New treatments for viral respiratory tract infections--opportunities and problems

Viruses are the most common cause of respiratory tract infections (RTIs), yet in contrast to the plethora of antibiotics available for the treatment of bacterial RTI, until very recently only three agents were widely approved for the treatment of viral RTIs: amantadine and rimantadine for influenza A, and ribavirin for respiratory syncytial virus (RSV) infection—and amantadine was first marketed in 1966. In 1999 the novel anti-influenza agents, zanamivir and oseltamivir, were launched. Controversy has attended the failure to reimburse zanamivir therapy in some countries, and the initial advice from the new National Institute for Clinical Excellence (NICE) in the UK that it should not be generally prescribed.1 With several new therapies for viral RTIs in late stages of clinical development, now is perhaps an appropriate time to take stock of the situation. The most frequent symptom complex due to viral infection of the respiratory tract is the common cold (coryza). This is most often caused by rhinoviruses (of which there are more than 100 serotypes). Some 20% of colds are caused by coronavirus infection; identical symptoms can be caused by influenza and parainfluenza viruses, adenoviruses, RSV and various enteroviruses.2 The same viruses cause descending infections of the respiratory tract, but the aetiology differs in frequency; adenoviruses are common causes of viral pharyngitis and tonsillitis, while croup (subglottic oedema due to laryngotracheitis) is particularly associated with parainfluenza virus infection.3 All these viruses can cause acute bronchitis in healthy people, and infective exacerbations in patients with chronic obstructive pulmonary disease (COPD).4 Viral RTIs are also implicated in exacerbations of asthma5 and cystic fibrosis.6 Acute bronchiolitis in infants is most commonly the result of RSV infection, but this virus is also an under-recognized cause of lower RTI in the elderly.7 Viral infection (particularly with influenza, parainfluenza and RSV) is a common cause of acute respiratory disorders leading to hospitalization in patients with chronic underlying conditions,8 particularly COPD, asthma, cardiac disease and diabetes. Viral pneumonias are uncommon in the previously healthy and are most commonly associated with influenza, but also occur rarely owing to measles and varicella-zoster infection.9 Life-threatening viral pneumonias may occur in immunocompromised patients; this increasing group includes subjects with advanced HIV infection, patients receiving anti-cancer treatment, transplant patients on immunosuppressive therapy and the very young (premature neonates) and very old. Pneumonia may be caused by any of the ‘conventional’ respiratory viruses described above, but is commonly due to herpesviruses, particularly cytomegalovirus (CMV) and herpes simplex virus (HSV).10 In addition to predisposing to opportunistic lung infections, HIV infection may be associated with lymphocytic and non-specific interstitial pneumonitis, and also appears to increase susceptibility to smoking-induced emphysema.11 Rare specific viral RTIs include recurrent respiratory papillomatosis (caused by the human papillomavirus) and the serious pneumonia caused by a hantavirus that has recently been described in parts of North and South America.12 Chronic or latent viral infection has been implicated in the aetiology of idiopathic pulmonary fibrosis (Epstein–Barr and hepatitis C viruses)13 and COPD (adenovirus),14 but these links remain unproven. Empirical therapy of idiopathic pulmonary fibrosis with nebulized ribavirin (a broad-spectrum antiviral) produced no clinical benefit15 (and N. J. C. Snell, unpublished observations). It has also been suggested that viral RTIs could be co-factors in the development of hypersensitivity pneumonitis.16 The British Medical Research Council's Common Cold Research Unit laboured for 43 years (1946–1989) without discovering a cure. Several compounds with promising anti-rhinovirus activity in vitro failed to demonstrate useful clinical activity. Both α- and β-interferon, given intranasally before viral challenge, were shown to be effective in protecting against rhinovirus, coronavirus, influenza and RSV infection; however, local side-effects and the fact that they were most effective given prophylactically inhibited their utility in these indications.17 Recently, better understanding of the morphology and mode of action of the rhinovirus has permitted the development of more specific antiviral agents. The discovery that a deep surface depression or ‘canyon’ on the surface of the rhinovirus was the site of receptor attachment18 led to the development of drugs that bind to this site. A series of compounds synthesized by Sterling-Winthrop bind to a hydrophobic pocket in the canyon floor and are thought to act by preventing viral uncoating, through stabilization of the viral capsid.19 The most promising of this series is pleconaril (WIN 63843), which has been licensed out to Viropharma for clinical development in rhinovirus and other picornavirus infections. It has good oral bioavailability and is widely distributed in the tissues, attaining high concentrations in nasal epithelium, and is well tolerated in animal models and in man.20 Prophylactic administration of pleconaril to healthy volunteers before intranasal inoculation of coxsackievirus A21 (a model of picornavirus RTI) led to significant reductions in viral shedding, nasal secretions and symptom scores compared with placebo.21 Phase II clinical trials in approximately 1500 patients presenting with a viral respiratory illness showed that pleconaril reduced the duration of symptomatic illness by about 3 days compared with placebo, and had a similar adverse event profile.22 However, a more detailed abstract of a single large (875 subject) placebo-controlled study found a 1–2.25 day reduction in symptoms that was statistically significant only in patients positive for picornavirus infection by culture or polymerase chain reaction (PCR), who were not taking concomitant cold medications.23 Agouron Pharmaceuticals has elucidated the structure of the rhinoviral enzyme 3C protease, which splits viral precursor proteins into structural and enzymic proteins essential for replication, and has synthesized a specific 3C protease inhibitor, AG-7088. This has similar in vitro antirhinoviral activity to pleconaril, and was well tolerated when given intranasally up to six times daily in volunteer studies. Phase II clinical trials in experimentally infected healthy volunteers showed significant reductions in symptoms, nasal secretions and viral concentrations compared with placebo.24 Other companies developing rhinovirus 3C protease inhibitors include Lilly, Cytoclonal Therapeutics and Apotex. Lilly is also studying a 2A protease inhibitor. All these projects are currently at the preclinical stage.25 Rhinoviruses attach to specific cellular receptors in order to initiate infection. It has been shown that 90% of rhinovirus serotypes attach to a cell surface glycoprotein known as intercellular adhesion molecule-1 (ICAM-1). The remaining 10% probably all utilize members of the low-density lipoprotein receptor (LDLR) family.26 Two pharmaceutical companies (Boehringer Ingelheim and Bayer) have managed to produce truncated, soluble forms of ICAM-1 by genetic engineering; since free ICAM-1 will attach to the rhinovirus binding sites, the virus should effectively be ‘neutralized’ and prevented from attaching to the cell-surface receptors and initiating replication. Boehringer's product, tremacamra, has demonstrated a potent inhibitory effect on human rhinovirus in vitro.27 In phase II clinical trials, when given intranasally, tremacamra significantly reduced the symptoms of experimental rhinovirus colds, regardless of whether it was administered before or after viral challenge. There were no adverse effects, and drug administration was not associated with the development of neutralizing antibodies.28 Bayer's product, given intranasally to chimpanzees, has been shown to protect against infection on subsequent challenge with virus.29 Despite these promising findings clinical development of both projects is apparently on hold. One problem is the short residence time of intranasal medication, owing to mucociliary clearance and evacuation by sneezing and nose-blowing;30 another is the fact that protection is specific for only 90% of rhinovirus strains and not for other causes of the common cold. The difficulty in attaining and maintaining effective concentrations of drug in the nasopharynx is probably the reason for the failure of a number of compounds that showed promise in preclinical studies—for example, the compound 7-thia-8-oxoguanosine (NARI 10146) was highly effective as prophylaxis against an otherwise lethal coronavirus infection in a rat model, but had no influence on the course of an experimental coronavirus infection in human volunteers.31 On the other hand, the anti-influenza agent zanamavir has been proved to be efficacious when administered intranasally; positron emission tomography has shown that 50% of the deposited drug remains in situ for at least 1.5 h.32 The reason for this long residence time is unclear, although in subjects with active influenzal infection mucociliary clearance may be impaired. It may prove possible to prolong the intranasal residence time of inhaled drugs by utilizing thixotropic formulations.33 The anti-influenza activity of amantadine was first described in 1964. It and its analogue rimantadine have been shown to be effective both in the prophylaxis and treatment of influenza A infection.34 Their activity appears to be because of interaction with the M2 membrane protein of the influenza A virus, which acts as an ion channel with a pH regulatory function.35 However, their usefulness is limited by their specificity for influenza A (they have no activity against influenza B, which does not possess the M2 membrane protein), and by the occurrence of central nervous system side-effects (less frequent with rimantadine).36 Both compounds are fetotoxic in rodent studies.34 Administration by nebulization has been tried in an attempt to improve the risk:benefit ratio, but has not become an accepted route of treatment.37 Resistance to both agents develops readily during treatment (see below). Until recently the only other agent available for the treatment of influenza was the broad-spectrum antiviral nucleoside, ribavirin. This is active against both influenza A and B in vitro; it showed low clinical efficacy in a series of trials when given orally, but by the nebulized route was shown to accelerate recovery from influenza A and B infections in infants and young children,38 although it has not been widely approved for this indication. Advances in our knowledge of the biology of the influenza virus have led to the recent development of a new generation of anti-influenza agents. The major influenza virus surface proteins are haemagglutinin and neuraminidase (sialidase). Haemagglutinin mediates binding and fusion of the viral and host cell membranes; it is the major target for neutralizing antibodies (and hence influenza vaccines) but is highly variable. Neuraminidase is essential for facilitating release of new virions from the host cell surface and preventing their aggregation. Although there is also variability in this protein, the amino acid sequence and three-dimensional structure of the enzyme's active site are highly conserved, making it a suitable therapeutic target.39 Several neuraminidase inhibitors are now in preclinical or clinical development,40 and two (GlaxoWellcome's zanamivir and Roche/Gilead's oseltamivir) have received marketing authorization. Both have been the subject of recent comprehensive reviews.41–43 Zanamivir has poor oral bioavailability and is administered by po inhalation from a dry-powder inhaler (the Diskhaler), although in early volunteer studies it was given intranasally. Clinical trials have shown that it shortens the symptomatic duration of the disease and the time taken to resume normal activities by at least a day, and its use is associated with a reduced consumption of over-the-counter medications and prescribed antibiotics. It has also given promising results when used for the prophylaxis of influenza,44 but this is not yet an approved indication. The fact that the nasopharynx is bypassed when administering medication is a potential drawback, and may relate to the fact that treatment has no effect on the incidence of complicating sinusitis and otitis media,45 although concentrations in excess of the viral neuraminidase MIC50 have been demonstrated to persist in nasal washings for at least 12 h after oral inhalation.46 On the other hand, po inhalation does limit systemic exposure and hence potential systemic side-effects. In contrast, oseltamivir is well absorbed orally and widely distributed throughout the tissues, attaining high concentrations throughout the respiratory tract. A plasma half-life of approximately 8 h allows bd dosing (zanamivir is also recommended for bd administration, although the serum half-life is shorter at 4–5 h). The zanamivir and oseltamivir clinical trials are not strictly comparable, but overall the oseltamivir studies show a shortening of symptom duration of about 1.5 days, and a greater reduction than for zanamivir in associated antibiotic prescribing, for secondary infections of both the upper and lower respiratory tract.43,47 Both drugs are well tolerated, although a few cases of bronchospasm following inhalation of zanamivir have been reported;48 a small study in mild to moderate asthmatics found no significant effects of zanamivir inhalation on lung function or airway responsiveness.49 Several more neuraminidase inhibitors are under development, including analogues of zanamivir and oseltamavir, in addition to novel compounds.40 The most advanced of these is a cyclopentane derivative, RWJ-270201 (BCX-1812),50 which is under joint development by Johnson and Johnson and BioCryst Pharmaceuticals. Given orally in mouse models of influenza A and B infection it appears to be at least as effective as oseltamivir, with no observed toxicity. Phase II clinical data were promising, and it is currently in phase III clinical trials.51 Abbott Laboratories is studying a series of novel substituted pyrrolidine neuraminidase inhibitors.52 Other recently described agents with potentially useful activity include a series of compounds derived from podocarpic acid53 and antisense phosphorothioate oligonucleotides,54 both of which exhibit in vivo activity against influenza A. Provir (SP303), a naturally occurring phenolic polymer derived from a plant of the Euphorbiaceae family, showed promising activity against influenza viruses in vitro and in vivo (and also against RSV and parainfluenza type 1),55 but proved to have very poor oral bioavailability, and clinical development in these indications has been discontinued. There is currently no effective vaccine against RSV infection; clinical trials with a formalin-inactivated vaccine in the 1960s not only demonstrated a lack of protective effect, but infected infants actually experienced more severe disease, probably because of an immune-mediated response. Efforts to develop an effective vaccine continue.56 Meanwhile it has been shown that both hyperimmune globulin56,57 and a humanized RSV-specific monoclonal antibody (palivizumab)58 can reduce the incidence of RSV bronchiolitis requiring hospitalization when given prophylactically. Palivizumab significantly decreased the of RSV in secretions of but is not currently licensed for treatment of It is and it has been suggested that its use is not in the of with or without chronic lung The only approved therapy for RSV infection is the ribavirin. A series of clinical trials and studies the and of this agent when administered by and suggested efficacy in clinical and duration and of the However, most of these studies were and their and the of the clinical effects have been studies at effects of therapy on lung function and have given some some therapy is and are to for h although studies have shown effects from a use should probably be to infants with disorders or Several ribavirin analogues have been shown to RSV in but in vivo studies have not been has been shown to have effects on the course of RSV infection when given or as an but this mode of therapy does not to have been Several other novel agents are at an early of including a nebulized antisense and a number of compounds that with the viral protein and fusion with the host including the and a papillomatosis respiratory is a approximately 100 in the caused by the human and by recurrent of the tract, most the they can cause and respiratory to the and lung can and the can to The also when it is generally frequent with several antiviral agents has been has been associated with or in a of There have been of from and from A promising new appears to be the use of or have been known for years as the cause of with which from a mild in to a more serious in symptoms are not a However, in a of cases of severe respiratory disease in the South by pulmonary oedema and a high were shown to be due to a hantavirus and cases due to the same or viruses have been in both North and South America.12 ribavirin has been shown to reduce in but an in hantavirus pulmonary was not associated with a effect on with has given promising results in South America.12 particularly and transplant are to develop severe viral viruses influenza, parainfluenza and RSV) are commonly but a specific problem in these patients is severe infections, most due to and The of patients and the fact that they are the subjects of have clinical trials of antiviral agents There are no therapeutic agents approved for the treatment of parainfluenza or because of its of antiviral ribavirin has been tried in RSV and with of The of infections in transplant patients has been the subject of a recent from a of the British for The antiviral agent has been shown to be of in the prophylaxis of associated with and while is to in the prophylaxis of infection and bronchiolitis in lung transplant therapy for is a of with on studies that a significantly on this compared with and significantly better with the therapy than with or is also active against but its use is limited by toxicity. is clinical agents are under an new is the use of a a and potent inhibitor, which is highly active against in was in the treatment of following but is currently the recommended agent for prophylaxis and treatment of and also for varicella-zoster virus although both and exhibit better oral and may well become the of in these two infections. The problem of increasing to antiviral agents was in an in the of in However, of a of influenza A virus in vivo with to amantadine was demonstrated as early as The of to rimantadine during therapy was first in subsequent have the development of to both amantadine and rimantadine during The genetic for the development of appears to be a single amino acid in the of the M2 protein, which is the target for these two antiviral agents to of viral fusion or Although of influenza virus has been demonstrated in the and probably during and may occur in of strains in the does not to be a perhaps owing to the of new the development of during therapy appears to have effect on the clinical in although it does limit the use of the for treatment of an and prophylaxis of A of rimantadine in of influenza A virus in 43 and in some of which rimantadine has been widely used for more than found only of to be drug which is The antiviral has a of activity against respiratory tract and other In contrast to amantadine and viral to ribavirin has not been This may be because at least three of antiviral activity have been of cellular of of and of influenza virus of both influenza A and B virus to the neuraminidase zanamivir have been produced by in owing to in the haemagglutinin or However, to zanamivir develops readily than it does to amantadine and rimantadine in similar and has not been shown in animal models under that readily for to amantadine and The strains to well in culture and are very in than the In clinical only of developing to drug during therapy has been in an immunocompromised receiving treatment with influenza virus has been in in vitro and in of from patients; this is because of at the active site of which are associated with in that the development of is to limit the clinical usefulness of this of drugs in for therapy or The development of by to specific antiviral agents has been well least three have been described in two in the viral enzyme the other in the viral Although is generally to have reduced cases of severe pneumonia due to strains of virus have been of have also been In the development of has been associated with in immunocompromised The use of soluble receptor therapy as prophylaxis against rhinovirus several could a on viruses that not use ICAM-1 as their receptor and they become in the of rhinovirus to several novel agents including and of which is in development, have been can be to limit the development of viral with bacterial infections can a that of acute viral infections in patients with normal host to the development of significant of chronic infections is more particularly in the was a with and the same had to be in the treatment of HIV or effects of of agents active against influenza viruses have been and it may be to whether should be for viral RTI, the is or treatment is to be therapy with and has been for the treatment of patients with a high viral that have a effective for most viral RTIs is a it be to to a similar to that with agents, has because of viral of the respiratory tract, approved therapy and antiviral agents clinical trials or with of clinical activity viral of the respiratory tract, approved therapy and antiviral agents clinical trials or with of clinical activity