potent neuraminidase inhibitor, with oseltamivir in patients with seasonal influenza virus infection. In a multinational, multicenter, double-blind, double-dummy randomized controlled study, patients aged ≥ 20 years with influenza A or B virus infection were randomly assigned to receive either a single intravenous infusion of peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day [b.i.d.] for 5 days). To demonstrate the noninferiority of peramivir in reducing the time to alleviation of influenza symptoms with hazard model analysis and a noninferiority margin of 0.170, we planned to recruit 1,050 patients in South Korea, Japan, and Taiwan. A total of 1,091 patients (364 receiving 300 mg and 362 receiving 600 mg of peramivir; 365 receiving oseltamivir) were included in the intent-to-treat infected population. The median durations of influenza symptoms were 78.0, 81.0, and 81.8 h in the groups treated with 300 mg of peramivir, 600 mg of peramivir, and oseltamivir, respectively. The hazard ratios of the 300- and 600-mg-peramivir groups compared to the oseltamivir group were 0.946 (97.5% confidence interval [CI], 0.793, 1.129) and 0.970 (97.5% CI, 0.814, 1.157), respectively. Both peramivir groups were noninferior to the oseltamivir group (97.5% CI, <1.170). The overall incidence of adverse drug reactions was significantly lower in the 300-mg-peramivir group, but the incidence of severe reactions in either peramivir group was not different from that in the oseltamivir group. Thus, a single intravenous dose of peramivir may be an alternative to a 5-day oral dose of oseltamivir for patients with seasonal influenza virus infection.

Topics: Acids, Carbocyclic; Administration, Oral; Adult; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Double-Blind Method; Drug Administration Schedule; Female; Guanidines; Humans; Influenza, Human; Injections, Intravenous; Male; Middle Aged; Oseltamivir; Young Adult

Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Influenza, Human; Injections, Intraventricular; Middle Aged; Orthomyxoviridae; Treatment Outcome; Young Adult

Oseltamivir is the only oral neuraminidase inhibitor currently available; we determined the tolerability and antiviral efficacy of oral peramivir for treatment and prophylaxis of experimental human influenza A and B.. 288 susceptible, healthy volunteers (ages 18-45) were inoculated intranasally with A/Texas/36/ 91/H1N1 or B/Yamagata/16/88 virus in four randomized, double-blind, placebo-controlled trials.. For treatment dosing was initiated at 24 h after inoculation with peramivir doses ranging from 100-800 mg/day for 5 days. For prophylaxis dosing was initiated 24 h before inoculation and continued for 4 days with peramivir doses ranging from 50-800 mg/day.. The primary outcome measure for treatment was quantitative viral detection defined by the area under the curve (AUC) for nasal wash viral titres. For prophylaxis the primary outcome measure was the incidence of virus recovery.. In influenza A treatment, peramivir 400 mg q24h and 200mg q12h, but not lower doses, resulted in significant reductions in viral titre AUC. In influenza B treatment, both 400 and 800/400 mg once daily dose groups reduced AUC values. In influenza A prophylaxis, the percentage of individuals with nasal viral shedding did not differ significantly in the placebo (58%), 50 mg (61%), 200 mg (37%) and 400 mg (31%) dose groups. In influenza B prophylaxis, shedding frequencies were similar in placebo (55%), 200 mg (41%), 400 mg (35%) and 800 mg (47%) dose groups. The drug was well tolerated in all four studies, with nausea and headache being the most common side effects. No drug-resistant variants were detected.. Early treatment with peramivir was associated with significant antiviral effects in experimentally induced influenza in humans. Prophylaxis did not significantly reduce viral shedding. The relatively low blood peramivir concentrations observed may explain the lack of more robust antiviral effects, and parenteral dosing should be studied.

Topics: Acids, Carbocyclic; Administration, Oral; Adolescent; Adult; Cyclopentanes; Double-Blind Method; Drug Administration Schedule; Guanidines; Headache; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Influenza, Human; Middle Aged; Nasal Lavage Fluid; Nausea; Neuraminidase; Treatment Outcome

Our objective was to assess the pharmacokinetics and pharmacodynamics of RWJ-270201 (BCX-1812), an oral neuraminidase inhibitor for the treatment of influenza A and B virus in healthy volunteers.. This was a double-blind, randomized, placebo-controlled, parallel group study. A total of 80 adult male and female subjects were enrolled for the influenza A challenge study. This was a 5-arm study (100 mg/qd, 200 mg/qd, 200 mg/bid, 400 mg/qd, and placebo). In the challenge B virus model, 60 subjects were enrolled for a 3-arm study (800 mg on Day 1 followed by 400 mg on Days 2-5; 800 mg on Days 1-5; and placebo). The pharmacokinetics of RWJ-270201 (BCX-1812) were characterized with the use of a population approach and were described by a 2-compartmental model with first-order absorption and elimination. The pharmacodynamic data, mean log viral titers, were described with the use of an empirical equation relating the viral growth and the effect of drug on changes in viral titers.. Pharmacokinetic analyses show that weight was the most significant covariate for all estimated pharmacokinetic parameters. The pharmacodynamic data, mean log viral titers showed a decrease in viral titers with increase in plasma exposure. The decrease in viral titer started to occur 12 hours following the drug dosing, and viral suppression lasted 72 hours to 96 hours. The exposures associated with a 50% decrease in viral titers were 1089 ng-h/mL and 1898 ng-h/mL, respectively.. A PK/PD model was well utilized to characterize the effect of RWJ-270201 (BCX-1812) on the influenza A and B virus. The results from this model showed that both the loading dose and the standard dose regimens are efficacious against A and B virus. RWJ-270201 (BCX-1812) is under clinical development for the treatment of influenza A and B infections in adult and high-risk populations. It is a potent and selective inhibitor of both influenza A and B virus neuraminidases and inhibits the viral cleavage of sialic acid from cell surface glycoproteins and glycolipids. Consequently, RWJ-270201 (BCX-1812) prevents infection by stopping the release of newly formed virus from the surface of infected cells and preventing viral spread across the mucous lining of the respiratory tract. It therefore represents an attractive agent for antiviral therapy.

Topics: Acids, Carbocyclic; Adult; Cyclopentanes; Double-Blind Method; Female; Guanidines; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Male; Neuraminidase; Viral Load

The effectiveness of oseltamivir versus peramivir in children infected with influenza remains unclear. This study aimed to evaluate their effectiveness in young children (aged 0-5 years) infected with severe influenza A virus (IAV) or influenza B virus (IBV).. We analyzed a cohort of 1662 young children with either IAV (N = 1095) or IBV (N = 567) who received oseltamivir or peramivir treatment from January 1, 2018 to March 31, 2022. Propensity score matching methods were applied to match children who were oseltamivir-treated versus peramivir-treated.. Children who were IAV-infected and IBV-infected shared similar features, such as influenza-associated symptoms and comorbidities at baseline. Among children infected with IAV with bacterial coinfection, the recovery rate was significantly greater in children treated with oseltamivir than in children treated with peramivir (15.6% vs 4.4%, P = 0.01). The median duration of hospitalization was also shorter in children treated with oseltamivir. Among children infected with IAV without bacterial coinfection, the recovery rate was greater in children treated with oseltamivir than in children treated with peramivir (21.1% vs 3.7%, P = 0.002). However, oseltamivir and peramivir offered similar recovery rates and duration of hospitalization (P >0.05 for both) among children infected with IBV.. Oseltamivir and peramivir exhibit similar effectiveness in young children with severe influenza B, whereas oseltamivir demonstrated improved recovery and shorter hospitalization in the treatment of severe influenza A in hospitalized children.

Topics: Antiviral Agents; Child; Child, Hospitalized; Child, Preschool; Coinfection; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Oseltamivir; Treatment Outcome

To optimize the medication administered to children with influenza, we evaluated the effectiveness of peramivir in hospitalized children with influenza A/H3N2 and influenza B/Victoria.. A retrospective study was conducted from October 2019 to March 2020 in children aged 29 days to 18 years with influenza A/H3N2 or B/Victoria. A total of 97 patients were enrolled and treated with intravenous infusion of peramivir.. The duration of influenza virus nucleic acid positivity in the influenza A/H3N2 group (3 days) was shorter than that in the influenza B/Victoria group (4 days) (P = 0.008). The remission time of fever symptoms in the influenza A/H3N2 group was 14 h, which was significantly shorter than that in the influenza B/Victoria group (26 h) (P = 0.042). In the 6-18 years age group, the median duration of virus nucleic acid positivity for children with influenza B/Victoria (4 days) was longer than that for children with influenza A/H3N2 (2 days) (P = 0.005). The incidence of adverse drug reactions (ADRs) with peramivir in the influenza A/H3N2 group and the influenza B/Victoria group was 2.04% (n = 1/49) and 4.17% (n = 2/48), respectively (P = 0.617).. A difference in the effectiveness of peramivir against different subtypes of influenza was observed. Compared to those infected with influenza B/Victoria, the children infected with influenza A/H3N2 experienced a significantly shorter duration of influenza virus nucleic acid positivity and remission time of fever symptoms.

Topics: Adolescent; Antiviral Agents; Child; Child, Hospitalized; Guanidines; Humans; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Nucleic Acids; Retrospective Studies

Influenza A viruses (IAV) have been a major cause of mortality. Given the potential for future deadly pandemics, effective drugs are needed for the treatment of severe influenzas, such as those caused by H5N1 IAV. The anti-malaria drugs artemisinin and its derivates, including artesunate (AS), have been reported to have broad antiviral activities. Here, we showed AS's antiviral activity against H5N1, H1N1, H3N2 and oseltamivir-resistant influenza A(H1N1)virus in vitro. Moreover, we showed that AS treatment significantly protected mice from lethal challenges with H1N1 and H5N1 IAV. Strikingly, the combination of AS and peramivir treatment significantly improved survival outcomes compared to their monotherapy with either AS or peramivir. Furthermore, we demonstrated mechanistically that AS affected the later stages of IAV replication and limited nuclear export of viral ribonucleoprotein (vRNP) complexes. In A549 cells, we demonstrated for the first time that AS treatment induced cAMP accumulation via inhibiting PDE4, and consequently reduced ERK phosphorylation and blocked IAV vRNP export, and thus suppressed IAV replication. These AS's effects were reversed by the pre-treatment with a cAMP inhibitor SQ22536. Our findings suggest that AS could serve as a novel IAV inhibitor by interfering vRNP nuclear export to prevent and treat IAV infection.

Topics: Active Transport, Cell Nucleus; Animals; Antiviral Agents; Artesunate; Humans; Influenza A virus; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza, Human; Mice; Ribonucleoproteins; Virus Replication

Whether prophylactic administration of antibiotics to patients with influenza reduces the hospitalisation risk is unknown. We aimed to examine the association between antibiotic prescription in outpatients with influenza infection and subsequent hospitalisation.. We conducted a cohort study using health insurance records of Japanese clinic and hospital visits between 2012 and 2016. Participants were outpatients (age, 0-74 years) with confirmed influenza infection who were prescribed anti-influenza medicine. The primary outcomes were the hospitalisation risk from all causes and pneumonia and the duration of hospitalisation due to pneumonia.. We analysed 903,104 outpatient records with 2469 hospitalisations. The risk of hospitalisation was greater in outpatients prescribed anti-influenza medicine plus antibiotics (0.31% for all causes and 0.18% for pneumonia) than in those prescribed anti-influenza medicine only (0.27% and 0.17%, respectively). However, the risk of hospitalisation was significantly lower in patients prescribed peramivir and antibiotics than in those prescribed peramivir only. Patients who received add-on antibiotics had a significantly longer hospital stay (4.12 days) than those who received anti-influenza medicine only (3.77 days). In all age groups, the hospitalisation risk from pneumonia tended to be greater in those who received antibiotics than in those prescribed anti-influenza medicine only. However, among older patients (65-74 years), those provided add-on antibiotics had an average 5.24-day shorter hospitalisation due to pneumonia than those provided anti-influenza medicine only (not significant).. In outpatient cases of influenza, patients who are prescribed antibiotics added to antiviral medicines have a higher risk of hospitalisation and longer duration of hospitalisation due to pneumonia.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Child; Child, Preschool; Cohort Studies; Hospitalization; Humans; Infant; Infant, Newborn; Influenza, Human; Insurance; Middle Aged; Outpatients; Pneumonia; Prescriptions; Young Adult

An epidemic of avian type H7N9 influenza virus, which took place in China in 2013, was enhanced by a naturally occurring R294K mutation resistant against Oseltamivir at the catalytic site of the neuraminidase. To cope with such drug-resistant neuraminidase mutations, we applied the molecular docking technique to evaluate the fitness of the available drugs such as Oseltamivir, Zanamivir, Peramivir, Laninamivir, L-Arginine and Benserazide hydrochloride concerning the N9 enzyme with single (R294K, R119K, R372K), double (R119_294K, R119_372K, R294_372K) and triple (R119_294_372K) mutations in the pocket. We found that the drugs Peramivir and Zanamivir score best amongst the studied compounds, demonstrating their high binding potential towards the pockets with the considered mutations. Despite the fact that mutations changed the shape of the pocket and reduced the binding strength for all drugs, Peramivir was the only drug that formed interactions with the key residues at positions 119, 294 and 372 in the pocket of the triple N9 mutant, while Zanamivir demonstrated the lowest RMSD value (0.7 Å) with respect to the reference structure.

Topics: Acids, Carbocyclic; Antiviral Agents; Arginine; Benserazide; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H7N9 Subtype; Influenza, Human; Molecular Docking Simulation; Mutation; Neuraminidase; Oseltamivir; Zanamivir

We aimed to investigate the association between anaphylaxis and anti-influenza drug use using the Japanese Adverse Drug Event Report (JADER) database, a national spontaneous reporting database in Japan. We surveyed registered cases from the JADER database between April 2004 and November 2019. The target drugs were five anti-influenza drugs, namely oseltamivir, zanamivir, peramivir, laninamivir, and baloxavir. Adverse events associated with anaphylaxis, "anaphylactic reaction," "anaphylactic shock," "anaphylactoid reaction," and "anaphylactoid shock," were evaluated. The association between anaphylaxis and anti-influenza drug use was assessed by calculating the reporting odds ratio (ROR) and information component (IC) as a measure of disproportionality. Signals were considered positive if the lower limit of the 95% confidence interval (CI) of ROR was > 1, and that of IC was > 0. The number of anaphylaxis cases associated with anti-influenza drug use was 199 (0.9%). Signals were detected for inhaled laninamivir (ROR: 4.24 [95% CI: 3.06-5.88], IC: 1.83 [1.35-2.30]), intravenous peramivir (ROR: 2.97 [2.11-4.17], IC: 1.40 [0.90-1.89]), and oral baloxavir (ROR: 3.05 [2.22-4.18], IC: 1.44 [0.98-1.90]). Conversely, signals were not detected for oral oseltamivir or inhaled zanamivir. Although zanamivir and laninamivir were used as dry powder inhalers containing lactose as an additive, they differed in terms of signal detection. Our analysis indicated that the signal of anaphylaxis may varies based on the main component or dosage form of each anti-influenza drug. Appropriate use of these drugs is essential to prevent anaphylaxis and improve health status.

Topics: Acids, Carbocyclic; Adult; Adverse Drug Reaction Reporting Systems; Anaphylaxis; Antiviral Agents; Databases, Factual; Dibenzothiepins; Female; Guanidines; Humans; Influenza, Human; Japan; Male; Middle Aged; Morpholines; Pyrans; Pyridones; Sialic Acids; Triazines; Young Adult

The risk factors and the impact of NAI treatments in patients with severe influenza A-associated pneumonia remain unclear.. A multicenter, retrospective, observational study was conducted in Zhejiang, China during a severe influenza epidemic in August 2017-May 2018. Clinical records of patients (>14 y) hospitalized with laboratory-confirmed influenza A virus infection and who developed severe pneumonia were compared to those with mild-to-moderate pneumonia. Risk factors related to pneumonia severity and effects of NAI treatments (monotherapy and combination of peramivir and oseltamivir) were analyzed.. 202 patients with influenza A-associated severe pneumonia were enrolled, of whom 84 (41.6%) had died. Male gender (OR = 1.782; 95% CI: 1.089-2.917; P = 0.022), chronic pulmonary disease (OR = 2.581; 95% CI: 1.447-4.603; P = 0.001) and diabetes mellitus (OR = 2.042; 95% CI: 1.135-3.673; P = 0.017) were risk factors related to influenza A pneumonia severity. In cox proportional hazards model, severe pneumonia patients treated with double dose oseltamivir (300mg/d) had a better survival rate compared to those receiving a single dose (150 mg/d) (HR = 0.475; 95%CI: 0.254-0.887; P = 0.019). However, different doses of peramivir (300 mg/d vs. 600 mg/d) and combination therapy (oseltamivir-peramivir vs. monotherapy) showed no differences in 60-day mortality (P = 0.392 and P = 0.658, respectively).. Patients with male gender, chronic pulmonary disease, or diabetes mellitus were at high risk of developing severe pneumonia after influenza A infection. Double dose oseltamivir might be considered in treating influenza A-associated severe pneumonia.

Topics: Acids, Carbocyclic; Antiviral Agents; China; Cyclopentanes; Epidemics; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Male; Middle Aged; Neuraminidase; Oseltamivir; Pneumonia, Viral; Proportional Hazards Models; Retrospective Studies; Risk Factors

The recommended antiviral drugs available for the treatment and prevention of influenza are neuraminidase inhibitors (NAIs). The aim of this study was to evaluate age-related clinical manifestations of adverse events (AEs) related to NAIs. FAERS and WebMD data were downloaded. The available NAIs selected for the analysis were oseltamivir, peramivir, zanamivir, and laninamivir. Disproportionality was analyzed using the proportional reporting ratio (PRR), the reporting odds ratio (ROR), and the information component (IC) methods. In total, 16729 AEs from 4598 patients and 575 AEs from 440 patients in the FAERS and WebMD, respectively, were included in the analysis. In the FAERS, AEs were more common among those who were younger (<19 years) for zanamivir, while for those who were older (>65 years) for peramivir. A disproportionality analysis showed that signals for vomiting and hallucinations were detected in younger patients given oseltamivir, while an abnormal hepatic function, cardiac failure, shock, and cardio-respiratory arrest were detected in older patients given peramivir. Psychiatric disorders were most common in younger and older patients, while gastrointestinal disorders were most common in adult given oseltamivir in the WebMD. Adverse symptoms related to NAIs varied and depended on the drugs used and the age of the patient.

Topics: Acids, Carbocyclic; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza, Human; Internet; Male; Middle Aged; Neuraminidase; Odds Ratio; Oseltamivir; Patient Participation; Pyrans; Risk Factors; Sialic Acids; United States; United States Food and Drug Administration; Young Adult; Zanamivir

Our earlier study investigated the incidence of severe abnormal behavior associated with neuraminidase inhibitors (NIs), but some studies have specifically examined the association of oseltamivir use and moderately abnormal behavior. Therefore, this study was undertaken to assess associations between moderately abnormal behavior and administered drugs. All cases of patients with influenza who exhibited moderately abnormal behavior were reported to us by physicians of all sentinel clinics and hospitals for influenza throughout Japan. Open Data of the National Database of Electronic Medical Claims include the numbers of patients diagnosed as having influenza who were prescribed NI. Incidence by NI was tested using Fisher's exact test. We received 518 moderately abnormal cases in 5-9-year-olds and 207 moderately abnormal behavior cases in 10-19-year-olds. The incidence among NI ranged from 193 per one million influenza patients in laninamivir among 10-19-year-olds to 1021 for peramivir among 5-9-year-olds. Estimation results revealed the order of risk among NIs as peramivir, oseltamivir, zanamivir and laninamivir in moderate abnormal behavior. Because of data limitations, risk among patients with and without NI cannot be compared.

Topics: Acids, Carbocyclic; Adolescent; Antiviral Agents; Child; Cyclopentanes; Enzyme Inhibitors; Guanidines; Humans; Illness Behavior; Influenza, Human; Japan; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Young Adult; Zanamivir

Baloxavir marboxil is a new anti-influenza drug, but data on the clinical efficacy of a combination treatment of baloxavir and peramivir is scarce. We conducted a single-center retrospective analysis comparing the mortality of a combination of baloxavir and peramivir (B & P, n = 10) and peramivir without baloxavir (P-mono, n = 132) in hospitalized adults with influenza A between 2011 and 2019 in Yokohama City, Japan. Sequencing analysis was conducted in the B & P group to check the I38 mutation in polymerase acidic protein which is associated with baloxavir resistance. The 30-day mortality rates were 0 (0%) in the B & P group and 6 (4.5%) in the P-mono group, respectively, which was not statistically significant. The I38 mutation was not detected before and after the combination treatment. A combination treatment of baloxavir and peramivir might be more effective than peramivir without baloxavir and prevent the emergence of baloxavir resistance in hospitalized adults with influenza A.

Topics: Acids, Carbocyclic; Administration, Oral; Aged, 80 and over; Antiviral Agents; Dibenzothiepins; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Japan; Male; Morpholines; Pyridones; Retrospective Studies; Triazines

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Dibenzothiepins; Drug Resistance, Viral; Guanidines; Humans; Indonesia; Influenza B virus; Influenza, Human; Japan; Male; Microbial Sensitivity Tests; Morpholines; Mutation; Neuraminidase; Pyrans; Pyridones; Sialic Acids; Triazines; Zanamivir

A 50-year-old woman presented with coma and hemorrhagic shock. A rapid influenza antigen test revealed influenza A infection; other laboratory examinations ruled out any other suspected infections. She was diagnosed with hemorrhagic shock and encephalopathy syndrome (HSES) induced by influenza A. She was administered methylprednisolone pulse therapy and peramivir. Subsequently, she was discharged without any sequelae. Only a few cases of influenza-induced HSES have been reported, and the clinical outcomes were very poor. We herein report a successfully treated adult case of influenza-induced HSES and review this rare syndrome.

Topics: Acids, Carbocyclic; Anti-Inflammatory Agents; Antiviral Agents; Blood Coagulation Disorders; Brain Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Methylprednisolone; Middle Aged; Shock, Hemorrhagic; Syndrome

Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir.. A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/μL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2.. In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Dibenzothiepins; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Influenza A Virus, H3N2 Subtype; Influenza, Human; Male; Middle Aged; Morpholines; Mutation; Neuraminidase; Oseltamivir; Oxazines; Pyridines; Pyridones; Thiepins; Transplantation, Homologous; Treatment Outcome; Triazines; Viral Proteins

The emergence of influenza viruses resistant to anti-influenza drugs is a threat to global public health. The Korea Centers for Disease Control and Prevention operates the Korea Influenza and Respiratory Viruses Surveillance System (KINRESS) to monitor epidemics of influenza and Severe Acute Respiratory Infection (SARI) to identify mutated influenza viruses affecting drug resistance, pathogenesis, and transmission.. Oropharyngeal swab samples were collected from KINRESS and SARI during the 2018-2019 season. The specimens confirmed influenza virus using real-time RT-PCR on inoculated MDCK cells. HA and NA sequences of the influenza viruses were analyzed for phylogeny and mutations. Neuraminidase inhibition and hemagglutination inhibition assays were utilized to characterize the isolates.. Two A(H1N1)pdm09 isolates harboring an H275Y substitution in the neuraminidase sequence were detected in patients with acute hematologic cancer. They had prolonged respiratory symptoms, with the virus present in the respiratory tract despite oseltamivir and peramivir treatment. Through the neuraminidase inhibition assay, both viruses were found to be resistant to oseltamivir and peramivir, but not to zanamivir. Although hemagglutinin and neuraminidase phylogenetic analyses suggested that the 2 A(H1N1)pdm09 isolates were not identical, their antigenicity was similar to that of the 2018-19 influenza vaccine virus.. Our data indicate the utility of monitoring influenza-infected immunocompromised patients in general hospitals for the early detection of emerging neuraminidase inhibitor-resistant viruses and maintaining continuous laboratory surveillance of patients with influenza-like illness in sentinel clinics to monitor the spread of such new variants. Finally, characterization of the virus can inform the risk assessment for future epidemics and pandemics caused by drug-resistant influenza viruses.

Topics: Acids, Carbocyclic; Adult; Amino Acid Substitution; Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Female; Guanidines; Humans; Immunocompromised Host; Influenza A Virus, H1N1 Subtype; Influenza, Human; Mutation; Neuraminidase; Oropharynx; Oseltamivir; Phylogeny; Republic of Korea; Sequence Analysis, DNA; Zanamivir

Human infection with H7N9 virus has provoked global public health concern due to the substantial morbidity and mortality. Neuraminidase inhibitors (NAIs) are used as first-line drugs to treat the infection. However, virus quasispecies can evolve rapidly under drug pressure, which may alter various biological characteristics of virus. Using an in vitro evolution platform and next-generation sequencing, we found the presence of peramivir led to changes to the dominant populations of the virus. Two important amino acid substitutions were identified in NA, I222T and H274Y, which caused reduced susceptibilities to oseltamivir or both oseltamivir and peramivir as confirmed by enzyme- and cell-based assays. The NA-H274Y variant showed decreased replicative fitness at the early stage of infection accompanied with impaired NA function. The quasispecies evolution of H7N9 virus and the potential emergence of these two variants should be closely monitored, which may guide the adjustment of antiviral strategies.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Animals; Antiviral Agents; Cyclopentanes; Dogs; Drug Resistance, Viral; Evolution, Molecular; Gene Expression; Guanidines; Humans; Influenza A Virus, H7N9 Subtype; Influenza, Human; Madin Darby Canine Kidney Cells; Neuraminidase; Oseltamivir; Viral Load; Viral Proteins; Virus Replication

To describe the peramivir (PRV) pharmacokinetics in critically ill children treated for influenza A or B viral infections.. Retrospective electronic medical record review of prospectively collected data from critically ill children receiving peramivir for influenza A or B viral infections in the pediatric intensive care unit (PICU).. A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA.. Critically ill children admitted to the PICU who were infected with influenza between January 1, 2016 and March 31, 2018.. None.. Eleven patients, two females (18%) and nine males (82%), accounted for 24 peramivir samples for therapeutic drug management. The median age was 5 years (interquartile range 1.5-6.5 yrs) with a median weight of 16.4 kg (interquartile range 14-24 kg). Ten (91%) patients demonstrated a larger volume of distribution, 11 (100%) patients demonstrated an increase in clearance, and 11 (100%) patients demonstrated a shorter half-life estimate as compared with the package insert and previous pediatric trial data for peramivir. Eight (73%) patients tested positive for a strain of influenza A and 3 (27%) patients tested positive for influenza B; 4 of 11 (36%) patients tested positive for multiple viruses. All patients had adjustments made to their dosing interval to a more frequent interval. Ten (91%) patients were adjusted to an every-12-hour regimen and 1 (9%) patient was adjusted to an every-8-hour regimen. No adverse events were associated with peramivir treatment.. The pharmacokinetics of PRV demonstrated in this PICU cohort differs in comparison to healthy pediatric and adult patients, and alterations to dosing regimens may be needed in PICU patients to achieve pharmacodynamic exposures. Additional investigations in the PICU population are needed to confirm these findings.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cohort Studies; Critical Illness; Cyclopentanes; Drug Administration Schedule; Female; Guanidines; Half-Life; Hospitalization; Humans; Infant; Influenza A virus; Influenza B virus; Influenza, Human; Intensive Care Units, Pediatric; Male; Retrospective Studies; Tissue Distribution

Eosinophilic gastrointestinal disorder (EGID) is an uncommon disease that is accompanied by intestinal eosinophil infiltration without a secondary cause of eosinophilia. Eosinophilic enteritis is a secondary portion of EGID that can present a range of gastrointestinal symptoms according to the affected depth of the intestinal layer. The subserosal type of eosinophilic enteritis presenting as ascites is relatively rarer than the mucosal type. In general, eosinophilic enteritis occurs in patients with food allergies, but its mechanism is unclear. The authors experienced a 29-year-old female patient with a large amount of ascites with diarrhea and abdominal pain. The patient was diagnosed with an influenza A infection one week earlier. Peripheral eosinophilia (absolute eosinophil count: 6,351 cells/mm

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Ascites; Colonoscopy; Cyclopentanes; Enteritis; Eosinophilia; Eosinophils; Female; Gastritis; Guanidines; Humans; Influenza A virus; Influenza, Human; Steroids; Tomography, X-Ray Computed

Topics: Acids, Carbocyclic; Administration, Intravenous; Aged; Antiparkinson Agents; Antiviral Agents; Cyclopentanes; Disease Progression; Guanidines; Humans; Influenza A virus; Influenza, Human; Male; Parkinson Disease; Syndrome

To evaluate the difference of clinical efficacy of peramivir alone and peramivir combined with immunomodulators (either ribonucleic acid or thymopetidum) in the treatment of severe influenza A with primary viral pneumonia.. A retrospective analysis was applied to 45 patients who were diagnosed with severe influenza A with primary viral pneumonia in our hospital from December 2017 to March 2018. The cases were divided into three groups: the peramivir group, the peramivir combined with ribonucleic acid group, and the peramivir combined with thymopetidum group.. The duration of viral nucleic acid positivity in the peramivir group, the peramivir combined with ribonucleic acid group, and the peramivir combined with thymopetidum group was 6.13 ± 2.06, 6.53 ± 2.72, and 6.10 ± 1.37 days, respectively. The remission time of the clinical symptoms of the peramivir group, the peramivir combined with ribonucleic acid group, and the peramivir combined with thymopetidum group was 8.06 ± 2.73, 7.94 ± 2.89, and 7.67 ± 1.58 days, respectively. Comparisons between the peramivir group and the peramivir combined with ribonucleic acid group or the peramivir combined with thymopetidum group revealed no significant differences in the duration of virus nucleic acid positivity, remission time of clinical symptoms, time to fever alleviation, and time to cough alleviation.. There is no observed benefit in the addition of ribonucleic acid or thymopetidum when peramivir sodium chloride injection is used in the treatment of severe influenza A with primary viral pneumonia. This trial is registered with ChiCTR1800019417.

Topics: Acids, Carbocyclic; Adult; Aged; Antiviral Agents; Cyclopentanes; Drug Therapy, Combination; Female; Guanidines; Humans; Immunologic Factors; Influenza A virus; Influenza, Human; Male; Middle Aged; Pneumonia, Viral; Retrospective Studies; RNA; Young Adult

Few studies have investigated patients with severe influenza who receive intravenous peramivir for salvage therapy.. We retrospectively analyzed data from 71 patients with severe influenza who received intravenous peramivir therapy in the intensive care units of three medical centers between 2012 and 2016. All patients received oseltamivir or zanamivir before the administration of peramivir.. A total of 44 men and 27 women with a median age of 55 years were enrolled. Fifty-five (78%) had underlying comorbidities and 57 (80%) patients were infected with influenza type A. Forty-four (62%) patients survived and 27 (38%) died. Five patients (7%) had attributable adverse events, including elevated hepatic aminotransferase levels (n = 2), hyperbilirubinemia (n = 2), leukopenia (n = 1), and skin rash (n = 1). Multivariable logistic regression analysis revealed that initial bacteremia (odds ratio [OR], 27.59; 95% confidence interval [95% CI], 2.36-322.07; P = 0.008) and septic shock (OR, 8.00; 95% CI, 1.69-37.90; P = 0.009) were the independent predictors of mortality. However, there was also a trend towards a positive correlation between mortality and steroid use (OR, 11.29; 95% CI, 0.67-188.86; P = 0.092).. As a salvage therapy, intravenous peramivir provided a survival rate of 62% and was well tolerated in patients with severe influenza. The initiation of effective antiviral treatment as early as possible within 48 h is recommended for hospitalized patients.

Topics: Acids, Carbocyclic; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Female; Guanidines; Humans; Infant; Influenza, Human; Intensive Care Units; Male; Middle Aged; Prognosis; Retrospective Studies; Salvage Therapy; Steroids; Taiwan; Treatment Outcome; Young Adult

Several subtypes of avian influenza viruses (AIVs) are emerging as novel human pathogens, and the frequency of related infections has increased in recent years. Although neuraminidase (NA) inhibitors (NAIs) are the only class of antiviral drugs available for therapeutic intervention for AIV-infected patients, studies on NAI resistance among AIVs have been limited, and markers of resistance are poorly understood. Previously, we identified unique NAI resistance substitutions in AIVs of the N3, N7, and N9 NA subtypes. Here, we report profiles of NA substitutions that confer NAI resistance in AIVs of the N4, N5, N6, and N8 NA subtypes using gene-fragmented random mutagenesis. We generated libraries of mutant influenza viruses using reverse genetics (RG) and selected resistant variants in the presence of the NAIs oseltamivir carboxylate and zanamivir in MDCK cells. In addition, two substitutions, H274Y and R292K (N2 numbering), were introduced into each NA gene for comparison. We identified 37 amino acid substitutions within the NA gene, 16 of which (4 in N4, 4 in N5, 4 in N6, and 4 in N8) conferred resistance to NAIs (oseltamivir carboxylate, zanamivir, or peramivir) as determined using a fluorescence-based NA inhibition assay. Substitutions conferring NAI resistance were mainly categorized as either novel NA subtype specific (G/N147V/I, A246V, and I427L) or previously reported in other subtypes (E119A/D/V, Q136K, E276D, R292K, and R371K). Our results demonstrate that each NA subtype possesses unique NAI resistance markers, and knowledge of these substitutions in AIVs is important in facilitating antiviral susceptibility monitoring of NAI resistance in AIVs.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Animals; Antiviral Agents; Birds; Cyclopentanes; Dogs; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza in Birds; Influenza, Human; Madin Darby Canine Kidney Cells; Mutagenesis; Neuraminidase; Orthomyxoviridae; Oseltamivir; Reverse Genetics; Zanamivir

We herein report a case of a 31-year-old Japanese man who simultaneously had a positive influenza A virus antigen test result and Vogt-Koyanagi-Harada disease (VKHD), demonstrated by both diffuse multiple early hyperfluorescent points on fluorescein fundus photography and serous retinal detachments on optical coherence tomography. He had meningitis. It was difficult to determine whether the main cause of meningitis was influenza A or VKHD. After initial treatment with peramivir for influenza A and then methylprednisolone pulse with subsequent corticosteroid therapy for VKHD, his symptoms improved gradually. These findings suggest that influenza A virus infection contributes to the onset or exacerbation of VKHD.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Glucocorticoids; Guanidines; Humans; Influenza A virus; Influenza, Human; Male; Methylprednisolone; Retinal Detachment; Tomography, Optical Coherence; Uveomeningoencephalitic Syndrome

Immune response after intravenous peramivir administration, which is approved for children with influenza infection in Japan, is unclear.. Kinetics of viral load and serum cytokine levels before and after peramivir therapy were analysed in 17 and 8 hospitalized children infected with influenza A and B, respectively. Additionally, haemagglutination inhibition (HI) titre was measured. The first day of hospital admission was defined as day 0.. Serum interleukin (IL)-6 levels in influenza-A-infected children significantly decreased after peramivir administration, unlike in those with influenza B where a decrease on day 1 was followed by an increase on day 2. Serum IL-6 kinetics were similar to viral load kinetics in both influenza-A- and B-infected children between days 0 and 2. Serum IL-8 levels gradually decreased after peramivir therapy in influenza-A-infected children but increased between days 1 and 2 in influenza-B-infected children. Conversely, serum IL-10 levels gradually decreased over time. Serum interferon-γ and granulocyte macrophage colony-stimulating factor levels remained low until day 5. Day 0-4 serum HI titres were <4-fold in all children infected with influenza A or B. Additionally, day 5 HI titres were positive in 4 of 6 influenza A cases and all 3 influenza B cases.. Our results suggest that viral load and inflammatory cytokine kinetics were associated with the antiviral therapy used and that second peramivir administration should be considered in influenza B. The results also highlight antiviral agents as key determinants of the clinical course of influenza virus infection in children.

Topics: Acids, Carbocyclic; Administration, Intravenous; Adolescent; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Guanidines; Hemagglutination Inhibition Tests; Hospitalization; Humans; Immunity, Innate; Infant; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Interferon-gamma; Interleukin-10; Interleukin-6; Interleukin-8; Male; Retrospective Studies; Viral Load

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A- or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A- or B-infected patients aged 5-9 years was 2.13-times greater than that in patients aged 10-18 years (p = 0.012).

Topics: Acids, Carbocyclic; Adolescent; Betainfluenzavirus; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza A virus; Influenza, Human; Japan; Male; Neuraminidase; Oseltamivir; Pyrans; Seasons; Sialic Acids; Treatment Outcome; Zanamivir

Neuraminidase inhibitors are recommended for children hospitalized with influenza-related respiratory infections, and oseltamivir is the first choice of treatment in most situations. However, little is known regarding the recent trend in using neuraminidase inhibitors and their difference in health economy. The aim of this study was to reveal recent trends in neuraminidase inhibitor use and compare hospitalization costs across different treatment regimens.. We retrospectively obtained the hospital discharge records of inpatients under 18 years of age with a diagnosis of influenza-related respiratory infections using a national inpatient database in Japan. We excluded patients with chronic medical conditions from the analyses. Multivariable mixed effects regression models were used to investigate the recent treatment trends and healthcare costs.. We identified 27 771 inpatients with influenza-related respiratory infections. The proportions of neuraminidase inhibitor use increased from 62.6% in 2010 to 71.8% in2014 (P. We observed an increasing trend in peramivir use and decreasing trends in use of oseltamivir and zanamivir. Treatment with peramivir required higher hospitalization costs.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Drug Utilization; Enzyme Inhibitors; Female; Guanidines; Hospitalization; Humans; Infant; Influenza, Human; Japan; Male; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Zanamivir

The safety and clinical effectiveness data of peramivir in the real clinical field are limited. A prospective observational study was conducted based on the post-marketing surveillance data to evaluate the post-marketing safety and effectiveness of peramivir in Korean adults with seasonal influenza.. Among adults aged 20 years or older who were diagnosed with influenza A or B, patients who started peramivir within 48 hours from the initial symptoms of influenza were enrolled. All adverse events (AEs) that occurred within 7 days after administration of peramivir were checked. For the evaluation of effectiveness, changes in the severity of influenza symptoms and daily living performance were examined before and 7 days after the administration of peramivir. The date on which influenza related symptoms disappeared was checked.. A total of 3,024 patients were enrolled for safety evaluation and 2,939 patients were for effectiveness evaluation. In the safety evaluation, 42 AEs were observed in 35 (1.16%) patients. The most common AE was fever. AEs were mostly rated as mild in severity. Serious AEs were observed in 10 patients and two of them died. However, both deaths were considered to be less relevant to peramivir. In the effectiveness evaluation, the severity of influenza symptoms decreased by 10.68 ± 4.01 points and daily living performance was improved 5.59 ± 2.16 points. Influenza related symptoms disappeared on average 3.02 ± 2.39 days after peramivir administration.. Peramivir showed a tolerable safety profile and acceptable effectiveness in Korean adult patients with seasonal influenza.

Topics: Acids, Carbocyclic; Adult; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Female; Guanidines; Humans; Influenza, Human; Male; Marketing; Middle Aged; Prospective Studies; Republic of Korea; Young Adult

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Influenza, Human; Marketing; Prospective Studies; Treatment Outcome

The prevention strategies for mother-to-fetus/infant transmission of H7N9 virus have not been well understood, and the study on this subject will provide further insights.. Reverse transcriptase polymerase chain reaction assay was undertaken to detect H7N9 virus in samples from a pregnant women, a postpartum woman, and their fetus/infant. Pathological features of tissues from the dead fetus were evaluated with hematoxylin and eosin staining. Hemagglutination inhibition assay was used to detect virus-specific antibodies. Furthermore, relevant literatures were reviewed and analyzed.. A 28-year-old pregnant woman was hospitalized for H7N9 infection and prescribed with oseltamivir and peramivir for 2 days before admission. The fetal heart beating stopped on day 4, the dead fetus was delivered on day 13, and the woman expired on day 26. All fetal tissues were H7N9 virus-negative. A 28-year-old woman delivered a newborn on December 20, 2016. Five days later, she developed influenza-like symptoms and was confirmed with H7N9 infection. She had close contact with her infant for 9 days. Oseltamivir and peramivir were prescribed within 2 days after illness onset. A throat swab and a pair of serum samples from the infant were all negative for H7N9 virus during 4-week follow-up. In total, ten studies referring to transplacental transmission and four reports on maternal infection of H7N9 virus were reviewed and analyzed.. No evidence showed H7N9 virus infection in both fetus and infant. The early administration of neuraminidase inhibitor seemed beneficial in preventing mother-to-fetus/infant transmission of H7N9 virus.

Topics: Acids, Carbocyclic; Adult; Cyclopentanes; Enzyme Inhibitors; Fatal Outcome; Female; Fetal Death; Fetus; Guanidines; Humans; Infant; Influenza A Virus, H7N9 Subtype; Influenza, Human; Maternal-Fetal Exchange; Mothers; Neuraminidase; Oseltamivir; Pregnancy; Secondary Prevention; Treatment Outcome

Topics: Acids, Carbocyclic; Antiviral Agents; Central Nervous System; Cyclopentanes; Electroencephalography; Guanidines; Humans; Influenza, Human; Male; Meningoencephalitis; Middle Aged; Treatment Outcome

A 19-year-old man presented with a fever, convulsions, and loss of consciousness at our hospital. The patient had a Glasgow Coma Scale score of 12. Influenza B virus infection was diagnosed using the rapid test kit, and an eight-fold increase in the serum levels of anti-influenza B virus antibody was confirmed using the complement fixation test. Brain magnetic resonance imaging showed multifocal high-signal lesions, and an electroencephalogram showed diffuse slowing of the background activity, indicating acute encephalopathy. After treatment with peramivir and methylprednisolone for 3 days, the patient was discharged without any neurological impairment. This was a case of influenza B infection associated with acute encephalopathy in a healthy young man.

Topics: Acids, Carbocyclic; Antibodies, Viral; Brain Diseases; Cyclopentanes; Electroencephalography; Guanidines; Humans; Influenza B virus; Influenza, Human; Magnetic Resonance Imaging; Male; Methylprednisolone; Young Adult

We retrospectively analyzed data of 38 elderly patients, each with an underlying disease, to evaluate peramivir safety and efficacy. Six patients (15.8%) experienced adverse events, all tolerated. Median time from administration until the return to normal temperatures was 31.5 h (95% CI: 22.4-40.6). Results confirm intravenous peramivir's usefulness.

Topics: Acids, Carbocyclic; Administration, Intravenous; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Drug-Related Side Effects and Adverse Reactions; Female; Guanidines; Humans; Influenza, Human; Male; Retrospective Studies; Treatment Outcome

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Epidemiological Monitoring; Global Health; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Influenza, Human; Inhibitory Concentration 50; Microbial Sensitivity Tests; Neuraminidase; Oseltamivir; Pyrans; Seasons; Sialic Acids; World Health Organization; Zanamivir

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

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Databases, Genetic; Drug Resistance, Multiple, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H7N9 Subtype; Influenza, Human; Inhibitory Concentration 50; Neuraminidase; Oseltamivir; Protein Conformation; Pyrans; Recombinant Proteins; Sialic Acids; Viral Proteins; Zanamivir

Neuraminidase inhibitors (NAIs) including oseltamivir and peramivir are used for influenza treatment. A systemic corticosteroid is usually administrated for acute respiratory distress syndrome. The aim of this study was to investigate the effect of a systemic corticosteroid and its interaction with NAIs in patients with influenza infection and respiratory distress.. A retrospective survey of hospitalized patients infected with influenza from January 2012 to May 2014 was conducted in a medical center in Taiwan.. Eighty-six patients were hospitalized during the study period. Forty-eight patients had respiratory distress and 39 of them (81.3%, 39/48) were supported by a mechanical ventilator. All patients with respiratory distress received oseltamivir; 60.4% (29/48) and 31.3% (15/48) of them received a corticosteroid and salvage intravenous peramivir, respectively. All-cause mortality was 29.1% (14/48), 20% (3/15), and 31% (9/29) in patients with respiratory distress, patients who received salvage peramivir, and patients who received a systemic corticosteroid, respectively. Salvage peramivir seemed to improve prognosis in patients with H1pdm09 or type B virus infection and respiratory distress (p = 0.05). Early initiating corticosteroid had a worse prognosis than initiation after 72 hours of NAI treatment (p = 0.024). In particular, a systemic corticosteroid seemed to lead to a shorter survival time in patients with chronic lung disease (p = 0.05).. Salvage peramivir provided a better prognosis than monotherapy with oseltamivir in patients who were infected with H1pdm09 or type B virus and who developed respiratory distress. A systemic corticosteroid should be administered after initiating NAI therapy, especially in patients with chronic lung disease.

Topics: Acids, Carbocyclic; Adrenal Cortex Hormones; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Metabolic Syndrome; Middle Aged; Neuraminidase; Orthomyxoviridae; Oseltamivir; Respiratory Distress Syndrome; Retrospective Studies; Taiwan; Treatment Outcome

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Child; Child, Preschool; Community-Acquired Infections; Cross Infection; Cyclopentanes; Drug Resistance, Viral; Female; Genes, Viral; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Japan; Male; Middle Aged; Mutation; Oseltamivir; Phylogeny; Seasons; Young Adult

We evaluated the environmental fate of new three anti-influenza drugs, favipiravir (FAV), peramivir (PER), and laninamivir (LAN), and an active prodrug of LAN, laninamivir octanoate (LANO), in comparison with four conventional drugs, oseltamivir (OS), oseltamivir carboxylate (OC), amantadine (AMN), and zanamivir (ZAN) by photodegradation, biodegradation, and sorption to river sediments. In addition, we conducted 9-month survey of urban rivers in the Yodo River basin from 2015 to 2016 (including the influenza season) to investigate the current status of occurrence of these drugs in the river environment. The results clearly showed that FAV and LAN rapidly disappeared through photodegradation (half-lives 1 and 8 h, respectively), followed by LANO which gradually disappeared through biodegradation (half-life, 2 days). The remained PER and conventional drugs were, however, persistent and transported from upstream to downstream sites. Rates of their sorption to river sediments were negligibly small. Detected levels remained were in the range from N.D. to 89 ng/L for the river waters and from N.D. to 906 ng/L in sewage effluent. However, all of the remained drugs were effectively removed by ozonation after chlorination at a sewage treatment plant. These findings suggest the importance of introducing ozonation for reduction of pollution loads in rivers, helping to keep river environments safe. To the best of our knowledge, this is the first evaluation of the removal effects of natural sunlight, biodegradation, and sorption to river sediments on FAV, PER, LAN, LANO, and a conventional drug, AMN.

Topics: Acids, Carbocyclic; Amides; Antiviral Agents; Biodegradation, Environmental; Cyclopentanes; Environmental Monitoring; Fresh Water; Guanidines; Half-Life; Humans; Influenza, Human; Japan; Prodrugs; Pyrans; Pyrazines; Rivers; Seasons; Sewage; Sialic Acids; Water Pollutants, Chemical; Zanamivir

High morbidity and mortality associated with human cases of highly pathogenic avian influenza (HPAI) viruses, including H5N1 influenza virus, have been reported. The purpose of the present study was to evaluate the antiviral effects of peramivir against HPAI viruses. In neuraminidase (NA) inhibition and virus replication inhibition assays, peramivir showed strong inhibitory activity against H5N1, H7N1 and H7N7 HPAI viruses with sub-nanomolar activity in enzyme assays. In H5N1 viruses containing the NA H275Y mutation, the antiviral activity of peramivir against the variant was lower than that against the wild-type. Evaluation of the in vivo antiviral activity showed that a single intravenous treatment of peramivir (10 mg/kg) prevented lethality in mice infected with wild-type H5N1 virus and also following infection with H5N1 virus with the H275Y mutation after a 5 day administration of peramivir (30 mg/kg). Furthermore, mice injected with peramivir showed low viral titers and low levels of proinflammatory cytokines in the lungs. These results suggest that peramivir has therapeutic activity against HPAI viruses even if the virus harbors the NA H275Y mutation.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Cyclopentanes; Cytokines; Disease Models, Animal; Guanidines; Humans; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N1 Subtype; Influenza A Virus, H7N7 Subtype; Influenza, Human; Lung; Mice; Mutation; Neuraminidase; Orthomyxoviridae Infections; Viral Load; Virus Replication

Background In Japan, four neuraminidase inhibitors (NAIs) are currently prescribed to patients with influenza A and B. To know the backgrounds and clinical courses of patients with influenza who were treated with NAIs is important in the selection of appropriate medications. Methods We conducted a multicenter observational study in Osaka with postcard questionnaires. Patients who were prescribed NAIs were provided postcard questionnaires containing questions on their backgrounds, body temperatures, and durations of other influenza symptoms. We analyzed the factors that were associated with early fever alleviation using a logistic regression model. Results The postcard response rate was 31% (326 of 1050), and 307 patients were enrolled in this study [150 patients who were under 10 years old (type A, 118; and type B, 32) and 157 patients who were 10 or older (type A, 114; and type B, 43)]. In the patients under 10, the multivariate analysis showed that influenza type (Type B vs Type A; Odds Ratio, 0.13; 95% Confidence Interval: 0.04-0.38) was associated with early fever alleviation. However, NAIs were not related to early fever alleviation. Laninamivir tended to contribute more to early fever alleviation compared to oseltamivir in patients under 10 (Odds Ratio, 2.50;$95% Confidence Interval: 0.90-7.80). Conclusions The types,of prescibed NAIs were not significantly related to early fever alleviation. However, the fever durations of the patients under 10 who were prescribed laninamivir were shorter than those of patients under 10 who were prescribed oseltamivir or zanamivir.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Disease Outbreaks; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Influenza, Human; Japan; Male; Middle Aged; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Surveys and Questionnaires; Treatment Outcome; Zanamivir

Since the novel H7N9 avian influenza outbreak occurred in China in 2013, neuraminidase inhibitors (NAIs) such as oseltamivir and peramivir have been used as first-line drugs to treat the influenza virus infection. This study aimed to compare the efficacy of oseltamivir-peramivir combination therapy versus oseltamivir monotherapy.. A retrospective study of 82 H7N9 confirmed patients was conducted by reviewing medical charts at the First Affiliated Hospital of ZheJiang University in China from April 1, 2013 to Feb 28, 2014. The patients' clinical information was collected systematically, and we compared the virology and clinical data between oseltamivir monotherapy group (43 patients) and oseltamivir-peramivir combination group (39 patients).. The median duration from NAIs administration to H7N9 virus-negative in oseltamivir monotherapy group and oseltamivir-peramivir combination group was 6.50 and 7.00 days (p >0.05), respectively. The median decline of Day 2 to Day 0 (initiation of NAIs therapy) viral load was 0.00 and 0.69 log10 copies/μl (p >0.05) respectively in the monotherapy vs. combination therapy groups. The incidence of new Acute Respiratory Distress Syndrome during NAI administration was 63.89 and 77.78 % (p >0.05); while the mortality rates were 25.58 and 43.59 % (p >0.05) in the oseltamivir group vs. oseltamivir-peramivir group.. Our results suggest that in adults with H7N9 virus infection, the use of oseltamivir-peramivir combination therapy was not superior to oseltamivir monotherapy.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Antiviral Agents; China; Cyclopentanes; Drug Therapy, Combination; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H7N9 Subtype; Influenza, Human; Male; Middle Aged; Neuraminidase; Oseltamivir; Respiratory Distress Syndrome; Retrospective Studies; Viral Load; Young Adult

A 79-year-old man experienced severe chronic obstructive pulmonary disease (COPD) and was receiving treatment for ischemic heart disease. Starting from dizziness and chilliness, he lost consciousness after few days. He was taken to our emergency department. On initial evaluation, he complained of dyspnea and was afebrile with a pulse rate, blood pressure, and respiratory rate of 105 beats/min, 112/98mmHg, and 28 breath/min, respectively. His respiratory sounds were clear and chest radiography did not show any abnormal shadows, but his arterial blood gas examination showed type II respiratory failure. Because the nasopharyngeal seasonal influenza A virus (IAV) test was positive, the patient was admitted with the diagnosis of acute exacerbation of COPD due to IAV. We administered peramivir, a specific anti-influenza drug, and started mechanical ventilation. Over time, he started to show signs of disseminated intravascular coagulation, such as multiple organ failure and thrombocytopenia. Subsequently, blood tests showed elevation of ferritin and soluble interleukin 2 receptor (sIL2R); microscopic examination of the peripheral blood revealed hemophagocytosis. Secondary hemophagocytic lymphohistiocytosis (HLH) due to IAV was diagnosed and together with corticosteroid therapy, intravenous gamma globulin was administered from the 3rd clinical day. The patint was saved with our early diagnosis and treatment of HLH and was discharged on the 92nd clinical day. Viral-induced HLH, formerly known as virus-associated hemophagocytic syndrome (VAHS), leads to multiple organ failure due to a cytokine storm scattered by viral-infected pathogenic inflammatory cells. It is well known that pandemic swine flu causes secondary HLH leading to poor outcomes. Currently, not much is known about HLH due to seasonal flu; particularly, IAV (H3N2)-related HLH cases are rare and reported cases showed poor outcomes as well. With an early diagnosis and minimum immunotherapy, we report herein on a case of IAV (H3N2)-related HLH which was treated successfully.

Topics: Acids, Carbocyclic; Aged; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Influenza A Virus, H3N2 Subtype; Influenza, Human; Lymphohistiocytosis, Hemophagocytic; Male; Seasons

We present systemsDock, a web server for network pharmacology-based prediction and analysis, which permits docking simulation and molecular pathway map for comprehensive characterization of ligand selectivity and interpretation of ligand action on a complex molecular network. It incorporates an elaborately designed scoring function for molecular docking to assess protein-ligand binding potential. For large-scale screening and ease of investigation, systemsDock has a user-friendly GUI interface for molecule preparation, parameter specification and result inspection. Ligand binding potentials against individual proteins can be directly displayed on an uploaded molecular interaction map, allowing users to systemically investigate network-dependent effects of a drug or drug candidate. A case study is given to demonstrate how systemsDock can be used to discover a test compound's multi-target activity. systemsDock is freely accessible at http://systemsdock.unit.oist.jp/.

Topics: Acids, Carbocyclic; Cyclopentanes; Guanidines; Humans; Influenza, Human; Internet; Ligands; Molecular Docking Simulation; Orthomyxoviridae; Oseltamivir; Pharmacology; Software; User-Computer Interface

Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Cyclopentanes; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanidines; Humans; Influenza, Human; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Neuraminidase; Rabbits; Structure-Activity Relationship

An open-label trial on intravenous peramivir was conducted among adult patients hospitalised for influenza-associated lower respiratory tract complications (LRTCs). Virus culture and quantitative reverse transcription PCR (qRT-PCR) were performed serially until Day 10. Peramivir treatment was associated with viral RNA decline as well as culture and RNA negativity, which occurred at rates comparable with those of oseltamivir: by Day 5, viral load decline -2.5 log10 copies/mL [βinteraction -0.071, standard error (SE) 0.121, 95% confidence interval (CI) -0.309 to 0.167]; culture-negative, 94% (vs. 95%); and RNA-negative, 44% (vs. 36%). Extended treatment of >5 days was required in 69% of cases because of slow clinical resolution and viral clearance in LRTCs. Peramivir was well tolerated. These data are useful for future trial design in this unique population.

Topics: Acids, Carbocyclic; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Bronchopneumonia; Cyclopentanes; Female; Guanidines; Humans; Influenza, Human; Male; Middle Aged; Real-Time Polymerase Chain Reaction; RNA, Viral; Treatment Outcome; Viral Load; Virus Cultivation; Young Adult

An influenza A(H1N1)pdm09 virus carrying a G147R substitution in combination with an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir, was detected from an immunocompromised inpatient in Japan, March 2016. This dual H275Y/G147R mutant virus exhibited enhanced cross-resistance to both drugs compared with the single H275Y mutant virus and reduced susceptibility to zanamivir, although it showed normal inhibition by laninamivir.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Japan; Middle Aged; Mutation; Neuraminidase; Oseltamivir; Treatment Outcome

We herein report the case of an 80-year-old man with malignant lymphoma who became persistently infected with influenza A virus. Although he was repeatedly treated with NA inhibitors, such as oseltamivir or peramivir, nasal cavity swab tests for influenza A antigen continued to be positive for more than 2 months. Virological analyses revealed that he was infected with the NA inhibitor-resistant A (H3N2) virus possessing an R292K substitution in the NA protein. These findings suggest that a drug-resistant influenza virus strain might selectively survive antiviral therapy in elderly patients with refractory malignant lymphoma undergoing multiple chemotherapies.

Topics: Acids, Carbocyclic; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H3N2 Subtype; Influenza, Human; Lymphoma; Male; Mutation; Neuraminidase; Oseltamivir

Peramivir, the only injectable anti-influenza neuraminidase inhibitor medically available in Japan at present, is considered first-line treatment in patients with high risk factors for influenza exacerbation. We conducted a drug-use investigation of peramivir in inpatients with high risk factors (old age, pregnancy, and underlying disease such as chronic respiratory disease) from January 2010 to March 2013. Data of 772 patients from 124 facilities across Japan were collected; peramivir's safety in 770 patients and effectiveness in 688 patients were examined. In total, 412 adverse events were observed in 219 patients (28.4%). Of these, 155 events were adverse drug reactions (ADRs) observed in 98 patients (12.7%). Major ADRs (≥2%) were increased aspartate aminotransferase (5.1%), increased alanine aminotransferase (3.8%) and decreased white blood cell count (2.5%). Fourteen serious ADRs were observed in 12 patients (1.6%). All serious ADRs were resolved or improved except for two events for which outcomes were unknown. Multivariate analyses revealed that ADR incidences were significantly associated with these four backgrounds of patients: medical history, no influenza vaccination, renal impairment and other infection(s). With regard to its effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration, which was the same as in other previous surveillance studies. This surveillance study indicated the safety of peramivir in the treatment of influenza inpatients with high risk factors under routine clinical settings.

Topics: Acids, Carbocyclic; Administration, Intravenous; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Disease Progression; Female; Guanidines; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Inpatients; Japan; Male; Middle Aged; Neuraminidase; Pregnancy; Risk Factors; Treatment Outcome; Young Adult

Peramivir is an intravenously administered neuraminidase inhibitor for influenza. The clinical efficacy of peramivir remains unclear because it is used in a limited number of countries. We compared the clinical efficacy of peramivir with that of oseltamivir in influenza patients during the 2012-2013 season.. Thirty-two influenza patients who were hospitalized at Teikyo University Hospital, a teaching hospital in Tokyo, Japan, from October 2012 to March 2013 were enrolled. Among them, 23 and 9 were treated with peramivir and oseltamivir, respectively. The end points of this study were the time to defervescence and survival rate.. There were no significant differences in the clinical backgrounds of the two groups. However, patients treated with peramivir tended to have a higher incidence of consciousness disturbance [34.8% (8/23) vs 0.00% (0/9), P = 0.064]. There were no significant differences between the peramivir and oseltamivir groups with respect to the time to defervescence (30.9 ± 18.7 h vs 34.7 ± 18.6 h) or survival rate [95.7% (22/23) vs 100% (9/9), respectively].. The clinical efficacy of peramivir is non-inferior to that of oseltamivir, although peramivir tended to be used in patients with serious complications. Intravenous administration of peramivir may be useful for patients with serious complications, such as consciousness disturbances.

Topics: Acids, Carbocyclic; Adult; Aged; Aged, 80 and over; Antiviral Agents; Cyclopentanes; Female; Guanidines; Hospitalization; Humans; Influenza A virus; Influenza, Human; Japan; Male; Middle Aged; Oseltamivir; Retrospective Studies; Seasons; Treatment Outcome

Shedding of the pandemic virus during an influenza pandemic is thought to persist longer than shedding of influenza viruses during annual influenza seasons, because people have much less immunity against a pandemic influenza. A correlation is thought to exist between the length of virus shedding and the clinical severity of influenza illness.. We compared the virus isolation rates of children with pandemic A H1N1/09 influenza infection and children with A H3N2 influenza infection after the patients had been treated with one of three neuraminidase inhibitors (NAI) such as peramivir, laninamivir and oseltamivir. The clinical effectiveness of each NAI was assessed on the basis of the duration of the febrile period after the start of treatment.. Influenza viruses were isolated from 15 of the 34 patients in the A H3N2 group (mean age 6.2 years) and from 4 of the 25 patients in the A H1N1/09 (mean age 5.6 years) virus group (44.1% versus 16.0%; P<0.05). However, the differences between the duration of fever in the patients in the A H3N2 group and A H1N1/09 group after treatment with the NAIs were not significant.. The virus isolation rates after treatment with each of the NAIs were significantly lower in the A H1N1/09 group, suggesting that the pandemic A H1N1/09 virus was more sensitive to the NAIs than the seasonal A H3N2 virus was. Clinically, there were no significant differences in the effectiveness of the NAIs between the H1N1/09 infected group and H3N2 infected group.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Fever; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Male; Neuraminidase; Oseltamivir; Pyrans; Severity of Illness Index; Sialic Acids; Time Factors; Treatment Outcome; Viral Proteins; Virus Shedding; Zanamivir

The neuraminidase inhibitors (NAIs) oseltamivir phosphate (Tamiflu(®)), zanamivir (Relenza(®)), laninamivir octanoate (Inavir(®)), and peramivir (Rapiacta(®)) have been available for the treatment of influenza in Japan since 2010. The emergence of resistant virus to any of the NAIs is a great concern for influenza treatment. To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of each NAI for influenza virus isolates in the 2012-2013 influenza season and compared the results to those of the 2010-2011 and 2011-2012 influenza seasons. Viral isolation of specimens obtained prior to treatment was done using Madine-Darby canine kidney cells, and the type and subtype of influenza, A(H1N1)pdm09, A(H3N2), or influenza B, was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 329 influenza viruses were isolated:5 influenza A(H1N1)pdm09 (1.5%), 316 influenza A(H3N2) (96.1%), and 8 influenza B (2.4%). No isolate showed an IC50 value exceeding 50 nM for any of the neuraminidase inhibitors. The IC50 values for A(H3N2) and B were similar to those of the 2010-2011 and 2011-2012 seasons. No isolate showed an increased IC50 value for A(H1N1)pdm09. These results indicate that the currently epidemic influenza viruses are susceptible to all four neuraminidase inhibitors, with no trend for IC50 values to increase at present.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Dogs; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Infant; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Inhibitory Concentration 50; Japan; Madin Darby Canine Kidney Cells; Middle Aged; Neuraminidase; Oseltamivir; Young Adult; Zanamivir

Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. In October 2010, an additional indication for pediatric use was approved. We conducted a pediatric drug use investigation of peramivir from October 2010 to February 2012 and evaluated its real-world safety and effectiveness in pediatric patients. We collected the data of 1254 peramivir-treated pediatric patients from 161 facilities across Japan and examined the safety in 1199 patients and effectiveness in 1188 patients. In total, 245 adverse events were observed with an incidence rate of 14.01% (168/1199). Of these, 115 events were adverse drug reactions (ADRs) with an incidence rate of 7.67% (92/1199). Common ADRs were diarrhea and abnormal behavior, with incidence rates of 2.50% (30/1199) and 2.25% (27/1199), respectively. Fourteen serious ADRs were observed in 12 patients (1.00%), including 5 cases each of abnormal behavior and neutrophil count decreased. While 87.0% (100 events) of ADRs occurred within 3 days after the initiation of peramivir administration, 87.8% (101 events) resolved or improved within 7 days after onset. Multivariate analyses indicated that the presence or absence of underlying diseases/complications was significantly related to ADR incidence. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. Thus, this study confirms the pediatric safety of peramivir without any concerns about effectiveness under routine clinical settings.

Topics: Acids, Carbocyclic; Adolescent; Antiviral Agents; Child; Child Behavior Disorders; Child, Preschool; Cyclopentanes; Diarrhea; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza, Human; Injections, Intravenous; Male; Neuraminidase; Product Surveillance, Postmarketing; Treatment Outcome

We estimated the efficacy of the current single administration of peramivir on the basis of peramivir pharmacokinetics in the upper respiratory tract (URT) and determined the predictive peramivir concentration-time curve to assess its efficacy against viruses with decreased susceptibility to neuraminidase inhibitors. Serum, nasal swab, or aspiration samples were collected from 28 patients treated with 10 mg/kg body weight peramivir. The sequential influenza viral RNA load and susceptibility after peramivir administration were measured using a quantitative real-time reverse transcription-PCR and neuraminidase inhibition assay. The peramivir concentrations in the serum and URT after a single administration at 10 mg/kg were measured, and the predictive blood and URT peramivir concentration-time curves were determined to assess various administration regimens against resistant variants. The peramivir concentration decreased to <0.1% of the maximum concentration of drug in serum (Cmax) at 24 h after administration. Rapid elimination of peramivir from the URT by 48 h after administration may contribute to an increase in the influenza A viral load after day 3 but not to a decrease in the influenza B viral load, despite the absence of a decrease in the susceptibility to peramivir. A longer maintenance of a high level of peramivir in the URT is expected by divided administration rather than once-daily administration. When no clinical improvement is observed in patients with normal susceptibility influenza A and B, peramivir readministration should be considered. In severe cases caused by resistant variants, better inhibitory effectiveness and less frequent adverse events are expected by divided administration rather than once-daily administration with an increased dosage.

Topics: Acids, Carbocyclic; Adolescent; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Influenza A virus; Influenza B virus; Influenza, Human; Kinetics; Male; Neuraminidase; Viral Load; Viral Proteins

We aimed to study factors influencing outcomes of adults hospitalised for seasonal and pandemic influenza.  Individual-patient data from three Asian cohorts (Hong Kong, Singapore and Beijing; N=2649) were analysed. Adults hospitalised for laboratory-confirmed influenza (prospectively diagnosed) during 2008-2011 were studied. The primary outcome measure was 30-day survival. Multivariate Cox regression models (time-fixed and time-dependent) were used. Patients had high morbidity (respiratory/nonrespiratory complications in 68.4%, respiratory failure in 48.6%, pneumonia in 40.8% and bacterial superinfections in 10.8%) and mortality (5.9% at 30 days and 6.9% at 60 days). 75.2% received neuraminidase inhibitors (NAI) (73.8% received oseltamivir and 1.4% received peramivir/zanamivir; 44.5% of patients received NAI ≤2 days and 65.5% ≤5 days after onset of illness); 23.1% received systemic corticosteroids. There were fewer deaths among NAI-treated patients (5.3% versus 7.6%; p=0.032). NAI treatment was independently associated with survival (adjusted hazard ratio (HR) 0.28, 95% CI 0.19-0.43), adjusted for treatment-propensity score and patient characteristics. Superinfections increased (adjusted HR 2.18, 95% CI 1.52-3.11) and chronic statin use decreased (adjusted HR 0.44, 95% CI 0.23-0.84) death risks. Best survival was shown when treatment started within ≤2 days (adjusted HR 0.20, 95% CI 0.12-0.32), but there was benefit with treatment within 3-5 days (adjusted HR 0.35, 95% CI 0.21-0.58). Time-dependent analysis showed consistent results of NAI treatment (adjusted HR 0.39, 95% CI 0.27-0.57). Corticosteroids increased superinfection (9.7% versus 2.7%) and deaths when controlled for indications (adjusted HR 1.73, 95% CI 1.14-2.62). Early NAI treatment was associated with shorter length of stay in a subanalysis. NAI treatment may improve survival of hospitalised influenza patients; benefit is greatest from, but not limited to, treatment started within 2 days of illness. Superinfections and corticosteroids increase mortality. Antiviral and non-antiviral management strategies should be considered.

Topics: Acids, Carbocyclic; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Beijing; Cohort Studies; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Hong Kong; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Influenza, Human; Male; Middle Aged; Multivariate Analysis; Neuraminidase; Oseltamivir; Pneumonia, Bacterial; Proportional Hazards Models; Prospective Studies; Protective Factors; Respiratory Insufficiency; Retrospective Studies; Risk Factors; Singapore; Superinfection; Young Adult; Zanamivir

The Centers for Disease Control and Prevention estimated that up to 88 million H1N1 influenza cases, 398,000 hospitalizations, and up to 18,050 related deaths, including significant racial and ethnic disparities, occurred between April 2009 and March 13, 2010. The Food and Drug Administration (FDA) approved emergency use authorizations (EUAs), which allowed the distribution of unapproved drugs or the off-label use of approved drugs. In late 2009, peramivir was granted an EUA for patients with severe disease. This study examined factors associated with willingness to take peramivir.. In 2010 we conducted a nationally representative survey with 2079 respondents randomly drawn from the Knowledge Networks research panel. Our completion rate was 56%. Respondents received information about peramivir from a fact sheet and then answered questions about their willingness to take the drug.. Overall, 48% of participants indicated that they would probably or definitely take peramivir. Seventy-nine percent definitely would take the drug if their doctor recommended it and there were no alternative treatments. There were significant racial differences in willingness. The term experimental to refer to the drug decreased willingness to accept peramivir among both whites and blacks.. Trust in the FDA was important for peramivir acceptance. Particular care must be taken to ensure that patients and their families understand the complex nature of EUA drugs. Lessons learned can inform communication about future EUAs. (Disaster Med Public Health Preparedness. 2015;9:166-174).

Topics: Acids, Carbocyclic; Cyclopentanes; Emergency Treatment; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Patient Acceptance of Health Care; Surveys and Questionnaires

Prolonged treatment of an immunocompromised child with oseltamivir and zanamivir for A(H1N1)pdm09 virus infection led to the emergence of viruses carrying H275Y and/or E119G in the neuraminidase (NA). When phenotypically evaluated by NA inhibition, the dual H275Y-E119G substitution caused highly reduced inhibition by 4 NA inhibitors: oseltamivir, zanamivir, peramivir, and laninamivir.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Immunocompromised Host; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Mutation, Missense; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Viral Proteins; Zanamivir

The clinical efficacy of peramivir in the treatment of severe seasonal influenza in critically ill patients admitted to an intensive care unit (ICU) is not well established. The aim of this study was to compare the clinical efficacy of peramivir with that of oseltamivir in such critically ill patients. From September 2010 through March 2014, sixty patients with influenza confirmed by RT-PCR and hospitalized in our ICU were enrolled and reviewed retrospectively. Thirty-four and twenty-six patients received initial peramivir and oseltamivir, respectively. The median sequential organ failure assessment score was higher in the patients treated with peramivir (11 vs. 8.5, P= 0.029). There was no significant difference between the two groups in the median duration of use of antiviral agents. There were also no significant differences between the groups in 14-day (17.6% in peramivir vs. 7.7% in oseltamivir, P = 0.446), or 28-day mortality (35.3% in peramivir vs. 34.6% in oseltamivir, P = 0.813) or in the median length of ICU stay (11 days in peramivir vs. 12 days in oseltamivir, P=0.852). Peramivir has the similar clinical efficacy to oseltamivir in the treatment of severe seasonal influenza in the critically ill patients admitted to ICU.

Topics: Acids, Carbocyclic; Administration, Oral; Adult; Aged; Aged, 80 and over; Antiviral Agents; Critical Illness; Cyclopentanes; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Intensive Care Units; Length of Stay; Middle Aged; Organ Dysfunction Scores; Oseltamivir; Retrospective Studies; Seasons; Time Factors; Treatment Outcome; Young Adult

A 47-year-old man with a fever was highly suspected of having influenza A infection since his wife and son who lived with him had been diagnosed with influenza A. Although repeated rapid tests with a nasopharyngeal swab showed negative findings, the patient developed bilateral pneumonia and reverse transcription polymerase chain reaction (PCR) for A (H1N1) pdm09 virus in the bronchoalveolar lavage fluid was positive. We therefore diagnosed him with primary influenza pneumonia and initiated treatment with peramivir plus corticosteroids, which rapidly improved his condition. During the influenza season, sample collection from the lower airway and PCR should be considered for the definitive diagnosis of primary influenza viral pneumonia.

Topics: Acids, Carbocyclic; Adrenal Cortex Hormones; Bronchoalveolar Lavage Fluid; Cyclopentanes; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Pneumonia, Viral; Reverse Transcriptase Polymerase Chain Reaction

The number of patients infected with H7N9 influenza virus has been increasing since 2013. We examined the efficacy of neuraminidase (NA) inhibitors and the efficacy of a vaccine against an H7N9 influenza virus, A/Anhui/1/2013 (H7N9), isolated from a patient in a cynomolgus macaque model. NA inhibitors (oseltamivir and peramivir) barely reduced the total virus amount because of the emergence of resistant variants with R289K or I219T in NA [residues 289 and 219 in N9 of A/Anhui/1/2013 (H7N9) correspond to 292 and 222 in N2, respectively] in three of the six treated macaques, whereas subcutaneous immunization of an inactivated vaccine derived from A/duck/Mongolia/119/2008 (H7N9) prevented propagation of A/Anhui/1/2013 (H7N9) in all vaccinated macaques. The percentage of macaques in which variant H7N9 viruses with low sensitivity to the NA inhibitors were detected was much higher than that of macaques in which variant H5N1 highly pathogenic influenza virus was detected after treatment with one of the NA inhibitors in our previous study. The virus with R289K in NA was reported in samples from human patients, whereas that with I219T in NA was identified for the first time in this study using macaques, though no variant H7N9 virus was reported in previous studies using mice. Therefore, the macaque model enables prediction of the frequency of emerging H7N9 virus resistant to NA inhibitors in vivo. Since H7N9 strains resistant to NA inhibitors might easily emerge compared to other influenza viruses, monitoring of the emergence of variants is required during treatment of H7N9 influenza virus infection with NA inhibitors.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza Vaccines; Influenza, Human; Macaca; Mice; Neuraminidase; Orthomyxoviridae Infections; Oseltamivir; Primates; Vaccination; Viral Proteins; Virus Replication

To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of neuraminidase inhibitors (NAIs) for the influenza virus isolates in the 2013-2014 influenza season and compared the results to those of the 2010-2011 to 2012-2013 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 327 influenza viruses were isolated: 172 influenza A(H1N1)pdm09 (52.6%), 49 A(H3N2) (15.0%), and 106 B (32.4%). Numbers of Victoria and Yamagata lineage isolates were 36 and 70, respectively. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM) exceeding by 100 times the geometric mean of the IC50 of oseltamivir for A(H1N1)pdm09 isolates (0.76 nM). No isolate showed a very high IC50 for A(H3N2) or B. The IC50 of the NAIs except for oseltamivir for A(H1N1) pdm09 were significantly higher than those of the 2010-2011 season (P < 0.05). The IC50 of all four NAIs for A(H3N2) were significantly lower than those of the 2012-2013 season (P < 0.001). The IC50 of the NAIs for B except for oseltamivir were significantly lower than those of the 2012-2013 season (P < 0.001). Although there are some isolates that show highly reduced sensitivity to oseltamivir among A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2) and B viruses are susceptible to all four NAIs with no trend toward decreased sensitivity.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Inhibitory Concentration 50; Japan; Male; Middle Aged; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Time Factors; Young Adult; Zanamivir

A 52-year-old man was admitted to our hospital due to shortness of breath that developed one week after the diagnosis of influenza infection. He had a past history of myocarditis associated with influenza B infection 16 years before the current admission. The patient's left ventricular function showed diffuse hypokinesis with a left ventricular ejection fraction of 28%. Due to the progression of heart failure, the infusion of catecholamines and insertion of an intra-aortic balloon pump were required. The patient was discharged uneventfully on the 23rd hospital day. A significant increase in the serum antibody titer against influenza A virus subtype H3N2 led to a diagnosis of recurrent fulminant influenza myocarditis.

Topics: Acids, Carbocyclic; Adult; Antibodies, Viral; Antiviral Agents; Catecholamines; Cyclopentanes; Dyspnea; Electrocardiography; Guanidines; Heart-Assist Devices; Hemodynamics; Humans; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Intra-Aortic Balloon Pumping; Magnetic Resonance Imaging; Male; Myocarditis; Pericarditis; Recurrence; Ultrasonography; Ventricular Dysfunction, Left

Six influenza A(H1N1)pdm09 viruses were detected in Sapporo, Japan, between November and December 2013. All six viruses possessed an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir. No epidemiological link among the six cases could be identified; none of them had received neuraminidase inhibitors before specimen collection. The haemagglutinin and neuraminidase genes of the six viruses were closely related to one another, suggesting clonal spread of a single resistant virus.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; DNA, Viral; Drug Resistance, Viral; Female; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Japan; Male; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Neuraminidase; Oseltamivir; Phylogeny; Sequence Analysis, DNA; Treatment Outcome

Influenza viruses collected from regions of Asia, Africa and Oceania between 2009 and 2012 were tested for their susceptibility to two new neuraminidase inhibitors, peramivir and laninamivir. All viruses tested had normal laninamivir inhibition. However, 3·2% (19/599) of A(H1N1)pdm09 viruses had highly reduced peramivir inhibition (due to H275Y NA mutation) and <1% (6/1238) of influenza B viruses had reduced or highly reduced peramivir inhibition, with single occurrence of variants containing I221T, A245T, K360E, A395E, D432G and a combined G145R+Y142H mutation. These data demonstrate that despite an increase in H275Y variants in 2011, there was no marked change in the frequency of peramivir- or laninamivir-resistant variants following the market release of the drugs in Japan in 2010.

Topics: Acids, Carbocyclic; Africa; Antiviral Agents; Asia; Cyclopentanes; Guanidines; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Japan; Microbial Sensitivity Tests; Mutation, Missense; Neuraminidase; Oceania; Pyrans; Sialic Acids; Viral Proteins; Zanamivir

The purpose of this study was to investigate the relationship between pharmacokinetic (PK) parameters of intravenous (IV) peramivir and in vivo antiviral activity pharmacodynamic (PD) outcomes in a mouse model of influenza virus infection. Peramivir was administrated to mice in three dosing schedules; once, twice and four times after infection of A/WS/33 (H1N1). The survival rate at day 14 after virus infection was employed as the antiviral activity outcome for analysis. The relationship between day 14 survival and PK parameters, including area under the concentration-time curve (AUC), maximum concentration (Cmax) and time that drug concentration exceeds IC95 (T(>IC95)), was estimated using a logistic regression model, and model fitness was evaluated by calculation of the Akaike information criterion (AIC) index. The AIC indices of AUC, Cmax and T(>IC95) were about 114, 151 and 124, respectively. The AIC of AUC and T(>IC95) were smaller than that of Cmax. Therefore, both AUC and T(>IC95) were the PK parameters that correlated best with the antiviral activity of peramivir IV against influenza virus infection in mice.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Cyclopentanes; Disease Models, Animal; Female; Guanidines; Humans; Influenza, Human; Mice; Mice, Inbred BALB C

Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) is sporadic, often follows exposure to NAIs, but occasionally occurs in the absence of NAI pressure. The emergence and global spread in 2007/2008 of A(H1N1) influenza viruses showing clinical resistance to oseltamivir due to neuraminidase (NA) H275Y substitution, in the absence of drug pressure, warrants continued vigilance and monitoring for similar viruses. Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 11,387 viruses collected by WHO-recognized National Influenza Centres (NIC) between May 2012 and May 2013 to determine 50% inhibitory concentration (IC50) data for oseltamivir, zanamivir, peramivir and laninamivir. The data were evaluated using normalized IC50 fold-changes rather than raw IC50 data. Nearly 90% of the 11,387 viruses were from three WHO regions: Western Pacific, the Americas and Europe. Only 0.2% (n=27) showed highly reduced inhibition (HRI) against at least one of the four NAIs, usually oseltamivir, while 0.3% (n=39) showed reduced inhibition (RI). NA sequence data, available from the WHO CCs and from sequence databases (n=3661), were screened for amino acid substitutions associated with reduced NAI susceptibility. Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=18), A(H3N2) with NA E119V (n=3) or NA R292K (n=1) and B/Victoria-lineage with NA H273Y (n=2); amino acid position numbering is A subtype and B type specific. Overall, approximately 99% of circulating viruses tested during the 2012-2013 period were sensitive to all four NAIs. Consequently, these drugs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A virus; Influenza, Human; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Zanamivir

Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. We conducted a drug use investigation of peramivir from October 2010 to February 2012 and evaluated its safety and effectiveness under routine clinical settings. We collected data of 1309 patients from 189 facilities across Japan and examined safety in 1174 patients and effectiveness in 1158 patients. In total, 143 adverse events were observed with an incidence rate of 7.33% (86/1174). Of these, 78 events were adverse drug reactions (ADRs) with an incidence rate of 4.34% (51/1174). The most frequently reported ADRs were diarrhea, vomiting, and nausea, with incidence rates of 1.87% (22/1174), 0.85% (10/1174), and 0.68% (8/1174), respectively. Moreover, no ADR was reported as serious. ADR onset was within 3 days after the start of peramivir administration in 91.0% (71 events) of the 78 ADRs, and ADRs were resolved or improved within 7 days after onset in 96.2% (75 events) of the 78 ADRs. Neither patient characteristics nor treatment factors appeared to significantly affect drug safety. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. The present study demonstrates the safety and effectiveness of peramivir under routine clinical settings.

Topics: Acids, Carbocyclic; Administration, Intravenous; Adolescent; Adult; Aged; Antiviral Agents; Cyclopentanes; Diarrhea; Female; Guanidines; Humans; Influenza, Human; Japan; Male; Middle Aged; Nausea; Neuraminidase; Product Surveillance, Postmarketing; Time Factors; Vomiting; Young Adult

Immunocompromised patients are predisposed to infections caused by influenza virus. Influenza virus may produce considerable morbidity, including protracted illness and prolonged viral shedding in these patients, thus prompting higher doses and prolonged courses of antiviral therapy. This approach may promote the emergence of resistant strains. Characterization of neuraminidase (NA) inhibitor (NAI)-resistant strains of influenza A virus is essential for documenting causes of resistance. In this study, using quantitative real-time PCR along with conventional Sanger sequencing, we identified an NAI-resistant strain of influenza A (H3N2) virus in an immunocompromised patient. In-depth analysis by deep gene sequencing revealed that various known markers of antiviral resistance, including transient R292K and Q136K substitutions and a sustained E119K (N2 numbering) substitution in the NA protein emerged during prolonged antiviral therapy. In addition, a combination of a 4-amino-acid deletion at residues 245 to 248 (Δ245-248) accompanied by the E119V substitution occurred, causing resistance to or reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir). Resistant variants within a pool of viral quasispecies arose during combined antiviral treatment. More research is needed to understand the interplay of drug resistance mutations, viral fitness, and transmission.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Fatal Outcome; Female; Guanidines; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Influenza A Virus, H3N2 Subtype; Influenza, Human; Leukemia, B-Cell; Models, Molecular; Mutation; Neuraminidase; Oseltamivir; Transplantation, Homologous; Viral Proteins; Zanamivir

To genetically characterize human influenza viruses and their susceptibilities to antivirals during two post-pandemic seasons in Lebanon.. Influenza virus was isolated from nasopharyngeal swabs that were obtained from patients with influenza-like illness during 2010-2012 and further analyzed both phenotypically and genotypically.. During the 2010-2011 season, both 2009 pandemic H1N1 (H1N1p) and B viruses co-circulated with equal prevalence, while the H3N2 virus predominated during the 2011-2012 season. All H3N2 and H1N1 viruses were resistant to amantadine. Importantly, all viruses of the influenza A and B types were susceptible to the neuraminidase (NA) inhibitors oseltamivir, zanamivir, peramivir, and laninamivir. Nonetheless, all 2011-2012 H1N1p isolates had three mutations (V241I, N369K, and N386S) in the NA gene that were suggested to be permissive of the H275Y mutation, which confers resistance to oseltamivir. We also detected one H1N1p virus during the 2010-2011 season with a 4-fold decrease in susceptibility to oseltamivir due to an NA-S247N mutation. This isolate was phylogenetically distinct from other H1N1p viruses that were isolated in other regions.. Influenza A viruses with reduced susceptibility to oseltamivir and mutations permissive for acquiring NA resistance-conferring mutation with minimal burden on their fitness were isolated in Lebanon.

Topics: Acids, Carbocyclic; Amantadine; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Lebanon; Microbial Sensitivity Tests; Mutation; Neuraminidase; Oseltamivir; Pandemics; Phylogeny; Pyrans; Sialic Acids; Zanamivir

A 44-year-old man whose platelet count had been at the lower limit of the normal range for years visited the urgent care department of our hospital for treatment of a high fever and severe fatigue. The influenza A virus was detected, and the patient therefore received the intravenous antiviral agent, peramivir. One week later, he developed systemic petechial rashes. A peripheral blood examination showed a markedly decreased platelet count (3.0×10(9) cells/L), and the bone marrow findings were compatible with a diagnosis of immune thrombocytopenia (ITP). Furthermore, a drug-induced lymphocyte-stimulating test was positive for peramivir. The thrombocytopenia slowly responded to treatment with oral prednisolone. This case suggests that neuraminidase inhibitors, including peramivir, can elicit or worsen ITP.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Influenza A virus; Influenza, Human; Male; Platelet Count; Prednisolone; Thrombocytopenia

Peramivir is a neuraminidase inhibitor having activity against various influenza A and B subtypes. The main route of elimination is the kidney and a dose reduction is justified for multiple-day therapy when the creatinine clearance is < 50 mL/min. Before the 2009 influenza pandemic, dosing guidelines did not exist for patients receiving continuous renal replacement therapy (CRRT). This case report provides data on the dialysis membrane saturation coefficient (SA) and pharmacokinetic parameters of peramivir in a 29-year-old female receiving continuous veno-venous hemodiafiltration (CVVHDF), a mode of CRRT.. Plasma and effluent samples were collected to calculate the saturation coefficient, plasma half-life, maximum and minimum plasma concentrations, and area under the plasma drug concentration-time curve (AUC) for peramivir. CVVHDF was performed using a Prisma pump and an AN69 filter. During peramivir sampling, the dialysate flow rate was 16.7 mL/min. The mean total ultrafiltrate produced was 14.2 mL/min. To calculate a saturation coefficient (SA), simultaneous sampling of blood and effluent was performed. Pre- and post-filter as well as effluent samples were obtained 4.5 and 8.5 hours following the 3rd dose of 480 mg. Plasma concentrations were also obtained at several time points and the AUC estimated from 0 to 24 hours (AUC0-24).. The maximum plasma concentration (C30min) was 19,477 ng/mL, the minimum plasma concentration (Cmin) 2,750 ng/mL, and AUC0-24 196,166 ng x h/mL. The estimated plasma half-life was 8.2 hours with a log-linear decrease over the 24-hour period suggesting significant extracorporeal clearance. The calculated SA was 0.98, similar to an estimated SA of 1.. Peramivir is readily cleared by CVVHDF having a calculated SA close to 1. The maximum and minimum plasma concentrations, AUC0-24, and plasma half-life was similar to those previously reported. These data will be useful in determining appropriate peramivir dosing regimens for severely ill influenza patients with acute renal impairment managed by CVVHDF.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Female; Guanidines; Hemodiafiltration; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Neuraminidase

Neuraminidase (NA) inhibitors (NAIs) are currently the only antivirals effective against influenza infections due to widespread resistance to M2 inhibitors.. Influenza A and B viruses (n = 1079) collected worldwide between April 01, 2011, and September 30, 2011, were assessed for susceptibility to FDA-approved NAIs, oseltamivir and zanamivir, and investigational peramivir, using the fluorescent-based NA-Fluor™ Influenza Neuraminidase Assay Kit. A subset of viruses (n = 98) were tested for susceptibility to the investigational NAI, laninamivir.. Influenza A(H1N1)pdm09 viruses (n = 326) were sensitive to all NAIs, except for two (0.6%) with H275Y (N1 numbering; H274Y in N2 numbering) substitution, which exhibited elevated IC50 s for oseltamivir and peramivir, and a third with previously unreported N325K substitution, exhibiting reduced susceptibility to oseltamivir. Influenza A(H3N2) viruses (n = 407) were sensitive to all NAIs. Influenza B viruses (n = 346) were sensitive to all NAIs, except two (0.6%) with H273Y (N1 numbering; H274Y in N2 numbering) substitution, exhibiting reduced susceptibility to oseltamivir and peramivir, and one with previously unreported G140R and N144K substitutions, exhibiting reduced susceptibility to oseltamivir, zanamivir, and peramivir. All influenza A and B viruses were sensitive to laninamivir. It is unknown whether substitutions N325K, G140R, and N144K were present in the virus prior to culturing because clinical specimens were unavailable for testing.. This study summarizes NAI susceptibility of influenza viruses circulating worldwide during the 2011 Southern Hemisphere (SH) season, assessed using the NA-Fluor™ Kit. Despite low resistance to NAIs among tested influenza viruses, constant surveillance of influenza virus susceptibility to NAIs should be emphasized.

Topics: Acids, Carbocyclic; Africa; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Global Health; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Neuraminidase; Oceania; Oseltamivir; Pyrans; Seasons; Sentinel Surveillance; Sialic Acids; South America; Zanamivir

On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9.. We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome.. All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment.. Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning.. National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National Natural Science Foundation of China.

Topics: Acids, Carbocyclic; Aged; Aged, 80 and over; Antiviral Agents; Base Sequence; China; Cyclopentanes; Drug Resistance, Viral; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Male; Middle Aged; Molecular Sequence Data; Oseltamivir; RNA, Viral; Virus Shedding

Japan has the highest frequency of neuraminidase (NA) inhibitor use against influenza in the world. Therefore, Japan could be at high risk of the emergence and spread of NA inhibitor-resistant viruses. The aim of this study was to monitor the emergence of NA inhibitor-resistant viruses and the possibility of human-to-human transmission during four influenza seasons in Japan.. To monitor antiviral-resistant A(H1N1)pdm09 viruses, we examined viruses isolated in four seasons from the 2008-2009 season through the 2011-2012 season in Japan by allelic discrimination, NA gene sequencing, and NA inhibitor susceptibility.. We found that 157 (1·3%) of 12 026 A(H1N1)pdm09 isolates possessed an H275Y substitution in the NA protein that confers about 400- and 140-fold decreased susceptibility to oseltamivir and peramivir, respectively, compared with 275H wild-type viruses. The detection rate of resistant viruses increased from 1·0% during the pandemic period to 2·0% during the post-pandemic period. The highest detection rate of the resistant viruses was found in patients who were 0-9 years old. Furthermore, among the cases with resistant viruses, the percentage of no known exposure to antiviral drugs increased from 16% during the pandemic period to 44% during the post-pandemic period, implying that suspected human-to-human transmission of the resistant viruses gradually increased in the post-pandemic period.. A(H1N1)pdm09 viruses resistant to oseltamivir and peramivir were sporadically detected in Japan, but they did not spread throughout the community. No viruses resistant to zanamivir and laninamivir were detected.

Topics: Acids, Carbocyclic; Alleles; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Genotype; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Japan; Neuraminidase; Oseltamivir; Pandemics; RNA, Viral; Sequence Analysis, DNA; Viral Proteins

Two new influenza virus neuraminidase inhibitors (NAIs), peramivir and laninamivir, were approved in 2010 which resulted to four NAIs that were used during the 2010-2011 influenza season in Japan. This study aims to monitor the susceptibility of influenza virus isolates in 2009-2010 and 2010-2011 influenza seasons in Japan to the four NAIs using the fluorescence-based 50% inhibitory concentration (IC₅₀) method. Outliers were identified using box-and-whisker plot analysis and full NA gene sequencing was performed to determine the mutations that are associated with reduction of susceptibility to NAIs. A total of 117 influenza A(H1N1)pdm09, 59 A(H3N2), and 18 type B viruses were tested before NAI treatment and eight A(H1N1)pdm09 and 1 type B viruses were examined from patients after NAI treatment in the two seasons. NA inhibition assay showed type A influenza viruses were more susceptible to NAIs than type B viruses. The peramivir and laninamivir IC₅₀ values of both type A and B viruses were significantly lower than the oseltamivir and zanamivir IC₅₀ values. Among influenza A(H1N1)pdm09 viruses, the prevalence of H274Y viruses increased from 0% in the 2009-2010 season to 3% in the 2010-2011 season. These H274Y viruses were resistant to oseltamivir and peramivir with 200-300 fold increase in IC₅₀ values but remained sensitive to zanamivir and laninamivir. Other mutations in NA, such as I222T and M241I were identified among the outliers. Among influenza A(H3N2) viruses, two outliers were identified with D151G and T148I mutations, which exhibited a reduction in susceptibility to oseltamivir and zanamivir, respectively. Among type B viruses, no outliers were identified to the four NAIs. For paired samples that were collected before and after drug treatment, three (3/11; 27.3%) H274Y viruses were identified among A(H1N1)pdm09 viruses after oseltamivir treatment but no outliers were found in the laninamivir-treatment group (n=3). Despite widespread use of NAIs in Japan, the prevalence of NAI-resistant influenza viruses is still low.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Japan; Microbial Sensitivity Tests; Neuraminidase; Pandemics; Pyrans; Seasons; Sialic Acids; Viral Proteins; Zanamivir

We characterized the A/Shanghai/1/2013 virus isolated from the first confirmed human case of A/H7N9 disease in China. The A/Shanghai/1/2013 isolate contained a mixed population of R (65%; 15/23 clones) and K (35%; 8/23 clones) at neuraminidase (NA) residue 292, as determined by clonal sequencing. A/Shanghai/1/2013 with mixed R/K at residue 292 exhibited a phenotype that is sensitive to zanamivir and oseltamivir carboxylate by the enzyme-based NA inhibition assay. The plaque-purified A/Shanghai/1/2013 with dominant K292 (94%; 15/16 clones) showed sensitivity to zanamivir that had decreased by >30-fold and to oseltamivir carboxylate that had decreased by >100-fold compared to its plaque-purified wild-type counterpart possessing dominant R292 (93%, 14/15 clones). In Madin-Darby canine kidney (MDCK) cells, the plaque-purified A/Shanghai/1/2013-NAK292 virus exhibited no reduction in viral titer under conditions of increasing concentrations of oseltamivir carboxylate (range, 0 to 1,000 µM) whereas the replication of the plaque-purified A/Shanghai/1/2013-NAR292 and the A/Shanghai/2/2013 viruses was completely inhibited at 250 µM and 31.25 µM of oseltamivir carboxylate, respectively. Although the plaque-purified A/Shanghai/1/2013-NAK292 virus exhibited lower NA enzyme activity and a higher Km for 2'-(4-methylumbelliferryl)-α-d-N-acetylneuraminic acid than the wild-type A/Shanghai/1/2013-NAR292 virus, the A/Shanghai/1/2013-NAK292 virus formed large plaques and replicated efficiently in vitro. Our results confirmed that the NA R292K mutation confers resistance to oseltamivir, peramivir, and zanamivir in the novel human H7N9 viruses. Importantly, detection of the resistance phenotype may be masked in the clinical samples containing a mixed population of R/K at NA residue 292 in the enzyme-based NA inhibition assay.. The neuraminidase (NA) inhibitors oseltamivir and zanamivir are currently the front-line therapeutic options against the novel H7N9 influenza viruses, which possess an S31N mutation that confers resistance to the M2 ion channel blockers. It is therefore important to evaluate the sensitivity of the clinical isolates to NA inhibitors and to monitor for the emergence of resistant variants. We characterized the A/Shanghai/1/2013 (H7N9) isolate which contained a mixed population of R/K at NA residue 292. While the clinical isolate exhibited a phenotype of sensitivity to NA inhibitors using the enzyme-based NA inhibition assay, the plaque-purified A/Shanghai/1/2013 virus with dominant K292 was resistant to zanamivir, peramivir, and oseltamivir. Resistance to NA inhibitors conferred by the R292K mutation in a human influenza virus H7N9 isolate can be masked by a mixed R/K viral population, and this should be taken into consideration while monitoring antiviral resistance in patients with H7N9 infection.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; China; Coinfection; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H7N9 Subtype; Influenza, Human; Microbial Sensitivity Tests; Mutation, Missense; Neuraminidase; Oseltamivir; Viral Plaque Assay; Viral Proteins; Zanamivir

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H7N9 Subtype; Influenza, Human; Neuraminidase; Oseltamivir; Pulmonary Ventilation; Zanamivir

Timely treatment with neuraminidase inhibitor (NAI) drugs appears to improve survival in adults hospitalized with influenza. We analyzed California surveillance data to determine whether NAI treatment improves survival in critically ill children with influenza.. We analyzed data abstracted from medical records to characterize the outcomes of patients aged 0 to 17 years hospitalized in ICUs with laboratory-confirmed influenza from April 3, 2009, through September 30, 2012.. Seven hundred eighty-four influenza cases aged <18 years hospitalized in ICUs had information on treatment. Ninety percent (532 of 591) of cases during the 2009 H1N1 pandemic (April 3, 2009-August 31, 2010) received NAI treatment compared with 63% (121 of 193) of cases in the postpandemic period (September 1, 2010-September 30, 2012; P < .0001). Of 653 cases NAI-treated, 38 (6%) died compared with 11 (8%) of 131 untreated cases (odds ratio = 0.67, 95% confidence interval: 0.34-1.36). In a multivariate model that included receipt of mechanical ventilation and other factors associated with disease severity, the estimated risk of death was reduced in NAI-treated cases (odds ratio 0.36, 95% confidence interval: 0.16-0.83). Treatment within 48 hours of illness onset was significantly associated with survival (P = .04). Cases with NAI treatment initiated earlier in illness were less likely to die.. Prompt treatment with NAIs may improve survival of children critically ill with influenza. Recent decreased frequency of NAI treatment of influenza may be placing untreated critically ill children at an increased risk of death.

Topics: Acids, Carbocyclic; Adolescent; Betainfluenzavirus; California; Child; Child, Preschool; Critical Care; Critical Illness; Cyclopentanes; Drug Administration Schedule; Enzyme Inhibitors; Guanidines; Hospitalization; Humans; Infant; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza, Human; Logistic Models; Multivariate Analysis; Neuraminidase; Odds Ratio; Oseltamivir; Pandemics; Population Surveillance; Treatment Outcome; Zanamivir

The emergence of a novel H7N9 avian influenza that infects humans is a serious cause for concern. Of the genome sequences of H7N9 neuraminidase available, one contains a substitution of arginine to lysine at position 292, suggesting a potential for reduced drug binding efficacy. We have performed molecular dynamics simulations of oseltamivir, zanamivir and peramivir bound to H7N9, H7N9-R292K, and a structurally related H11N9 neuraminidase. They show that H7N9 neuraminidase is structurally homologous to H11N9, binding the drugs in identical modes. The simulations reveal that the R292K mutation disrupts drug binding in H7N9 in a comparable manner to that observed experimentally for H11N9-R292K. Absolute binding free energy calculations with the WaterSwap method confirm a reduction in binding affinity. This indicates that the efficacy of antiviral drugs against H7N9-R292K will be reduced. Simulations can assist in predicting disruption of binding caused by mutations in neuraminidase, thereby providing a computational 'assay.'

Topics: Acids, Carbocyclic; Antiviral Agents; Computational Biology; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H7N9 Subtype; Influenza, Human; Molecular Dynamics Simulation; Mutation; Neuraminidase; Oseltamivir; Protein Binding; Zanamivir

Amino acid substitutions at residue I223 of the neuraminidase (NA) protein have been identified in 2009 pandemic influenza (pH1N1) variants with altered susceptibilities to NA inhibitors (NAIs). We used reverse genetics and site-directed mutagenesis to generate the recombinant A/Québec/144147/09 pH1N1 wild-type virus (WT) and five (I223R, I223V, H275Y, I223V-H275Y, and I223R-H275Y) NA mutants. A fluorimetry-based assay was used to determine 50% inhibitory concentrations (IC(50)s) of oseltamivir, zanamivir, and peramivir. Replicative capacity was analyzed by viral yield assays in ST6GalI-MDCK cells. Infectivity and transmission of the WT, H275Y, and I223V-H275Y recombinant viruses were evaluated in ferrets. As expected, the H275Y mutation conferred resistance to oseltamivir (982-fold) and peramivir (661-fold) compared to the drug-susceptible recombinant WT. The single I223R mutant was associated with reduced susceptibility to oseltamivir (53-fold), zanamivir (7-fold) and peramivir (10-fold), whereas the I223V virus had reduced susceptibility to oseltamivir (6-fold) only. Interestingly, enhanced levels of resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir (1,647-, 17,347-, and 16-fold increases in IC(50)s, respectively) were observed for the I223R-H275Y recombinant, while the I223V-H275Y mutant exhibited 1,733-, 2,707-, and 2-fold increases in respective IC(50)s. The I223R and I223V changes were associated with equivalent or higher viral titers in vitro compared to the recombinant WT. Infectivity and transmissibility in ferrets were comparable between the recombinant WT and the H275Y or I223V-H275Y recombinants. In conclusion, amino acid changes at residue I223 may alter the NAI susceptibilities of pH1N1 variants without compromising fitness. Consequently, I223R and I223V mutations, alone or with H275Y, need to be thoroughly monitored.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Animals; Antiviral Agents; Cell Line; Cyclopentanes; Dogs; Drug Resistance, Viral; Ferrets; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Inhibitory Concentration 50; Male; Models, Molecular; Mutagenesis, Site-Directed; Mutation; Neuraminidase; Orthomyxoviridae Infections; Oseltamivir; Pandemics; Reverse Genetics; Viral Proteins; Virus Replication; Zanamivir

Peramivir (BioCryst Pharmaceuticals) is a novel investigational intravenous neuraminidase inhibitor that exhibits potent antiviral activity against influenza A and B viruses. Peramivir is created by a structure-based drug design and consists of a cyclopentane backbone with a positively charged guanidinyl group and lipophilic side chains. Peramivir was made available in the USA through the Emergency Investigational New Drug regulations and under an Emergency Use Authorization for hospitalized patients with known or suspected influenza during the 2009 H1N1 influenza pandemic. In trials involving ambulatory adult subjects, intravenous peramivir is safe and has a pharmacokinetic profile that supports once-daily dosing. The drug is licensed in Japan and South Korea and is currently undergoing Phase III trials in the USA. Viral resistance mechanisms to peramivir have not been fully delineated and ongoing surveillance is important. Given the serious health threat of influenza at all ages and limitations in vaccine delivery, peramivir is a promising addition to the currently limited treatment options for the treatment of severe influenza infection.

Topics: Acids, Carbocyclic; Adult; Animals; Antiviral Agents; Child; Clinical Trials, Phase III as Topic; Cyclopentanes; Drug Administration Routes; Drug Administration Schedule; Drug Design; Drug Dosage Calculations; Female; Ferrets; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Mice; Middle Aged; Molecular Structure; Neuraminidase; Viral Proteins

The half maximal inhibitory concentration (IC(50)) of four neuraminidase inhibitors (NAIs), oseltamivir, zanamivir, laninamivir, and peramivir; was measured using influenza viruses isolated in the 2010-2011 influenza season in Japan. Clinical samples for viral isolation were obtained from nasal aspiration, nasopharyngeal swab, or self-blown nasal discharge and cultured with Madin-Darby canine kidney cells. The type and subtype of H3N2 or B were determined by reverse transcriptase polymerase chain reaction (RT-PCR). For the A(H1N1)pdm09 virus, the subtype was determined by real-time RT-PCR. IC(50)s to oseltamivir carboxylate, zanamivir, laninamivir, and peramivir were determined by a fluorescence-based neuraminidase inhibition assay. Influenza viruses were isolated from 269 patients. A(H1N1)pdm09, H3N2, and B were isolated from 185, 54, and 30 patients, respectively. The geometric means of IC(50) for oseltamivir were 0.86 and 0.73 nM to A (H1N1) pdm09, except for the two outlier viruses described below and H3N2, respectively, and 33.12 nM for B. The geometric means of IC(50) for the other three NAIs were lowest to A(H1N1)pdm09 and highest to B. Two A(H1N1)pdm09 isolates showed very high IC(50) values for oseltamivir (840 and 600 nM) and peramivir (19 and 24 nM). No isolate showed significantly high IC(50) values for zanamivir or laninamivir. Continuous surveillance against the emergence or spread of influenza virus with high IC(50) values for anti-influenza drugs is important.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Inhibitory Concentration 50; Japan; Male; Microbial Sensitivity Tests; Middle Aged; Neuraminidase; Oseltamivir; Zanamivir

Favipiravir, an influenza virus RNA polymerase inhibitor, and peramivir, an influenza virus neuraminidase inhibitor, were evaluated alone and in combination against pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Infected mice were treated twice daily for 5 d starting 4 h after virus challenge. Favipiravir was 40%, 70%, and 100% protective at 20, 40, and 100 mg/kg/d. Peramivir was 30% protective at 0.5 mg/kg/d, but ineffective at lower doses when used as monotherapy. Combinations of favipiravir and peramivir increased the numbers of survivors by 10-50% when the 0.025, 0.05, and 0.1 mg/kg/d doses of peramivir were combined with 20 mg/kg/d favipiravir and when all doses of peramivir were combined with 40 mg/kg/d favipiravir. Three-dimensional analysis of drug interactions using the MacSynergy method indicates strong synergy for these drug combinations. In addition, an increase in lifespan for groups of mice treated with drug combinations, compared to the most effective monotherapy group, was observed for the 0.025, 0.05, and 0.1 mg/kg/d doses of peramivir combined with favipiravir at the 20 mg dose level. Therefore, the 20 mg/kg/d dose of favipiravir was selected for further combination studies. Increased survival was exhibited when this dose was combined with peramivir doses of 0.1, 0.25 and 0.5 mg/kg/d (1 mg/kg/d of peramivir alone was 100% protective in this experiment). Improved body weight relative to either compound alone was evident using 0.25, 0.5, and 1 mg/kg/d of peramivir. Significant reductions in lung hemorrhage score and lung weight were evident on day 6 post-infection. In addition, virus titers were reduced significantly on day 4 post-infection by combination therapy containing favipiravir combined with peramivir at 0.25 and 0.5 mg/kg/d. These data demonstrate that combinations of favipiravir and peramivir perform better than suboptimal doses of each compound alone for the treatment of influenza virus infections in mice.

Topics: Acids, Carbocyclic; Amides; Animals; Antiviral Agents; California; Cyclopentanes; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Mice; Mice, Inbred BALB C; Pandemics; Pyrazines

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Emergency Treatment; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Pregnancy

On 23 October 2009, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for intravenous peramivir, an unapproved antiviral, to treat suspected or confirmed 2009 H1N1 influenza A virus infection. Eligible hospitalized patients were unresponsive to or unable to tolerate available antivirals or lacked dependable oral or inhaled drug delivery routes. The EUA required healthcare providers to report medication errors, selected adverse events (AEs), serious AEs, and deaths to the FDA.. An FDA safety team analyzed reports submitted to the Adverse Event Reporting System (AERS) and sought follow-up in selected cases.. The FDA received AERS reports for 344 patients (including 28 children and 3 pregnant women). Many patients were critically ill on mechanical ventilation (41%) and renal replacement therapies (19%); 38% had received oseltamivir. The most frequently reported serious AEs by MedDRA preferred term were death (15%), H1N1 influenza (8%), respiratory failure (8%), acute renal failure (7%), and acute respiratory distress syndrome (7%). Six medication errors were reported. Most deaths occurred among patients who were obese, immunosuppressed, aged >65 years, or received oseltamivir. Rash was the only treatment-emergent AE attributable to peramivir. Influenza severity, comorbidities, and concomitant medications confounded additional peramivir AE assessments. Missing clinical and laboratory data precluded evaluation of some reports.. Many peramivir recipients under the EUA were critically ill and at risk for influenza-related complications. The safety data were insufficient to assess whether peramivir affected outcome or caused adverse reactions other than rash. Clinical trials in hospitalized patients with serious influenza infections should provide additional information.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Female; Guanidines; Hospitalization; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Pregnancy; Risk Factors; United States; United States Food and Drug Administration

In response to the influenza A(H1N1)pdm09 (pH1N1) pandemic, peramivir, an investigational intravenous neuraminidase inhibitor, was made available for treatment of hospitalized patients with pH1N1 in the United States under an Emergency Use Authorization (EUA). The Centers for Disease Control and Prevention (CDC) implemented a program to manage peramivir distribution to requesting clinicians under EUA. We describe results of the CDC's peramivir program and 3 related surveys.. We analyzed data on peramivir requests made by clinicians to the CDC through an electronic request system. Three surveys were administered to enhance clinician compliance with adverse event reporting, to conduct product accountability, and to collect data on peramivir-treated patients. Descriptive analyses were performed, and 2-source capture-recapture analysis based on the 3 surveys was used to estimate the number of patients who received peramivir through the EUA.. From 23 October 2009 to 23 June 2010, CDC received 1371 clinician requests for peramivir and delivered 2129 five-day adult treatment course equivalents of peramivir to 563 hospitals. Based on survey responses, at least 1274 patients (median age, 43 years; range, 0-92 years; 49% male) received ≥1 doses of peramivir (median duration, 6 days). Capture-recapture analysis yielded estimates for the potential total number of peramivir recipients ranging from 1185 (95% confidence interval [CI], 1076-1293) to 1490 (95% CI, 1321-1659).. Approximately 1274 hospitalized patients received peramivir through EUA program during the pH1N1 pandemic. Further analyses are needed to assess the clinical effectiveness of peramivir treatment of hospitalized patients with pH1N1.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Drug Utilization; Emergency Treatment; Female; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Pandemics; United States

The H275Y oseltamivir resistance mutation confers high-level resistance to oseltamivir in isolates of human A(H1N1) influenza. We report the recovery and identification of an influenza B virus with the H273Y neuraminidase point mutation directly from a human patient. The H273Y influenza B isolate is resistant to oseltamivir and peramivir but sensitive to zanamivir.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Catalytic Domain; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza B virus; Influenza, Human; Male; Molecular Sequence Data; Mutation, Missense; Neuraminidase; Oseltamivir; Point Mutation; RNA, Viral; Sequence Analysis, DNA; Zanamivir

Oral antiviral agents to treat influenza are challenging to administer in the intensive care unit (ICU). We describe 57 critically ill patients treated with the investigational intravenous neuraminidase inhibitor drug peramivir for influenza A (H1N1)pdm09 [pH1N1]. Most received late peramivir treatment following clinical deterioration in the ICU on enterically-administered oseltamivir therapy. The median age was 40 years (range 5 months-81 years). Common clinical complications included pneumonia or acute respiratory distress syndrome requiring mechanical ventilation (54; 95%), sepsis requiring vasopressor support (34/53; 64%), acute renal failure requiring hemodialysis (19/53; 36%) and secondary bacterial infection (14; 25%). Over half (29; 51%) died. When comparing the 57 peramivir-treated cases with 1627 critically ill cases who did not receive peramivir, peramivir recipients were more likely to be diagnosed with pneumonia/acute respiratory distress syndrome (p = 0.0002) or sepsis (p = <0.0001), require mechanical ventilation (p = <0.0001) or die (p = <0.0001). The high mortality could be due to the pre-existing clinical severity of cases prior to request for peramivir, but also raises questions about peramivir safety and effectiveness in hospitalized and critically ill patients. The use of peramivir merits further study in randomized controlled trials, or by use of methods such as propensity scoring and matching, to assess clinical effectiveness and safety.

Topics: Acids, Carbocyclic; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; California; Child; Child, Preschool; Critical Illness; Cyclopentanes; Female; Guanidines; Humans; Infant; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Pandemics; Retrospective Studies; Severity of Illness Index; Young Adult

We describe a patient with multiple myeloma who developed a pandemic influenza A (H1N1) 2009 virus infection during chemotherapy. The clinical condition of the patient worsened and viral shedding persisted despite 10 days of peramivir treatment; however viral shedding ceased and the patient recovered completely with inhaled zanamivir.

Topics: Acids, Carbocyclic; Administration, Inhalation; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Multiple Myeloma; Salvage Therapy; Treatment Outcome; Virus Shedding; Zanamivir

Neuraminidase inhibitors (NAIs) play a key role in the management of influenza epidemics and pandemics. Given the novel pandemic influenza A(H1N1) (pH1N1) virus and the restricted number of approved anti-influenza drugs, evaluation of potential drug-resistant variants is of high priority.. Recombinant pH1N1 viruses were generated by reverse genetics, expressing either the wild-type or any of 9 mutant neuraminidase (NA) proteins (N2 numbering: E119G, E119V, D198G, I222V, H274Y, N294S, S334N, I222V-H274Y, and H274Y-S334N). We evaluated these recombinant viruses for their resistance phenotype to 4 NAIs (oseltamivir, zanamivir, peramivir, and A-315675), NA enzymatic activity, and replicative capacity.. The E119G and E119V mutations conferred a multidrug resistance phenotype to many NAIs but severely compromised viral fitness. The oseltamivir- and peramivir-resistance phenotype was confirmed for the H274Y and N294S mutants, although both viruses remained susceptible to zanamivir. Remarkably, the I222V mutation had a synergistic effect on the oseltamivir- and peramivir-resistance phenotype of H274Y and compensated for reduced viral fitness, raising concerns about the potential emergence and dissemination of this double-mutant virus.. This study highlights the importance of continuous monitoring of antiviral drug resistance in clinical samples as well as the need to develop new agents and combination strategies.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Microbial Sensitivity Tests; Mutation, Missense; Neuraminidase; Oseltamivir; Pyrrolidines; Recombination, Genetic; Viral Plaque Assay; Viral Proteins; Virus Replication; Zanamivir

The 2009 H1N1 influenza pandemic prompted the US Food and Drug Administration (FDA) to issue an emergency use authorization (EUA) for the intravenous antiviral peramivir, an unapproved neuraminidase inhibitor (NAI) currently under development. Peramivir use was limited to patients for whom other NAI therapy had failed or in whom oral or inhalational drug absorption was believed to be unreliable. This introduced a patient selection bias that precluded safety and efficacy assessment. Despite the challenges and risks, there was a compelling public health need for an intravenous agent during the 2009 H1N1 pandemic.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Approval; Drug Industry; Emergency Medical Services; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; United States; United States Food and Drug Administration

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Drugs, Investigational; Female; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Pregnancy; Survival Analysis; Treatment Outcome; United States; Young Adult

Peramivir, an investigational intravenous neuraminidase inhibitor in Phase 3 trials for hospitalized patients, was made available during the 2009 H1N1 influenza pandemic under the Emergency Investigational New Drug (eIND) regulations. We describe the clinical characteristics and outcomes of all patients for whom peramivir was requested under the eIND.. After obtaining eIND approval from the Food and Drug Administration and local institutional review board approval, clinicians caring for hospitalized patients with influenza administered intravenous peramivir and collected information on demographic characteristics, clinical characteristics, and outcomes.. From April through October 2009, peramivir was requested for 42 patients and administered to 20 adults and 11 children. At hospitalization, all patients had rapidly progressing, radiographically confirmed viral pneumonia with respiratory failure, and all but 1 patient required mechanical ventilation. In most patients, including 1 person with documented oseltamivir-resistant infection, the illness had progressed despite oseltamivir treatment. Peramivir was administered for 1-14 days (median duration, 10 days). The 14-day, 28-day, and 56-day survival rates were 76.7%, 66.7%, and 59.0%, respectively. Peramivir was generally well tolerated.. Intravenous peramivir was well tolerated and was associated with recovery in most patients hospitalized with severe 2009 H1N1 influenza viral pneumonia and treated under an eIND.

Topics: Acids, Carbocyclic; Adolescent; Adult; Aged; Antiviral Agents; Child; Child, Preschool; Critical Illness; Cyclopentanes; Drugs, Investigational; Female; Guanidines; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Pregnancy; Survival Analysis; Treatment Outcome; United States; Young Adult

To develop 3 computer simulation models to determine the potential economic effect of using intravenous (IV) antiviral agents to treat hospitalized patients with influenza-like illness, as well as different testing and treatment strategies.. Stochastic decision analytic computer simulation model.. During the 2009 influenza A(H1N1) pandemic, the Food and Drug Administration granted emergency use authorization of IV neuraminidase inhibitors for hospitalized patients with influenza, creating a need for rapid decision analyses to help guide use. We compared the economic value from the societal and third-party payer perspectives of the following 4 strategies for a patient hospitalized with influenza-like illness and unable to take oral antiviral agents: Strategy 1: Administration of IV antiviral agents without polymerase chain reaction influenza testing. Strategy 2: Initiation of IV antiviral treatment, followed by polymerase chain reaction testing to determine whether the treatment should be continued. Strategy 3: Performance of polymerase chain reaction testing, followed by initiation of IV antiviral treatment if the test results are positive. Strategy 4: Administration of no IV antiviral agents. Sensitivity analyses varied the probability of having influenza (baseline, 10%; range, 10%-30%), IV antiviral efficacy (baseline, oral oseltamivir phosphate; range, 25%-75%), IV antiviral daily cost (range, $20-$1000), IV antiviral reduction of illness duration (baseline, 1 day; range, 1-2 days), and ventilated vs nonventilated status of the patient.. When the cost of IV antiviral agents was no more than $500 per day, the incremental cost-effectiveness ratio for most of the IV antiviral treatment strategies was less than $10,000 per quality-adjusted life-year compared with no treatment. When the cost was no more than $100 per day, all 3 IV antiviral strategies were even more cost-effective. The order of cost-effectiveness from most to least was strategies 3, 1, and 2. The findings were robust to changing risk of influenza, influenza mortality, IV antiviral efficacy, IV antiviral daily cost, IV antiviral reduction of illness duration, and ventilated vs nonventilated status of the patient for both societal and third-party payer perspectives.. Our study supports the use of IV antiviral treatment for hospitalized patients with influenza-like illness.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Computer Simulation; Confidence Intervals; Cyclopentanes; Decision Support Techniques; Female; Guanidines; Health Care Costs; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Infusions, Intravenous; Male; Middle Aged; Models, Economic; Models, Statistical; Monte Carlo Method; Polymerase Chain Reaction; Quality-Adjusted Life Years; Stochastic Processes; United States; Young Adult

With the continued threat of morbidity and mortality from influenza and the development of resistance to influenza antiviral drugs, there is increasing interest in new treatments, such as the investigational intravenous drug peramivir, and in combination treatments. In this study, we determined the impact of oseltamivir carboxylate on the binding affinity of peramivir/neuraminidase (NA) enzyme complex and vice versa. Influenza NA was incubated with peramivir and oseltamivir carboxylate alone and in combination. Dissociation rates of the enzyme-inhibitor complex measured in the presence of NA substrate for peramivir alone and the combination were similar, suggesting that peramivir competitively inhibits the neuraminidase enzyme and that oseltamivir carboxylate when added to peramivir does not impact the binding affinity of peramivir to the NA enzyme.

Topics: Acids, Carbocyclic; Antiviral Agents; Buffers; Cyclopentanes; Drug Combinations; Drug Interactions; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Neuraminidase; Oseltamivir; Protein Binding; Solutions; Spectrometry, Fluorescence; Viral Proteins

Topics: Acids, Carbocyclic; Adult; Child; Child, Preschool; Cyclopentanes; Drug Utilization; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Infusions, Intravenous; Inpatients; Middle Aged; Population Surveillance; Practice Patterns, Physicians'; United States; Zanamivir

2009 H1N1 influenza A disproportionately affected pregnant and postpartum women compared with the general population, with higher rates of hospitalization and severe illness. We present a case of the use and pharmacokinetics of intravenous peramivir in the treatment of a patient with severe influenza.. A 28-year-old woman at 37 weeks of gestation presented to the hospital with severe respiratory symptoms. 2009 H1N1 influenza reverse transcriptase polymerase chain reaction returned positive results and intravenous peramivir was started. She showed rapid improvement and was discharged 29 days after admission.. The pharmacokinetic parameters in this patient were unexpected because the clearances occurred more quickly than in phase I trials. These differences highlight the need for additional pharmacokinetic reporting of peramivir in pregnant and postpartum women.

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cesarean Section; Cyclopentanes; Disease Outbreaks; Female; Guanidines; Humans; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oseltamivir; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Severity of Illness Index; Treatment Outcome

Oseltamivir is 1 of 2 antiviral medications available for the treatment of influenza B virus infections. We describe and characterize a cluster of influenza B viruses circulating in North Carolina with a mutation in the neuraminidase active site that may reduce susceptibility to oseltamivir and the investigational drug peramivir but not to zanamivir.

Topics: Acids, Carbocyclic; Adolescent; Adult; Antiviral Agents; Catalytic Domain; Child; Child, Preschool; Cyclopentanes; Drug Resistance, Viral; Guanidines; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Infant; Influenza B virus; Influenza, Human; Microbial Sensitivity Tests; Middle Aged; Mutation; Neuraminidase; North Carolina; Oseltamivir; Phylogeny; Polymorphism, Single Nucleotide; Young Adult

To report a sieving coefficient for peramivir in a patient receiving continuous venovenous hemofiltration (CVVH).. An 18-year-old male presented with chills, myalgias, and dyspnea and was hospitalized. Nasal secretions were positive for influenza by rapid antigen test at an outside facility and oseltamivir was commenced. Oral absorption was predicted to be unreliable, and intravenous peramivir was accessed as an emergency investigational new drug applicaiton (eIND). CVVH was initiated after the development of acute renal failure, with blood samples collected to determine peramivir concentrations.. Peramivir, an intravenous investigational neuraminidase inhibitor with activity against influenza viruses, has limited data for dosing in the setting of CVVH. A single patient received 600 mg of peramivir intravenously and had blood and ultrafiltrate concentrations measured serially. A sieving coefficient of approximately 0.9 was identified.. Peramivir is well cleared by CVVH, and drug exposure is potentially predictable based on flow rates. Further study is necessary.

Topics: Acids, Carbocyclic; Acute Kidney Injury; Adolescent; Cyclopentanes; Guanidines; Hemofiltration; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Oseltamivir

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Neuraminidase; Oseltamivir; Zanamivir

The clinical effect of peramivir was examined retrospectively in 30 children aged 23 days to 8 years; they had been treated with peramivir at our hospital within 48 hours after the onset of influenza from November 2010 to April 2011. Intravenous dripping of peramivir at a dose of 10 mg/kg was performed only once for 15 to 30 minutes. To examine the clinical effect of peramivir, the time from dosing to defervescence (body temperature <37.5 degrees C) was evaluated. To compare the clinical effects of peramivir and oseltamivir, the time required for the defervescence was evaluated in a similar manner in 30 children aged 7 months to 8 years who had been treated for influenza with oseltamivir at a dose of 4 mg/kg/day. The influenza type was type A (n=25) and type B (n=5) in the peramivir group and type A (n=26) and type B (n=4) in the oseltamivir group. In the peramivir group, 5 (16.7%), 16 (53.3%), and 24 (80.0%) patients achieved defervescence within 6, 12, and 24 hours, respectively. In the oseltamivir group, 3 (10.0%) and 6 (20.0%) patients had defervescence within 12 and 24 hours, respectively. The difference between these groups was statistically significant (p<0.05). An increase in the levels of AST and ALT was observed as an adverse reaction in 1 patient. Thus, peramivir was determined to be effective to influenza in children.

Topics: Acids, Carbocyclic; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Guanidines; Humans; Infant; Infant, Newborn; Influenza A virus; Influenza B virus; Influenza, Human; Infusions, Intravenous; Oseltamivir; Retrospective Studies; Time Factors; Treatment Outcome

The neuraminidase inhibitors (NAIs), oseltamivir and zanamivir, are essential for treatment and prevention of influenza A and B infections. Oseltamivir resistance among influenza A (H1N1) viruses rapidly emerged and spread globally during the 2007-2008 and 2008-2009 influenza seasons. Approximately 20% and 90% of viruses tested for NAI susceptibility at CDC during these seasons, respectively, were resistant to oseltamivir (IC(50) approximately 100-3000 time>those of sensitive viruses), based on the chemiluminescent NA inhibition assay. Pyrosequencing analysis confirmed H274Y mutation (H275Y in N1 numbering) in the neuraminidase (NA) gene of oseltamivir-resistant viruses. Full NA sequence analysis of a subset of oseltamivir-resistant and sensitive virus isolates from both seasons (n=725) showed that 53 (7.3%) had mutations at residue D151 (D-->E/G/N), while 9 (1.2%) had mutations at Q136 (Q-->K) and 2 (0.3%) had mutations at both residues. Viruses with very high IC(50) for oseltamivir and peramivir, and elevated IC(50) for zanamivir, had H274Y in addition to mutations at D151 and/or Q136, residues which can potentially confer NAI resistance based on recent N1 NA crystal structure data. Mutations at D151 without H274Y, did not elevate IC(50) for any tested NAI, however, Q136K alone significantly reduced susceptibility to zanamivir (36-fold), peramivir (80-fold) and A-315675 (114-fold) but not oseltamivir. Mutations at D151 and Q136 were present only in MDCK grown viruses but not in matching original clinical specimens (n=33) which were available for testing, suggesting that these variants were the result of cell culture selection or they were present in very low proportions. Our findings provide evidence that propagation of influenza virus outside its natural host may lead to selection of virus variants with mutations in the NA that affect sensitivity to NAIs and thus poses implications for drug resistance monitoring and diagnostics.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Animals; Antiviral Agents; Cell Line; Cyclopentanes; Dogs; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Inhibitory Concentration 50; Molecular Sequence Data; Mutation, Missense; Neuraminidase; Oseltamivir; RNA, Viral; Sequence Analysis, DNA; Viral Proteins; Zanamivir

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Approval; Emergency Medical Services; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; United States; United States Food and Drug Administration

Topics: Acids, Carbocyclic; Antiviral Agents; Clinical Trials as Topic; Cyclopentanes; Disease Outbreaks; Drug Approval; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; United States; United States Food and Drug Administration

Pandemic 2009 H1N1 virus isolates containing the neuraminidase inhibitor resistance mutation H275Y have been reported. We describe rapid selection for the H275Y resistance mutation during therapy in 2 immunocompromised individuals at 9 and 14 days of therapy, as well as the first described case of clinically significant resistance to peramivir.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Female; Guanidines; Humans; Immunocompromised Host; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Oseltamivir; RNA, Viral; Selection, Genetic; Sequence Analysis, DNA; Young Adult

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Therapy, Combination; Guanidines; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Influenza A Virus, H1N1 Subtype; Influenza, Human; Pneumonia, Viral; Respiratory Insufficiency; RNA, Viral

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Cyclopentanes; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Neuraminidase; Renal Dialysis

The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.

Topics: Acids, Carbocyclic; Animals; Cell Line; Cyclopentanes; Dogs; Enzyme Assays; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Inhibitory Concentration 50; Neuraminidase; Oseltamivir; Zanamivir

Influenza viruses of the N1 neuraminidase (NA) subtype affecting both animals and humans caused the 2009 pandemic. Anti-influenza virus NA inhibitors are crucial early in a pandemic, when specific influenza vaccines are unavailable. Thus, it is urgent to confirm the antiviral susceptibility of the avian viruses, a potential source of a pandemic virus. We evaluated the NA inhibitor susceptibilities of viruses of the N1 subtype isolated from wild waterbirds, swine, and humans. Most avian viruses were highly or moderately susceptible to oseltamivir (50% inhibitory concentration [IC(50)], <5.1 to 50 nM). Of 91 avian isolates, 7 (7.7%) had reduced susceptibility (IC(50), >50 nM) but were sensitive to the NA inhibitors zanamivir and peramivir. Oseltamivir susceptibility ranged more widely among the waterbird viruses (IC(50), 0.5 to 154.43 nM) than among swine and human viruses (IC(50), 0.33 to 2.56 nM). Swine viruses were sensitive to oseltamivir, compared to human seasonal H1N1 isolated before 2007 (mean IC(50), 1.4 nM). Avian viruses from 2007 to 2008 were sensitive to oseltamivir, in contrast to the emergence of resistant H1N1 in humans. Susceptibility remained high to moderate over time among influenza viruses. Sequence analysis of the outliers did not detect molecular markers of drug-resistance (e.g., H275Y NA mutation [N1 numbering]) but revealed mutations outside the NA active site. In particular, V267I, N307D, and V321I residue changes were found, and structural analyses suggest that these mutations distort hydrophobic pockets and affect residues in the NA active site. We determined that natural oseltamivir resistance among swine and wild waterbirds is rare. Minor naturally occurring variants in NA can affect antiviral susceptibility.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Birds; Catalytic Domain; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A virus; Influenza A Virus, H1N1 Subtype; Influenza in Birds; Influenza, Human; Models, Molecular; Mutation; Neuraminidase; Orthomyxoviridae Infections; Oseltamivir; Protein Conformation; Species Specificity; Swine; Swine Diseases; Viral Proteins; Zanamivir

A 36-year-old man with underlying systemic lupus erythematosus complicated by autoimmune hemolytic anemia underwent immunosuppressive treatment. After showing a low-grade fever for two days, his fever spiked. He was confirmed to have pandemic (H1N1) 2009 by real-time reverse transcription polymerase chain reaction (PCR). His condition deteriorated to acute respiratory distress syndrome (ARDS), and mechanical ventilation became necessary. The lowest PaO(2)/FIO(2) ratio was 77, and he was placed on extracorporeal membrane oxygenation (ECMO). Based on our observation, the emergency use of ECMO in addition to peramivir might be useful. A noteworthy point is that once ARDS deteriorates due to pandemic (H1N1) 2009, intensive supportive care should be started.

Topics: Acids, Carbocyclic; Adult; Anemia, Hemolytic, Autoimmune; Antiviral Agents; Combined Modality Therapy; Cyclopentanes; Disease Outbreaks; Emergencies; Extracorporeal Membrane Oxygenation; Guanidines; Humans; Immunocompromised Host; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Influenza, Human; Lupus Erythematosus, Systemic; Male; Neuraminidase; Oxygen Inhalation Therapy; Prednisolone; Radiography; Respiration, Artificial; Respiratory Distress Syndrome; Viral Proteins

Docking and molecular dynamics were used to study the nine ligands (see Scheme 1) at the neuraminidase (NA) active sites. Their binding modes are structurally and energetically different, with details given in the text. Compared with 1A (oseltamivir carboxylate), the changes of core template or/and functional groups in the other ligands cause the reductions of interaction energies and numbers of H-bonds with the NA proteins. Nonetheless, all these ligands occupy the proximity space at the NA active sites and share some commonness in their binding modes. The fragment approach was then used to analyze and understand the binding specificities of the nine ligands. The contributions of each core template and functional group were evaluated. It was found that the core templates rather than functional groups play a larger role during the binding processes; in addition, the binding qualities are determined by the synergistic effects of the core templates and functional groups. Among the nine ligands, 1A (oseltamivir carboxylate) has the largest synergistic energy and its functional groups fit perfectly with the NA active site, consistent with the largest interaction energy, numerous H-bonds with the NA active-site residues as well as experimentally lowest IC(50) value. Owing to the poorer metabolizability than oseltamivir, large contribution of the benzene core template and fine synergistic effects of the functional groups, the 4-(N-acetylamino)-5-guanidino-3-(3-pentyloxy)benzoic acid should be an ideal lead compound for optimizing NA drugs.

Topics: Acids, Carbocyclic; Benzoates; Catalytic Domain; Cyclohexenes; Cyclopentanes; Drug Design; Guanidines; Humans; Hydrogen Bonding; Influenza, Human; Inhibitory Concentration 50; Ligands; Models, Molecular; Molecular Dynamics Simulation; Molecular Structure; Neuraminidase; Orthomyxoviridae; Oseltamivir; Protein Binding; Static Electricity; Structure-Activity Relationship; Thermodynamics

To determine the pharmacokinetics of intravenous peramivir-an investigational neuraminidase inhibitor for the treatment of 2009 H1N1 infection or nonsubtypable influenza A thought to be the 2009 H1N1 virus-in patients concurrently receiving continuous renal replacement therapy (CRRT).. Pharmacokinetic analysis.. Critical care unit at a university-affiliated hospital.. Two critically ill women with 2009 H1N1 influenza A treated with compassionate-use intravenous peramivir administered as a daily infusion of 600 mg over 30 minutes while receiving continuous venovenous hemodiafiltration (CVVHDF), a form of CRRT.. Plasma samples were collected from the two patients before and 30 minutes after the fourth (first patient) and ninth (second patient) peramivir infusion to estimate minimum (C(min)) and maximum (C(max)) plasma concentrations, respectively. Two additional postinfusion concentrations were measured from each patient to estimate noncompartmental pharmacokinetic parameters of peramivir while receiving CVVHDF. In the two patients, respectively, C(min) was 2170 and 251 ng/ml, C(max) was 18,400 and 20,300 ng/ml, area under the plasma concentration-time curve from 0-24 hours (AUC(0-24)) was 178,000 and 94,400 ng·hour/ml, drug clearance was 56 and 106 ml/minutes, and plasma half-life was 7.6 and 3.7 hours. The volume of distribution adjusted for ideal body weight at steady state was 0.51 and 0.54 L/kg, respectively.. The first patient had a slower peramivir plasma clearance compared with the second patient, but both patients had higher peramivir clearances as calculated from AUC(0-24) than those predicted by CRRT. Thus, the dosage of intravenous peramivir was appropriate in these patients. Additional pharmacokinetic data are needed to confirm these results and help guide dosing in patients receiving various forms of CRRT.

Topics: Acids, Carbocyclic; Adult; Area Under Curve; Compassionate Use Trials; Cyclopentanes; Female; Guanidines; Half-Life; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Neuraminidase; Renal Replacement Therapy; Young Adult

On 23 October 2009, the commissioner of the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for peramivir for intravenous injection, an unapproved neuraminidase inhibitor used for treating certain hospitalized adult and pediatric patients infected with 2009 H1N1 influenza. This was the first EUA of an unapproved drug product. This report summarizes the critical contributions of the clinical pharmacology review team in support of the peramivir EUA.

Topics: Acids, Carbocyclic; Adolescent; Adult; Antiviral Agents; Child; Child, Preschool; Cyclopentanes; Drug Approval; Emergency Medical Services; Enzyme Inhibitors; Evidence-Based Medicine; Government Regulation; Guanidines; Health Policy; Hospitalization; Humans; Infant; Infant, Newborn; Influenza A Virus, H1N1 Subtype; Influenza, Human; Injections, Intravenous; Neuraminidase; Risk Assessment; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Acids, Carbocyclic; C-Reactive Protein; Critical Illness; Cyclopentanes; Diabetic Nephropathies; Female; Guanidines; Humans; Influenza A virus; Influenza, Human; Middle Aged; Neuraminidase; Respiratory Insufficiency

Oseltamivir resistance in pandemic 2009 influenza A/H1N1 is caused by the neuraminidase mutation H275Y. This mutation has also been associated with in vitro resistance to peramivir, but few clinical cases have been described to date. Using allele-specific real-time reverse transcriptase polymerase chain reaction assay for the H275Y mutation, we were able to identify resistant H1N1 in a hematopoietic cell transplant recipient receiving intravenous peramivir therapy, and through serial testing we determined the molecular evolution of resistance. This case demonstrates that an H275Y mutant population can emerge early and replicate in vivo under peramivir antiviral pressure to become the major viral population.

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Resistance, Viral; Fatal Outcome; Guanidines; Hematopoietic Stem Cell Transplantation; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Mutation; Neuraminidase; Oseltamivir

Antiviral drugs are an important option for managing infections caused by influenza viruses. This study assessed the drug susceptibility of 2009 pandemic influenza A (H1N1) viruses collected globally between April 2009 and January 2010.. Virus isolates were tested for adamantane susceptibility, using pyrosequencing to detect the S31N marker of adamantane resistance in the M2 protein and biological assays to assess viral replication in cell culture. To assess neuraminidase (NA) inhibitor (NAI) susceptibility, virus isolates were tested in chemiluminescent NA inhibition assays and by pyrosequencing to detect the H275Y (H274Y in N2 numbering) marker of oseltamivir resistance in the NA.. With the exception of three, all viruses that were tested for adamantane susceptibility (n=3,362) were resistant to this class of drugs. All viruses tested for NAI susceptibility (n=3,359) were sensitive to two US Food and Drug Administration-approved NAIs, oseltamivir (mean ±sd 50% inhibitory concentration [IC(50)] 0.25 ±0.12 nM) and zanamivir (mean IC(50) 0.29 ±0.09 nM), except 23 (0.7%), which were resistant to oseltamivir, but sensitive to zanamivir. Oseltamivir-resistant viruses had the H275Y mutation in their NA and were detected in patients exposed to the drug through prophylaxis or treatment. NA activity of all viruses was inhibited by the NAIs peramivir, laninamivir (R-125489) and A-315675, except for H275Y variants, which exhibited approximately 100-fold reduction in peramivir susceptibility.. This report provides data regarding antiviral susceptibility of 2009 pandemic influenza A (H1N1) surveillance viruses, the majority of which were resistant to adamantanes and sensitive to NAIs. These findings provide information essential for antiviral resistance monitoring and development of novel diagnostic tests for detecting influenza antiviral resistance.

Topics: Acids, Carbocyclic; Adamantane; Amino Acid Substitution; Animals; Antiviral Agents; Cell Line; Cyclopentanes; Dogs; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Microbial Sensitivity Tests; Mutation, Missense; Neuraminidase; Oseltamivir; Pyrans; Pyrrolidines; Sialic Acids; Viral Plaque Assay; Zanamivir

The outbreak and spread of the new influenza A subtype H1N1 reached pandemic levels during 2009, with greater numbers of cases reported daily and numerous complications described. The present report concerns an atypical manifestation of the disease in a previously healthy middle-aged patient who presented with severe, refractory cardiogenic shock 4 days after being diagnosed as having influenza A. The patient was considered for emergency heart transplant. Successful treatment involved the use of a left ventricular assist device, extracorporeal membrane oxygenation, intravenous immunoglobulin and peramivir as therapeutics and bridging therapies for transplant. This case is a report of H1N1 fulminant myocarditis and illustrates the usefulness of a multidisciplinary approach in the care of these patients.

Topics: Acids, Carbocyclic; Antiviral Agents; Combined Modality Therapy; Cyclopentanes; Extracorporeal Membrane Oxygenation; Female; Guanidines; Humans; Immunoglobulins, Intravenous; Influenza A Virus, H1N1 Subtype; Influenza, Human; Middle Aged; Myocarditis; Shock, Cardiogenic

The neuraminidase inhibitors (NAIs) are an effective class of antiviral drugs for the treatment of influenza A and B infections. Until recently, only a low prevalence of NAI resistance (<1%) had been detected in circulating viruses. However, surveillance in Europe in late 2007 revealed significant numbers of A(H1N1) influenza strains with a H274Y neuraminidase mutation that were highly resistant to the NAI oseltamivir. We examined 264 A(H1N1) viruses collected in 2008 from South Africa, Oceania and SE Asia for their susceptibility to NAIs oseltamivir, zanamivir and peramivir in a fluorescence-based neuraminidase inhibition assay. Viruses with reduced oseltamivir susceptibility were further analysed by pyrosequencing assay. The frequency of the oseltamivir-resistant H274Y mutant increased significantly after May 2008, resulting in an overall proportion of 64% (168/264) resistance among A(H1N1) strains, although this subtype represented only 11.6% of all isolates received during 2008. H274Y mutant viruses demonstrated on average a 1466-fold reduction in oseltamivir susceptibility and 527-fold reduction in peramivir sensitivity compared to wild-type A(H1N1) viruses. The mutation had no impact on zanamivir susceptibility. Ongoing surveillance is essential to monitor how these strains may spread or persist in the future and to evaluate the effectiveness of treatments against them.

Topics: Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Asia, Southeastern; Cluster Analysis; Cyclopentanes; Drug Resistance, Viral; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Microbial Sensitivity Tests; Mutation, Missense; Neuraminidase; Oceania; Oseltamivir; Phylogeny; RNA, Viral; Sequence Analysis, DNA; Sequence Homology; South Africa; Viral Proteins; Zanamivir

Topics: Acids, Carbocyclic; Antiviral Agents; Cyclopentanes; Drug Approval; Drugs, Investigational; Emergencies; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Injections, Intravenous; Investigational New Drug Application; Neuraminidase; United States; United States Food and Drug Administration

Topics: Acids, Carbocyclic; Adult; Antiviral Agents; Centers for Disease Control and Prevention, U.S.; Child; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Critical Care; Cyclopentanes; Drugs, Investigational; Emergency Medical Services; Guanidines; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; United States

The replication efficiency and multi-organ dissemination of some influenza A (H5N1) viruses requires a rapid re-evaluation of the available antiviral strategies. We assessed five regimens of the neuraminidase (NA) inhibitor peramivir in mice inoculated with H5N1 virus. The regimens differed by: (1) frequency of administration on first day (once vs twice); (2) duration of administration (1 day vs 8 days); (3) route of administration (intramuscular [IM] injection alone or followed by oral administration). In all regimens, BALB/c mice were administered 30 mg/kg peramivir IM 1 h after lethal challenge with 5 MLD(50) of A/Vietnam/1203/04 (H5N1) influenza virus. When given only on the day of inoculation, a single IM injection produced a 33% survival rate, which increased to 55% with two injections. Eight-day regimens significantly increased survival; two IM injections followed by seven daily IM injections was the most effective regimen (100% survival; inhibition of replication in lungs and brain). When this 8-day regimen began at 24h after inoculation, 78% of mice survived; 56% survived when treatment began at 48 hours. Anti-HA antibody titer differed with the peramivir regimen and corresponded to the severity of disease. Overall, our results demonstrate that IM administration of peramivir is effective in promoting the survival of mice infected with systemically replicating H5N1 virus.

Topics: Acids, Carbocyclic; Animals; Antibodies, Viral; Antiviral Agents; Brain; Cell Line; Chick Embryo; Cyclopentanes; Dogs; Drug Administration Routes; Drug Administration Schedule; Drug Resistance, Viral; Enzyme Inhibitors; Female; Guanidines; Humans; Influenza A Virus, H5N1 Subtype; Influenza, Human; Lung; Mice; Mice, Inbred BALB C; Neuraminidase; Survival; Viral Proteins

Since 2003, highly pathogenic A(H5N1) influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. A group of 55 influenza A(H5N1) viruses isolated from various regions of South East Asia between 2004 and 2006 were tested for their susceptibility to the anti-influenza drugs the neuraminidase inhibitors and adamantanes. The majority of strains were found to be fully sensitive to the neuraminidase inhibitors oseltamivir carboxylate, zanamivir and peramivir; however two strains demonstrated increased IC50 values. Sequence analysis of these strains revealed mutations in the normally highly conserved residues 116 and 117 of the N1 neuraminidase. Sequence analysis of the M2 gene showed that all of the A(H5N1) viruses from Vietnam, Malaysia and Cambodia contained mutations (L26I and S31N) associated with resistance to the adamantane drugs (rimantadine and amantadine), while strains from Indonesia were found to be a mix of both adamantane resistant (S31N) and sensitive viruses. None of the A(H5N1) viruses from Myanmar contained mutations known to confer adamantane resistance. These results support the use of neuraminidase inhibitors as the most appropriate class of antiviral drug to prevent or treat human A(H5N1) virus infections.

Topics: Acids, Carbocyclic; Amantadine; Animals; Antiviral Agents; Base Sequence; Birds; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A Virus, H5N1 Subtype; Influenza in Birds; Influenza, Human; Neuraminidase; Oseltamivir; Zanamivir

An influenza B virus from an infant with no history of treatment or contact with neuraminidase inhibitors demonstrated a significant reduction in sensitivity to these drugs. Here, we describe the analysis of a mixed viral population that contained a novel D197E amino acid substitution that was responsible for this reduction.

Topics: Acetamides; Acids, Carbocyclic; Amino Acid Substitution; Antiviral Agents; Baculoviridae; Base Sequence; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Female; Guanidines; Humans; Infant; Influenza B virus; Influenza, Human; Inhibitory Concentration 50; Microbial Sensitivity Tests; Molecular Sequence Data; Neuraminidase; Oseltamivir; Pyrans; Recombinant Proteins; Sialic Acids; Zanamivir

A convergent and versatile racemic total synthesis of the anti-influenza agent BCX-1812 (RWJ-270201) was accomplished on the basis of a sequence of stereoselective reactions. Despite intensive research to develop neuraminidase inhibitors to treat infections due to influenza, currently available agents are still in the need of optimization with respect to selectivity and potency, as well as to minimize adverse effects. Our synthetic approach, introduced in this report, is highly exploitable for further derivatization due to flexibility that will eventually accommodate diversified substituents. In addition, the size of the core ring can be varied depending on the size of the diene used for the preparation of the key cycloadduct 10 using an acylnitroso-based hetero-Diels-Alder reaction. Elaboration of 10 to methyl ester 14 followed by a precedented [3+2] dipolar cycloaddition gave bicyclic isoxazoline 17 in a regio- and stereoselective fashion. Incorporation of the peripheral guanidino group and subsequent deprotection provided the target molecule. The details of the synthesis are described herein.

Topics: Acids, Carbocyclic; Antiviral Agents; Catalysis; Cyclopentanes; Enzyme Inhibitors; Guanidines; Humans; Indicators and Reagents; Influenza, Human; Neuraminidase; Stereoisomerism; Triazines

With the use of neuraminidase (NA) inhibitors (BCX-1812, oseltamivir, or zanamivir), drug-resistant variants of influenza A viruses were generated that lacked characteristic markers of resistance, such as substitutions in the NA active center or in the hemagglutinin. Drug resistance was associated with the accumulation of defective (Delta) RNA segments encoding NA. This phenomenon could be explained by reduced dependence of the virus on its NA activity. Analysis of the last isolates recovered from 11 volunteers, experimentally infected with influenza virus and treated with BCX-1812, revealed that they maintained full susceptibility to the drug in the NA inhibition assay (50% inhibitory concentration, 0.35-0.5 nM). The presence of DeltaRNA segments was detected in 1 of these isolates but was not found in the isolates recovered from placebo recipients (n = 8). Because of a lack of cell culture-based assays for susceptibility testing of human influenza viruses, detection of DeltaRNA segments should be considered an additional assay for monitoring of NA inhibitor resistance.

Topics: Acetamides; Acids, Carbocyclic; Animals; Cell Line; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A virus; Influenza, Human; Microbial Sensitivity Tests; Molecular Sequence Data; Neuraminidase; Oseltamivir; Viral Plaque Assay

Forty-two influenza A and 23 influenza B isolates collected from untreated subjects during the 1999-2000 influenza season in Canada were tested for their susceptibility to three neuraminidase inhibitors (zanamivir, oseltamivir carboxylate and RWJ-270201 or BCX-1812) using a chemiluminescent neuraminidase assay. Influenza B isolates were less susceptible than A viruses to all tested drugs. RWJ-270201 was the most potent drug against both influenza A(H3N2) (mean IC(50): 0.60 nM) and B (mean IC(50): 0.87 nM) viruses. Oseltamivir carboxylate was more active than zanamivir for influenza A(H3N2) isolates (mean IC(50): 0.73 vs. 2.09 nM) whereas it was less potent against B viruses (mean IC(50): 11.53 vs. 4.15 nM).

Topics: Acetamides; Acids, Carbocyclic; Canada; Cyclopentanes; Drug Resistance, Viral; Enzyme Inhibitors; Fluorometry; Guanidines; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Inhibitory Concentration 50; Luminescent Measurements; Neuraminidase; Oseltamivir; Pyrans; Sialic Acids; Zanamivir

The novel influenza virus neuraminidase (NA) inhibitor, (1S,2S,3R,4R)-3-[(1S)-(acetylamino)-2-ethylbutyl]-4-[(aminoiminomethyl)amino]-2-hydroxy-cyclopentanecarboxylic acid (RWJ-270201, BCX-1812), is a potent inhibitor of influenza A and B viruses in cell culture and in infected mice. A mouse-adapted strain of influenza A/Shangdong/09/93 (H3N2) virus was serially passaged in the presence of 1 microM compound. After the fourth passage, breakthrough of resistant virus occurred. By the tenth passage, a twice plaque purified isolate was obtained which could replicate in 10 microM inhibitor. The 50% effective concentration (EC(50)) values for RWJ-270201 against wild-type and resistant viruses, determined by using a cytopathic effect inhibition assay, were 0.007 and 23 microM, respectively. Cross-resistance to zanamivir and oseltamivir carboxylate was observed. The hemagglutinin (HA) and NA genes of the virus were sequenced to determine the mutation(s) which conferred drug resistance. No differences were found between the resistant and wild-type viruses in the NA gene. However, a point mutation resulting in a single amino acid change (Lys189Glu) was found in the resistant viral HA. The wild-type and resistant viruses were compared for virulence in BALB/c mice. The resistant virus was approximately tenfold less virulent than the wild-type virus based upon virus challenge dose. Mice infected with a lethal dose of the resistant virus could still be effectively treated with RWJ-270201. Thus, the HA mutation may allow for the spread of the virus in cell culture in the presence of the NA inhibitor, but not in mice.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Cell Line; Cell Line, Transformed; Cyclopentanes; Dogs; Drug Resistance, Viral; Enzyme Inhibitors; Guanidines; Humans; Influenza A virus; Influenza A Virus, H3N2 Subtype; Influenza, Human; Mice; Mice, Inbred BALB C; Mutation; Neuraminidase; Virulence