Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors

Development of effective drugs for the treatment or prevention of epidemic and pandemic influenza is important in order to reduce its impact. Adamantanes and neuraminidase inhibitors are two classes of anti-influenza drugs available for influenza therapy currently. However, emergence of resistance to these drugs has been detected, which raises concerns regarding their widespread use. In this review, resistance to the adamantanes and neuraminidase inhibitors will be discussed in relation to both epidemic and pandemic influenza viruses.     

Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors

Development of effective drugs for the treatment or prevention of epidemic and pandemic influenza is important in order to reduce its impact. Adamantanes and neuraminidase inhibitors are two classes of anti-influenza drugs available for influenza therapy currently. However, emergence of resistance to these drugs has been detected, which raises concerns regarding their widespread use. In this review, resistance to the adamantanes and neuraminidase inhibitors will be discussed in relation to both epidemic and pandemic influenza viruses.     

New millennium antivirals against pandemic and epidemic influenza: the neuraminidase inhibitors

The mushroom shaped outer spike protein of influenza, neuraminidase, was first discovered nearly 60 years ago. Its importance in viral replication was soon recognised both at the point of viral release from the cell and also enabling passage of virus through nasal fluid to reach the cell. The enzyme active site was identified by x-ray crystallography, allowing an atomic study of interaction of enzyme with the sialic acid substrate. Analogues could then be identified and synthesized and became a focused target for antivirals. With the current threat of bioterrorism and the potential for the emergence of a new pandemic strain in the near future, efforts are underway to develop more potent second-generation anti-neuraminidase inhibitors with enhanced protective and therapeutic effects. Here we review older and newer neuraminidase inhibitors and the role that they will play in the fight against influenza in its epidemic and pandemic face.     

Use of neuraminidase inhibitors to combat pandemic influenza

Since the last influenza pandemic in 1968, neuraminidase (NA) inhibitors have been licensed for the treatment and prophylaxis of seasonal influenza. Continuing outbreaks of highly pathogenic avian influenza H5N1 since 2004 have focused attention on the timing of the next pandemic and preparedness plans. Although immunization is the principal means of influenza prophylaxis, a well-matched efficacious vaccine is unlikely to be widely available for several months following the emergence of the pandemic strain. NA inhibitors could be used to contain and eliminate an emerging pandemic virus at source. If unsuccessful, they could still play a crucial role in reducing the medical impact of pandemic influenza as it spreads through countries. Accordingly, many authorities are creating stockpiles of NA inhibitors. However, the use of stockpiled drugs for treatment or prophylaxis, the rapid delivery to newly diagnosed cases and unknown characteristics of an emergent pandemic strain pose significant challenges to determining optimal use of stockpiles.     

Review of the clinical effectiveness of the neuraminidase inhibitors against influenza B viruses

Influenza A and B viruses cause significant morbidity and mortality worldwide each year. The neuraminidase inhibitors (NAIs) are the most commonly used class of influenza antiviral drugs for the treatment of infected patients. In vitro studies have shown that influenza B viruses are significantly less susceptible to oseltamivir and other neuraminidase inhibitors compared with influenza A viruses. Following analysis of published clinical studies, we show that oseltamivir does appear to have lower effectiveness in patients infected with influenza B virus compared with influenza A infected patients, but due to insufficient studies on zanamivir, laninamivir or peramivir, it was not possible to conclude the relative effectiveness of these drugs against influenza A virus compared with B virus.     

The threat of avian influenza H5N1: 'do we have the tools for the job'?

For the first time in human history virologists have the knowledge about the avian origin of pandemic influenza A viruses. Furthermore, in the last two decades a new class of anti influenza drugs, the neuraminidase inhibitors (NIs), has been developed from an academic discovery to a series of antiviral drugs to be used in the clinic. At present vaccinologists are producing influenza A (H5N1) vaccines to be stockpiled alongside the NIs to combat the first wave of an anticipated influenza pandemic. Studies from the 1918 infection calamity, the Spanish influenza, and the succeeding pandemics of 1957 and 1968, all caused by avian influenza A viruses, have shown how quickly such a virus can mutate to become less virulent (starting with 50% case fatality) and more infectious. Such a mutation cluster could lead to a rapid increase in world deaths, currently 170, to many millions. However there are optimistic analyses: judicious and swift application of NIs, vaccine and hygiene to an outbreak epicentre, most likely in South-East Asia, could break the chain of transmission.     

Anti-influenza virus agent

The necessity of newly anti-influenza agents is increasing rapidly after the prevalence of pandemic influenza A (H1N1) 2009. In addition to the existing anti-influenza drugs, novel neuraminidase inhibitors such as peramivir (a first intravenous anti-influenza agent) and laninamivir (long acting inhaled anti-influenza agent) can be available. Moreover favipiravir, which shows a novel anti-influenza mechanism acting as RNA polymerase inhibitor, has been developing. These drugs are expected to improve the prognosis of severe cases caused by not only seasonal influenza but pandemic influenza A (H1N1) 2009 virus and H5N1 avian influenza, and also treat oseltamivir-resistant influenza effectively.     

Influenza update 2007-2008: vaccine advances, pandemic preparation

Influenza vaccination remains our best measure to prevent epidemic and pandemic influenza. We must continue to improve vaccination rates for targeted populations. Antiviral options are currently limited to the neuraminidase inhibitors.     

Preexisting human antibodies neutralize recently emerged H7N9 influenza strains

The emergence and seasonal persistence of pathogenic H7N9 influenza viruses in China have raised concerns about the pandemic potential of this strain, which, if realized, would have a substantial effect on global health and economies. H7N9 viruses are able to bind to human sialic acid receptors and are also able to develop resistance to neuraminidase inhibitors without a loss in fitness. It is not clear whether prior exposure to circulating human influenza viruses or influenza vaccination confers immunity to H7N9 strains. Here, we demonstrate that 3 of 83 H3 HA-reactive monoclonal antibodies generated by individuals that had previously undergone influenza A virus vaccination were able to neutralize H7N9 viruses and protect mice against homologous challenge. The H7N9-neutralizing antibodies bound to the HA stalk domain but exhibited a difference in their breadth of reactivity to different H7 influenza subtypes. Mapping viral escape mutations suggested that these antibodies bind at least two different epitopes on the stalk region. Together, these results indicate that these broadly neutralizing antibodies may contribute to the development of therapies against H7N9 strains and may also be effective against pathogenic H7 strains that emerge in the future.     

Potential benefits and limitations of various strategies to mitigate the impact of an influenza pandemic

The recent avian influenza outbreaks underscore the importance of improving our preparedness for an impending influenza pandemic. Various strategies, including pharmaceutical interventions (such as vaccines and antivirals) and nonpharmaceutical interventions (such as quarantine, isolation, and social distancing) may be implemented to mitigate the impact of a pandemic. It is necessary to understand the potential benefits and limitations of each strategy to determine the most appropriate strategies to be implemented. In this article, each strategy is reviewed to define its potential benefits and limitations during a pandemic. Vaccines are probably the most effective measure to reduce morbidity and mortality. However, vaccines are not likely to be available at an early stage of a pandemic. The supply of vaccines is most likely to be insufficient due to limited worldwide production capacity. Antivirals, particularly neuraminidase inhibitors, are expected to be effective against a pandemic influenza strain and are the only available pharmaceutical intervention until enough vaccines are produced. Shortage of supply and high cost is still a major limiting factor in amassing large stockpiles of neuraminidase inhibitors. The possible emergence of resistant strains should also be considered. Nonpharmaceutical interventions can be effective in preventing the spread of the virus under certain conditions. The effectiveness of nonpharmaceutical interventions depends on how influenza viruses are transmitted. There are still significant gaps in the scientific evidence of the way in which influenza viruses are transmitted. Further studies should be conducted to define the basic transmission patterns of influenza viruses.     

Emergence of a novel drug resistant H7N9 influenza virus: evidence based clinical potential of a natural IFN-α for infection control and treatment

The novel avian H7N9 influenza virus has caused more than 130 human infections with 43 deaths (as of September, 2013) in China. Because of the lack of existing immunity against H7 subtype influenza viruses in the human population and the absence of a licensed commercial vaccine, antiviral drugs are critical tools for the treatment of infection with this novel H7N9. Both M2-ion channel blockers and neuraminidase inhibitors are used as antiviral drugs for influenza infections of humans. The emerging H7N9 viruses are resistant to the M2-ion channel blockers because of a S31N mutation in the M2 protein; additionally, some H7N9 isolates have gained neuraminidase R292K substitution resulting in broad resistance to neuraminidase inhibitors. In this study we report that Alferon N can inhibit wild type and 292K H7N9 viruses replication in vitro. Since Alferon N is approved for clinical use, this would allow a rapid regulatory approval process for this drug under pandemic threat.     

Antiviral therapy in seasonal influenza and 2009 H1N1 pandemic influenza: Korean experiences and perspectives

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

Zanamivir, at 600 milligrams twice daily, inhibits oseltamivir-resistant 2009 pandemic H1N1 influenza virus in an in vitro hollow-fiber infection model system

In 2009, a novel H1N1 influenza A virus emerged and spread worldwide, initiating a pandemic. Various isolates obtained from disparate parts of the world were shown to be uniformly resistant to the adamantanes but sensitive to the neuraminidase inhibitors oseltamivir and zanamivir. Over time, resistance to oseltamivir became more prevalent among pandemic H1N1 virus isolates, while most remained susceptible to zanamivir. The government has proposed the use of intravenous (i.v.) zanamivir to treat serious influenza virus infections among hospitalized patients. To use zanamivir effectively for patients with severe influenza, it is necessary to know the optimal dose and schedule of administration of zanamivir that will inhibit the replication of oseltamivir-sensitive and -resistant influenza viruses. Therefore, we performed studies using the in vitro hollow-fiber infection model system to predict optimal dosing regimens for zanamivir against an oseltamivir-sensitive and an oseltamivir-resistant virus. Our results demonstrated that zanamivir, at a dose of 600 mg given twice a day (Q12h), inhibited the replication of oseltamivir-sensitive and oseltamivir-resistant influenza viruses throughout the course of the experiment. Thus, our findings suggest that intravenous zanamivir, at a dose of 600 mg Q12h, could be used to treat hospitalized patients suffering from serious infections with oseltamivir-sensitive or -resistant influenza viruses.     

Influenza vaccine, anti-influenza drugs, and rapid diagnosis in Japan

The percentage of individuals receiving influenza vaccine is markedly lower in Japan than in many other economically advanced countries. To increase the rate of coverage, the current practice of giving people two inoculations instead of one needs to be changed. In addition, free vaccination services for the elderly and high-risk patients need to be offered. Amantadine is available for the treatment of influenza type A infection in Japan. Moreover, zanamivir, a neuraminidase inhibitor effective against both influenza type A and B viruses, has been approved in Japan. A rapid diagnosis kit for influenza type A virus is available in Japan. With the current threat of new pandemic influenza viruses emerging, it is necessary to actively confront influenza in Japan by increasing the vaccine coverage rate, by employing amantadine and neuraminidase inhibitors for influenza virus infection, and by providing rapid diagnosis of influenza. Received: January 13, 2000 / Accepted: January 31, 2000     

Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic

Recent cross species transmission of avian influenza has highlighted the threat of pandemic influenza. Oseltamivir (Tamiflu) has been shown to be effective in the treatment and prevention of epidemic influenza infection in adults, adolescents and children (> or = 1 year). Although oseltamivir has not been approved for prophylactic use in children, it has been shown to be effective. Oseltamivir is also active against avian influenza virus strains. Evidence suggests that lower doses or shorter durations of treatment/chemoprophylaxis other than those approved may not be effective and may contribute to emergence of viral resistance. Safety data from dose ranging studies show that 5 day courses of 150 mg twice daily for treatment and 6 week courses of 75 mg twice daily for prophylaxis were as well tolerated as the approved dose regimens. The use of oseltamivir in a pandemic is influenced by the goals of the pandemic plan developed by the responsible Government and Health Authority. To optimize use of antiviral medications, processes will be needed to collect, collate and report outcome data from treated patients and/or from use for chemoprophylaxis of pandemic influenza during the first-wave outbreaks. If oseltamivir is included in a national or regional pandemic plan, stockpiling of the material, either in the form of capsules or the bulk active pharmaceutical ingredient will be necessary. In the absence of a stockpile, there is no guarantee that an adequate supply of oseltamivir will be available.     

Avian influenza: a new pandemic threat?

In December 2003, the largest outbreak of highly pathogenic avian influenza H5N1 occurred among poultry in 8 Asian countries. A limited number of human H5N1 infections have been reported from Vietnam and Thailand, with a mortality rate approaching 70%. Deaths have occurred in otherwise healthy young individuals, which is reminiscent of the 1918 Spanish influenza pandemic. The main presenting features were fever, pneumonitis, lymphopenia, and diarrhea. Notably, sore throat, conjunctivitis, and coryza were absent. The H5N1 strains are resistant to amantadine and rimantadine but are susceptible to neuraminidase inhibitors, which can be used for treatment and prophylaxis. The widespread epidemic of avian influenza in domestic birds increases the likelihood for mutational events and genetic reassortment. The threat of a future pandemic from avian influenza is real. Adequate surveillance, development of vaccines, outbreak preparedness, and pandemic influenza planning are important. This article summarizes the current knowledge on avian influenza, including the virology, epidemiology, diagnosis, and management of this emerging disease.     

Digitalis

Abstract

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

Direct Administration in the Respiratory Tract Improves Efficacy of Broadly Neutralizing Anti-Influenza Virus Monoclonal Antibodies

The emergence of influenza virus strains resistant to approved neuraminidase inhibitors and the time constrains after infection when these drugs can be effective constitute major drawbacks for this class of drugs. This highlights a critical need to discover new therapeutic agents that can be used for the treatment of influenza virus-infected patients. The use of broadly neutralizing anti-influenza monoclonal antibodies (MAbs) has been sought as an alternative immunotherapy against influenza infection. Here, we tested in mice previously characterized broadly neutralizing anti-hemagglutinin (HA) stalk MAbs prophylactically and therapeutically using different routes of administration. The efficacy of treatment against an influenza H1N1 pandemic virus challenge was compared between two systemic routes of administration, intraperitoneal (i.p.) and intravenous (i.v.), and two local routes, intranasal (i.n.) and aerosol (a.e.). The dose of MAb required for prophylactic protection was reduced by 10-fold in animals treated locally (i.n. or a.e.) compared with those treated systemically (i.p. or i.v.). Improved therapeutic protection was observed in animals treated i.n. on day 5 postinfection (60% survival) compared with those treated via the i.p. route (20% survival). An increase in therapeutic efficacy against other influenza virus subtypes (H5N1) was also observed when a local route of administration was used. Our findings demonstrate that local administration significantly decreases the amount of broadly neutralizing monoclonal antibody required for protection against influenza, which highlights the potential use of MAbs as a therapeutic agent for influenza-associated disease.     

The course and management of the 2009 H1N1 pandemic influenza

The 2009 influenza A (H1N1) pandemic provided a major test to the public health system in the United States and abroad. Although the virus was rapidly identified, it took longer than expected to bring an effective vaccine to market. During the interim the virus demonstrated a predilection for infecting younger persons, particularly those with medical conditions such as asthma or pregnancy, placing them at risk. Early treatment with neuraminidase inhibitors was found to be of some benefit. When the 2009 H1N1 influenza A vaccine became available, there were distribution issues in matching the number of doses to areas of need.