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Current influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Encouragingly, several new compounds which inhibit the polymerase of influenza viruses have recently been shown to have enhanced pre-clinical and clinical effectiveness compared to the neuraminidase inhibitors, the mainstay of influenza antiviral therapy over the last two decades. In this review we focus on four compounds which inhibit polymerase function, baloxavir marboxil, favipiravir, pimodivir and AL-794 and discuss their clinical and virological effectiveness, their propensity to select for resistance and their potential for future combination therapy with the most commonly used neuraminidase inhibitor, oseltamivir., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: High usage of the neuraminidase inhibitor (NAI) oseltamivir in Japan since 2003 led the Neuraminidase Inhibitor Susceptibility Network to assess the susceptibility of community isolates of influenza viruses to oseltamivir and zanamivir., Methods: Isolates were tested by the enzyme inhibition assay and by neuraminidase (NA) sequence analysis., Results: Among 1,141 A(H3N2) viruses and 171 type B viruses collected in Japan during the 2003-2004 season, 3 (0.3%) A(H3N2) isolates showed high 50% inhibitory concentrations (IC(50)) to oseltamivir. Each possessed a known resistance NA mutation at R292K or E119V. During the 2004-2005 season, no resistance was found among 567 influenza A(H3N2) or 60 A(H1N1) isolates, but 1 of 58 influenza B isolates had an NAI resistance mutation (D197N). Sequence analysis found that 4 (3%) of 132 A(H1N1) viruses from 2005-2006 had known NA resistance mutations (all H274Y), but no additional resistant isolates were detected from that or the subsequent 2006-2007 season. Concurrent testing of a selection of 500 influenza B viruses from 2000 to 2006 showed significant variations between seasons in both oseltamivir and zanamivir IC(50) values, but no persistent increases over this period., Conclusions: Our findings suggested possible low-level transmission of resistant variants from oseltamivir-treated patients in several seasons in Japan but no sustained reductions in NAI susceptibility or consistently increased frequency of detecting resistant variants for any strain or subtype, despite high levels of drug use. In particular, although oseltamivir-resistant A(H1N1) viruses with the H274Y mutation spread globally in 2007-2008, we found little evidence for increasing levels of resistant A(H1N1) variants in Japan in preceding years.

Recent spread of avian influenza A (H5N1) virus to poultry and wild birds has increased the threat of human infections with H5N1 virus worldwide. Despite international agreement to stockpile antivirals, evidence-based guidelines for their use do not exist. WHO assembled an international multidisciplinary panel to develop rapid advice for the pharmacological management of human H5N1 virus infection in the current pandemic alert period. A transparent methodological guideline process on the basis of the Grading Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to develop evidence-based guidelines. Our development of specific recommendations for treatment and chemoprophylaxis of sporadic H5N1 infection resulted from the benefits, harms, burden, and cost of interventions in several patient and exposure groups. Overall, the quality of the underlying evidence for all recommendations was rated as very low because it was based on small case series of H5N1 patients, on extrapolation from preclinical studies, and high quality studies of seasonal influenza. A strong recommendation to treat H5N1 patients with oseltamivir was made in part because of the severity of the disease. Similarly, strong recommendations were made to use neuraminidase inhibitors as chemoprophylaxis in high-risk exposure populations. Emergence of other novel influenza A viral subtypes with pandemic potential, or changes in the pathogenicity of H5N1 virus strains, will require an update of these guidelines and WHO will be monitoring this closely.

The development of the currently available classes of antivirals, the M2 proton channel inhibitors and the neuraminidase inhibitors, provides valuable perspectives relevant to the field of antiviral chemotherapy in general and insights into aspects of viral pathogenesis and antiviral resistance relevant specifically to influenza. The efficacy observed with these antiviral drugs has proven the importance of these antiviral targets, as well as the principle that chemoprophylaxis and early treatment are possible in influenza infections with small molecular weight inhibitors.

Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) develops at a low level following drug treatment, and person-to-person transmission of resistant virus has not been recognized to date. The Neuraminidase Inhibitor Susceptibility Network (NISN) was established to follow susceptibility of isolates and occurrence of NAI resistance at a population level in various parts of the world. Isolates from the WHO influenza collaborating centers were screened for susceptibilities to oseltamivir and zanamivir by a chemiluminescent enzyme inhibition assay, and those considered potentially resistant were analyzed by sequence analysis of the neuraminidase genes. During the first 3 years of NAI use (1999 to 2002), 2,287 isolates were tested. Among them, eight (0.33%) viruses had a >10-fold decrease in susceptibility to oseltamivir, one (0.22%) in 1999 to 2000, three (0.36%) in 2000 to 2001, and four (0.41%) in 2001 to 2002. Six had unique changes in the neuraminidase gene compared to neuraminidases of the same subtype in the influenza sequence database. Although only one of the mutations had previously been recognized in persons receiving NAIs, none were from patients who were known to have received the drugs. During the 3 years preceding NAI use, no resistant variants were detected among 1,054 viruses. Drug use was relatively stable during the period, except for an approximate 10-fold increase in oseltamivir use in Japan during the third year. The frequency of variants with decreased sensitivity to the NAIs did not increase significantly during this period, but continued surveillance is required, especially in regions with higher NAI use.

Influenza is a highly infectious disease characterized by recurrent annual epidemics and unpredictable major worldwide pandemics. Rapid spread of the highly pathogenic avian H5N1 strain and escalating human infections by the virus have set off the alarm for a global pandemic. To provide an urgently needed alternative treatment modality for influenza, we have generated a recombinant fusion protein composed of a sialidase catalytic domain derived from Actinomyces viscosus fused with a cell surface-anchoring sequence. The sialidase fusion protein is to be applied topically as an inhalant to remove the influenza viral receptors, sialic acids, from the airway epithelium. We demonstrate that a sialidase fusion construct, DAS181, effectively cleaves sialic acid receptors used by both human and avian influenza viruses. The treatment provides long-lasting effect and is nontoxic to the cells. DAS181 demonstrated potent antiviral and cell protective efficacies against a panel of laboratory strains and clinical isolates of IFV A and IFV B, with virus replication inhibition 50% effective concentrations in the range of 0.04 to 0.9 nM. Mouse and ferret studies confirmed significant in vivo efficacy of the sialidase fusion in both prophylactic and treatment modes.

Influenza virus with resistance to antiviral drugs emerges with increased frequency in immunocompromised patients and can limit the benefit of M2 and neuraminidase (NA) inhibitors. We document 3 cases of influenza in severely immunocompromised patients from whom virus variants with molecular markers of resistance to anti-influenza drugs were recovered. Virus variants recovered from 2 patients had mutations in the M2, NA (with a previously recognized Glu119Val NA substitution), and hemagglutinin genes. We describe a novel Asp198Asn NA mutation in an influenza B virus and its decreased susceptibility to both oseltamivir and zanamivir.

We developed an immunocompromised murine model of influenza virus infection and demonstrated comparable efficacy of oral oseltamivir and A-322278 (both given at dosages of 10 mg/kg/day) in reducing viral replication, decreasing weight loss, and prolonging survival. Once the treatment was discontinued, severe combined immunodeficient (SCID) mice had progressive viral replication and clinical decline. Drug-resistant variants were detected in 4 (29%) of 14 and 2 (13%) of 15 mice (both BALB/c and SCID) treated with oseltamivir or A-322278, respectively; no resistant variants were detected in placebo-treated mice. Amino acid substitutions in the hemagglutinin receptor-binding site at aa 137 or 225 were detected in cloned resistant isolates. A substitution in the neuraminidase (NA) active site (Arg292Lys) was detected in the cloned virus recovered from an oseltamivir-treated mouse. This model would be useful for elucidation of the molecular mechanisms of resistance to NA inhibitors and for testing of anti-influenza therapy options that might prevent the emergence of resistant variants.

The susceptibilities of five zanamivir-resistant and six oseltamivir-resistant influenza viruses were assessed against four neuraminidase (NA) inhibitors, including peramivir and A-315675, by a fluorometric NA activity inhibition assay. The enzyme activity of a majority of the variants was effectively inhibited by either A-315675 or both peramivir and A-315675 (50% inhibitory concentration, <10 nM). A novel oseltamivir-resistant influenza virus B variant carrying substitution at residue 198 (Asp-->Asn) (N2 numbering) retained susceptibility to peramivir and A-315675. In vivo, the Asn198 variant showed no apparent fitness impairment as judged by its recovery on day 5 from the nasal washes of ferrets coinfected with equal doses of the wild-type virus and the Asn198 variant. Based on the sequence analysis of the virus in the nasal washes, oseltamivir treatment (5 mg/kg twice daily for 5 days) did not provide growth advantage to the Asn198 variant. Nevertheless, treatment with A-315675 (prodrug A-322278) reduced the number of the animals (two of seven) shedding the Asn198 variant. These studies indicate that different patterns of susceptibility and cross-resistance between NA inhibitors may prove important if antiviral resistance to zanamivir and oseltamivir were to emerge.

Inhibition of neuraminidase (NA) activity prevents release of progeny virions from influenza-infected cells and removal of neuraminic (sialic) acid moieties from glycans attached to hemagglutinin (HA). Neuraminic acid moieties situated near the HA receptor-binding site can reduce the efficiency of virus binding and decrease viral dependence on NA activity for replication. With the use of reverse genetics technique, we investigated the effect of glycans attached at Asn 94a, 129, and 163 on the virus susceptibility to NA inhibitors in MDCK cells and demonstrated that the glycan attached at Asn 163 plays a dominant role in compensation for the loss of NA activity.

We assessed the cost-effectiveness and cost-utility of treating influenza with neuraminidase inhibitors (oseltamivir and zanamivir) from a health care payer's and societal perspective in the United Kingdom. A simulation model was developed to predict morbidity and mortality due to influenza and its specified complications, comparing neuraminidase inhibitors with usual care in an otherwise healthy adult population. Robustness of the results was tested by one-way and multiway as well as probabilistic sensitivity analyses. Treatment with either neuraminidase inhibitor results in reduced morbidity and faster return to normal activities. However, oseltamivir dominates zanamivir in cost-utility analysis due to its lower costs. Comparing oseltamivir with usual care, the costs are pound14.36 per day of normal activity gained and pound5,600 per quality-adjusted life-year gained from the healthcare payer perspective. Oseltamivir dominates usual care from the societal perspective. Treatment with oseltamivir is a cost-effective strategy for otherwise healthy adults in the UK from both the healthcare payer and societal perspective.

Protective efficacy of the intranasal immunization with the neuraminidase (NA)-deficient mutant of the influenza A virus was investigated in ferrets. Despite the highly attenuated replication in vivo, the mutant completely protected the animals against the wild type virus challenge. When challenge was done with antigenic drift variants, significant reductions in the viral titers, inflammatory cell counts, and protein concentrations were observed in the nasal washes of the immunized animals. The genetically engineered NA-deficient mutant also protected animals against the challenge and induced humoral immune response against the foreign protein that replaced the NA. We conclude that the NA as antigen is dispensable in the live attenuated influenza virus vaccine and that the NA-lacking mutant can be used as a virus vector.

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

Background: Oseltamivir is an effective inhibitor of influenza virus neuraminidase. Although viruses resistant to oseltamivir emerge less frequently than those resistant to amantadine or rimantadine, information on oseltamivir-resistant viruses arising during clinical use of the drug in children is limited. Our aim was to investigate oseltamivir resistance in a group of children treated for influenza., Methods: We analysed influenza A viruses (H3N2) collected from 50 children before and during treatment with oseltamivir. We sequenced the genes for neuraminidase and haemagglutinin and studied the mutant neuraminidases for their sensitivity to oseltamivir carboxylate., Findings: We found neuraminidase mutations in viruses from nine patients (18%), six of whom had mutations at position 292 (Arg292Lys) and two at position 119 (Glu119Val), which are known to confer resistance to neuraminidase inhibitors. We also identified another mutation (Asn294Ser) in one patient. Sensitivity testing to oseltamivir carboxylate revealed that the neuraminidases of viruses that have an Arg292Lys, Glu119Val, or Asn294Ser mutation were about 10(4)-10(5)-fold, 500-fold, or 300-fold more resistant than their pretreatment neuraminidases, respectively. Oseltamivir-resistant viruses were first detected at day 4 of treatment and on each successive day of the study. More than 10(3) infectious units per mL of virus were detected in some of the patients who did not shed drug-resistant viruses, even after 5 days of treatment., Interpretation: Oseltamivir-resistant mutants in children being treated for influenza with oseltamivir arise more frequently than previously reported. Furthermore, children can be a source of viral transmission, even after 5 days of treatment with oseltamivir.

Both influenza A virus surface glycoproteins, the haemagglutinin (HA) and neuraminidase (NA), interact with neuraminic acid-containing receptors. The influenza virus A/Charlottesville/31/95 (H1N1) has shown a substantially reduced sensitivity to NA inhibitor compared with the A/WSN/33 (H1N1) isolate by plaque-reduction assays in Madin-Darby canine kidney (MDCK) cells. However, there was no difference in drug sensitivity in an NA inhibition assay. The replacement of the HA gene of A/WSN/33 with the HA gene of A/Charlottesville/31/95 led to a drastic reduction in sensitivity of A/WSN/33 to NA inhibitor in MDCK cells. Passage of A/Charlottesville/31/95 in cell culture in the presence of an NA inhibitor resulted in the emergence of mutant viruses (delNA) whose genomes lacked the coding capacity for the NA active site. The delNA mutants were plaque-to-plaque purified and further characterized. The delNA-31 mutant produced appreciable yields ( approximately 10(6) p.f.u./ml) in MDCK cell culture supernatants in the absence of viral or bacterial NA activity. Sequence analysis of the delNA mutant genome revealed no compensatory substitutions in the HA or other genes compared with the wild-type. Our data indicate that sialylation of the oligosaccharide chains in the vicinity of the HA receptor-binding site of A/Charlottesville/31/95 virus reduces the HA binding efficiency and thus serves as a compensatory mechanism for the loss of NA activity. Hyperglycosylation of HA is common in influenza A viruses circulating in humans and has the potential to reduce virus sensitivity to NA inhibitors.

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

We previously characterized influenza viruses whose selection in the presence of neuraminidase (NA) inhibitors resulted in a substituted residue (position 119,152,274, or 292) in the NA active center. To identify the most favorable conditions for detecting NA inhibitor-resistant viruses we compared the results of four modifications of the NA inhibition assay utilizing a fluorogenic substrate. The IC50 values were highly dependent upon assay conditions, and most mutant enzymes were more sensitive to changes in assay conditions (e.g. addition of PO4(3-), Ca2+, DMSO, or EDTA) than wild-type enzymes or a mutant NA with an Arg292-->Lys substitution. Although the levels of resistance to zanamivir, oseltamivir carboxylate, and BCX-1812 (RWJ-270201) for each mutant varied among assays, mutants with substitutions at framework residues 119 or 274 exhibited sensitivity to at least one inhibitor. Viruses with substitutions at catalytic residues 152 or 292 were resistant to each inhibitor in all assays. Monitoring resistance in a clinical setting will require a panel of resistant viruses to ensure that assay conditions are favorable for detecting variants with substituted residues in the NA active center. Because variants selected in the presence of one NA inhibitor could be variably resistant to other inhibitors, all three inhibitors should be used in drug susceptibility testing.

The goals of antiviral treatment for influenza are to decrease symptoms and functional disability and, more important, to decrease associated complications, hospitalizations, and mortality. Four drugs have been approved for treatment of and prophylaxis against influenza in the United States, but they are underutilized. The M2 ion channel inhibitors amantadine and rimantadine are effective for prophylaxis, and they decrease the duration of symptoms if they are used for early treatment of influenza A. The rapid emergence of resistance during therapy and, recently, the circulation of resistant H3N2 viruses in the community have decreased the usefulness of these M2 ion channel inhibitors. Early therapy with neuraminidase (NA) inhibitors, either oseltamivir or zanamivir, reduces the duration of symptoms, the duration of disability, and the risk of lower respiratory tract complications. Oseltamivir has been shown to decrease antibiotic use, the number of hospitalizations, and, probably, the risk of death after influenza. NA inhibitors might provide substantial benefits in the treatment of pandemic influenza, with reductions in the numbers of hospitalizations and deaths occurring if such treatment (1) is made available in sufficient time, through rapid distribution, and (2) is available in sufficient quantities as a result of stockpiling. Both of the aforementioned NA inhibitors are highly effective for prophylaxis. Geographically targeted mass chemoprophylaxis might contain the spread of a pandemic virus, but multiple hurdles to successful implementation exist. Resistance to oseltamivir occurs with the H274Y variant in viruses that contain N1; however, to date, such variants have been less fit, have not been transmitted from person to person, and have retained susceptibility to zanamivir. Alternative agents and approaches, including parenteral and combination therapy, for the treatment of influenza are needed in the near and long term. [ABSTRACT FROM AUTHOR]

Abstract: An inbred murine model (BALB/c) was utilized to assess the protective effect of the immunomodulator methyl inosine 5′-monophosphate (MIMP) against infection with influenza A/PR/8/34 (H1N1) virus. Contrary to the data reported for outbred mice (NMRI) infected with the aerosolized virus (Masihi, Hadden, 2003. J. Int. Immunopharmacol. 3, 1205–1215), there were no improvements in the outcomes of infection in the inbred animals treated with MIMP intranasally 1 day before the challenge and/or orally after the challenge for 5 days (up to 10mg/kg/day). Nevertheless, complete protection against lethality was afforded by the treatment with the neuraminidase inhibitor peramivir given once daily for 5 days after the challenge (10mg/kg/day). We speculate that the rapid progression of the disease in inbred mice caused by the intranasal challenge may render the MIMP-treatment ineffective. Our results emphasize the need for careful consideration of murine strains and routes of virus challenge in the design of experiments utilizing lethal influenza virus infection. [Copyright &y& Elsevier]

Available evidence indicates that the neuraminidase inhibitors (NAIs), particularly oseltamivir, are the preferred antiviral agents for treatment of influenza, although more data are needed from elderly and high-risk populations. Although widely available, amantadine has a narrower antiviral spectrum and therapeutic margin, greater need for individual dosing, and much higher risk for emergence of drug-resistant variants compared with NAIs. Despite documented efficacy and reasonable cost-effectiveness, the NAIs are under-utilized for treatment of acute influenza in most countries of the world. Cost and rapid access to care are major hurdles to broader application. Both of these country- or health care system-related impediments require solution, if patients are to benefit from available drugs. In addition to addressing these problems, stockpiling of antiviral agents will be essential to mount an effective antiviral response to the next major epidemic or pandemic. [Copyright &y& Elsevier]

Features a study on the potential for the emergence of oseltamivir-resistant variants in human volunteers treated with neuraminidase inhibitor, after experimental infection with an influenza A virus. Inhibitors of influenza virus NA; Methodology; Results.

Reports on a randomized controlled trial to evaluate the efficacy and safety of the oral neuraminidase inhibitor oseltamivir in the treatment of naturally acquired influenza infection. Design; Setting; Participants; Interventions; Main outcome measures; Results; Conclusions.

It is more than 20 years since the neuraminidase inhibitors, oseltamivir and zanamivir were approved for the treatment and prevention of influenza. Guidelines for global surveillance and methods for evaluating resistance were established initially by the Neuraminidase Inhibitor Susceptibility Network (NISN), which merged 10 years ago with the International Society for influenza and other Respiratory Virus Diseases (isirv) to become the isirv-Antiviral Group (isirv-AVG). With the ongoing development of new influenza polymerase inhibitors and recent approval of baloxavir marboxil, the isirv-AVG held a closed meeting in August 2019 to discuss the impact of resistance to these inhibitors. Following this meeting and review of the current literature, this article is intended to summarize current knowledge regarding the clinical impact of resistance to polymerase inhibitors and approaches for surveillance and methods for laboratory evaluation of resistance, both in vitro and in animal models. We highlight limitations and gaps in current knowledge and suggest some strategies for addressing these gaps, including the need for additional clinical studies of influenza antiviral drug combinations. Lessons learned from influenza resistance monitoring may also be helpful for establishing future drug susceptibility surveillance and testing for SARS-CoV-2. • Current knowledge regarding the clinical impact of resistance to influenza polymerase inhibitors is summarized. • Current surveillance strategies for detection of variants with reduced susceptibility to polymerase inhibitors are discussed. • Methods for laboratory evaluation of resistance in vitro and in animal models, along with their limitations are presented. [ABSTRACT FROM AUTHOR]

Context: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered.Objective: To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans.Design: Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997.Setting: Individual hotel rooms; 2 large US university medical schools.Participants: A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer < or =1:8).Interventions: All subjects were inoculated intranasally with influenza A/Texas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n = 16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days.Main Outcome Measures: Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers.Results: In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n = 69), the viral titer area under the curve of the combined oseltamivir groups (n = 56) was lower (median [interquartile range [IQR]], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food.Conclusions: In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza. [ABSTRACT FROM AUTHOR]

The authors discuss the developments in the global medical sector. They focus on the possible emergence of resistance during treatment with neuraminidase inhibitors due to the detection of an Arg292Lys mutation (N2 numbering) in the virus neuraminidase (NA) gene within two days of starting oseltamivir treatment in the first reported treatment of avian A (H7N9) influenza virus infection in human. The report by Yunwen Hu and colleagues on the subject is also cited.

Examines the short-term treatment with neuraminidase inhibitor Zanamivir to prevent influenza. Comparison of the effects of intranasal and/or inhaled zanamivir; Efficacy of the short-term treatment with intranasal zanamivir; Effect of inhaled zanamivir treatment on the rate of influenza.

Please cite this paper as: Hayden FG. (2012) Newer Influenza Antivirals, Biotherapeutics and Combinations. Influenza and Other Respiratory Viruses 7(Suppl. 1), 63-75. This summary provides an overview of investigational antiviral agents for influenza and of future directions for development of influenza therapeutics. While progress in developing clinically useful antiviral agents for influenza has been generally slow, especially with respect to seriously ill and high-risk patients, important clinical studies of intravenous neuraminidase inhibitors, antibodies and drug combinations are currently in progress. The current decade offers the promise of developing small molecular weight inhibitors with novel mechanisms of action, including host-directed therapies, new biotherapeutics and drug combinations, that should provide more effective antiviral therapies and help mitigate the problem of antiviral resistance. Immunomodulatory interventions also offer promise but need to be based on better understanding of influenza pathogenesis, particularly in seriously ill patients. The development of combination interventions, immunomodulators and host-directed therapies presents unique clinical trial design and regulatory hurdles that remain to be addressed. [ABSTRACT FROM AUTHOR]

Background: As prophylaxis against influenza in families, amantadine and rimantadine have had inconsistent effectiveness, partly because of the transmission of drug-resistant variants from treated index patients. We performed a double-blind, placebo-controlled study of inhaled zanamivir for the treatment and prevention of influenza in families. Methods: We enrolled families (with two to five members and at least one child who was five years of age or older) before the 1998–1999 influenza season. If an influenza-like illness developed in one member, the family was randomly assigned to receive either inhaled zanamivir or placebo. The family member with the index illness was treated with either 10 mg of inhaled zanamivir (163 subjects) or placebo (158) twice a day for 5 days, and the other family members received either 10 mg of zanamivir (414 subjects) or placebo (423) once a day as prophylaxis for 10 days. The primary end point was the proportion of families in which at least one household contact had symptomatic, laboratory-confirmed influenza. Results: The proportion of families with at least one initially healthy household contact in whom influenza developed was smaller in the zanamivir group than in the placebo group (4 percent vs. 19 percent, P<0.001); the difference represented a 79 percent reduction in the proportion of families with at least one affected contact. Zanamivir provided protection against both influenza A and influenza B. A neuraminidase-inhibition assay and sequencing of the neuraminidase and hemagglutinin genes revealed no zanamivir-resistant variants. Among the subjects with index cases of laboratory-confirmed influenza, the median duration of symptoms was 2.5 days shorter in the zanamivir group than in the placebo group (5.0 vs. 7.5 days, P=0.01). Zanamivir was well tolerated. Conclusions: When combined with the treatment of index cases, prophylactic treatment of family members with once-daily inhaled zanamivir is well tolerated and prevents the development of influenza. In this study there was no evidence of the emergence of resistant influenza variants. (N Engl J Med 2000;343:1282-9.) [ABSTRACT FROM AUTHOR]

Background: The sialic acid analogue zanamivir (GG167) is a selective inhibitor of influenza A and B virus neuraminidases. These viral enzymes are essential for the release of virus from infected cells, and they may also reduce the inactivation of virus by respiratory secretions. When administered experimentally directly to the respiratory tract, zanamivir has potent antiviral effects. We assessed the therapeutic activity of zanamivir in adults with acute influenza. Methods: We conducted separate randomized, double-blind studies in 38 centers in North America and 32 centers in Europe during the influenza season of 1994–1995. A total of 417 adults with influenza-like illness of <48 hours' duration were randomly assigned to one of three treatments: 6.4 mg of zanamivir by intranasal spray plus 10 mg by inhalation, 10 mg of zanamivir by inhalation plus placebo spray, or placebo by both routes. Treatments were self-administered twice daily for five days. Results: Of 262 patients with confirmed influenzavirus infection (63 percent of all patients), the median length of time to the alleviation of all major symptoms was one day shorter (four days vs. five days) in the 88 patients given inhaled and intranasal zanamivir (P=0.02) and the 85 patients given inhaled zanamivir alone (P=0.05) than in the 89 patients given placebo. Among the infected patients who were febrile at enrollment and among those who began treatment within 30 hours after the onset of symptoms, the median time to the alleviation of major symptoms was four days in both zanamivir groups and seven days in the placebo group (P<0.01). Viral titers of nasal washings in the group given inhaled and intranasal zanamivir were significantly lower than those in the placebo group. The topically administered zanamivir was well tolerated. Conclusions: In adults with influenza A or B virus infections, direct administration of a selective neuraminidase inhibitor, zanamivir, to the respiratory tract is safe and reduces symptoms if begun early. (N Engl J Med 1997;337:874-80.) [ABSTRACT FROM AUTHOR]

Summary Observational data suggest that the treatment of influenza infection with neuraminidase inhibitors decreases progression to more severe illness, especially when treatment is started soon after symptom onset. However, even early treatment might fail to prevent complications in some patients, particularly those infected with novel viruses such as the 2009 pandemic influenza A H1N1, avian influenza A H5N1 virus subtype, or the avian influenza A H7N9 virus subtype. Furthermore, treatment with one antiviral drug might promote the development of antiviral resistance, especially in immunocompromised hosts and critically ill patients. An obvious strategy to optimise antiviral therapy is to combine drugs with different modes of action. Because host immune responses to infection might also contribute to illness pathogenesis, improved outcomes might be gained from the combination of antiviral therapy with drugs that modulate the immune response in an infected individual. We review available data from preclinical and clinical studies of combination antiviral therapy and of combined antiviral-immunomodulator therapy for influenza. Early-stage data draw attention to several promising antiviral combinations with therapeutic potential in severe infections, but there remains a need to substantiate clinical benefit. Combination therapies with favourable experimental data need to be tested in carefully designed aclinical trials to assess their efficacy. [ABSTRACT FROM AUTHOR]

Summary: Influenza A H1N1 2009 virus caused the first pandemic in an era when neuraminidase inhibitor antiviral drugs were available in many countries. The experiences of detecting and responding to resistance during the pandemic provided important lessons for public health, laboratory testing, and clinical management. We propose recommendations for antiviral susceptibility testing, reporting results, and management of patients infected with 2009 pandemic influenza A H1N1. Sustained global monitoring for antiviral resistance among circulating influenza viruses is crucial to inform public health and clinical recommendations for antiviral use, especially since community spread of oseltamivir-resistant A H1N1 2009 virus remains a concern. Further studies are needed to better understand influenza management in specific patient groups, such as severely immunocompromised hosts, including optimisation of antiviral treatment, rapid sample testing, and timely reporting of susceptibility results. [Copyright &y& Elsevier]

Currently, little is known about the viral kinetics of influenza A during infection within an individual. We utilize a series of mathematical models of increasing complexity, which incorporate target cell limitation and the innate interferon response, to examine influenza A virus kinetics in the upper respiratory tracts of experimentally infected adults. The models were fit to data from an experimental H1N1 influenza A/Hong Kong/123/77 infection and suggest that it is important to include the eclipse phase of the viral life cycle in viral dynamic models. Doing so, we estimate that after a delay of ∼6 h, infected cells begin producing influenza virus and continue to do so for ∼5 h. The average lifetime of infected cells is ∼11 h, and the half-life of free infectious virus is ∼3 h. We calculated the basic reproductive number, R0, which indicated that a single infected cell could produce ∼22 new productive infections. This suggests that antiviral treatments have a large hurdle to overcome in moderating symptoms and limiting infectiousness and that treatment has to be initiated as early as possible. For about 50% of patients, the curve of viral titer versus time has two peaks. This bimodal behavior can be explained by incorporating the antiviral effects of interferon into the model. Our model also compared well to an additional data set on viral titer after experimental infection and treatment with the neuraminidase inhibitor zanamivir, which suggests that such models may prove useful in estimating the efficacies of different antiviral therapies for influenza A infection. [ABSTRACT FROM AUTHOR]