Developing New Antiviral Agents for Influenza Treatment: What Does the Future Hold?

Clinical Infectious Diseases, Jan 2009

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

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Developing New Antiviral Agents for Influenza Treatment: What Does the Future Hold?

New Antiviral Agents for Influenza Treatment • CID Developing New Antiviral Agents for Influenza Treatment: What Does the Future Hold? Frederick Hayden 0 0 Global Influenza Programme, World Health Organization , Geneva , Switzerland; and University of Virginia School of Medicine , Charlottesville Antiviral agents for the treatment of influenza are urgently needed to circumvent the limitations of current drugs in several critical areas: high frequencies of resistance to M2 inhibitors among currently circulating strains and variable frequencies of resistance to oseltamivir among A(H1N1) strains, limited efficacy of treatment and treatment-emergent antiviral resistance in cases of avian influenza A(H5N1) illness in humans, and lack of parenteral agents for seriously ill patients. Two neuraminidase inhibitors (NAIs), zanamivir and peramivir, have undergone or are undergoing clinical trials for use by intravenous or intramuscular administration, and one long-acting NAI, designated CS-8958, is under study for use by inhalation. Advances in understanding the mechanisms involved in influenza virus replication have revealed a number of potential targets that might be exploited in the development of new agents. Among these agents are T-705, a polymerase inhibitor, and DAS181, an attachment inhibitor. Combination therapy with currently available agents is supported by data from animal models but has received limited clinical study to date. Three principal factors drive the medical need for the development of new antiviral agents for the treatment of influenza: antiviral resistance; limited antiviral efficacy in severe cases of influenza, including in influenza A(H5N1) disease; and a lack of parenteral agents. Since 2003, the frequency of viral resistance to the M2 ionchannel inhibitors (i.e., M2 inhibitors, or adamantanes)—namely, amantadine (e.g., Symmetrel; Endo Laboratories) and rimantadine (e.g., Flumadine; Forest Laboratories)—has increased rapidly among seasonal influenza A(H3N2) viruses and is now so widespread that this class of drugs has been rendered mostly ineffective, although they retain activity against most influenza A(H1N1) viruses [ 1, 2 ]. The 2007–2008 influenza season also was notable for the community circulation of influenza A(H1N1) viruses resistant to oseltamivir in many countries [3]. Emergence of resistance to M2 inhibitors and to neuraminidase inhibitors (NAIs) also has been a clinical problem in some highly immunocompromised hosts. Administration of the oral NAI oseltamivir appears to be beneficial in the treatment of seasonal influenza in hospitalized patients [ 4– 6 ] and of some cases of highly pathogenic avian influenza A(H5N1) in humans, but it has not reduced the overall case-fatality rate to below ∼50% for avian influenza A(H5N1) [ 7 ]. Multiple factors likely contribute to this high mortality, including late presentation for care, emergence of resistance to oseltamivir, and possibly reduced bioavailability in some patients. In this regard, and of particular relevance in the clinical management of seriously ill, hospitalized patients, no parenteral agents for the treatment of influenza are currently available. Each of these factors contributes to the need for alternative antiviral treatments, particularly with regard to pandemic preparedness, and for the consideration of combination therapy. Several of the agents that are undergoing clinical testing will be highlighted in this article. M2-INHIBITOR RESISTANCE Emergence of resistance during the therapeutic use of M2 inhibitors is well known; estimates of the prevalence of M2-inhibitor resistance that occurs during thera a Antiviral resistance detected in individual patients, but frequency not reported. peutic use are shown in table 1 [ 9, 10, 12, 15, 17 ]. In addition, in recent years, the prevalence of resistance to M2 inhibitors among community A(H3N2) isolates has increased dramatically and spread globally, as shown in figure 1 [ 1, 2 ]. In 2006, this led to changes in the US Advisory Committee on Immunization Practices recommendations regarding the use of this entire class of antiviral drugs [18]. Earlier surveillance studies found that primary resistance occurred at low frequencies among seasonal isolates and that, historically, the frequency of resistance was 1%–3%. Increasing frequencies of M2-inhibitor resistance first appeared among influenza virus A(H3N2) isolates from China and Hong Kong during the 2003 influenza season and then spread globally, with rates during the 2005– 2006 influenza season of 190% not only in Asia but also in the United States and of nearly 50% in Europe. Data from the 2006–2007 influenza season showed rates of M2-inhibitor resistance of 180% in Asia and the United States and 150% in parts of Europe. Very high frequencies of resistant A(H3N2) viruses continued to be detected during the 2007–2008 influenza season in the northern hemisphere. A geographically variable, increased frequency of resistance among A(H1N1) viruses also has been observed, although the overall proportion of resistant A(H1N1) viruses is not as high as that for A(H3N2) viruses. Resistance in recent A(H3N2) and A(H1N1) virus isolates has been due to a serine-to-asparagine substitution at position 31 in the M2 protein. Unfortunately, resistance to either of the current M2 inhibitors, amantadine or rimantadine, confers resistance to the entire class of M2 inhibitors, although M2 inhibitor–resistant viruses are still susceptible to the NAIs. From a public health perspective, these variants retain their virulence and their transmissibility from person to person. No loss of biological fitness has been ascertained in the laboratory or in epidemiologic studies. Resistance to the M2-inhibitor class of antiviral drugs is also seen in many A(H5N1) viruses [ 19 ]. The clade 1 viruses that first appeared in Vietnam, Thailand, and Cambodia also are resistant because of a serine-to-asparagine substitution at position 31, the same mutation found in the resistant A(H3N2) viruses. A high frequency of M2-inhibitor resistance also has been seen in clade 2.1 viruses that circulate in Indonesia, because of this mutation or of one at position 27. On the other hand, most (190%) of the clade 2.2 viruses that have spread across Eurasia to Europe and Africa and clade 2.3 viruses have retained sensitivity to the M2 inhibitors. Limited data suggest that amantadine was effective in some individual patients with M2 inhibitor–susceptible A(H5N1) disease in Hong Kong in 1997, when these viruses were first found to cause illness in humans [ 20 ]. NAI RESISTANCE Resistance to NAIs occurs during therapeutic use (table 1) [ 8, 11, 13, 14, 16, 21 ] and at low frequencies among community isolates [ 22–24 ]. New mutations associated with reduced susceptibility continue to be recognized, as more-detailed surveillance is used. However, the inhibitory activity of NAIs against all 9 neuraminidase subtypes recognized in avian viruses predicts that NAIs would likely be active against a pandemic strain whether it is an A(H5N1) virus or some other novel virus that has gained its hemagglutinin and neuraminidase from an animal virus. Within the NAI class of antiviral drugs, there is an interesting phenomenon of variable cross-resistance that depends on the neuraminidase type and subtype, the drug, and the particular neuraminidase mutation, because of different interactions of the drugs within the active enzyme site. The practical consequence is that zanamivir (Relenza; GlaxoSmithKline) retains full inhibitory activity for several neuraminidase subtypes when mutations that confer resistance to oseltamivir (Tamiflu; Roche Laboratories) are present. Resistance to oseltamivir also has been documented in outpatient adults, outpatient children, and inpatient children (table 1) [ 8, 11, 14, 16, 21 ]. The frequency of resistance to oseltamivir is much lower than that observed for M2 inhibitors but is not insignificant, particularly among children; resistant variants were detected in nearly 1 in 5 pediatric patients in one study conducted in Japan [ 1 ]. Not surprisingly, the frequency with which resistant virus is detected in children is substantially higher than that for adults because, in general, children have higher viral replication loads and a correspondingly greater opportunity for the emergence of resistant variants. NAI-resistant variants usually have reduced infectivity and virulence in animal models of influenza but not always. Some oseltamivirresistance mutations are associated with full replication competence and transmissibility in animal models. Earlier studies of community isolates found that viruses with resistance mutations (based on N2 numbering) in influenza A (arginine to lysine at 292, glutamic acid to valine at 119 in the N2 neuraminidase, and histidine to tyrosine at 274 in the N1 neuraminidase) and B neuraminidases (aspartic acid to asparagine at 198, isoleucine to threonine at 222, and serine to glycine at 250) probably have been transmitted from person to person [ 23, 24 ]. Influenza A(H1N1) viruses resistant to oseltamivir because of the histidine-to-tyrosine mutation at position 274 appeared in many countries for the first time during the 2007– 2008 influenza season [3]. This phenomenon has occurred in the apparent absence of selective drug pressure and indicates that these resistant variants are efficiently transmitted from person to person and capable of causing typical influenza [ 25 ]. Emergence of resistance has been documented in influenza A(H5N1) virus–infected patients treated with oseltamivir. In a case-series study of 8 patients from Vietnam, de Jong et al. [ 26 ] (figure 2) observed that a standard course of oseltamivir therapy begun a median of 6 days after the onset of illness was associated temporally with reductions in pharyngeal viral loads in half the patients and that pharyngeal viral RNA clearance at the end of the treatment course was linked with survival. In contrast, those patients who had increasing viral loads over time or failure to clear virus succumbed to their illness. Two of these individuals had treatment-emergent oseltamivir-resistant viral variants with a histidine-to-tyrosine mutation at position 274, the most common mutation observed in N1 neuraminidase–containing viruses. N1 neuraminidase with this mutation shows marked reductions (1400-fold) in susceptibility to oseltamivir but remains inhibited by zanamivir [ 27, 28 ]. Oseltamivir treatment and prophylaxis has been used with apparent benefit in immunocompromised hosts with influenza virus infection [ 29–33 ]. However, emergence of oseltamivirresistant variants has occurred in some immunocompromised hosts and appears to be correlated with protracted viral replication and poor clinical outcomes [ 16 ]. In some highly immunocompromised hosts, sequential therapy with both antiviral drug classes has been used, in part because viral clearance failed in these patients. Unfortunately, in this population, dual resistance to both M2 inhibitors and NAIs has been found [ 16 ]. The approach of sequential drug use in the management of influenza should be avoided for immunocompromised hosts. LIMITATIONS OF CURRENT ANTIVIRAL TREATMENTS FOR INFLUENZA The efficacy of current antiviral treatments is limited or uncertain in certain populations and situations. For example, oseltamivir carboxylate, the active metabolite of oseltamivir, is substantially less active against influenza B than against influenza A neuraminidases (table 2). This finding has been corroborated in several studies from Japan, which have indicated that among children, particularly young children, the treatment of influenza B with oseltamivir is associated with delayed antiviral effects and clinical resolution, compared with the treatment of influenza A [ 35–37 ]. Furthermore, no controlled studies have been completed in high-risk or hospitalized populations, although emerging evidence suggests that even delayed treatment is beneficial for adults hospitalized with serious seasonal influenza [ 4–6 ]. The efficacy of oral oseltamivir is limited in A(H5N1) disease, for which overall mortality is ∼60% [ 38 ]. The case-fatality ratio among those receiving oseltamivir has hovered around 50%, compared with nearly 90% among those not receiving antiviral treatment [ 7 ]. Multiple contributing factors are likely, particularly delayed time from illness onset to antiviral treatment, and early administration (within 3–4 days after illness onset) has been associated with reduced mortality. The World Health Organization (WHO) updated its clinical management advice for avian influenza A(H5N1) virus infection in humans in 2006 and again in 2007 [ 39, 40 ]. The updated guidelines are based in part on clinical reports shared at a meeting in Turkey in March 2007 [41], and they address both antiviral treatment and supportive care and discuss the theoretical use of immunomodulators. These guidelines provide guidance on what appears to help (i.e., oseltamivir, oxygen therapy, and lung-protective ventilatory-support strategies) and on what does not (including antibiotic prophylaxis, high-dose corticosteroids, and M2-inhibitor monotherapy, especially when the virus strain is resistant to M2 inhibitors). In fact, use of corticosteroids appears to be associated with an increased risk of mortality [ 7 ]. NEW ANTIVIRAL AGENTS FOR INFLUENZA TREATMENT Multiple potential targets are now being explored actively in the search for new antiviral treatments for influenza. Some of the potential sites of intervention are shown in figure 3 [ 42 ]. Several recent review articles have discussed comprehensively the state of the science with regard to both targets for new antiviral drug development and the status of some of the antiviral agents, particularly those in preclinical and early clinical development [ 42–44 ]. Of the many antiviral agents now in various stages of development, some agents and formulations that have shown preclinical activity and that are now being tested in human trials are listed in table 3. Parenteral NAIs. Current antiviral treatments are given either orally or by inhalation. These routes may not provide rapid, reliable drug delivery in seriously ill patients. For example, failure of zanamivir therapy for the treatment of pneumonia in a bone-marrow transplant recipient has been reported, even though the influenza A(H1N1) virus with which the patient was infected was sensitive to zanamivir [ 45 ]. In addition, the oral bioavailability of oseltamivir, especially when given by nonstandard means (e.g., via nasogastric tube), is uncertain, although a recent report on 3 patients found adequate absorption under such circumstances [ 46 ]. Parenteral administration would circumvent these limitations by guaranteeing rapid delivery and high levels in blood to increase the likelihood of drug delivery to sites of infection, especially in those with pneumonia or, for patients with influenza A(H5N1) virus infection, extrapulmonary infection. The poor oral bioavailability of zanamivir (∼2%) is well documented [ 47 ] and provides the impetus for the development of alternate administration routes for the drug. Although an inhaled formulation is approved, intravenous zanamivir has been evaluated in phase 2a testing [ 48 ]. In healthy volunteers receiving 600 mg zanamivir or placebo intravenously twice daily for 5 days prior to a virus challenge, zanamivir was found to be highly protective against experimental infection (14% vs. 100%, respectively, were infected), to reduce viral shedding (0% vs. 100%, respectively, had viral shedding), and to prevent illness [ 48 ]. Intravenous zanamivir is active in a primate model of A(H5N1) virus infection [ 49 ], and the Southeast Asia Influenza Clinical Research Network [ 50 ] is developing a protocol to study it in patients with avian influenza A(H5N1) illness. More recently, the NAI peramivir (BioCryst Pharmaceuticals) is currently in phase 2 trials for both intravenous and New Antiviral Agents for Influenza Treatment • CID 2009:48 (Suppl 1) • S7 intramuscular routes of administration. In vitro IC50 data for oseltamivir, zanamivir, and peramivir show that all 3 agents are potent inhibitors of influenza virus neuraminidases in the low nanomolar range (table 2) [ 34 ]. In an animal model of influenza A(H5N1) virus infection, mice receiving multiple oral doses of oseltamivir over 5 consecutive days or peramivir (administered as either a single intramuscular injection or as 5 intramuscular injections over 5 consecutive days), starting at 1 h after virus inoculation, were more likely to survive than were control mice injected with saline (table 4) [ 51 ]. The multiple-dose peramivir regimen was the only regimen that prevented paralysis by day 15 (table 4). However, intramuscular peramivir provided incomplete protection against neuroinvaS8 • CID 2009:48 (Suppl 1) • Hayden sive A(H5N1) disease in a second animal model. Among ferrets infected with 1 of 3 different doses of influenza A(H5N1) virus, overall survival improved with multiple doses of intramuscular peramivir (70%–86%), compared with survival among those given an intramuscular injection of saline (11%–43%); encephalitis was less common among peramivir recipients (32% [8/25]), compared with saline recipients (50% [13/26]); and paralysis developed in 8% (2/25) of animals that received treatment with multiple intramuscular doses of peramivir, compared with 42% (11/26) of animals given intramuscular doses of saline [ 51 ]. Peramivir has a prolonged plasma elimination half-life in humans and also appears to bind to the enzyme for a prolonged time [ 52 ]—2 factors that permit infrequent dosing regimens. In dose-ranging studies performed with healthy volunteers, the peak plasma concentrations for intramuscular and intravenous peramivir (10,000–20,000 ng/mL) are nearly 2 orders of magnitude higher than those achieved with standard doses of oral oseltamivir (∼350 ng/mL; figure 4) [ 53 ]. It remains to be determined in clinical trials to what extent these higher levels in blood may provide greater antiviral efficacy and perhaps reduced frequency of resistance emergence. Future studies will need to determine whether such high plasma NAI levels will translate into greater clinical benefits for high-risk or hospitalized patients with influenza. A recent report indicated that a single 300- or 600-mg dose of intravenous peramivir was efficacious in the treatment of uncomplicated influenza in adult outpatients [ 54 ] Long-acting NAIs. Biota Holdings of Australia and Sankyo Pharmaceuticals of Japan are codeveloping long-acting inhaled NAIs. CS-8958 (also known as R-118958) shows good activity in murine models of influenza treatment with once weekly dosing [ 55, 56 ]. Rennecke et al. [56] reported that, in healthy male subjects, R-118958 doses of 1, 2, 5, or 10 mg administered by inhalation did not result in the active metabolite being detectable in plasma, although it was detected in urine for up to 144 h after administration of the 5-mg and 10-mg doses. No serious adverse events or clinically significant changes in laboratory tests were noted. Available data suggest that CS-8958 may permit a more convenient topical dosing regimen, and the sponsors of a phase 2 study in Japan recently announced that a single inhaled dose was found to be as effective as a standard 5-day course of oseltamivir in the treatment of uncomplicated influenza [ 57 ]. Polymerase inhibition. T-705 (Toyama Chemical) is not only active against all 3 influenza virus types (A, B, and C) but also has some activity against other RNA viruses, including some of the hemorrhagic fever viruses [ 58, 59 ]. T-705 undergoes ribosylation and then phosphorylation and thus functions like a nucleoside. Its primary mechanism of action is the inhibition of viral RNA polymerase. It appeared to show a more favorable therapeutic index than did ribavirin in preclinical tests of toxicity, including those done with human cells (table 5) [59], and has been shown to be active in murine models of influenza A(H5N1) virus infection (figure 5) [ 60 ]. These data demonstrated a survival benefit as late as 48 h after virus inoculation in a cohort given a 300-mg/kg/day dose and up to 60 h after virus inoculation in a cohort given the 600-mg/kg/ day dose. Initial unpublished data on human pharmacology are encouraging with regard to oral absorption and tolerability, and phase 2 efficacy studies have been ongoing in Japan during the 2007–2008 influenza season. Attachment inhibition. DAS181 (Fludase; NexBio) is a fusion construct that incorporates the sialidase from Actinomyces viscosus, a common oral bacterium linked to a human epithelium-anchoring domain; it can be mass produced in Escherichia coli [ 61 ]. The sialidase targets the viral attachment process, an early event in the replication of influenza virus. When this molecule is exposed to cells, it cleaves off the surface receptors on respiratory epithelium that are recognized by influenza hemagglutinin—both the a2,6-sialic acid–linked receptors to which human viruses attach and the a2,3-sialic acid–linked receptors to which avian viruses attach. DAS181 is inhibitory for a range of influenza A and B viruses, with in vitro EC90 values ranging from !1 to 56 nmol/L [ 61 ]. The epithelial tag on this molecule increases its activity by an order of magnitude (∼5–30-fold) [ 61 ]. In vitro removal of receptors by DAS181 leads to a prolonged antiviral effect, although it is not clear whether this effect will translate into a less-frequent dosing regimen in the clinic. The molecule is not inhibitory for human cell growth. Intranasal dosing has shown prophylactic and therapeutic activity in mice and antiviral effects with reduced inflammatory responses in ferrets [ 61 ]. Figure 6 illustrates the effect of DAS181 when administered intranasally in a rodent model of influenza [ 61 ]. In a murine model of highly pathogenic avian influenza using influenza A/Vietnam/1203/2004(H5N1)—a stringent test of an antiviral agent—DAS181 was active both prophylactically and therapeutically [ 62 ]. Administered prophylactically, a DAS181 dosage of 1 mg/kg/day protected 100% of mice from fatal disease and prevented viral dissemination to the brain. Therapeutically, antiviral effects and increased survival of mice exposed to an A(H5N1) virus challenge were noted when treatment began as late as 72 h after infection [ 62 ]. COMBINATION THERAPY Combination therapy is not a new concept in the management of influenza. In fact, it initially was explored for the treatment of influenza in preclinical assays years before it became the standard of care in the management of HIV infection. Although a promising strategy, little data from controlled clinical trials of combination therapy for the treatment of influenza have been published. Several years ago, when circulating influenza A viruses were predictably susceptible to M2 inhibitors, the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group compared outcomes among hospitalized adults who received either nebulized zanamivir plus oral rimantadine or nebulized saline placebo plus oral rimantadine [ 63 ]. The small number of patients enrolled in this study limited its statistical power, but some encouraging trends were noted among patients who received combination therapy, compared with those who received rimantadine alone. Patients treated with zanamivir plus rimantadine demonstrated nonsignificant trends toward fewer days of viral shedding and reduced frequency of M2-inhibitor resistance. Patients assigned to combination therapy also were more likely to have either no cough or only a mild cough by the third day of treatment (15/16 [94%] vs. 11/20 [55%]; P p .01) [ 63 ]. No resistant variants were found in patients in the group receiving combination therapy, compared with 3 patients in the group receiving rimantadine alone. M2 inhibitor–NAI combination therapy also has been investigated for the treatment of A(H5N1) disease. Figure 7 shows the effect of single drugs and combination therapy on survival among mice inoculated with an amantadine-sensitive strain of influenza A(H5N1) virus [ 64 ]. Although monotherapy showed dose-related effects, the combination of amantadine and oseltamivir at higher doses resulted in the highest level of survival and antiviral effects in this animal model. In contrast, no greater benefit was noted beyond the effects of oseltamivir alone when the infecting A(H5N1) virus was resistant to M2 inhibitors. This suggests that M2 inhibitor–NAI combination therapy is a potential treatment option for seriously ill patients if the influenza virus causing the infection is susceptible to M2 inhibitors. As previously noted, some A(H5N1) strains retain susceptibility to M2 inhibitors; consequently, the possibility of combination therapy has been suggested in recent WHO management guidelines [ 40 ]. Various other antiviral combinations have been studied or proposed, as shown in table 6 [ 65–73 ]. Further preclinical studies and eventually clinical trials will be invaluable for determining whether these new agents or suggested combinations will offer clinically meaningful benefits beyond those attained S10 • CID 2009:48 (Suppl 1) • Hayden with current agents. However, until such clinical trial data are available, physicians must make difficult treatment decisions based on knowledge of patient characteristics and likely or actual antiviral susceptibility patterns. The following 2 cases are examples of such choices. A kidney-transplant patient, aged 40 years, was admitted to the hospital with respiratory symptoms and influenza A virus infection in February 2007. In theory, this patient could have been treated with oseltamivir, zanamivir, or rimantadine, alone or in combination. Given the fact that the influenza virus infection was most likely due to an A(H3N2) virus that was resistant to the M2 inhibitors, there would be little point in the use of rimantadine, since it would have increased the risk of toxicity with little chance of improving the clinical outcome. Combination therapy with oseltamivir and zanamivir would have offered the benefit of providing 2 NAIs with differing spectrums of action and sites of drug delivery. Unfortunately, the efficacy and tolerability of orally inhaled zanamivir for hospitalized patients or of this combination approach in relevant animal models have not been studied adequately. High-dose oral ribavirin [ 74 ] and intravenous ribavirin [ 75 ] are other possibilities but are investigational for the treatment of influenza. Thus, at that time, oral oseltamivir was the most practical treatment option. By contrast, suppose that, during the course of an investigation into an avian influenza outbreak in Romania, a patient with confirmed poultry exposure is admitted to the hospital with a 5-day history of fever, cough, and now-increasing shortness of breath. Testing reveals influenza A(H5N1) virus infection, presumably owing to a clade 2.2 virus, and there is radiographic evidence of pneumonia. Currently, there is no evidence from randomized, controlled clinical trials to indicate selection of a specific antiviral intervention in this case. The updated WHO guidelines would recommend oseltamivir therapy but also would suggest consideration of alternative drug regimens, including combination treatment with an M2 inhibitor and oseltamivir, as well as doubling the oseltamivir dose and duration of therapy. Since almost all A(H5N1) viruses from clade 2.2 are susceptible to the M2 inhibitors, combination treatment with oseltamivir and rimantadine would be a reasonable approach. Given the low likelihood of survival of someone with pneumonic A(H5N1) disease, interventions that control replication as quickly as possible make sense. Hopefully, in future, parenteral agents, including specific monoclonal antibodies [ 76 ] or possibly convalescent plasma [ 77 ], will become available for study in such a patient. CURRENT TRENDS IN ANTIVIRAL DRUGS FOR INFLUENZA TREATMENT Numerous efforts are under way to develop new antiviral agents for influenza treatment that possess an improved spectrum of activity or better pharmacologic profiles, relative to current treatments. Some of the most desirable features of future antiviral agents for influenza treatment include greater potency that quickly curtails viral replication, longer plasma or pulmonary half-lives that permit fewer doses (or even a single therapeutic dose), reduction in the risk of development of resistant influenza virus strains, and completely new modes of antiviral action for use in combination therapies. Acknowledgments Financial support. BioCryst Pharmaceuticals, Inc., provided educational grant support to develop this article and the symposium on which it is based, “Antiviral Therapy for Influenza: Challenging the Status Quo” (San Diego), 4 October 2007. Supplement sponsorship. This article was published as part of a supplement entitled “Antiviral Therapy for Influenza: Challenging the Status Quo,” jointly sponsored by the Institute for Medical and Nursing Education and International Medical Press and supported by an educational grant from BioCryst Pharmaceuticals, Inc. Manuscript preparation. F.H. was a staff member of the World Health Organization at the time of the symposium and during the writing of this manuscript; the views expressed in this article are those of the author and do not necessarily represent the decisions or the stated policy of the World Health Organization. Margery Tamas of International Medical Press (Atlanta) provided assistance in preparing and editing the manuscript. Potential conflicts of interest. F.H.: no conflicts. S12 • CID 2009:48 (Suppl 1) • Hayden 1. Bright RA , Medina MJ , Xu X , et al. Incidence of adamantane resistance among influenza A(H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern . Lancet 2005 ; 366 : 1175 - 81 . 2. Deyde VM , Xu X , Bright RA , et al. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide . J Infect Dis 2007 ; 196 : 249 - 57 . 3. World Health Organization (WHO). Epidemic and pandemic alert and response (EPR): influenza A(H1N1) virus resistance to oseltamivir . Geneva: WHO , 6 March 2008 . Available at: http://www.who.int/csr/ disease/influenza/h1n1_table/en/index.html. Accessed 7 March 2008 . 4. McGeer A , Green KA , Plevneshi A , et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario , Canada. Clin Infect Dis 2007 ; 45 : 1568 - 75 . 5. Lee N , Chan PK , Choi KW , et al. Factors associated with early hospital discharge of adult influenza patients . Antivir Ther 2007 ; 12 : 501 - 8 . 6. Lee N , Cockram C , Chan P , Hui D , Choi KW , Sung J . Antiviral treatment for patients hospitalized with severe influenza may affect clinical outcomes . Clin Infect Dis 2008 ; 46 : 1323 - 4 . 7. Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus. Update on avian influenza A(H5N1) virus infection in humans . N Engl J Med 2008 ; 358 : 261 - 73 . 8. Roberts NA . Treatment of influenza with neuraminidase inhibitors: virological implications . Philos Trans R Soc Lond B Biol Sci 2001 ; 356 : 1895 - 7 . 9. Hayden FG , Sperber SJ , Belshe RB , Clover RD , Hay AJ , Pyke S. Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine . Antimicrob Agents Chemother 1991 ; 35 : 1741 - 7 . 10. Hayden FG , Belshe RB , Clover RD , Hay AJ , Oakes MG , Soo W. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families . N Engl J Med 1989 ; 321 : 1696 - 702 . 11. Whitley RJ , Hayden FG , Reisinger KS , et al. Oral oseltamivir treatment of influenza in children . Pediatr Infect Dis J 2001 ; 20 : 127 - 33 (erratum: Pediatr Infect Dis J 2001 ; 20 : 421 ). 12. Hall CB , Dolin R , Gala CL , et al. Children with influenza A infection: treatment with rimantadine . Pediatrics 1987 ; 80 : 275 - 82 . 13. Ward P , Small I , Smith J , Suter P , Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic . J Antimicrob Chemother 2005 ; 55 ( Suppl 1 ): i5 - 21 . 14. Kiso M , Mitamura K , Sakai-Tagawa Y , et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study . Lancet 2004 ; 364 : 759 - 65 . 15. Shiraishi K , Mitamura K , Sakai-Tagawa Y , Goto H , Sugaya N , Kawaoka Y. High frequency of resistant viruses harboring different mutations in amantadine-treated children with influenza . J Infect Dis 2003 ; 188 : 57 - 61 . 16. Ison MG , Gubareva LV , Atmar RL , Treanor J , Hayden FG . Recovery of drug-resistant influenza virus from immunocompromised patients: a case series . J Infect Dis 2006 ; 193 : 760 - 4 . 17. Englund JA , Champlin RE , Wyde PR , et al. Common emergence of New Antiviral Agents for Influenza Treatment • CID 2009:48 (Suppl 1) • S11 amantadine- and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults . Clin Infect Dis 1998 ; 26 : 1418 - 24 . 18. Smith NM , Bresee JS , Shay DK , et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) . MMWR Recomm Rep 2006 ; 55 (RR-10): 1 - 42 . 19. Cox NJ. FDA H5N1 update: classification of H5N1 viruses and development of vaccine reference strains . US Food and Drug Administration Vaccines and Related Biological Products Advisory Committee presentation (Gaithersburg , Maryland), 2007 . Available at: http:// www.fda.gov/ohrms/dockets/AC/07/slides/2007-4282S2_ 9 .ppt. Accessed 17 August 2007 . 20. Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A(H5N1) infection in humans . N Engl J Med 2005 ; 353 : 1374 - 85 . 21. Whitley RJ , Monto AS . Prevention and treatment of influenza in highrisk groups: children, pregnant women, immunocompromised hosts, and nursing home residents . J Infect Dis 2006 ; 194 ( Suppl 2 ): S133 - 8 . 22. Neuraminidase Inhibitor Susceptibility Network . Use of influenza antivirals during 2003-2004 and monitoring of neuraminidase inhibitor resistance . Wkly Epidemiol Rec 2005 ; 80 : 156 . 23. Monitoring of neuraminidase inhibitor resistance among clinical influenza virus isolates in Japan during the 2003-2006 influenza seasons . Wkly Epidemiol Rec 2007 ; 82 : 149 - 50 . 24. Hatakeyama S , Sugaya N , Ito M , et al. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors . JAMA 2007 ; 297 : 1435 - 42 . 25. World Health Organization (WHO). Epidemic and pandemic alert and response (EPR): WHO/ECDC frequently asked questions for oseltamivir resistance . Geneva: WHO , 15 February 2008 . Available at: http: //www.who.int/csr/disease/influenza/oseltamivir_faqs/en/index.html. Accessed 7 March 2008 . 26. de Jong MD , Tran TT , Truong HK , et al. Oseltamivir resistance during treatment of influenza A(H5N1) infection . N Engl J Med 2005 ; 353 : 2667 - 72 . 27. Mishin VP , Hayden FG , Gubareva LV . Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors . Antimicrob Agents Chemother 2005 ; 49 : 4515 - 20 . 28. Wetherall NT , Trivedi T , Zeller J , et al. Evaluation of neuraminidase enzyme assays using different substrates to measure susceptibility of influenza virus clinical isolates to neuraminidase inhibitors: report of the Neuraminidase Inhibitor Susceptibility Network . J Clin Microbiol 2003 ; 41 : 742 - 50 . 29. Chik KW , Li CK , Chan PK , et al. Oseltamivir prophylaxis during the influenza season in a paediatric cancer centre: prospective observational study . Hong Kong Med J 2004 ; 10 : 103 - 6 . 30. Vu D , Peck AJ , Nichols WG , et al. Safety and tolerability of oseltamivir prophylaxis in hematopoietic stem cell transplant recipients: a retrospective case-control study . Clin Infect Dis 2007 ; 45 : 187 - 93 . 31. Chemaly RF , Ghosh S , Bodey GP , et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center . Medicine (Baltimore) 2006 ; 85 : 278 - 87 . 32. Nichols WG , Guthrie KA , Corey L , Boeckh M. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy . Clin Infect Dis 2004 ; 39 : 1300 - 6 . 33. Machado CM , Boas LS , Mendes AV , et al. Use of oseltamivir to control influenza complications after bone marrow transplantation . Bone Marrow Transplant 2004 ; 34 : 111 - 4 . 34. Gubareva LV , Webster RG , Hayden FG . Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants . Antimicrob Agents Chemother 2001 ; 45 : 3403 - 8 . 35. Kawai N , Ikematsu H , Iwaki N , et al. Factors influencing the effectiveness of oseltamivir and amantadine for the treatment of influenza: a multicenter study from Japan of the 2002-2003 influenza season . Clin Infect Dis 2005 ; 40 : 1309 - 16 . 36. Kawai N , Ikematsu H , Iwaki N , et al. A comparison of the effectiveness of oseltamivir for the treatment of influenza A and influenza B: a Japanese multicenter study of the 2003-2004 and 2004-2005 influenza seasons . Clin Infect Dis 2006 ; 43 : 439 - 44 . 37. Sugaya N , Mitamura K , Yamazaki M , et al. Lower clinical effectiveness of oseltamivir against influenza B contrasted with influenza A infection in children . Clin Infect Dis 2007 ; 44 : 197 - 202 . 38. Update: WHO-confirmed human cases of avian influenza A(H5N1) infection, 25 November 2003-24 November 2006 . Wkly Epidemiol Rec 2007 ; 82 : 41 - 7 . 39. Schu¨ nemann HJ, Hill SR , Kakad M , et al. WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A(H5N1) virus . Lancet Infect Dis 2007 ; 7 : 21 - 31 . 40. World Health Organization (WHO). Epidemic and pandemic alert and response (EPR): clinical management of human infection with avian influenza A(H5N1) virus; updated advice . Geneva: WHO , 15 August 2007 . Available at: http://www.who.int/csr/disease/avian_influenza/ guidelines/clinicalmanage07/en/index.html. Accessed 5 September 2007 . 41. World Health Organization (WHO). Epidemic and pandemic alert and response (EPR): the second WHO consultation on clinical aspects of human infection with avian influenza A(H5N1) virus (Antalya, Turkey) . Geneva: WHO , 2007 . Available at: http://www.who.int/csr/disease/influenza/meeting2007_ 03 _19/en/index.html. Accessed 4 January 2008 . 42. De Clercq E. Antiviral agents active against influenza A viruses . Nat Rev Drug Discov 2006 ; 5 : 1015 - 25 . 43. Hsieh HP , Hsu JT . Strategies of development of antiviral agents directed against influenza virus replication . Curr Pharm Des 2007 ; 13 : 3531 - 42 . 44. Beigel J , Bray M. Current and future antiviral therapy of severe seasonal and avian influenza . Antivir Res 2008 ; 78 : 91 - 102 . 45. Medeiros R , Rameix-Welti MA , Lorin V , et al. Failure of zanamivir therapy for pneumonia in a bone-marrow transplant recipient infected by a zanamivir-sensitive influenza A(H1N1) virus . Antivir Ther 2007 ; 12 : 571 - 6 . 46. Taylor WR , Thinh BN , Anh GT , et al. Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 influenza . PLoS ONE 2008 ; 3 : e3410 . 47. Cass LM , Efthymiopoulous C , Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers . Clin Pharmacokinet 1999 ; 36 ( Suppl 1 ): 1 - 11 . 48. Calfee DP , Peng AW , Cass LM , Lobo M , Hayden FG . Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection . Antimicrob Agents Chemother 1999 ; 43 : 1616 - 20 . 49. Stittelaar KJ , Tisdale M , van Amerongen G , et al. Evaluation of intravenous zanamivir against experimental influenza A(H5N1) virus infection in the cynomolgus macaques . Antivir Res 2008 ; 80 : 225 - 8 . 50. Higgs ES , Hayden FG , Chotpitayasunondh T , Whitworth J , Farrar J . The Southeast Asia Influenza Clinical Research Network: development and challenges for a new multilateral research endeavor . Antivir Res 2008 ; 78 : 64 - 8 . 51. Yun NE , Linde NS , Zacks MA , et al. Injectable peramivir mitigates disease and promotes survival in ferrets and mice infected with highly virulent influenza virus A /Vietnam/1203/04( H5N1 ). Virology 2008 ; 374 : 198 - 209 . 52. Bantia S , Arnold CS , Parker CD , Upshaw R , Chand P. Anti-influenza virus activity of peramivir in mice with single intramuscular injection . Antiviral Res 2006 ; 69 : 39 - 45 . 53. Kilpatrick JM , Harman LA , Collis PJ , Aitee G , Mead E , Alexander WJ . Pharmacokinetics and safety of peramivir by intramuscular administration [abstract P916] . In: Program and abstracts of the Options for the Control of Influenza VI Conference (Toronto) . London: International Society for Influenza and Other Respiratory Virus Diseases , 2007 . 54. Kohno S , Kida H , Mizuguchi M , Shimada J. A double-blind, placebocontrolled study of intravenous peramivir in acute influenza patients [abstract 302(V)] . Program and abstracts of the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting (Washington, DC). Washington, DC: American Society for Microbiology, 2008 : 328 . 55. Macdonald SJF , Watson KG , Cameron R , et al. Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at once-weekly dosing regimen . Antimicrob Agents Chemother 2004 ; 48 : 4542 - 9 . 56. Rennecke J , Hirota T , Puchler K . R- 118958 , a unique anti-influenza agent: safety, tolerability and pharmacokinetics (PK) in healthy male volunteers [abstract F-1834] . In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago). Washington, DC: American Society for Microbiology, 2003 . Available at: http://gateway.nlm.nih.gov/MeetingAbstracts/102266075 .html. Accessed August 2007 . 57. 105. Biota Holdings. LANI phase II completed-phase III scheduled [press release]. Melbourne: Biota Holdings, 31 July 2008 . 58. Furuta Y , Takahashi K , Fukuda Y , et al. In vitro and in vivo activities of anti-influenza virus compound T-705 . Antimicrob Agents Chemother 2002 ; 46 : 977 - 81 . 59. Furuta Y , Takahashi K , Kuno-Maekawa M , et al. Mechanism of action of T-705 against influenza virus . Antimicrob Agents Chemother 2005 ; 49 : 981 - 6 . 60. Sidwell RW , Barnard DL , Day CW , et al. Efficacy of orally administered T-705 on lethal avian influenza A(H5N1) virus infections in mice . Antimicrob Agents Chemother 2007 ; 51 : 845 - 51 . 61. Malakhov MP , Aschenbrenner LM , Smee DF , et al. Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection . Antimicrob Agents Chemother 2006 ; 50 : 1470 - 9 . 62. Belser JA , Lu X , Szretter KJ , et al. DAS181, a novel sialidase fusion protein, protects mice from lethal avian influenza H5N1 virus infection . J Infect Dis 2007 ; 196 : 1493 - 9 . 63. Ison MG , Gnann JW Jr, Nagy-Agren S , et al. Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza . NIAID Collaborative Antiviral Study Group. Antivir Ther 2003 ; 8 : 183 - 90 . 64. Ilyushina NA , Hoffmann E , Salomon R , Webster RG , Govorkova EA . Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice . Antivir Ther 2007 ; 12 : 363 - 70 . 65. Lavrov SV , Eremkina EI , Orlova TG , Galegov GA , Soloviev VD , Zhdanov VM . Combined inhibition of influenza virus reproduction in cell culture using interferon and amantadine . Nature 1968 ; 217 : 856 - 7 . 66. D'Agostini C , Palamara AT , Favalli C , et al. Efficacy of combination therapy with amantadine, thymosin alpha 1 and alpha/beta interferon in mice infected with influenza A virus . Int J Immunopharmacol 1996 ; 18 : 95 - 102 . 67. Sidwell RW , Bailey KW , Wong MH , Huffman JH . In vitro and in vivo sensitivity of a non-mouse-adapted influenza A (Beijing) virus infection to amantadine and ribavirin . Chemotherapy 1995 ; 41 : 455 - 61 . 68. Galabov AS , Simeonova L , Gegova G . Rimantadine and oseltamivir demonstrate synergistic combination effect in an experimental infection with type A(H3N2) influenza virus in mice . Antivir Chem Chemother 2006 ; 17 : 251 - 8 . 69. Ilyushina NA , Hay A , Yilmaz N , et al. Oseltamivir-ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice . Antimicrob Agents Chemother 2008 ; 52 : 3889 - 97 . 70. Hayden FG , Schlepushkin AN , Pushkarskaya NL . Combined interferon-alpha 2, rimantadine hydrochloride, and ribavirin inhibition of influenza virus replication in vitro . Antimicrob Agents Chemother 1984 ; 25 : 53 - 7 . 71. Zhou B , Zhong N , Guan Y. Treatment with convalescent plasma for influenza A(H5N1) infection . N Engl J Med 2007 ; 357 : 1450 - 1 . 72. Ong AK , Hayden FG . John F. Enders Lecture 2006 : antivirals for influenza . J Infect Dis 2007 ; 196 : 181 - 90 . 73. Hayden FG . Antivirals for influenza: historical perspectives and lessons learned . Antivir Res 2006 ; 71 : 372 - 8 . 74. Stein DS , Creticos CM , Jackson GG , et al. Oral ribavirin treatment of influenza A and B . Antimicrob Agents Chemother 1987 ; 31 : 1285 - 7 . 75. Hayden FG , Sable CA , Connor JD , Lane J . Intravenous ribavirin by constant infusion for serious influenza and parainfluenzavirus infection . Antivir Ther 1996 ; 1 : 51 - 6 . 76. Simmons CP , Bernasconi NL , Suguitan AL , et al. Prophylactic and therapeutic efficacy of human monoclonal antibodies against H5N1 influenza . PLoS Med 2007 ; 4 : e178 . 77. Kong LK , Zhou BP . Successful treatment of avian influenza with convalescent plasma . Hong Kong Med J 2006 ; 12 : 489 .


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Hayden, Frederick. Developing New Antiviral Agents for Influenza Treatment: What Does the Future Hold?, Clinical Infectious Diseases, 2009, S3-S13, DOI: 10.1086/591851