id000071
10.3205/id000071
urn:nbn:de:0183-id0000716
Review Article
Prophylaxis and treatment of influenza: options, antiviral susceptibility, and existing recommendations
Duwe
Duwe
Susanne C.
SC
Dr.
Robert Koch Institute, Unit 17: Influenza and Other Respiratory Viruses, National Reference Centre for Influenza, Seestr. 10, 13353 Berlin, GermanyRobert Koch Institute, Unit 17: Influenza and Other Respiratory Viruses, National Reference Centre for Influenza, Berlin, Germany
DuweS@rki.de
author
Schmidt
Schmidt
Barbara
B
Institute for Clinical Microbiology and Hygiene, Regensburg University Hospital, Regensburg, Germany
author
Gärtner
Gärtner
Barbara C.
BC
Institute of Medical Microbiology & Hygiene, Saarland University Medical Center, Homburg, Germany
author
Timm
Timm
Jörg
J
Institute for Virology, University Hospital Düsseldorf, Faculty of Medicine, University Düsseldorf, Germany
author
Adams
Adams
Ortwin
O
Institute for Virology, University Hospital Düsseldorf, Faculty of Medicine, University Düsseldorf, Germany
author
Fickenscher
Fickenscher
Helmut
H
Institute for Infection Medicine, University of Kiel and University Hospital Schleswig-Holstein, Kiel, Germany
author
Schmidtke
Schmidtke
Michaela
M
Section Experimental Virology, Department of Medical Microbiology, Jena University Hospital, Germany
author
German Medical Science GMS Publishing House
Düsseldorf
610
infection
neuraminidase
baloxavir
polymerase
resistance
20210430
engl
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung).
2195-8831
9
GMS Infectious Diseases
GMS Infect Dis
02
Influenza viruses of types A and B attack 5–10% of adults and 20–30% of children, thereby causing millions of acute respiratory infections in Germany annually. A significant number of these infections are associated with complications such as pneumonia and bacterial superinfections that need hospitalization and might lead to death. In addition to vaccines, drugs were developed that might support influenza prevention and that can be used to treat influenza patients. The timely application of anti-influenza drugs can inhibit virus replication, help reduce and shorten the symptoms, and prevent death as well as virus transmission.This review concisely describes the mechanism of action, the potential for prophylactic and therapeutic use, and the knowledge on resistance of anti-influenza drugs approved today. However, the main aim is to give an overview on the recommendations available in Germany for the proper use of these drugs. In doing so, the recommendations published in statements and guidelines of medical societies as well as the German influenza pandemic preparedness plan are summarized with the consideration of specific circumstances and groups of patients.
1 IntroductionInfluenza is a serious and frequently underestimated viral disease. For example, 25,100 influenza-associated deaths and 9 million influenza-attributable acute respiratory illnesses of patients seeking medical attention were estimated for Germany in the 2017–2018 season . Although the influenza season 2018–2019 was characterized by significantly lower case numbers, 3.8 million patients seeking medical attention for influenza-attributable acute respiratory illnesses, 2.3 million incapacities for work, and 18,000 influenza-related hospitalizations were estimated . These data confirm the known high influenza attack rates (5–10% in adults and 20–30% in children) .Most infections with influenza A and B viruses are asymptomatic or result in acute self-limiting uncomplicated influenza with sudden onset of fever (≥38.5°C), dry cough, sore throat, body aches and pains, and headaches. Fatigue, sweating, rhinorrhea, as well as nausea, vomiting, and diarrhea were reported as additional symptoms. In the absence of complications and risk factors, an influenza illness lasts 5–7 days . Influenza complications that prolong the disease and increase the severity of symptoms include pneumonia, bacterial superinfection, and a postinfectious elevated risk of myocardial infarctions as well as stroke associated with the influenza disease. Such complications need hospitalization of influenza patients and might cause more than 20,000 deaths as seen for example in Germany in the 2014–2015, 2016–2017, and 2017–2018 influenza seasons .Although non-pharmaceutical interventions (NPI) such as face masks and intensified hand hygiene may be effective in preventing influenza infection mainly in clinical settings or households, vaccination is considered the most effective way to prevent influenza . If vaccination is not available, e.g., upon emergence of a new virus or in vulnerable groups of patients where vaccination is less effective, antiviral prophylaxis and treatment represent an additional option . Most international and national public health institutions as well as medical and scientific societies recommend antiviral treatment of influenza at least for patients who are at high risk of developing serious influenza complications . In contrast, anti-influenza drugs are used to treat large numbers of uncomplicated influenza cases in Japan . Anti-influenza drugs are therefore an important part of a rational approach to epidemic influenza control, and are critical in planning a pandemic response .This review summarizes the recommendations available in Germany for the use of antiviral drugs for prophylaxis and treatment of influenza considering specific circumstances and groups of patients in statements and guidelines of medical societies as well as the German pandemic preparedness plan.
2 Antiviral medicinesThere are currently three classes of antiviral medicines authorized by the European Medicines Agency (EMA) for treatment and prophylaxis of influenza: the neuraminidase inhibitors (NAI), the M2 ion channel inhibitors (adamantanes), and the Cap-dependent endonuclease inhibitor baloxavir marboxil. The RNA polymerase inhibitor favipiravir is licensed in Japan for pandemic preparedness only (Table 1 ).Although combination therapy with two or more antiviral compounds might reduce the development of antiviral resistance and could increase antiviral potency especially in immunocompromised or seriously ill patients, all existing recommendations for influenza treatment relate to therapy with one antiviral drug (reviewed in ). In preclinical studies, the benefits of combination therapy over monotherapy were demonstrated , . Controlled clinical therapy trials are difficult to carry out, not only for organizational reasons, but also because of the limited number of active antivirals. However, the planning of such studies is ongoing.2.1 M2 ion channel blockerThe efficacy of adamantanes (amantadine and rimantadine) is limited by their inapplicability to influenza B viruses, as well as emergence and transmission of drug-resistant virus variants. Resistance to adamantanes emerges spontaneously due to natural polymorphisms or reassortment of influenza A viruses.2.1.1 Characteristics and mode of actionThe M2 ion channel inhibitor amantadine blocks the release of influenza virus RNA from the endosome into the cellular cytoplasm. This effect is achieved with therapeutic dosage of the drug for influenza A viruses only, because the structure of the ion channel is different for influenz<![CDATA[a B</PlainText></TextGroup> viruses <TextLink reference="12"></TextLink>.</Pgraph><SubHeadline2>2.1.2 Resistance</SubHeadline2><Pgraph>Since winter 2004–2005, adamantane-resistant influenza A(H3N2) viruses have spread worldwide. The emergence of the pandemic influenza A(H1N1) virus in 2009, carrying natural polymorphisms conferring reduced susceptibility to the adamantane class of antivirals (mainly the substitution S31N in the M2 ion channel), caused that currently all circulating human influenza A viruses are resistant t<TextGroup><PlainText>o adamantan</PlainText></TextGroup>es. These findings rendered this class of drug<TextGroup><PlainText>s mostl</PlainText></TextGroup>y ineffective <TextLink reference="13"></TextLink>. In summer 2017, some ada<TextGroup><PlainText>manta</PlainText></TextGroup>ne-sensitive influenza A(H3N2) viruses encoding serine at residue 31 of the M2 protein were detected in Australia, suggesting the reversion back to the drug-sensitive phenotype more than 10 years after the resistant strain had emerged <TextLink reference="14"></TextLink>. In Germany, approximately 25% (N=276) of the viruses detected by the German National Influenza Centre (NIC) during the 2018–2019 season were analyzed for M2 ion channel substitutions associated with resistance to the adamantane class of drugs. In all samples, the substitution M2-S31N and in addition in three viruses the molecular markers for resistance M2-L26F or M2-V27A/I were detected, suggesting that the circulating viruses of subtypes A(H1N1)pdm09 and A(H3N2) in Germany remain resistant to adamantanes <TextLink reference="13"></TextLink>.</Pgraph><SubHeadline2>2.1.3 Recommendations</SubHeadline2><Pgraph>Due to the current resistance of circulating influenza A viruses, the clinical use of adamantanes is not recommended presently, but might be an option in case of pandemic spread of a new influenza virus sensitive to adamantanes.</Pgraph><SubHeadline>2.2 Neuraminidase inhibitors</SubHeadline><SubHeadline2>2.2.1 Characteristics and mode of action</SubHeadline2><Pgraph>Neuraminidase inhibitors (NAI) are a class of antiviral agents acting against influenza A and B viruses by selectively inhibiting the viral neuraminidase and, thus, preventing the release of new viruses from infected cells as well as virus spread. Additionally, they affect viral invasion of the upper airways, and therefore suppress infection before virus entry into cells by blocking the cleavage of sialic acid moieties on the mucin by the viral neuraminidase <TextLink reference="15"></TextLink>. Based on several clinical studies, NAI have been considered effective for prevention and treatment of influenza infections. In this respect, treatment shortens the duration of symptoms of influenza by approximately 0.5 to 1.5 days when started within the first two days after the onset of illness <TextLink reference="6"></TextLink>. In critically ill, hospitalized patients, influenza treatment with NAI can be considered even when a longer time period has elapsed <TextLink reference="16"></TextLink>. In 2014, NAI have been subject for critical discussions concerning their effectiveness and safety, as well as the appropriateness of stockpiling these drugs for use in future influenza pandemics. The World Health Organization (WHO) has moved oseltamivir from the core to the complementary list. However, the treatment of influenza with NAI is recommended for patients at higher risk for developing severe illness or infected with avian influenza viruses like A(H5N1) by WHO, CDC, and various national associations. An expert opinion from the European Centre for Disease Prevention and Control (ECDC) and national authorities, as well as national virological, medical, and therapeutical societies (Society for Virology (GfV e.V.), German Association for the Control of Virus Diseases (DVV e.V.), Paul Ehrlich Society for Chemotherapy (PE<TextGroup><PlainText>G e.V</PlainText></TextGroup>.)) confirmed earlier assessments that there is no significant new evidence from randomized control trials to support any changes to the approved indication and recommended use of neuraminidase inhibitors in EU/EEA member states (Table 2 <ImgLink imgNo="2" imgType="table"/>). This position was consistent with guidance from WHO and other national public health organizations in the United States and Australia <TextLink reference="17"></TextLink>, <TextLink reference="18"></TextLink>, <TextLink reference="19"></TextLink>, <TextLink reference="20"></TextLink>.</Pgraph><SubHeadline2>2.2.2 Neuraminidase inhibitors for influenza prophylaxis</SubHeadline2><Pgraph><Mark1>Oseltamivir</Mark1> (Tamiflu™) and <Mark1>zanamivir</Mark1> (Relenza™) were approved and authorized by the <Mark2>European Medicines Agency</Mark2> (EMA) for prophylaxis of influenza in the European Union/European Economic Area (EU/EEA) in 2002 and 1999, respectively <TextLink reference="21"></TextLink>, <TextLink reference="22"></TextLink>.</Pgraph><Pgraph>Nosocomial influenza is a major threat since it can affect patients hospitalized for other, often severe underlying diseases. Consequently, the mortality is high. Nosocomial influenza is not a rare incidence and accounts for approximately 10–20% (range 5–45%) of all influenza cases in hospitals <TextLink reference="23"></TextLink>, <TextLink reference="24"></TextLink>, <TextLink reference="25"></TextLink>, <TextLink reference="26"></TextLink>, <TextLink reference="27"></TextLink>, <TextLink reference="28"></TextLink>, <TextLink reference="29"></TextLink>, <TextLink reference="30"></TextLink>.</Pgraph><Pgraph>Nosocomial outbreaks are frequently found and difficult to control. The virus might be introduced by asymptomatic/paucisymptomatic infected patients, visitors, or health care workers. Symptomatic persons are also a major source of infection in medical facilities with poor infection prevention awareness or in case of isolation measures breach. When controlling an influenza outbreak, it is challenging that the viral load is highest before symptoms are developed. Thus, the key measures usually taken in outbreak management such as isolation of symptomatic individuals are often not sufficient to stop transmission. In an outbreak situation, the use of neuraminidase inhibitors (NAI) might act as post-exposure prophylaxis in already infected individuals during the incubation period, or even as pre-exposure prophylaxis. NAI inhibit the viral replication and progression to disease sufficiently, especially when applied as early as for prophylaxis <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>. Therefore, the virus cannot be transmitted any longer <TextLink reference="34"></TextLink>. In quite a number of studies, NAI could be shown to inhibit transmission effectively, and often to be the only measure that stopped an outbreak <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>. It must be kept in mind that the use of antivirals should be offered to all individuals involved in the outbreak, and not only to patients or to health care workers.</Pgraph><Pgraph>Patients with native, acquired, or treatment-induced immunodeficiency are at a particular risk for complications due to influenza. This might especially come true for the growing number of patients treated with biologicals such as rituximab <TextLink reference="38"></TextLink>. It might be an important option in these patients to consider pre-exposure prophylaxis during the weeks with the highest infection risks to protect these highly vulnerable patients <TextLink reference="39"></TextLink>.</Pgraph><Pgraph>Usually, the dosage of NAI used for prophylaxis is only half of the dosage used for treatment. However, depending on the susceptibility of the virus strain, the prophylactic dose might even be doubled, e.g. for more resistant isolates that were sometimes found in avian influenza viruses <TextLink reference="40"></TextLink>. In post-exposure prophylaxis, the therapy should cover 10 days. In pre-exposure prophylaxis, zanamivir is approved for 28 days, whereas oseltamivir is approved for up to 6 weeks in the general population, and for 12 weeks in immunosuppressed individuals. Sometimes, a double dose of NAI is discussed as off-label use in NAI-resistant strains. However, it should be kept in mind that resistant strains are rare at present; and even in case of resistance, the strains are often not resistant to all NAI. E.g., the H274Y A(H1N1) circulating in 2007–2008 was resistant against oseltamivir, but remained susceptible to zanamivir. Thus, the use of a double dose should only be taken into consideration in case no other options are availabe.</Pgraph><SubHeadline2>2.2.3 Neuraminidase inhibitors for influenza treatment</SubHeadline2><Pgraph>Oseltamivir (Tamiflu™) and zanamivir (Relenza™) were also approved and authorized by EMA for treatment of influenza in the European Union/European Economic Area (EU/EEA) in 2002 and 1999, respectively <TextLink reference="22"></TextLink>, <TextLink reference="41"></TextLink>. Additionally, EMA approved <Mark1>peramivir</Mark1> (Alpivab™) in April 2018 and intravenous <Mark1>zanamivir</Mark1> (Dectova™) in April 2019 for treatment of influenza <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>.</Pgraph><Pgraph><Mark1>Oseltamivir</Mark1> is licensed by EMA for the prophylaxis and treatment of adults and children including full-term newborns. It represents a prodrug, and is available as oseltamivir phosphate in the form of capsules and as a powder for oral suspension. The compound is biotransformed by esterases in the intestinal tract and in the liver into the active metabolite oseltamivir carboxylate <TextLink reference="22"></TextLink>.</Pgraph><Pgraph><Mark1>Zanamivir</Mark1> showed unsatisfactory oral bioavailability and was therefore mixed with lactose and inhaled as a dry powder. Zanamivir is approved by EMA for the treatment and prevention of influenza infections in patients starting from five years of age. In 2019, EMA approved intrav<TextGroup><PlainText>enous (</PlainText></TextGroup>i.v.) zanamivir for the treatment of complicated and potentially life-threatening influenza caused by either influenza A or B viruses in adults and children from <TextGroup><PlainText>6 m</PlainText></TextGroup>onths of age <TextLink reference="43"></TextLink>.</Pgraph><Pgraph><Mark1>Peramivir</Mark1> (Alpivab™) was developed as an intramuscularly (i.m.) or intravenously (i.v.) applicable drug due to its poor oral bioavailability. In 2018, EMA approved peramivir as a single intravenous dose within 48 hours of the onset of influenza symptoms for the treatment of uncomplicated influenza in adults and children older than 2 years and withdrew the marketing authorization at the request of the marketing-authorization holder in December 2020 <TextLink reference="44"></TextLink>, <TextLink reference="45"></TextLink>.</Pgraph><Pgraph><Mark1>Laninamivir octanoate</Mark1> (Japan: Inavir<Superscript>®</Superscript>) is approved in Japan only for influenza treatment and prevention of adults and children. Laninamivir octanoate presents as an octanoyl ester prodrug and showed therapeutic efficacy after one single nasal inhalation (long-acting neuraminidase inhibitor, LANI) <TextLink reference="46"></TextLink>. After inhalation, laninamivir octanoate is absorbed by the respiratory tract’s epithelial cells and rapidly hydrolyzed to the active drug laninamivir <TextLink reference="47"></TextLink>, <TextLink reference="48"></TextLink>.</Pgraph><SubHeadline2>2.2.4 Resistance</SubHeadline2><Pgraph>In Europe, antiviral susceptibility of influenza viruses to neuraminidase inhibitors is monitored by the European Centre for Disease Prevention and Control (ECDC) and the WHO/Europe Influenza Surveillance (EuroFlu). Since the influenza season 2006–2007, NAI-resistance monitoring is based on the reports sent by national influenza centers (NIC) to “The ECDC Surveillance System” (TESSy). The German NIC collects and weekly reports antiviral susceptibility data according to WHO guidance for de<TextGroup><PlainText>termination of baseli</PlainText></TextGroup>ne and reduced antiviral susceptibility among circulating viruses <TextLink reference="13"></TextLink>, <TextLink reference="49"></TextLink>. Susceptibility of c<TextGroup><PlainText>irculatin</PlainText></TextGroup>g influenza viruses to the NAI oseltamivir, z<TextGroup><PlainText>anamivi</PlainText></TextGroup>r, and peramivir was analyzed for about 50<TextGroup><PlainText>0 v</PlainText></TextGroup>iruses collected for the NIC’s influenza sentinel (44<TextGroup><PlainText>% A</PlainText></TextGroup>(H1N1)pdm09 and 56% A(H3N2)) in Germany during the 2018–2019 season. All but one tested viruses showed full in-vitro sensitivity to NAI. The NAI-resistant virus was collected approximately three days after initiation of oseltamivir treatment. It showed reduced susceptibility to oseltamivir and peramivir due to the substitution NA-H275Y. Further substitutions known to confer antiviral resistance to NAI were not detected <TextLink reference="2"></TextLink>.</Pgraph><Pgraph>The analysis of antiviral resistance data reported from twelve EU/EAA countries to ECDC, as well as the global analysis of antiviral susceptibility of influenza viruses sent from NIC to WHO Influenza Collaboration Centers revealed a low prevalence of viruses with reduced susceptibility to NAI (0.2%–0.5%) during the last ten seasons <TextLink reference="50"></TextLink>, <TextLink reference="51"></TextLink>.</Pgraph><SubHeadline2>2.2.5 Recommendations</SubHeadline2><Pgraph>WHO, CDC, ECDC, and several national professional societies, e.g. Public Health England (PHE), the German Society for Pediatric Infectious Diseases (DGPI), and others, recommended to consider NAI for treatment of patients with confirmed or putative influenza who are hospitalized with medical conditions associated with an increased risk of influenza-related complications, or suffering from severe, complicated, and progressive course of disease (Table 2 <ImgLink imgNo="2" imgType="table"/>) <TextLink reference="6"></TextLink>, <TextLink reference="18"></TextLink>.</Pgraph><SubHeadline>2.3 Polymerase inhibitors</SubHeadline><Pgraph>The RNA-dependent RNA polymerase (RdRP) of influenza viruses comprises three subunits: PA endonuclease, PB<TextGroup><PlainText>1 p</PlainText></TextGroup>olymerase, and cap-binding PB2 subunit. PB1 synthesizes all viral RNA (mRNA, cRNA and vRNA). The cap-binding domain of the PB2 subunit (PB2cap) in the viral polymerase binds the cap of a host pre-mRNA molecule. PA represents a cap-dependent endonuclease. All three represent a promising target for anti-influenza drugs, but only PA and PB1 inhibitors are approved for treatment and prevention of influenza.</Pgraph><SubHeadline2>2.3.1 Cap-dependent endonuclease inhibitor (baloxavir marboxil)</SubHeadline2><SubHeadline3>2.3.1.1 Characteristics and mode of action</SubHeadline3><Pgraph><Mark1>Baloxavir marboxil</Mark1> (Xofluza™) was licensed in Japan and the US in 2018, and recently in Taiwan (August 2019) for treatment of acute uncomplicated influenza in patients of 12 years of age and older who have been symptomatic for less than 48 hours. In January 2021, Xofluza was authorized in the EU for treatment and post-exposure prophylaxis of uncomplicated influenza by the <Mark2>European Medicines Agency</Mark2> (EMA) <TextLink reference="52"></TextLink>.</Pgraph><Pgraph>Baloxavir marboxil is an oral prodrug administered as a single dose which is hydrolyzed by the enzyme arylacetamide deacetylase to the active form baloxavir acid (BXA) <TextLink reference="53"></TextLink>. A characteristic structural feature of the drug is represented by two oxygen atoms arranged in certain positions. These are able to enter into bivalent metal ion complexes. BXA inhibits the cap-snatching activity of the viral polymerase’s PA subunit, which prevents viral mRNA synthesis and thus virus multiplication. BXA acts as a chelator and complexes with the two 2-valent metal ions in the active site of the endonuclease, which are essential as cofactors for the efficacy of this viral enzyme <TextLink reference="54"></TextLink>. Baloxavir demonstrated broad spectrum coverage, and additionally could provide an option for patients with infections caused by NAI- or M2I-resistant influenza virus with its novel mechanism of action <TextLink reference="54"></TextLink>.</Pgraph><Pgraph>According to the prescribing information for baloxavir marboxil tablets for oral use, the co-administration with polyvalent cation-containing products may decrease plasma concentrations of baloxavir and thus reduce its efficacy. Therefore, co-administration of baloxavir with polyvalent cation-containing laxatives, antacids, or oral supplements (e.g. calcium, iron, magnesium, selenium, or zinc) should be avoided.</Pgraph><SubHeadline3>2.3.1.2 Resistance</SubHeadline3><Pgraph>Within the clinical trial, Capstone-1 variants of cap-d<TextGroup><PlainText>ependent e</PlainText></TextGroup>ndonuclease (CEN) of the viral polymerase’s PA subunit with I38T/M/F substitutions emerged in 2.2<TextGroup><PlainText>% o</PlainText></TextGroup>f patients infected with A(H1N1)pdm09, and 10.9<TextGroup><PlainText>% o</PlainText></TextGroup>f those with influenza subtype A(H3N2) infection (Table 3 <ImgLink imgNo="3" imgType="table"/>), suggesting a low barrier of resistance <TextLink reference="55"></TextLink>, <TextLink reference="56"></TextLink>. The PA-I38X substitutions conferred an increase of TCID50 of baloxavir in yield reduction or other phenotypic assays, e.g. focus-reduction assay or high-content imaging neutralization test <TextLink reference="57"></TextLink>. Results of <Mark2>in vitro</Mark2> viral comparative fitness assays suggest a detrimental effect of PA-I38X substitutions regarding the replicative capacity of viruses in MDCK cells <TextLink reference="58"></TextLink>. On the other hand, a human-to-human transmission within a family cluster of A(H3N2) bearing the PA-I38T substitution was reported recently <TextLink reference="59"></TextLink>, suggesting retained replication and transmission capability of treatment-selected viruses. Therefore and for public health issues, monitoring of seasonal influenza viruses for baloxavir susceptibility by using phenotypic assays and genetic analysis for detecting molecular markers of resistance is being included into the influenza surveillance (USA <TextLink reference="60"></TextLink>, Japan <TextLink reference="61"></TextLink>, <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink>, Asia-Pacific <TextLink reference="64"></TextLink>, Germany <TextLink reference="2"></TextLink>).</Pgraph><SubHeadline3>2.3.1.3 Recommendations</SubHeadline3><Pgraph>A systematic literature review and meta-analysis suggests that baloxavir marboxil demonstrated better or at least similar efficacy compared to other antivirals with a comparable safety profile <TextLink reference="65"></TextLink>. Based on the results of several ongoing and completed randomized controlled clinical trials, baloxavir marboxil was found to be comparable to oseltamivir regarding secondary end points, including time to alleviation of symptoms of influenza-like illness. Baloxavir marboxil reduced the length of viral shedding by about 2 days when compared with placebo. Additionally, comparison with placebo showed a significantly reduced risk of developing influenza by 86% when used as prophylaxis (Table 3 <ImgLink imgNo="3" imgType="table"/>) <TextLink reference="55"></TextLink>, <TextLink reference="66"></TextLink>, <TextLink reference="67"></TextLink>.</Pgraph><SubHeadline2>2.3.2 PB1 polymerase inhibitor</SubHeadline2><SubHeadline3>2.3.2.1 Characteristics and mode of action</SubHeadline3><Pgraph><Mark1>Favipiravir</Mark1> (formerly known as T-705) represents a pyrazinecarboxamide derivative. Favipiravir is ribophosphorylated by host cell enzymes to the active metab<TextGroup><PlainText>olite, T-</PlainText></TextGroup>705 ribofuranosyltriphosphate (T-705RTP) <TextLink reference="68"></TextLink>. <TextGroup><PlainText>T-705RTP m</PlainText></TextGroup>imics guanine and adenine, and acts as alternative substrate of the viral RNA-dependent RNA polymerase PB1. Its incorporation into progeny viral RNA during replication generates a high percentage of nonv<TextGroup><PlainText>iable i</PlainText></TextGroup>nfluenza viruses via lethal mutagenesis <TextLink reference="69"></TextLink>.</Pgraph><Pgraph>Favipiravir selectively inhibits a broad spectrum of RNA-dependent RNA polymerases, and thus inhibits the viral gene replication of influenza viruses and nine other RNA virus families <TextLink reference="69"></TextLink>, <TextLink reference="70"></TextLink>. However, the clinical and virological effects of favipiravir in clinical trials in patients with uncomplicated influenza were modest, and there is evidence of teratogenicity and embryo toxicity <TextLink reference="71"></TextLink>, <TextLink reference="72"></TextLink>. Today, favipiravir is approved for influenza pandemic preparedness in Japan only <TextLink reference="73"></TextLink>.</Pgraph><SubHeadline3>2.3.2.2 Resistance</SubHeadline3><Pgraph>The favipiravir resistance-conferring amino acid substitution PB1 K229R in A(H1N1)pdm09 viruses could be generated in cell culture, but was not detected in clinical trials so far <TextLink reference="74"></TextLink>, <TextLink reference="75"></TextLink>.</Pgraph><SubHeadline3>2.3.2.3 Recommendations</SubHeadline3><Pgraph>Favipiravir is part of the Japanese antiviral stockpile, and available in Japan only in case of an emerging new influenza virus, and may be used if the pandemic virus is resistant to other antivirals <TextLink reference="76"></TextLink>. Its use is limited due to modest effects on the time to alleviation of influenza symptoms, and concerns of teratogenicity suggest that a more widespread use of favipiravir is unlikely <TextLink reference="76"></TextLink>.</Pgraph></TextBlock>
<TextBlock linked="yes" name="3 Conclusions/Summary">
<MainHeadline>3 Conclusions/Summary</MainHeadline><Pgraph>Antivirals used as pre- and post-exposure prophylaxis represent an essential tool to stop outbreaks in institutions such as hospitals or nursery homes.</Pgraph><Pgraph>NAI, especially oseltamivir, remain the drug of choice for influenza treatment and prevention today. The low frequency of influenza viruses with reduced susceptibility to NAI over a ten-year period supports the use of NAI to treat influenza <TextLink reference="50"></TextLink>. However, antiviral treatment of influenza should be restricted to severe illness in critically ill hospitalized patients and should be considered for i<TextGroup><PlainText>n- and out</PlainText></TextGroup>patients who are at higher risk <TextLink reference="77"></TextLink>. Baloxavir marboxil presents a new therapeutic option with a single-dose oral regimen. Although it is a valuable addition to the available antivirals for treatment and prevention of influenza, novel antivirals are still needed. Therapeutic use of two or more anti-influenza compounds could increase clinical effectiveness and might be a promising approach for control of influenza in the future.</Pgraph></TextBlock>
<TextBlock linked="yes" name="Notes">
<MainHeadline>Notes</MainHeadline><SubHeadline>Acknowledgments</SubHeadline><Pgraph>This review was supported by the Scientific Advisory Board for Antiviral Therapy of the German Association for the Control of Virus Diseases (DVV) and the Society of Virology (GfV) as well as the Section for Antiviral Therapy of the Paul Ehrlich Society for Chemotherapy (PEG).</Pgraph><SubHeadline>Competing interests</SubHeadline><Pgraph>SD, BS, JT, OA, HF and MS declare that they have no competing interests.</Pgraph><Pgraph>BG received fees for talks and/or advisory board: Roche, Seqirus, Sanofi, GSK.</Pgraph></TextBlock>
<References linked="yes">
<Reference refNo="1">
<RefAuthor>Robert Koch-Institut</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2018</RefYear>
<RefBookTitle>Bericht zur Epidemiologie der Influenza in Deutschland Saison 2017/18</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Robert Koch-Institut. Bericht zur Epidemiologie der Influenza in Deutschland Saison 2017/18. Berlin: RKI; 2018. DOI: 10.17886/rkipubl-2018-003</RefTotal>
<RefLink>https://doi.org/10.17886/rkipubl-2018-003</RefLink>
</Reference>
<Reference refNo="2">
<RefAuthor>Robert Koch-Institut</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2019</RefYear>
<RefBookTitle>Bericht zur Epidemiologie der Influenza in Deutschland Saison 2018/19</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Robert Koch-Institut. Bericht zur Epidemiologie der Influenza in Deutschland Saison 2018/19. Berlin: RKI; 2019. DOI: 10.25646/6232</RefTotal>
<RefLink>https://doi.org/10.25646/6232</RefLink>
</Reference>
<Reference refNo="3">
<RefAuthor>Robert Koch-Institut</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2016</RefYear>
<RefBookTitle>Influenza (Teil 1): Erkrankungen durch saisonale Influenzaviren – RKI-Ratgeber</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Robert Koch-Institut. Influenza (Teil 1): Erkrankungen durch saisonale Influenzaviren – RKI-Ratgeber. Berlin: RKI; 2016 [last updated 2016 Feb 12]. Available from: https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_Influenza_saisonal.html#doc2382022bodyText1</RefTotal>
<RefLink>https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_Influenza_saisonal.html#doc2382022bodyText1</RefLink>
</Reference>
<Reference refNo="4">
<RefAuthor>Suess T</RefAuthor>
<RefAuthor>Remschmidt C</RefAuthor>
<RefAuthor>Schink S</RefAuthor>
<RefAuthor>Luchtenberg M</RefAuthor>
<RefAuthor>Haas W</RefAuthor>
<RefAuthor>Krause G</RefAuthor>
<RefAuthor>Buchholz U</RefAuthor>
<RefTitle>Facemasks and intensified hand hygiene in a German household trial during the 2009/2010 influenza A(H1N1) pandemic: adherence and tolerability in children and adults</RefTitle>
<RefYear>2011</RefYear>
<RefJournal>Epidemiol Infect</RefJournal>
<RefPage>1895-901</RefPage>
<RefTotal>Suess T, Remschmidt C, Schink S, Luchtenberg M, Haas W, Krause G, Buchholz U. Facemasks and intensified hand hygiene in a German household trial during the 2009/2010 influenza A(H1N1) pandemic: adherence and tolerability in children and adults. Epidemiol Infect. 2011 Dec;139(12):1895-901. DOI: 10.1017/S0950268810003006</RefTotal>
<RefLink>https://doi.org/10.1017/S0950268810003006</RefLink>
</Reference>
<Reference refNo="5">
<RefAuthor>Hayden FG</RefAuthor>
<RefTitle>Pandemic influenza: is an antiviral response realistic?</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>Pediatr Infect Dis J</RefJournal>
<RefPage>S262-9</RefPage>
<RefTotal>Hayden FG. Pandemic influenza: is an antiviral response realistic? Pediatr Infect Dis J. 2004 Nov;23(11 Suppl):S262-9. DOI: 10.1097/01.inf.0000144680.39895.ce</RefTotal>
<RefLink>https://doi.org/10.1097/01.inf.0000144680.39895.ce</RefLink>
</Reference>
<Reference refNo="6">
<RefAuthor>Lehnert R</RefAuthor>
<RefAuthor>Pletz M</RefAuthor>
<RefAuthor>Reuss A</RefAuthor>
<RefAuthor>Schaberg T</RefAuthor>
<RefTitle>Antiviral Medications in Seasonal and Pandemic Influenza</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Dtsch Arztebl Int</RefJournal>
<RefPage>799-807</RefPage>
<RefTotal>Lehnert R, Pletz M, Reuss A, Schaberg T. Antiviral Medications in Seasonal and Pandemic Influenza. Dtsch Arztebl Int. 2016;113(47):799-807. DOI: 10.3238/arztebl.2016.0799</RefTotal>
<RefLink>https://doi.org/10.3238/arztebl.2016.0799</RefLink>
</Reference>
<Reference refNo="7">
<RefAuthor>Sugaya N</RefAuthor>
<RefTitle>Widespread use of neuraminidase inhibitors in Japan</RefTitle>
<RefYear>2011</RefYear>
<RefJournal>J Infect Chemother</RefJournal>
<RefPage>595-601</RefPage>
<RefTotal>Sugaya N. Widespread use of neuraminidase inhibitors in Japan. J Infect Chemother. 2011;17(5):595-601. DOI: 10.1007/s10156-011-0288-0</RefTotal>
<RefLink>https://doi.org/10.1007/s10156-011-0288-0</RefLink>
</Reference>
<Reference refNo="8">
<RefAuthor>Moscona A</RefAuthor>
<RefTitle>Oseltamivir resistance – disabling our influenza defenses</RefTitle>
<RefYear>2005</RefYear>
<RefJournal>N Engl J Med</RefJournal>
<RefPage>2633-6</RefPage>
<RefTotal>Moscona A. Oseltamivir resistance – disabling our influenza defenses. N Engl J Med. 2005 Dec;353(25):2633-6. DOI: 10.1056/NEJMp058291</RefTotal>
<RefLink>https://doi.org/10.1056/NEJMp058291</RefLink>
</Reference>
<Reference refNo="9">
<RefAuthor>Dunning J</RefAuthor>
<RefAuthor>Baillie JK</RefAuthor>
<RefAuthor>Cao B</RefAuthor>
<RefAuthor>Hayden FG</RefAuthor>
<RefAuthor> International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)</RefAuthor>
<RefTitle>Antiviral combinations for severe influenza</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Lancet Infect Dis</RefJournal>
<RefPage>1259-70</RefPage>
<RefTotal>Dunning J, Baillie JK, Cao B, Hayden FG; International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Antiviral combinations for severe influenza. Lancet Infect Dis. 2014 Dec;14(12):1259-70. DOI: 10.1016/S1473-3099(14)70821-7</RefTotal>
<RefLink>https://doi.org/10.1016/S1473-3099(14)70821-7</RefLink>
</Reference>
<Reference refNo="10">
<RefAuthor>Beigel JH</RefAuthor>
<RefAuthor>Bao Y</RefAuthor>
<RefAuthor>Beeler J</RefAuthor>
<RefAuthor>Manosuthi W</RefAuthor>
<RefAuthor>Slandzicki A</RefAuthor>
<RefAuthor>Dar SM</RefAuthor>
<RefAuthor>Panuto J</RefAuthor>
<RefAuthor>Beasley RL</RefAuthor>
<RefAuthor>Perez-Patrigeon S</RefAuthor>
<RefAuthor>Suwanpimolkul G</RefAuthor>
<RefAuthor>Losso MH</RefAuthor>
<RefAuthor>McClure N</RefAuthor>
<RefAuthor>Bozzolo DR</RefAuthor>
<RefAuthor>Myers C</RefAuthor>
<RefAuthor>Holley HP Jr</RefAuthor>
<RefAuthor>Hoopes J</RefAuthor>
<RefAuthor>Lane HC</RefAuthor>
<RefAuthor>Hughes MD</RefAuthor>
<RefAuthor>Davey RT</RefAuthor>
<RefAuthor> IRC003 Study Team</RefAuthor>
<RefTitle>Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial</RefTitle>
<RefYear>2017</RefYear>
<RefJournal>Lancet Infect Dis</RefJournal>
<RefPage>1255-65</RefPage>
<RefTotal>Beigel JH, Bao Y, Beeler J, Manosuthi W, Slandzicki A, Dar SM, Panuto J, Beasley RL, Perez-Patrigeon S, Suwanpimolkul G, Losso MH, McClure N, Bozzolo DR, Myers C, Holley HP Jr, Hoopes J, Lane HC, Hughes MD, Davey RT; IRC003 Study Team. Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial. Lancet Infect Dis. 2017 Dec;17(12):1255-65. DOI: 10.1016/S1473-3099(17)30476-0</RefTotal>
<RefLink>https://doi.org/10.1016/S1473-3099(17)30476-0</RefLink>
</Reference>
<Reference refNo="11">
<RefAuthor>Govorkova EA</RefAuthor>
<RefAuthor>Webster RG</RefAuthor>
<RefTitle>Combination chemotherapy for influenza</RefTitle>
<RefYear>2010</RefYear>
<RefJournal>Viruses</RefJournal>
<RefPage>1510-29</RefPage>
<RefTotal>Govorkova EA, Webster RG. Combination chemotherapy for influenza. Viruses. 2010;2(8):1510-29. DOI: 10.3390/v2081510</RefTotal>
<RefLink>https://doi.org/10.3390/v2081510</RefLink>
</Reference>
<Reference refNo="12">
<RefAuthor>Wang J</RefAuthor>
<RefAuthor>Pielak RM</RefAuthor>
<RefAuthor>McClintock MA</RefAuthor>
<RefAuthor>Chou JJ</RefAuthor>
<RefTitle>Solution structure and functional analysis of the influenza B proton channel</RefTitle>
<RefYear>2009</RefYear>
<RefJournal>Nat Struct Mol Biol</RefJournal>
<RefPage>1267-71</RefPage>
<RefTotal>Wang J, Pielak RM, McClintock MA, Chou JJ. Solution structure and functional analysis of the influenza B proton channel. Nat Struct Mol Biol. 2009 Dec;16(12):1267-71. DOI: 10.1038/nsmb.1707</RefTotal>
<RefLink>https://doi.org/10.1038/nsmb.1707</RefLink>
</Reference>
<Reference refNo="13">
<RefAuthor>Duwe S</RefAuthor>
<RefTitle>Influenza viruses – antiviral therapy and resistance</RefTitle>
<RefYear>2017</RefYear>
<RefJournal>GMS Infect Dis</RefJournal>
<RefPage>Doc04</RefPage>
<RefTotal>Duwe S. Influenza viruses – antiviral therapy and resistance. GMS Infect Dis. 2017 Apr;5:Doc04. DOI: 10.3205/id000030</RefTotal>
<RefLink>https://doi.org/10.3205/id000030</RefLink>
</Reference>
<Reference refNo="14">
<RefAuthor>Hurt A</RefAuthor>
<RefAuthor>Komadina N</RefAuthor>
<RefAuthor>Deng YM</RefAuthor>
<RefAuthor>Kaye M</RefAuthor>
<RefAuthor>Sullivan S</RefAuthor>
<RefAuthor>Subbarao K</RefAuthor>
<RefAuthor>Barr I</RefAuthor>
<RefTitle>Detection of adamantane-sensitive influenza A(H3N2) viruses in Australia, 2017: a cause for hope?</RefTitle>
<RefYear>2017</RefYear>
<RefJournal>Euro Surveill</RefJournal>
<RefPage>17-00731</RefPage>
<RefTotal>Hurt A, Komadina N, Deng YM, Kaye M, Sullivan S, Subbarao K, Barr I. Detection of adamantane-sensitive influenza A(H3N2) viruses in Australia, 2017: a cause for hope? Euro Surveill. 2017 Nov;22(47):17-00731. DOI: 10.2807/1560-7917.ES.2017.22.47.17-00731</RefTotal>
<RefLink>https://doi.org/10.2807/1560-7917.ES.2017.22.47.17-00731</RefLink>
</Reference>
<Reference refNo="15">
<RefAuthor>Matrosovich MN</RefAuthor>
<RefAuthor>Matrosovich TY</RefAuthor>
<RefAuthor>Gray T</RefAuthor>
<RefAuthor>Roberts NA</RefAuthor>
<RefAuthor>Klenk HD</RefAuthor>
<RefTitle>Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>J Virol</RefJournal>
<RefPage>12665-7</RefPage>
<RefTotal>Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol. 2004 Nov;78(22):12665-7. DOI: 10.1128/JVI.78.22.12665-12667.2004</RefTotal>
<RefLink>https://doi.org/10.1128/JVI.78.22.12665-12667.2004</RefLink>
</Reference>
<Reference refNo="16">
<RefAuthor>Moscona A</RefAuthor>
<RefTitle>Neuraminidase inhibitors for influenza</RefTitle>
<RefYear>2005</RefYear>
<RefJournal>N Engl J Med</RefJournal>
<RefPage>1363-73</RefPage>
<RefTotal>Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med. 2005 Sep;353(13):1363-73. DOI: 10.1056/NEJMra050740</RefTotal>
<RefLink>https://doi.org/10.1056/NEJMra050740</RefLink>
</Reference>
<Reference refNo="17">
<RefAuthor>Schmidtke M</RefAuthor>
<RefAuthor>Mertens T</RefAuthor>
<RefAuthor> Gesellschaft für Virologie e. V. (GfV)</RefAuthor>
<RefAuthor> Deutsche Vereinigung zur Bekämpfung der Viruskrankheiten e.V. (DVV)</RefAuthor>
<RefAuthor> Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG)</RefAuthor>
<RefTitle>Brauchen wir die Grippemittel Tamiflu und Relenza?</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>GMS Infect Dis</RefJournal>
<RefPage>Doc06</RefPage>
<RefTotal>Schmidtke M, Mertens T; Gesellschaft für Virologie e.V. (GfV); Deutsche Vereinigung zur Bekämpfung der Viruskrankheiten e.V. (DVV); Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG). Brauchen wir die Grippemittel Tamiflu und Relenza? GMS Infect Dis. 2014;2:Doc06. DOI: 10.3205/id000014</RefTotal>
<RefLink>https://doi.org/10.3205/id000014</RefLink>
</Reference>
<Reference refNo="18">
<RefAuthor>European Centre for Disease Prevention and Control</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2017</RefYear>
<RefBookTitle>Expert opinion on neuraminidase inhibitors for the prevention and treatment of influenza – Review of recent systematic reviews and meta-analyses</RefBookTitle>
<RefPage></RefPage>
<RefTotal>European Centre for Disease Prevention and Control. Expert opinion on neuraminidase inhibitors for the prevention and treatment of influenza – Review of recent systematic reviews and meta-analyses. Stockholm: ECDC; 2017. DOI: 10.2900/01723</RefTotal>
<RefLink>https://doi.org/10.2900/01723</RefLink>
</Reference>
<Reference refNo="19">
<RefAuthor>Deutscher Bundestag</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2014</RefYear>
<RefBookTitle>Antwort der Bundesregierung auf die Kleine Anfrage der Abgeordneten Kordula Schulz-Asche, Dr. Harald Terpe, Maria Klein-Schmeink, weiterer Abgeordneter und der Fraktion BÜNDNIS 90/ DIE GRÜNEN – Drucksache 18/1227 – Zweifel an der Wirksamkeit der Neuraminidasehemmer Tamiflu und Relenza</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Deutscher Bundestag. Antwort der Bundesregierung auf die Kleine Anfrage der Abgeordneten Kordula Schulz-Asche, Dr. Harald Terpe, Maria Klein-Schmeink, weiterer Abgeordneter und der Fraktion BÜNDNIS 90/ DIE GRÜNEN – Drucksache 18/1227 – Zweifel an der Wirksamkeit der Neuraminidasehemmer Tamiflu und Relenza. 2014 May 09. Available from: http://dipbt.bundestag.de/dip21/btd/18/013/1801384.pdf</RefTotal>
<RefLink>http://dipbt.bundestag.de/dip21/btd/18/013/1801384.pdf</RefLink>
</Reference>
<Reference refNo="20">
<RefAuthor>Hurt AC</RefAuthor>
<RefAuthor>Kelly H</RefAuthor>
<RefTitle>Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Emerg Infect Dis</RefJournal>
<RefPage>949-55</RefPage>
<RefTotal>Hurt AC, Kelly H. Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza. Emerg Infect Dis. 2016 Jun;22(6):949-55. DOI: 10.3201/eid2206.151037</RefTotal>
<RefLink>https://doi.org/10.3201/eid2206.151037</RefLink>
</Reference>
<Reference refNo="21">
<RefAuthor>European Medicines Agency</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2011</RefYear>
<RefBookTitle>Summary on compassionate use for iv zanamivir</RefBookTitle>
<RefPage></RefPage>
<RefTotal>European Medicines Agency. Summary on compassionate use for iv zanamivir. London: EMA; 2011 Jun 23. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/03/WC500104028.pdf</RefTotal>
<RefLink>http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/03/WC500104028.pdf</RefLink>
</Reference>
<Reference refNo="22">
<RefAuthor>European Medicines Agency</RefAuthor>
<RefTitle></RefTitle>
<RefYear></RefYear>
<RefBookTitle>Tamiflu oseltamivir</RefBookTitle>
<RefPage></RefPage>
<RefTotal>European Medicines Agency. Tamiflu oseltamivir. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/tamiflu</RefTotal>
<RefLink>https://www.ema.europa.eu/en/medicines/human/EPAR/tamiflu</RefLink>
</Reference>
<Reference refNo="23">
<RefAuthor>Mitchell R</RefAuthor>
<RefAuthor>Taylor G</RefAuthor>
<RefAuthor>McGeer A</RefAuthor>
<RefAuthor>Frenette C</RefAuthor>
<RefAuthor>Suh KN</RefAuthor>
<RefAuthor>Wong A</RefAuthor>
<RefAuthor>Katz K</RefAuthor>
<RefAuthor>Wilkinson K</RefAuthor>
<RefAuthor>Amihod B</RefAuthor>
<RefAuthor>Gravel D</RefAuthor>
<RefAuthor> Canadian Nosocomial Infection Surveillance Program</RefAuthor>
<RefTitle>Understanding the burden of influenza infection among adults in Canadian hospitals: a comparison of the 2009–2010 pandemic season with the prepandemic and postpandemic seasons</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Am J Infect Control</RefJournal>
<RefPage>1032-7</RefPage>
<RefTotal>Mitchell R, Taylor G, McGeer A, Frenette C, Suh KN, Wong A, Katz K, Wilkinson K, Amihod B, Gravel D; Canadian Nosocomial Infection Surveillance Program. Understanding the burden of influenza infection among adults in Canadian hospitals: a comparison of the 2009–2010 pandemic season with the prepandemic and postpandemic seasons. Am J Infect Control. 2013 Nov;41(11):1032-7. DOI: 10.1016/j.ajic.2013.06.008</RefTotal>
<RefLink>https://doi.org/10.1016/j.ajic.2013.06.008</RefLink>
</Reference>
<Reference refNo="24">
<RefAuthor>Taylor G</RefAuthor>
<RefAuthor>Mitchell R</RefAuthor>
<RefAuthor>McGeer A</RefAuthor>
<RefAuthor>Frenette C</RefAuthor>
<RefAuthor>Suh KN</RefAuthor>
<RefAuthor>Wong A</RefAuthor>
<RefAuthor>Katz K</RefAuthor>
<RefAuthor>Wilkinson K</RefAuthor>
<RefAuthor>Amihod B</RefAuthor>
<RefAuthor>Gravel D</RefAuthor>
<RefAuthor> Canadian Nosocomial Infection Surveillance Program</RefAuthor>
<RefTitle>Healthcare-associated influenza in Canadian hospitals from 2006 to 2012</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Infect Control Hosp Epidemiol</RefJournal>
<RefPage>169-75</RefPage>
<RefTotal>Taylor G, Mitchell R, McGeer A, Frenette C, Suh KN, Wong A, Katz K, Wilkinson K, Amihod B, Gravel D; Canadian Nosocomial Infection Surveillance Program. Healthcare-associated influenza in Canadian hospitals from 2006 to 2012. Infect Control Hosp Epidemiol. 2014 Feb;35(2):169-75. DOI: 10.1086/674858</RefTotal>
<RefLink>https://doi.org/10.1086/674858</RefLink>
</Reference>
<Reference refNo="25">
<RefAuthor>Khandaker G</RefAuthor>
<RefAuthor>Rashid H</RefAuthor>
<RefAuthor>Zurynski Y</RefAuthor>
<RefAuthor>Richmond PC</RefAuthor>
<RefAuthor>Buttery J</RefAuthor>
<RefAuthor>Marshall H</RefAuthor>
<RefAuthor>Gold M</RefAuthor>
<RefAuthor>Walls T</RefAuthor>
<RefAuthor>Whitehead B</RefAuthor>
<RefAuthor>Elliott EJ</RefAuthor>
<RefAuthor>Booy R</RefAuthor>
<RefTitle>Nosocomial vs community-acquired pandemic influenza A (H1N1) 2009: a nested case-control study</RefTitle>
<RefYear>2012</RefYear>
<RefJournal>J Hosp Infect</RefJournal>
<RefPage>94-100</RefPage>
<RefTotal>Khandaker G, Rashid H, Zurynski Y, Richmond PC, Buttery J, Marshall H, Gold M, Walls T, Whitehead B, Elliott EJ, Booy R. Nosocomial vs community-acquired pandemic influenza A (H1N1) 2009: a nested case-control study. J Hosp Infect. 2012 Oct;82(2):94-100. DOI: 10.1016/j.jhin.2012.07.006</RefTotal>
<RefLink>https://doi.org/10.1016/j.jhin.2012.07.006</RefLink>
</Reference>
<Reference refNo="26">
<RefAuthor>Macesic N</RefAuthor>
<RefAuthor>Kotsimbos TC</RefAuthor>
<RefAuthor>Kelly P</RefAuthor>
<RefAuthor>Cheng AC</RefAuthor>
<RefTitle>Hospital-acquired influenza in an Australian sentinel surveillance system</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Med J Aust</RefJournal>
<RefPage>370-2</RefPage>
<RefTotal>Macesic N, Kotsimbos TC, Kelly P, Cheng AC. Hospital-acquired influenza in an Australian sentinel surveillance system. Med J Aust. 2013 Apr;198(7):370-2. DOI: 10.5694/mja12.11687</RefTotal>
<RefLink>https://doi.org/10.5694/mja12.11687</RefLink>
</Reference>
<Reference refNo="27">
<RefAuthor>Jhung MA</RefAuthor>
<RefAuthor>D’Mello T</RefAuthor>
<RefAuthor>Pérez A</RefAuthor>
<RefAuthor>Aragon D</RefAuthor>
<RefAuthor>Bennett NM</RefAuthor>
<RefAuthor>Cooper T</RefAuthor>
<RefAuthor>Farley MM</RefAuthor>
<RefAuthor>Fowler B</RefAuthor>
<RefAuthor>Grube SM</RefAuthor>
<RefAuthor>Hancock EB</RefAuthor>
<RefAuthor>Lynfield R</RefAuthor>
<RefAuthor>Morin C</RefAuthor>
<RefAuthor>Reingold A</RefAuthor>
<RefAuthor>Ryan P</RefAuthor>
<RefAuthor>Schaffner W</RefAuthor>
<RefAuthor>Sharangpani R</RefAuthor>
<RefAuthor>Tengelsen L</RefAuthor>
<RefAuthor>Thomas A</RefAuthor>
<RefAuthor>Thurston D</RefAuthor>
<RefAuthor>Yousey-Hindes K</RefAuthor>
<RefAuthor>Zansky S</RefAuthor>
<RefAuthor>Finelli L</RefAuthor>
<RefAuthor>Chaves SS</RefAuthor>
<RefTitle>Hospital-onset influenza hospitalizations – United States, 2010–2011</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Am J Infect Control</RefJournal>
<RefPage>7-11</RefPage>
<RefTotal>Jhung MA, D’Mello T, Pérez A, Aragon D, Bennett NM, Cooper T, Farley MM, Fowler B, Grube SM, Hancock EB, Lynfield R, Morin C, Reingold A, Ryan P, Schaffner W, Sharangpani R, Tengelsen L, Thomas A, Thurston D, Yousey-Hindes K, Zansky S, Finelli L, Chaves SS. Hospital-onset influenza hospitalizations – United States, 2010–2011. Am J Infect Control. 2014 Jan;42(1):7-11. DOI: 10.1016/j.ajic.2013.06.018</RefTotal>
<RefLink>https://doi.org/10.1016/j.ajic.2013.06.018</RefLink>
</Reference>
<Reference refNo="28">
<RefAuthor>Giannella M</RefAuthor>
<RefAuthor>Rodríguez-Sánchez B</RefAuthor>
<RefAuthor>Roa PL</RefAuthor>
<RefAuthor>Catalán P</RefAuthor>
<RefAuthor>Muñoz P</RefAuthor>
<RefAuthor>García de Viedma D</RefAuthor>
<RefAuthor>Bouza E</RefAuthor>
<RefAuthor> the Gregorio Marañón Task Force for Pneumonia (GANG)</RefAuthor>
<RefTitle>Should lower respiratory tract secretions from intensive care patients be systematically screened for influenza virus during the influenza season?</RefTitle>
<RefYear>2012</RefYear>
<RefJournal>Crit Care</RefJournal>
<RefPage>R104</RefPage>
<RefTotal>Giannella M, Rodríguez-Sánchez B, Roa PL, Catalán P, Muñoz P, García de Viedma D, Bouza E; the Gregorio Marañón Task Force for Pneumonia (GANG). Should lower respiratory tract secretions from intensive care patients be systematically screened for influenza virus during the influenza season? Crit Care. 2012;16(3):R104. DOI: 10.1186/cc11387</RefTotal>
<RefLink>https://doi.org/10.1186/cc11387</RefLink>
</Reference>
<Reference refNo="29">
<RefAuthor>Bischoff W</RefAuthor>
<RefAuthor>Russell G</RefAuthor>
<RefAuthor>Willard E</RefAuthor>
<RefAuthor>Stehle J Jr</RefAuthor>
<RefTitle>Impact of a novel mobile high-efficiency particulate air-ultraviolet air recirculation system on the bacterial air burden during routine care</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Am J Infect Control</RefJournal>
<RefPage>1025-7</RefPage>
<RefTotal>Bischoff W, Russell G, Willard E, Stehle J Jr. Impact of a novel mobile high-efficiency particulate air-ultraviolet air recirculation system on the bacterial air burden during routine care. Am J Infect Control. 2019 Aug;47(8):1025-7. DOI: 10.1016/j.ajic.2018.12.019</RefTotal>
<RefLink>https://doi.org/10.1016/j.ajic.2018.12.019</RefLink>
</Reference>
<Reference refNo="30">
<RefAuthor>Mombelli M</RefAuthor>
<RefAuthor>Lang BM</RefAuthor>
<RefAuthor>Neofytos D</RefAuthor>
<RefAuthor>Aubert JD</RefAuthor>
<RefAuthor>Benden C</RefAuthor>
<RefAuthor>Berger C</RefAuthor>
<RefAuthor>Boggian K</RefAuthor>
<RefAuthor>Egli A</RefAuthor>
<RefAuthor>Soccal PM</RefAuthor>
<RefAuthor>Kaiser L</RefAuthor>
<RefAuthor>Hirzel C</RefAuthor>
<RefAuthor>Pascual M</RefAuthor>
<RefAuthor>Koller M</RefAuthor>
<RefAuthor>Mueller NJ</RefAuthor>
<RefAuthor>van Delden C</RefAuthor>
<RefAuthor>Hirsch HH</RefAuthor>
<RefAuthor>Manuel O</RefAuthor>
<RefAuthor> Swiss Transplant Cohort Study</RefAuthor>
<RefTitle>Burden, epidemiology, and outcomes of microbiologically confirmed respiratory viral infections in solid organ transplant recipients – a nationwide, multi-season prospective cohort study</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>Am J Transplant</RefJournal>
<RefPage></RefPage>
<RefTotal>Mombelli M, Lang BM, Neofytos D, Aubert JD, Benden C, Berger C, Boggian K, Egli A, Soccal PM, Kaiser L, Hirzel C, Pascual M, Koller M, Mueller NJ, van Delden C, Hirsch HH, Manuel O; Swiss Transplant Cohort Study. Burden, epidemiology, and outcomes of microbiologically confirmed respiratory viral infections in solid organ transplant recipients – a nationwide, multi-season prospective cohort study. Am J Transplant. 2020 Oct 31. DOI: 10.1111/ajt.16383</RefTotal>
<RefLink>https://doi.org/10.1111/ajt.16383</RefLink>
</Reference>
<Reference refNo="31">
<RefAuthor>Hayden FG</RefAuthor>
<RefAuthor>Treanor JJ</RefAuthor>
<RefAuthor>Fritz RS</RefAuthor>
<RefAuthor>Lobo M</RefAuthor>
<RefAuthor>Betts RF</RefAuthor>
<RefAuthor>Miller M</RefAuthor>
<RefAuthor>Kinnersley N</RefAuthor>
<RefAuthor>Mills RG</RefAuthor>
<RefAuthor>Ward P</RefAuthor>
<RefAuthor>Straus SE</RefAuthor>
<RefTitle>Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment</RefTitle>
<RefYear>1999</RefYear>
<RefJournal>JAMA</RefJournal>
<RefPage>1240-6</RefPage>
<RefTotal>Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M, Kinnersley N, Mills RG, Ward P, Straus SE. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. 1999 Oct;282(13):1240-6. DOI: 10.1001/jama.282.13.1240</RefTotal>
<RefLink>https://doi.org/10.1001/jama.282.13.1240</RefLink>
</Reference>
<Reference refNo="32">
<RefAuthor>Doll MK</RefAuthor>
<RefAuthor>Winters N</RefAuthor>
<RefAuthor>Boikos C</RefAuthor>
<RefAuthor>Kraicer-Melamed H</RefAuthor>
<RefAuthor>Gore G</RefAuthor>
<RefAuthor>Quach C</RefAuthor>
<RefTitle>Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses</RefTitle>
<RefYear>2017</RefYear>
<RefJournal>J Antimicrob Chemother</RefJournal>
<RefPage>2990-3007</RefPage>
<RefTotal>Doll MK, Winters N, Boikos C, Kraicer-Melamed H, Gore G, Quach C. Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses. J Antimicrob Chemother. 2017 Nov;72(11):2990-3007. DOI: 10.1093/jac/dkx271</RefTotal>
<RefLink>https://doi.org/10.1093/jac/dkx271</RefLink>
</Reference>
<Reference refNo="33">
<RefAuthor>Jefferson T</RefAuthor>
<RefAuthor>Jones MA</RefAuthor>
<RefAuthor>Doshi P</RefAuthor>
<RefAuthor>Del Mar CB</RefAuthor>
<RefAuthor>Hama R</RefAuthor>
<RefAuthor>Thompson MJ</RefAuthor>
<RefAuthor>Spencer EA</RefAuthor>
<RefAuthor>Onakpoya I</RefAuthor>
<RefAuthor>Mahtani KR</RefAuthor>
<RefAuthor>Nunan D</RefAuthor>
<RefAuthor>Howick J</RefAuthor>
<RefAuthor>Heneghan CJ</RefAuthor>
<RefTitle>Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Cochrane Database Syst Rev</RefJournal>
<RefPage>CD008965</RefPage>
<RefTotal>Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014 Apr;2014(4):CD008965. DOI: 10.1002/14651858.CD008965.pub4</RefTotal>
<RefLink>https://doi.org/10.1002/14651858.CD008965.pub4</RefLink>
</Reference>
<Reference refNo="34">
<RefAuthor>Mizumoto K</RefAuthor>
<RefAuthor>Nishiura H</RefAuthor>
<RefAuthor>Yamamoto T</RefAuthor>
<RefTitle>Effectiveness of antiviral prophylaxis coupled with contact tracing in reducing the transmission of the influenza A (H1N1-2009): a systematic review</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Theor Biol Med Model</RefJournal>
<RefPage>4</RefPage>
<RefTotal>Mizumoto K, Nishiura H, Yamamoto T. Effectiveness of antiviral prophylaxis coupled with contact tracing in reducing the transmission of the influenza A (H1N1-2009): a systematic review. Theor Biol Med Model. 2013 Jan;10:4. DOI: 10.1186/1742-4682-10-4</RefTotal>
<RefLink>https://doi.org/10.1186/1742-4682-10-4</RefLink>
</Reference>
<Reference refNo="35">
<RefAuthor>Bowles SK</RefAuthor>
<RefAuthor>Lee W</RefAuthor>
<RefAuthor>Simor AE</RefAuthor>
<RefAuthor>Vearncombe M</RefAuthor>
<RefAuthor>Loeb M</RefAuthor>
<RefAuthor>Tamblyn S</RefAuthor>
<RefAuthor>Fearon M</RefAuthor>
<RefAuthor>Li Y</RefAuthor>
<RefAuthor>McGeer A</RefAuthor>
<RefAuthor> Oseltamivir Compassionate Use Program Group</RefAuthor>
<RefTitle>Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999–2000</RefTitle>
<RefYear>2002</RefYear>
<RefJournal>J Am Geriatr Soc</RefJournal>
<RefPage>608-16</RefPage>
<RefTotal>Bowles SK, Lee W, Simor AE, Vearncombe M, Loeb M, Tamblyn S, Fearon M, Li Y, McGeer A; Oseltamivir Compassionate Use Program Group. Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999–2000. J Am Geriatr Soc. 2002 Apr;50(4):608-16. DOI: 10.1046/j.1532-5415.2002.50153.x</RefTotal>
<RefLink>https://doi.org/10.1046/j.1532-5415.2002.50153.x</RefLink>
</Reference>
<Reference refNo="36">
<RefAuthor>Hagihara M</RefAuthor>
<RefAuthor>Kato Y</RefAuthor>
<RefAuthor>Kurumiya A</RefAuthor>
<RefAuthor>Takahashi T</RefAuthor>
<RefAuthor>Sakata M</RefAuthor>
<RefAuthor>Kato H</RefAuthor>
<RefAuthor>Sakanashi D</RefAuthor>
<RefAuthor>Yamada A</RefAuthor>
<RefAuthor>Suematsu H</RefAuthor>
<RefAuthor>Hirai J</RefAuthor>
<RefAuthor>Nishiyama N</RefAuthor>
<RefAuthor>Koizumi Y</RefAuthor>
<RefAuthor>Yamagishi Y</RefAuthor>
<RefAuthor>Mikamo H</RefAuthor>
<RefTitle>The Prophylactic Effect of Anti-influenza Agents for an Influenza Outbreak in a University Hospital</RefTitle>
<RefYear>2018</RefYear>
<RefJournal>Intern Med</RefJournal>
<RefPage>497-501</RefPage>
<RefTotal>Hagihara M, Kato Y, Kurumiya A, Takahashi T, Sakata M, Kato H, Sakanashi D, Yamada A, Suematsu H, Hirai J, Nishiyama N, Koizumi Y, Yamagishi Y, Mikamo H. The Prophylactic Effect of Anti-influenza Agents for an Influenza Outbreak in a University Hospital. Intern Med. 2018;57(4):497-501. DOI: 10.2169/internalmedicine.8854-17</RefTotal>
<RefLink>https://doi.org/10.2169/internalmedicine.8854-17</RefLink>
</Reference>
<Reference refNo="37">
<RefAuthor>Asiedu-Bekoe F</RefAuthor>
<RefAuthor>Adu DA</RefAuthor>
<RefAuthor>Offei A</RefAuthor>
<RefTitle>Mass oseltamivir prophylaxis halts pandemic influenza A H1N1 2009 outbreak in a secondary school in Ashanti Region, Ghana</RefTitle>
<RefYear>2012</RefYear>
<RefJournal>Ghana Med J</RefJournal>
<RefPage>219-24</RefPage>
<RefTotal>Asiedu-Bekoe F, Adu DA, Offei A. Mass oseltamivir prophylaxis halts pandemic influenza A H1N1 2009 outbreak in a secondary school in Ashanti Region, Ghana. Ghana Med J. 2012 Dec;46(4):219-24.</RefTotal>
</Reference>
<Reference refNo="38">
<RefAuthor>Eisenberg RA</RefAuthor>
<RefAuthor>Jawad AF</RefAuthor>
<RefAuthor>Boyer J</RefAuthor>
<RefAuthor>Maurer K</RefAuthor>
<RefAuthor>McDonald K</RefAuthor>
<RefAuthor>Prak ET</RefAuthor>
<RefAuthor>Sullivan KE</RefAuthor>
<RefTitle>Rituximab-treated patients have a poor response to influenza vaccination</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>J Clin Immunol</RefJournal>
<RefPage>388-96</RefPage>
<RefTotal>Eisenberg RA, Jawad AF, Boyer J, Maurer K, McDonald K, Prak ET, Sullivan KE. Rituximab-treated patients have a poor response to influenza vaccination. J Clin Immunol. 2013 Feb;33(2):388-96. DOI: 10.1007/s10875-012-9813-x</RefTotal>
<RefLink>https://doi.org/10.1007/s10875-012-9813-x</RefLink>
</Reference>
<Reference refNo="39">
<RefAuthor>Gärtner BC</RefAuthor>
<RefAuthor>Avery RK</RefAuthor>
<RefTitle>Respiratory viral infections in solid organ transplant recipients – New insights from multicenter data</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>Am J Transplant</RefJournal>
<RefPage></RefPage>
<RefTotal>Gärtner BC, Avery RK. Respiratory viral infections in solid organ transplant recipients – New insights from multicenter data. Am J Transplant. 2020 Nov 21. DOI: 10.1111/ajt.16408</RefTotal>
<RefLink>https://doi.org/10.1111/ajt.16408</RefLink>
</Reference>
<Reference refNo="40">
<RefAuthor>Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus</RefAuthor>
<RefAuthor>Abdel-Ghafar AN</RefAuthor>
<RefAuthor>Chotpitayasunondh T</RefAuthor>
<RefAuthor>Gao Z</RefAuthor>
<RefAuthor>Hayden FG</RefAuthor>
<RefAuthor>Nguyen DH</RefAuthor>
<RefAuthor>de Jong MD</RefAuthor>
<RefAuthor>Naghdaliyev A</RefAuthor>
<RefAuthor>Peiris JS</RefAuthor>
<RefAuthor>Shindo N</RefAuthor>
<RefAuthor>Soeroso S</RefAuthor>
<RefAuthor>Uyeki TM</RefAuthor>
<RefTitle>Update on avian influenza A (H5N1) virus infection in humans</RefTitle>
<RefYear>2008</RefYear>
<RefJournal>N Engl J Med</RefJournal>
<RefPage>261-73</RefPage>
<RefTotal>Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus, Abdel-Ghafar AN, Chotpitayasunondh T, Gao Z, Hayden FG, Nguyen DH, de Jong MD, Naghdaliyev A, Peiris JS, Shindo N, Soeroso S, Uyeki TM. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med. 2008 Jan;358(3):261-73. DOI: 10.1056/NEJMra0707279</RefTotal>
<RefLink>https://doi.org/10.1056/NEJMra0707279</RefLink>
</Reference>
<Reference refNo="41">
<RefAuthor>Oxford JS</RefAuthor>
<RefTitle>Zanamivir (Glaxo Wellcome)</RefTitle>
<RefYear>2000</RefYear>
<RefJournal>IDrugs</RefJournal>
<RefPage>447-59</RefPage>
<RefTotal>Oxford JS. Zanamivir (Glaxo Wellcome). IDrugs. 2000 Apr;3(4):447-59.</RefTotal>
</Reference>
<Reference refNo="42">
<RefAuthor>European Medicines Agency</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2018</RefYear>
<RefBookTitle>Alpivab Peramivir</RefBookTitle>
<RefPage></RefPage>
<RefTotal>European Medicines Agency. Alpivab Peramivir. Amsterdam: EMA; 2018 [last updated 2020 Dec 09]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/alpivab</RefTotal>
<RefLink>https://www.ema.europa.eu/en/medicines/human/EPAR/alpivab</RefLink>
</Reference>
<Reference refNo="43">
<RefAuthor>European Medicines Agency</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2019</RefYear>
<RefBookTitle>Dectova Zanamivir</RefBookTitle>
<RefPage></RefPage>
<RefTotal>European Medicines Agency. Dectova Zanamivir. Amsterdam: EMA; 2019. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/dectova</RefTotal>
<RefLink>https://www.ema.europa.eu/en/medicines/human/EPAR/dectova</RefLink>
</Reference>
<Reference refNo="44">
<RefAuthor>BioCryst</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2020</RefYear>
<RefBookTitle>Ravipab: Peramivir injection</RefBookTitle>
<RefPage></RefPage>
<RefTotal>BioCryst. Ravipab: Peramivir injection. 2020. Available from: http://www.rapivab.com</RefTotal>
<RefLink>http://www.rapivab.com</RefLink>
</Reference>
<Reference refNo="45">
<RefAuthor>Alame MM</RefAuthor>
<RefAuthor>Massaad E</RefAuthor>
<RefAuthor>Zaraket H</RefAuthor>
<RefTitle>Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza Infections</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Front Microbiol</RefJournal>
<RefPage>450</RefPage>
<RefTotal>Alame MM, Massaad E, Zaraket H. Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza Infections. Front Microbiol. 2016 Mar;7:450. DOI: 10.3389/fmicb.2016.00450</RefTotal>
<RefLink>https://doi.org/10.3389/fmicb.2016.00450</RefLink>
</Reference>
<Reference refNo="46">
<RefAuthor>Hideyuki Ikematsu</RefAuthor>
<RefAuthor>Naoki Kawai</RefAuthor>
<RefTitle>Laninamivir octanoate: a new long-acting neuraminidase inhibitor for the treatment of influenza</RefTitle>
<RefYear>2011</RefYear>
<RefJournal>Expert Rev Anti Infect Ther</RefJournal>
<RefPage>851-7</RefPage>
<RefTotal>Hideyuki Ikematsu, Naoki Kawai. Laninamivir octanoate: a new long-acting neuraminidase inhibitor for the treatment of influenza. Expert Rev Anti Infect Ther. 2011 Oct;9(10):851-7. DOI: 10.1586/eri.11.112</RefTotal>
<RefLink>https://doi.org/10.1586/eri.11.112</RefLink>
</Reference>
<Reference refNo="47">
<RefAuthor>Watanabe A</RefAuthor>
<RefAuthor>Chang SC</RefAuthor>
<RefAuthor>Kim MJ</RefAuthor>
<RefAuthor>Chu DW</RefAuthor>
<RefAuthor>Ohashi Y</RefAuthor>
<RefAuthor> MARVEL Study Group</RefAuthor>
<RefTitle>Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial</RefTitle>
<RefYear>2010</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>1167-75</RefPage>
<RefTotal>Watanabe A, Chang SC, Kim MJ, Chu DW, Ohashi Y; MARVEL Study Group. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial. Clin Infect Dis. 2010 Nov;51(10):1167-75. DOI: 10.1086/656802</RefTotal>
<RefLink>https://doi.org/10.1086/656802</RefLink>
</Reference>
<Reference refNo="48">
<RefAuthor>Sugaya N</RefAuthor>
<RefAuthor>Ohashi Y</RefAuthor>
<RefTitle>Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection</RefTitle>
<RefYear>2010</RefYear>
<RefJournal>Antimicrob Agents Chemother</RefJournal>
<RefPage>2575-82</RefPage>
<RefTotal>Sugaya N, Ohashi Y. Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection. Antimicrob Agents Chemother. 2010 Jun;54(6):2575-82. DOI: 10.1128/AAC.01755-09</RefTotal>
<RefLink>https://doi.org/10.1128/AAC.01755-09</RefLink>
</Reference>
<Reference refNo="49">
<RefAuthor>WHO</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2018</RefYear>
<RefBookTitle>Practical guidance for national influenza centres establishing or implementing neuraminidase inhibitor susceptibility surveillance</RefBookTitle>
<RefPage></RefPage>
<RefTotal>WHO. Practical guidance for national influenza centres establishing or implementing neuraminidase inhibitor susceptibility surveillance. Update 2018. Geneva: WHO; 2018. Available from: http://www.who.int/influenza/gisrs_laboratory/antiviral_susceptibility/practical_guidance/en/</RefTotal>
<RefLink>http://www.who.int/influenza/gisrs_laboratory/antiviral_susceptibility/practical_guidance/en/</RefLink>
</Reference>
<Reference refNo="50">
<RefAuthor>Oh DY</RefAuthor>
<RefAuthor>Hurt AC</RefAuthor>
<RefTitle>A Review of the Antiviral Susceptibility of Human and Avian Influenza Viruses over the Last Decade</RefTitle>
<RefYear>2014</RefYear>
<RefJournal>Scientifica (Cairo)</RefJournal>
<RefPage>430629</RefPage>
<RefTotal>Oh DY, Hurt AC. A Review of the Antiviral Susceptibility of Human and Avian Influenza Viruses over the Last Decade. Scientifica (Cairo). 2014;2014:430629. DOI: 10.1155/2014/430629</RefTotal>
<RefLink>https://doi.org/10.1155/2014/430629</RefLink>
</Reference>
<Reference refNo="51">
<RefAuthor>Lackenby A</RefAuthor>
<RefAuthor>Besselaar TG</RefAuthor>
<RefAuthor>Daniels RS</RefAuthor>
<RefAuthor>Fry A</RefAuthor>
<RefAuthor>Gregory V</RefAuthor>
<RefAuthor>Gubareva LV</RefAuthor>
<RefAuthor>Huang W</RefAuthor>
<RefAuthor>Hurt AC</RefAuthor>
<RefAuthor>Leang SK</RefAuthor>
<RefAuthor>Lee RTC</RefAuthor>
<RefAuthor>Lo J</RefAuthor>
<RefAuthor>Lollis L</RefAuthor>
<RefAuthor>Maurer-Stroh S</RefAuthor>
<RefAuthor>Odagiri T</RefAuthor>
<RefAuthor>Pereyaslov D</RefAuthor>
<RefAuthor>Takashita E</RefAuthor>
<RefAuthor>Wang D</RefAuthor>
<RefAuthor>Zhang W</RefAuthor>
<RefAuthor>Meijer A</RefAuthor>
<RefTitle>Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016–2017</RefTitle>
<RefYear>2018</RefYear>
<RefJournal>Antiviral Res</RefJournal>
<RefPage>38-46</RefPage>
<RefTotal>Lackenby A, Besselaar TG, Daniels RS, Fry A, Gregory V, Gubareva LV, Huang W, Hurt AC, Leang SK, Lee RTC, Lo J, Lollis L, Maurer-Stroh S, Odagiri T, Pereyaslov D, Takashita E, Wang D, Zhang W, Meijer A. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016–2017. Antiviral Res. 2018 Sep;157:38-46. DOI: 10.1016/j.antiviral.2018.07.001</RefTotal>
<RefLink>https://doi.org/10.1016/j.antiviral.2018.07.001</RefLink>
</Reference>
<Reference refNo="52">
<RefAuthor>European Medicines Agency</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2021</RefYear>
<RefBookTitle>Xofluza (baloxavir marboxil) – EMA/648596/2020</RefBookTitle>
<RefPage></RefPage>
<RefTotal>European Medicines Agency. Xofluza (baloxavir marboxil) – EMA/648596/2020. Amsterdam: EMA; 2021. Available from: https://www.ema.europa.eu/en/documents/overview/xofluza-epar-medicine-overview_en.pdf</RefTotal>
<RefLink>https://www.ema.europa.eu/en/documents/overview/xofluza-epar-medicine-overview_en.pdf</RefLink>
</Reference>
<Reference refNo="53">
<RefAuthor>Kawaguchi N</RefAuthor>
<RefAuthor>Koshimichi H</RefAuthor>
<RefAuthor>Ishibashi T</RefAuthor>
<RefAuthor>Wajima T</RefAuthor>
<RefTitle>Evaluation of Drug-Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects</RefTitle>
<RefYear>2018</RefYear>
<RefJournal>Clin Drug Investig</RefJournal>
<RefPage>1053-60</RefPage>
<RefTotal>Kawaguchi N, Koshimichi H, Ishibashi T, Wajima T. Evaluation of Drug-Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects. Clin Drug Investig. 2018 Nov;38(11):1053-60. DOI: 10.1007/s40261-018-0697-2</RefTotal>
<RefLink>https://doi.org/10.1007/s40261-018-0697-2</RefLink>
</Reference>
<Reference refNo="54">
<RefAuthor>Noshi T</RefAuthor>
<RefAuthor>Kitano M</RefAuthor>
<RefAuthor>Taniguchi K</RefAuthor>
<RefAuthor>Yamamoto A</RefAuthor>
<RefAuthor>Omoto S</RefAuthor>
<RefAuthor>Baba K</RefAuthor>
<RefAuthor>Hashimoto T</RefAuthor>
<RefAuthor>Ishida K</RefAuthor>
<RefAuthor>Kushima Y</RefAuthor>
<RefAuthor>Hattori K</RefAuthor>
<RefAuthor>Kawai M</RefAuthor>
<RefAuthor>Yoshida R</RefAuthor>
<RefAuthor>Kobayashi M</RefAuthor>
<RefAuthor>Yoshinaga T</RefAuthor>
<RefAuthor>Sato A</RefAuthor>
<RefAuthor>Okamatsu M</RefAuthor>
<RefAuthor>Sakoda Y</RefAuthor>
<RefAuthor>Kida H</RefAuthor>
<RefAuthor>Shishido T</RefAuthor>
<RefAuthor>Naito A</RefAuthor>
<RefTitle>In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit</RefTitle>
<RefYear>2018</RefYear>
<RefJournal>Antiviral Res</RefJournal>
<RefPage>109-17</RefPage>
<RefTotal>Noshi T, Kitano M, Taniguchi K, Yamamoto A, Omoto S, Baba K, Hashimoto T, Ishida K, Kushima Y, Hattori K, Kawai M, Yoshida R, Kobayashi M, Yoshinaga T, Sato A, Okamatsu M, Sakoda Y, Kida H, Shishido T, Naito A. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res. 2018 Dec;160:109-17. DOI: 10.1016/j.antiviral.2018.10.008</RefTotal>
<RefLink>https://doi.org/10.1016/j.antiviral.2018.10.008</RefLink>
</Reference>
<Reference refNo="55">
<RefAuthor>Hayden FG</RefAuthor>
<RefAuthor>Sugaya N</RefAuthor>
<RefAuthor>Hirotsu N</RefAuthor>
<RefAuthor>Lee N</RefAuthor>
<RefAuthor>de Jong MD</RefAuthor>
<RefAuthor>Hurt AC</RefAuthor>
<RefAuthor>Ishida T</RefAuthor>
<RefAuthor>Sekino H</RefAuthor>
<RefAuthor>Yamada K</RefAuthor>
<RefAuthor>Portsmouth S</RefAuthor>
<RefAuthor>Kawaguchi K</RefAuthor>
<RefAuthor>Shishido T</RefAuthor>
<RefAuthor>Arai M</RefAuthor>
<RefAuthor>Tsuchiya K</RefAuthor>
<RefAuthor>Uehara T</RefAuthor>
<RefAuthor>Watanabe A</RefAuthor>
<RefAuthor> Baloxavir Marboxil Investigators Group</RefAuthor>
<RefTitle>Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents</RefTitle>
<RefYear>2018</RefYear>
<RefJournal>N Engl J Med</RefJournal>
<RefPage>913-23</RefPage>
<RefTotal>Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A; Baloxavir Marboxil Investigators Group. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 Sep;379(10):913-23. DOI: 10.1056/NEJMoa1716197</RefTotal>
<RefLink>https://doi.org/10.1056/NEJMoa1716197</RefLink>
</Reference>
<Reference refNo="56">
<RefAuthor>Uehara T</RefAuthor>
<RefAuthor>Hayden FG</RefAuthor>
<RefAuthor>Kawaguchi K</RefAuthor>
<RefAuthor>Omoto S</RefAuthor>
<RefAuthor>Hurt AC</RefAuthor>
<RefAuthor>De Jong MD</RefAuthor>
<RefAuthor>Hirotsu N</RefAuthor>
<RefAuthor>Sugaya N</RefAuthor>
<RefAuthor>Lee N</RefAuthor>
<RefAuthor>Baba K</RefAuthor>
<RefAuthor>Shishido T</RefAuthor>
<RefAuthor>Tsuchiya K</RefAuthor>
<RefAuthor>Portsmouth S</RefAuthor>
<RefAuthor>Kida H</RefAuthor>
<RefTitle>Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>J Infect Dis</RefJournal>
<RefPage>346-55</RefPage>
<RefTotal>Uehara T, Hayden FG, Kawaguchi K, Omoto S, Hurt AC, De Jong MD, Hirotsu N, Sugaya N, Lee N, Baba K, Shishido T, Tsuchiya K, Portsmouth S, Kida H. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis. 2020 Jan;221(3):346-55. DOI: 10.1093/infdis/jiz244</RefTotal>
<RefLink>https://doi.org/10.1093/infdis/jiz244</RefLink>
</Reference>
<Reference refNo="57">
<RefAuthor>Mishin VP</RefAuthor>
<RefAuthor>Patel MC</RefAuthor>
<RefAuthor>Chesnokov A</RefAuthor>
<RefAuthor>De La Cruz J</RefAuthor>
<RefAuthor>Nguyen HT</RefAuthor>
<RefAuthor>Lollis L</RefAuthor>
<RefAuthor>Hodges E</RefAuthor>
<RefAuthor>Jang Y</RefAuthor>
<RefAuthor>Barnes J</RefAuthor>
<RefAuthor>Uyeki T</RefAuthor>
<RefAuthor>Davis CT</RefAuthor>
<RefAuthor>Wentworth DE</RefAuthor>
<RefAuthor>Gubareva LV</RefAuthor>
<RefTitle>Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir1</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Emerg Infect Dis</RefJournal>
<RefPage>1969-72</RefPage>
<RefTotal>Mishin VP, Patel MC, Chesnokov A, De La Cruz J, Nguyen HT, Lollis L, Hodges E, Jang Y, Barnes J, Uyeki T, Davis CT, Wentworth DE, Gubareva LV. Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir1. Emerg Infect Dis. 2019 Oct;25(10):1969-72. DOI: 10.3201/eid2510.190607</RefTotal>
<RefLink>https://doi.org/10.3201/eid2510.190607</RefLink>
</Reference>
<Reference refNo="58">
<RefAuthor>Omoto S</RefAuthor>
<RefAuthor>Speranzini V</RefAuthor>
<RefAuthor>Hashimoto T</RefAuthor>
<RefAuthor>Noshi T</RefAuthor>
<RefAuthor>Yamaguchi H</RefAuthor>
<RefAuthor>Kawai M</RefAuthor>
<RefAuthor>Kawaguchi K</RefAuthor>
<RefAuthor>Uehara T</RefAuthor>
<RefAuthor>Shishido T</RefAuthor>
<RefAuthor>Naito A</RefAuthor>
<RefAuthor>Cusack S</RefAuthor>
<RefTitle>Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil</RefTitle>
<RefYear>2018</RefYear>
<RefJournal>Sci Rep</RefJournal>
<RefPage>9633</RefPage>
<RefTotal>Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H, Kawai M, Kawaguchi K, Uehara T, Shishido T, Naito A, Cusack S. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep. 2018 Jun;8(1):9633. DOI: 10.1038/s41598-018-27890-4</RefTotal>
<RefLink>https://doi.org/10.1038/s41598-018-27890-4</RefLink>
</Reference>
<Reference refNo="59">
<RefAuthor>Takashita E</RefAuthor>
<RefAuthor>Ichikawa M</RefAuthor>
<RefAuthor>Morita H</RefAuthor>
<RefAuthor>Ogawa R</RefAuthor>
<RefAuthor>Fujisaki S</RefAuthor>
<RefAuthor>Shirakura M</RefAuthor>
<RefAuthor>Miura H</RefAuthor>
<RefAuthor>Nakamura K</RefAuthor>
<RefAuthor>Kishida N</RefAuthor>
<RefAuthor>Kuwahara T</RefAuthor>
<RefAuthor>Sugawara H</RefAuthor>
<RefAuthor>Sato A</RefAuthor>
<RefAuthor>Akimoto M</RefAuthor>
<RefAuthor>Mitamura K</RefAuthor>
<RefAuthor>Abe T</RefAuthor>
<RefAuthor>Yamazaki M</RefAuthor>
<RefAuthor>Watanabe S</RefAuthor>
<RefAuthor>Hasegawa H</RefAuthor>
<RefAuthor>Odagiri T</RefAuthor>
<RefTitle>Human-to-Human Transmission of Influenza A(H3N2) Virus with Reduced Susceptibility to Baloxavir, Japan, February 2019</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Emerg Infect Dis</RefJournal>
<RefPage>2108-11</RefPage>
<RefTotal>Takashita E, Ichikawa M, Morita H, Ogawa R, Fujisaki S, Shirakura M, Miura H, Nakamura K, Kishida N, Kuwahara T, Sugawara H, Sato A, Akimoto M, Mitamura K, Abe T, Yamazaki M, Watanabe S, Hasegawa H, Odagiri T. Human-to-Human Transmission of Influenza A(H3N2) Virus with Reduced Susceptibility to Baloxavir, Japan, February 2019. Emerg Infect Dis. 2019;25(11):2108-11. DOI: 10.3201/eid2511.190757</RefTotal>
<RefLink>https://doi.org/10.3201/eid2511.190757</RefLink>
</Reference>
<Reference refNo="60">
<RefAuthor>Gubareva LV</RefAuthor>
<RefAuthor>Mishin VP</RefAuthor>
<RefAuthor>Patel MC</RefAuthor>
<RefAuthor>Chesnokov A</RefAuthor>
<RefAuthor>Nguyen HT</RefAuthor>
<RefAuthor>De La Cruz J</RefAuthor>
<RefAuthor>Spencer S</RefAuthor>
<RefAuthor>Campbell AP</RefAuthor>
<RefAuthor>Sinner M</RefAuthor>
<RefAuthor>Reid H</RefAuthor>
<RefAuthor>Garten R</RefAuthor>
<RefAuthor>Katz JM</RefAuthor>
<RefAuthor>Fry AM</RefAuthor>
<RefAuthor>Barnes J</RefAuthor>
<RefAuthor>Wentworth DE</RefAuthor>
<RefTitle>Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016/17 and 2017/18 seasons</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Euro Surveill</RefJournal>
<RefPage>1800666</RefPage>
<RefTotal>Gubareva LV, Mishin VP, Patel MC, Chesnokov A, Nguyen HT, De La Cruz J, Spencer S, Campbell AP, Sinner M, Reid H, Garten R, Katz JM, Fry AM, Barnes J, Wentworth DE. Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016/17 and 2017/18 seasons. Euro Surveill. 2019 Jan;24(3):1800666. DOI: 10.2807/1560-7917.ES.2019.24.3.1800666</RefTotal>
<RefLink>https://doi.org/10.2807/1560-7917.ES.2019.24.3.1800666</RefLink>
</Reference>
<Reference refNo="61">
<RefAuthor>Takashita E</RefAuthor>
<RefAuthor>Kawakami C</RefAuthor>
<RefAuthor>Morita H</RefAuthor>
<RefAuthor>Ogawa R</RefAuthor>
<RefAuthor>Fujisaki S</RefAuthor>
<RefAuthor>Shirakura M</RefAuthor>
<RefAuthor>Miura H</RefAuthor>
<RefAuthor>Nakamura K</RefAuthor>
<RefAuthor>Kishida N</RefAuthor>
<RefAuthor>Kuwahara T</RefAuthor>
<RefAuthor>Mitamura K</RefAuthor>
<RefAuthor>Abe T</RefAuthor>
<RefAuthor>Ichikawa M</RefAuthor>
<RefAuthor>Yamazaki M</RefAuthor>
<RefAuthor>Watanabe S</RefAuthor>
<RefAuthor>Odagiri T</RefAuthor>
<RefAuthor> Influenza Virus Surveillance Group Of Japan</RefAuthor>
<RefTitle>Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Euro Surveill</RefJournal>
<RefPage>1800698</RefPage>
<RefTotal>Takashita E, Kawakami C, Morita H, Ogawa R, Fujisaki S, Shirakura M, Miura H, Nakamura K, Kishida N, Kuwahara T, Mitamura K, Abe T, Ichikawa M, Yamazaki M, Watanabe S, Odagiri T; Influenza Virus Surveillance Group Of Japan. Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018. Euro Surveill. 2019 Jan;24(3):1800698. DOI: 10.2807/1560-7917.ES.2019.24.3.1800698</RefTotal>
<RefLink>https://doi.org/10.2807/1560-7917.ES.2019.24.3.1800698</RefLink>
</Reference>
<Reference refNo="62">
<RefAuthor>Takashita E</RefAuthor>
<RefAuthor>Kawakami C</RefAuthor>
<RefAuthor>Ogawa R</RefAuthor>
<RefAuthor>Morita H</RefAuthor>
<RefAuthor>Fujisaki S</RefAuthor>
<RefAuthor>Shirakura M</RefAuthor>
<RefAuthor>Miura H</RefAuthor>
<RefAuthor>Nakamura K</RefAuthor>
<RefAuthor>Kishida N</RefAuthor>
<RefAuthor>Kuwahara T</RefAuthor>
<RefAuthor>Ota A</RefAuthor>
<RefAuthor>Togashi H</RefAuthor>
<RefAuthor>Saito A</RefAuthor>
<RefAuthor>Mitamura K</RefAuthor>
<RefAuthor>Abe T</RefAuthor>
<RefAuthor>Ichikawa M</RefAuthor>
<RefAuthor>Yamazaki M</RefAuthor>
<RefAuthor>Watanabe S</RefAuthor>
<RefAuthor>Odagiri T</RefAuthor>
<RefTitle>Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Euro Surveill</RefJournal>
<RefPage>1900170</RefPage>
<RefTotal>Takashita E, Kawakami C, Ogawa R, Morita H, Fujisaki S, Shirakura M, Miura H, Nakamura K, Kishida N, Kuwahara T, Ota A, Togashi H, Saito A, Mitamura K, Abe T, Ichikawa M, Yamazaki M, Watanabe S, Odagiri T. Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019. Euro Surveill. 2019 Mar;24(12):1900170. DOI: 10.2807/1560-7917.ES.2019.24.12.1900170</RefTotal>
<RefLink>https://doi.org/10.2807/1560-7917.ES.2019.24.12.1900170</RefLink>
</Reference>
<Reference refNo="63">
<RefAuthor>Takashita E</RefAuthor>
<RefAuthor>Morita H</RefAuthor>
<RefAuthor>Ogawa R</RefAuthor>
<RefAuthor>Nakamura K</RefAuthor>
<RefAuthor>Fujisaki S</RefAuthor>
<RefAuthor>Shirakura M</RefAuthor>
<RefAuthor>Kuwahara T</RefAuthor>
<RefAuthor>Kishida N</RefAuthor>
<RefAuthor>Watanabe S</RefAuthor>
<RefAuthor>Odagiri T</RefAuthor>
<RefTitle>Susceptibility of Influenza Viruses to the Novel Cap-Dependent Endonuclease Inhibitor Baloxavir Marboxil</RefTitle>
<RefYear>2018</RefYear>
<RefJournal>Front Microbiol</RefJournal>
<RefPage>3026</RefPage>
<RefTotal>Takashita E, Morita H, Ogawa R, Nakamura K, Fujisaki S, Shirakura M, Kuwahara T, Kishida N, Watanabe S, Odagiri T. Susceptibility of Influenza Viruses to the Novel Cap-Dependent Endonuclease Inhibitor Baloxavir Marboxil. Front Microbiol. 2018 Dec;9:3026. DOI: 10.3389/fmicb.2018.03026</RefTotal>
<RefLink>https://doi.org/10.3389/fmicb.2018.03026</RefLink>
</Reference>
<Reference refNo="64">
<RefAuthor>Koszalka P</RefAuthor>
<RefAuthor>Tilmanis D</RefAuthor>
<RefAuthor>Roe M</RefAuthor>
<RefAuthor>Vijaykrishna D</RefAuthor>
<RefAuthor>Hurt AC</RefAuthor>
<RefTitle>Baloxavir marboxil susceptibility of influenza viruses from the Asia-Pacific, 2012–2018</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Antiviral Res</RefJournal>
<RefPage>91-6</RefPage>
<RefTotal>Koszalka P, Tilmanis D, Roe M, Vijaykrishna D, Hurt AC. Baloxavir marboxil susceptibility of influenza viruses from the Asia-Pacific, 2012–2018. Antiviral Res. 2019 Apr;164:91-6. DOI: 10.1016/j.antiviral.2019.02.007</RefTotal>
<RefLink>https://doi.org/10.1016/j.antiviral.2019.02.007</RefLink>
</Reference>
<Reference refNo="65">
<RefAuthor>Taieb V</RefAuthor>
<RefAuthor>Ikeoka H</RefAuthor>
<RefAuthor>Ma FF</RefAuthor>
<RefAuthor>Borkowska K</RefAuthor>
<RefAuthor>Aballéa S</RefAuthor>
<RefAuthor>Tone K</RefAuthor>
<RefAuthor>Hirotsu N</RefAuthor>
<RefTitle>A network meta-analysis of the efficacy and safety of baloxavir marboxil versus neuraminidase inhibitors for the treatment of influenza in otherwise healthy patients</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Curr Med Res Opin</RefJournal>
<RefPage>1355-64</RefPage>
<RefTotal>Taieb V, Ikeoka H, Ma FF, Borkowska K, Aballéa S, Tone K, Hirotsu N. A network meta-analysis of the efficacy and safety of baloxavir marboxil versus neuraminidase inhibitors for the treatment of influenza in otherwise healthy patients. Curr Med Res Opin. 2019 Aug;35(8):1355-64. DOI: 10.1080/03007995.2019.1584505</RefTotal>
<RefLink>https://doi.org/10.1080/03007995.2019.1584505</RefLink>
</Reference>
<Reference refNo="66">
<RefAuthor>Dziewiatkowski NA</RefAuthor>
<RefAuthor>Osmon EN</RefAuthor>
<RefAuthor>Chahine EB</RefAuthor>
<RefAuthor>Thornby KA</RefAuthor>
<RefTitle>Baloxavir: A Novel Single-Dose Oral Antiviral for the Treatment of Influenza</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Sr Care Pharm</RefJournal>
<RefPage>243-52</RefPage>
<RefTotal>Dziewiatkowski NA, Osmon EN, Chahine EB, Thornby KA. Baloxavir: A Novel Single-Dose Oral Antiviral for the Treatment of Influenza. Sr Care Pharm. 2019 Apr;34(4):243-52. DOI: 10.4140/TCP.n.2019.243</RefTotal>
<RefLink>https://doi.org/10.4140/TCP.n.2019.243</RefLink>
</Reference>
<Reference refNo="67">
<RefAuthor>Ikematsu H</RefAuthor>
<RefAuthor>Hayden FG</RefAuthor>
<RefAuthor>Kawaguchi K</RefAuthor>
<RefAuthor>Kinoshita M</RefAuthor>
<RefAuthor>de Jong MD</RefAuthor>
<RefAuthor>Lee N</RefAuthor>
<RefAuthor>Takashima S</RefAuthor>
<RefAuthor>Noshi T</RefAuthor>
<RefAuthor>Tsuchiya K</RefAuthor>
<RefAuthor>Uehara T</RefAuthor>
<RefTitle>Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>N Engl J Med</RefJournal>
<RefPage>309-20</RefPage>
<RefTotal>Ikematsu H, Hayden FG, Kawaguchi K, Kinoshita M, de Jong MD, Lee N, Takashima S, Noshi T, Tsuchiya K, Uehara T. Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts. N Engl J Med. 2020 Jul;383(4):309-20. DOI: 10.1056/NEJMoa1915341</RefTotal>
<RefLink>https://doi.org/10.1056/NEJMoa1915341</RefLink>
</Reference>
<Reference refNo="68">
<RefAuthor>Furuta Y</RefAuthor>
<RefAuthor>Takahashi K</RefAuthor>
<RefAuthor>Kuno-Maekawa M</RefAuthor>
<RefAuthor>Sangawa H</RefAuthor>
<RefAuthor>Uehara S</RefAuthor>
<RefAuthor>Kozaki K</RefAuthor>
<RefAuthor>Nomura N</RefAuthor>
<RefAuthor>Egawa H</RefAuthor>
<RefAuthor>Shiraki K</RefAuthor>
<RefTitle>Mechanism of action of T-705 against influenza virus</RefTitle>
<RefYear>2005</RefYear>
<RefJournal>Antimicrob Agents Chemother</RefJournal>
<RefPage>981-6</RefPage>
<RefTotal>Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H, Shiraki K. Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother. 2005 Mar;49(3):981-6. DOI: 10.1128/AAC.49.3.981-986.2005</RefTotal>
<RefLink>https://doi.org/10.1128/AAC.49.3.981-986.2005</RefLink>
</Reference>
<Reference refNo="69">
<RefAuthor>Baranovich T</RefAuthor>
<RefAuthor>Wong SS</RefAuthor>
<RefAuthor>Armstrong J</RefAuthor>
<RefAuthor>Marjuki H</RefAuthor>
<RefAuthor>Webby RJ</RefAuthor>
<RefAuthor>Webster RG</RefAuthor>
<RefAuthor>Govorkova EA</RefAuthor>
<RefTitle>T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>J Virol</RefJournal>
<RefPage>3741-51</RefPage>
<RefTotal>Baranovich T, Wong SS, Armstrong J, Marjuki H, Webby RJ, Webster RG, Govorkova EA. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol. 2013 Apr;87(7):3741-51. DOI: 10.1128/JVI.02346-12</RefTotal>
<RefLink>https://doi.org/10.1128/JVI.02346-12</RefLink>
</Reference>
<Reference refNo="70">
<RefAuthor>Furuta Y</RefAuthor>
<RefAuthor>Gowen BB</RefAuthor>
<RefAuthor>Takahashi K</RefAuthor>
<RefAuthor>Shiraki K</RefAuthor>
<RefAuthor>Smee DF</RefAuthor>
<RefAuthor>Barnard DL</RefAuthor>
<RefTitle>Favipiravir (T-705), a novel viral RNA polymerase inhibitor</RefTitle>
<RefYear>2013</RefYear>
<RefJournal>Antiviral Res</RefJournal>
<RefPage>446-54</RefPage>
<RefTotal>Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013 Nov;100(2):446-54. DOI: 10.1016/j.antiviral.2013.09.015</RefTotal>
<RefLink>https://doi.org/10.1016/j.antiviral.2013.09.015</RefLink>
</Reference>
<Reference refNo="71">
<RefAuthor>Agrawal U</RefAuthor>
<RefAuthor>Raju R</RefAuthor>
<RefAuthor>Udwadia ZF</RefAuthor>
<RefTitle>Favipiravir: A new and emerging antiviral option in COVID-19</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>Med J Armed Forces India</RefJournal>
<RefPage>370-6</RefPage>
<RefTotal>Agrawal U, Raju R, Udwadia ZF. Favipiravir: A new and emerging antiviral option in COVID-19. Med J Armed Forces India. 2020 Oct;76(4):370-6. DOI: 10.1016/j.mjafi.2020.08.004</RefTotal>
<RefLink>https://doi.org/10.1016/j.mjafi.2020.08.004</RefLink>
</Reference>
<Reference refNo="72">
<RefAuthor>Kumagai Y</RefAuthor>
<RefAuthor>Murakawa Y</RefAuthor>
<RefAuthor>Hasunuma T</RefAuthor>
<RefAuthor>Aso M</RefAuthor>
<RefAuthor>Yuji W</RefAuthor>
<RefAuthor>Sakurai T</RefAuthor>
<RefAuthor>Noto M</RefAuthor>
<RefAuthor>Oe T</RefAuthor>
<RefAuthor>Kaneko A</RefAuthor>
<RefTitle>Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Int J Clin Pharmacol Ther</RefJournal>
<RefPage>866-74</RefPage>
<RefTotal>Kumagai Y, Murakawa Y, Hasunuma T, Aso M, Yuji W, Sakurai T, Noto M, Oe T, Kaneko A. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. Int J Clin Pharmacol Ther. 2015 Oct;53(10):866-74. DOI: 10.5414/CP202388</RefTotal>
<RefLink>https://doi.org/10.5414/CP202388</RefLink>
</Reference>
<Reference refNo="73">
<RefAuthor>Toyama Chemical</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2014</RefYear>
<RefBookTitle>The New Drug Application Approval of “AVIGAN® Tablet 200mg” in Japan for the anti-influenza virus drug</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Toyama Chemical. The New Drug Application Approval of “AVIGAN® Tablet 200mg” in Japan for the anti-influenza virus drug. 2014 Mar 24. Available from: http://fftc.fujifilm.co.jp/en/news/news140324e.html</RefTotal>
<RefLink>http://fftc.fujifilm.co.jp/en/news/news140324e.html</RefLink>
</Reference>
<Reference refNo="74">
<RefAuthor>Goldhill DH</RefAuthor>
<RefAuthor>Te Velthuis AJW</RefAuthor>
<RefAuthor>Fletcher RA</RefAuthor>
<RefAuthor>Langat P</RefAuthor>
<RefAuthor>Zambon M</RefAuthor>
<RefAuthor>Lackenby A</RefAuthor>
<RefAuthor>Barclay WS</RefAuthor>
<RefTitle>The mechanism of resistance to favipiravir in influenza</RefTitle>
<RefYear>2018</RefYear>
<RefJournal>Proc Natl Acad Sci U S A</RefJournal>
<RefPage>11613-8</RefPage>
<RefTotal>Goldhill DH, Te Velthuis AJW, Fletcher RA, Langat P, Zambon M, Lackenby A, Barclay WS. The mechanism of resistance to favipiravir in influenza. Proc Natl Acad Sci U S A. 2018 Nov;115(45):11613-8. DOI: 10.1073/pnas.1811345115</RefTotal>
<RefLink>https://doi.org/10.1073/pnas.1811345115</RefLink>
</Reference>
<Reference refNo="75">
<RefAuthor>Mifsud EJ</RefAuthor>
<RefAuthor>Hayden FG</RefAuthor>
<RefAuthor>Hurt AC</RefAuthor>
<RefTitle>Antivirals targeting the polymerase complex of influenza viruses</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Antiviral Res</RefJournal>
<RefPage>104545</RefPage>
<RefTotal>Mifsud EJ, Hayden FG, Hurt AC. Antivirals targeting the polymerase complex of influenza viruses. Antiviral Res. 2019 Sep;169:104545. DOI: 10.1016/j.antiviral.2019.104545</RefTotal>
<RefLink>https://doi.org/10.1016/j.antiviral.2019.104545</RefLink>
</Reference>
<Reference refNo="76">
<RefAuthor>Hurt AC</RefAuthor>
<RefTitle>Antiviral Therapy for the Next Influenza Pandemic</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Trop Med Infect Dis</RefJournal>
<RefPage>67</RefPage>
<RefTotal>Hurt AC. Antiviral Therapy for the Next Influenza Pandemic. Trop Med Infect Dis. 2019 Apr;4(2):67. DOI: 10.3390/tropicalmed4020067</RefTotal>
<RefLink>https://doi.org/10.3390/tropicalmed4020067</RefLink>
</Reference>
<Reference refNo="77">
<RefAuthor>Principi N</RefAuthor>
<RefAuthor>Camilloni B</RefAuthor>
<RefAuthor>Alunno A</RefAuthor>
<RefAuthor>Polinori I</RefAuthor>
<RefAuthor>Argentiero A</RefAuthor>
<RefAuthor>Esposito S</RefAuthor>
<RefTitle>Drugs for Influenza Treatment: Is There Significant News?</RefTitle>
<RefYear>2019</RefYear>
<RefJournal>Front Med (Lausanne)</RefJournal>
<RefPage>109</RefPage>
<RefTotal>Principi N, Camilloni B, Alunno A, Polinori I, Argentiero A, Esposito S. Drugs for Influenza Treatment: Is There Significant News? Front Med (Lausanne). 2019 May;6:109. DOI: 10.3389/fmed.2019.00109</RefTotal>
<RefLink>https://doi.org/10.3389/fmed.2019.00109</RefLink>
</Reference>
<Reference refNo="78">
<RefAuthor>Anonym</RefAuthor>
<RefTitle>Antiviral drugs for influenza</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>Med Lett Drugs Ther</RefJournal>
<RefPage>1-4</RefPage>
<RefTotal>Antiviral drugs for influenza. Med Lett Drugs Ther. 2020 Jan 13;62(1589):1-4.</RefTotal>
</Reference>
<Reference refNo="79">
<RefAuthor>Braun S</RefAuthor>
<RefAuthor>Behrens T</RefAuthor>
<RefAuthor>Kulp W</RefAuthor>
<RefAuthor>Eberle A</RefAuthor>
<RefAuthor>Greiner W</RefAuthor>
<RefAuthor>Ahrens W</RefAuthor>
<RefAuthor>von der Schulenburg JM</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2005</RefYear>
<RefBookTitle>Neuraminidasehemmer in der Therapie und Postexpositionsprophylaxe der Influenza</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Braun S, Behrens T, Kulp W, Eberle A, Greiner W, Ahrens W, von der Schulenburg JM. Neuraminidasehemmer in der Therapie und Postexpositionsprophylaxe der Influenza. Köln: DIMDI; 2005. (Health Technology Assessment; Bd. 25). Available from: https://portal.dimdi.de/de/hta/hta_berichte/hta116_bericht_de.pdf</RefTotal>
<RefLink>https://portal.dimdi.de/de/hta/hta_berichte/hta116_bericht_de.pdf</RefLink>
</Reference>
<Reference refNo="80">
<RefAuthor>Wutzler P</RefAuthor>
<RefAuthor>Kossow KD</RefAuthor>
<RefAuthor>Lode H</RefAuthor>
<RefAuthor>Ruf BR</RefAuthor>
<RefAuthor>Scholz H</RefAuthor>
<RefAuthor>Vogel GE</RefAuthor>
<RefAuthor> Expert Group</RefAuthor>
<RefAuthor>German Association for the Control of Virus Diseases and Paul-Ehrlich Society of Germany</RefAuthor>
<RefTitle>Antiviral treatment and prophylaxis of influenza in primary care: German recommendations</RefTitle>
<RefYear>2004</RefYear>
<RefJournal>J Clin Virol</RefJournal>
<RefPage>84-91</RefPage>
<RefTotal>Wutzler P, Kossow KD, Lode H, Ruf BR, Scholz H, Vogel GE; Expert Group, German Association for the Control of Virus Diseases and Paul-Ehrlich Society of Germany. Antiviral treatment and prophylaxis of influenza in primary care: German recommendations. J Clin Virol. 2004 Oct;31(2):84-91. DOI: 10.1016/j.jcv.2004.05.009</RefTotal>
<RefLink>https://doi.org/10.1016/j.jcv.2004.05.009</RefLink>
</Reference>
<Reference refNo="81">
<RefAuthor>Berner R</RefAuthor>
<RefAuthor> Deutsche Gesellschaft für Pädiatrische Infektiologie e. V. (DGPI)</RefAuthor>
<RefTitle>Aktualisierte Empfehlung der DGPI zur Diagnostik, Therapie und Prophylaxe der Infektion mit dem Neuen Influenza A/H1N1v-Virus bei Kindern und Jugendlichen</RefTitle>
<RefYear>2009</RefYear>
<RefTotal>Berner R; Deutsche Gesellschaft für Pädiatrische Infektiologie e.V. (DGPI). Aktualisierte Empfehlung der DGPI zur Diagnostik, Therapie und Prophylaxe der Infektion mit dem Neuen Influenza A/H1N1v-Virus bei Kindern und Jugendlichen. Berlin: DGPI; 2009 [last updated 2009 Nov 09]. Available from: https://www.aerztekammer-berlin.de/40presse/15_meldungen/00688_Schweinegrippe/00688_Aktualisierte_Empfehlungen_DGPI_zur_Therapie_und_Prophylaxe_bei_Kindern_und_Jugendlichen_20_August_2009.pdf</RefTotal>
<RefLink>https://www.aerztekammer-berlin.de/40presse/15_meldungen/00688_Schweinegrippe/00688_Aktualisierte_Empfehlungen_DGPI_zur_Therapie_und_Prophylaxe_bei_Kindern_und_Jugendlichen_20_August_2009.pdf</RefLink>
</Reference>
<Reference refNo="82">
<RefAuthor>Mertens T</RefAuthor>
<RefTitle>Influenza – Prophylaxe und Therapie: Für Neuraminidasehemmer gibt es noch keinen Ersatz</RefTitle>
<RefYear>2015</RefYear>
<RefJournal>Dtsch Arztebl</RefJournal>
<RefPage>A-464/B-394/C-86</RefPage>
<RefTotal>Mertens T. Influenza – Prophylaxe und Therapie: Für Neuraminidasehemmer gibt es noch keinen Ersatz. Dtsch Arztebl. 2015 Mar;112(11):A-464/B-394/C-86.</RefTotal>
</Reference>
<Reference refNo="83">
<RefAuthor>Ewig S</RefAuthor>
<RefAuthor>Höffken G</RefAuthor>
<RefAuthor>Kern WV</RefAuthor>
<RefAuthor>Rohde G</RefAuthor>
<RefAuthor>Flick H</RefAuthor>
<RefAuthor>Krause R</RefAuthor>
<RefAuthor>Ott S</RefAuthor>
<RefAuthor>Bauer T</RefAuthor>
<RefAuthor>Dalhoff K</RefAuthor>
<RefAuthor>Gatermann S</RefAuthor>
<RefAuthor>Kolditz M</RefAuthor>
<RefAuthor>Krüger S</RefAuthor>
<RefAuthor>Lorenz J</RefAuthor>
<RefAuthor>Pletz M</RefAuthor>
<RefAuthor>de Roux A</RefAuthor>
<RefAuthor>Schaaf B</RefAuthor>
<RefAuthor>Schaberg T</RefAuthor>
<RefAuthor>Schütte H</RefAuthor>
<RefAuthor>Welte T</RefAuthor>
<RefTitle>Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie und Prävention – Update 2016</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Pneumologie</RefJournal>
<RefPage>151-200</RefPage>
<RefTotal>Ewig S, Höffken G, Kern WV, Rohde G, Flick H, Krause R, Ott S, Bauer T, Dalhoff K, Gatermann S, Kolditz M, Krüger S, Lorenz J, Pletz M, de Roux A, Schaaf B, Schaberg T, Schütte H, Welte T. Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie und Prävention – Update 2016 [Management of Adult Community-acquired Pneumonia and Prevention – Update 2016]. Pneumologie. 2016 Mar;70(3):151-200. DOI: 10.1055/s-0042-101873</RefTotal>
<RefLink>https://doi.org/10.1055/s-0042-101873</RefLink>
</Reference>
<Reference refNo="84">
<RefAuthor>Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin e. V. (DGP)</RefAuthor>
<RefAuthor> Deutsche Gesellschaft für Infektiologie e.V. (DGI)</RefAuthor>
<RefAuthor> Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG)</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2016</RefYear>
<RefBookTitle>Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie und Prävention – Update 2016. S3-Leitlinie. AWMF-Registernummer 020-020</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin e.V. (DGP); Deutsche Gesellschaft für Infektiologie e.V. (DGI); Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG). Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie und Prävention – Update 2016. S3-Leitlinie. AWMF-Registernummer 020-020. Berlin: AWMF; 2016.</RefTotal>
</Reference>
<Reference refNo="85">
<RefAuthor>Rodríguez A</RefAuthor>
<RefAuthor>Díaz E</RefAuthor>
<RefAuthor>Martín-Loeches I</RefAuthor>
<RefAuthor>Sandiumenge A</RefAuthor>
<RefAuthor>Canadell L</RefAuthor>
<RefAuthor>Díaz JJ</RefAuthor>
<RefAuthor>Figueira JC</RefAuthor>
<RefAuthor>Marques A</RefAuthor>
<RefAuthor>Alvarez-Lerma F</RefAuthor>
<RefAuthor>Vallés J</RefAuthor>
<RefAuthor>Baladín B</RefAuthor>
<RefAuthor>García-López F</RefAuthor>
<RefAuthor>Suberviola B</RefAuthor>
<RefAuthor>Zaragoza R</RefAuthor>
<RefAuthor>Trefler S</RefAuthor>
<RefAuthor>Bonastre J</RefAuthor>
<RefAuthor>Blanquer J</RefAuthor>
<RefAuthor>Rello J</RefAuthor>
<RefAuthor> H1N1 SEMICYUC Working Group</RefAuthor>
<RefTitle>Impact of early oseltamivir treatment on outcome in critically ill patients with 2009 pandemic influenza A</RefTitle>
<RefYear>2011</RefYear>
<RefJournal>J Antimicrob Chemother</RefJournal>
<RefPage>1140-9</RefPage>
<RefTotal>Rodríguez A, Díaz E, Martín-Loeches I, Sandiumenge A, Canadell L, Díaz JJ, Figueira JC, Marques A, Alvarez-Lerma F, Vallés J, Baladín B, García-López F, Suberviola B, Zaragoza R, Trefler S, Bonastre J, Blanquer J, Rello J; H1N1 SEMICYUC Working Group. Impact of early oseltamivir treatment on outcome in critically ill patients with 2009 pandemic influenza A. J Antimicrob Chemother. 2011 May;66(5):1140-9. DOI: 10.1093/jac/dkq511</RefTotal>
<RefLink>https://doi.org/10.1093/jac/dkq511</RefLink>
</Reference>
<Reference refNo="86">
<RefAuthor>Louie JK</RefAuthor>
<RefAuthor>Yang S</RefAuthor>
<RefAuthor>Acosta M</RefAuthor>
<RefAuthor>Yen C</RefAuthor>
<RefAuthor>Samuel MC</RefAuthor>
<RefAuthor>Schechter R</RefAuthor>
<RefAuthor>Guevara H</RefAuthor>
<RefAuthor>Uyeki TM</RefAuthor>
<RefTitle>Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09</RefTitle>
<RefYear>2012</RefYear>
<RefJournal>Clin Infect Dis</RefJournal>
<RefPage>1198-204</RefPage>
<RefTotal>Louie JK, Yang S, Acosta M, Yen C, Samuel MC, Schechter R, Guevara H, Uyeki TM. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis. 2012 Nov;55(9):1198-204. DOI: 10.1093/cid/cis636</RefTotal>
<RefLink>https://doi.org/10.1093/cid/cis636</RefLink>
</Reference>
<Reference refNo="87">
<RefAuthor>Gesellschaft für Virologie (GfV e.V.)</RefAuthor>
<RefAuthor> Deutsche Vereinigung zur Bekämpfung der Viruskrankheiten (DVV e.V.)</RefAuthor>
<RefTitle></RefTitle>
<RefYear>2019</RefYear>
<RefBookTitle>Virusinfektionen bei Organ- und allogen Stammzell-Transplantierten: Diagnostik, Prävention und Therapie. S2k-Leitlinie. AWMF-Registernummer 093-002</RefBookTitle>
<RefPage></RefPage>
<RefTotal>Gesellschaft für Virologie (GfV e.V.); Deutsche Vereinigung zur Bekämpfung der Viruskrankheiten (DVV e.V.). Virusinfektionen bei Organ- und allogen Stammzell-Transplantierten: Diagnostik, Prävention und Therapie. S2k-Leitlinie. AWMF-Registernummer 093-002. Berlin: AWMF; 2019. Available from: https://www.awmf.org/leitlinien/detail/ll/093-002.html</RefTotal>
<RefLink>https://www.awmf.org/leitlinien/detail/ll/093-002.html</RefLink>
</Reference>
<Reference refNo="88">
<RefAuthor>von Lilienfeld-Toal M</RefAuthor>
<RefAuthor>Berger A</RefAuthor>
<RefAuthor>Christopeit M</RefAuthor>
<RefAuthor>Hentrich M</RefAuthor>
<RefAuthor>Heussel CP</RefAuthor>
<RefAuthor>Kalkreuth J</RefAuthor>
<RefAuthor>Klein M</RefAuthor>
<RefAuthor>Kochanek M</RefAuthor>
<RefAuthor>Penack O</RefAuthor>
<RefAuthor>Hauf E</RefAuthor>
<RefAuthor>Rieger C</RefAuthor>
<RefAuthor>Silling G</RefAuthor>
<RefAuthor>Vehreschild M</RefAuthor>
<RefAuthor>Weber T</RefAuthor>
<RefAuthor>Wolf HH</RefAuthor>
<RefAuthor>Lehners N</RefAuthor>
<RefAuthor>Schalk E</RefAuthor>
<RefAuthor>Mayer K</RefAuthor>
<RefTitle>Community acquired respiratory virus infections in cancer patients – Guideline on diagnosis and management by the Infectious Diseases Working Party of the German Society for haematology and Medical Oncology</RefTitle>
<RefYear>2016</RefYear>
<RefJournal>Eur J Cancer</RefJournal>
<RefPage>200-12</RefPage>
<RefTotal>von Lilienfeld-Toal M, Berger A, Christopeit M, Hentrich M, Heussel CP, Kalkreuth J, Klein M, Kochanek M, Penack O, Hauf E, Rieger C, Silling G, Vehreschild M, Weber T, Wolf HH, Lehners N, Schalk E, Mayer K. Community acquired respiratory virus infections in cancer patients – Guideline on diagnosis and management by the Infectious Diseases Working Party of the German Society for haematology and Medical Oncology. Eur J Cancer. 2016 Nov;67:200-12. DOI: 10.1016/j.ejca.2016.08.015</RefTotal>
<RefLink>https://doi.org/10.1016/j.ejca.2016.08.015</RefLink>
</Reference>
<Reference refNo="89">
<RefAuthor>Ison MG</RefAuthor>
<RefAuthor>Portsmouth S</RefAuthor>
<RefAuthor>Yoshida Y</RefAuthor>
<RefAuthor>Shishido T</RefAuthor>
<RefAuthor>Mitchener M</RefAuthor>
<RefAuthor>Tsuchiya K</RefAuthor>
<RefAuthor>Uehara T</RefAuthor>
<RefAuthor>Hayden FG</RefAuthor>
<RefTitle>Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>Lancet Infect Dis</RefJournal>
<RefPage>1204-14</RefPage>
<RefTotal>Ison MG, Portsmouth S, Yoshida Y, Shishido T, Mitchener M, Tsuchiya K, Uehara T, Hayden FG. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial. Lancet Infect Dis. 2020;20(10):1204-14. DOI: 10.1016/S1473-3099(20)30004-9</RefTotal>
<RefLink>https://doi.org/10.1016/S1473-3099(20)30004-9</RefLink>
</Reference>
<Reference refNo="90">
<RefAuthor>Baker J</RefAuthor>
<RefAuthor>Block SL</RefAuthor>
<RefAuthor>Matharu B</RefAuthor>
<RefAuthor>Burleigh Macutkiewicz L</RefAuthor>
<RefAuthor>Wildum S</RefAuthor>
<RefAuthor>Dimonaco S</RefAuthor>
<RefAuthor>Collinson N</RefAuthor>
<RefAuthor>Clinch B</RefAuthor>
<RefAuthor>Piedra PA</RefAuthor>
<RefTitle>Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2)</RefTitle>
<RefYear>2020</RefYear>
<RefJournal>Pediatr Infect Dis J</RefJournal>
<RefPage>700-5</RefPage>
<RefTotal>Baker J, Block SL, Matharu B, Burleigh Macutkiewicz L, Wildum S, Dimonaco S, Collinson N, Clinch B, Piedra PA. Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2). Pediatr Infect Dis J. 2020 Aug;39(8):700-5. DOI: 10.1097/INF.0000000000002747</RefTotal>
<RefLink>https://doi.org/10.1097/INF.0000000000002747</RefLink>
</Reference>
</References>
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<Caption><Pgraph><Mark1>Table 1: List of approved anti-influenza drugs (adopted and modified from [13], [78])</Mark1></Pgraph></Caption>
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<Caption><Pgraph><Mark1>Table 2: Treatment recommendations for treatment of suspected and/or laboratory-confirmed influenza available from German Guidelines and recommendations</Mark1></Pgraph></Caption>
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<MediaID>3</MediaID>
<Caption><Pgraph><Mark1>Table 3: Summary of clinical trials phase 3 on influenza with baloxavir marboxil, oseltamivir and placebo</Mark1></Pgraph></Caption>
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