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Antiviral therapy for influenza virus infections
Antiviral Therapy for Influenza Virus Infections Charles G. Prober, MD Every year, influenza viruses cause global epidemics that result in significant morbidity and mortality. Influenza infections can be serious in children, especially infants and toddlers. Four antiviral agents, amantadine, rimantadine, oseltamivir, and zanamivir, are available for the treatment or prophylaxis of influenza. Experience with the use of these antiviral drugs for influenza in children is limited. Given the small degree of therapeutic gain that is reported from clinical trials, considerations about cost effectiveness are important in deciding whether to use these agents in the treatment of suspected or proven influenza infections in healthy children. Copyright 2002, Elsevier Science (USA). All rights reserved.
he influenza viruses consist of the influenza A and the influenza B subgroups.1,2 These viruses are ubiquitous human pathogens that cause annual epidemics because of their distinctive capacity to undergo frequent antigenic changes in the viral hemagglutinin (HA) and neuraminidase (NA) proteins that mediate infectivity. Influenza infections almost always are limited to the respiratory tract, and most serious morbidity and influenza-associated mortality results from influenza pneumonia or secondary bacterial pneumonia. Reinfection is a common occurrence because alterations in the major viral proteins allow influenza A and B viruses to escape the adaptive immune responses acquired during previous infections. Antiviral drugs that are available for the treatment of influenza in children and adolescents include amantadine, which was one of the first drugs used to treat viral infection, and the new neuraminidase inhibitors, zanimivir and oseltamivir.
T
The Virus Influenza A and B viruses are enveloped, single-stranded RNA viruses that contain a segmented genome.1,2 Eight RNA segments, each of which encodes 1 or 2 viral proteins, exist; the complete virion is composed of 5 internal and 3 membrane proteins. Although both influenza A and B viruses have the 8-component, negative-sense RNA genome, major differences are identified in the genes encoded by 2 of the 8 segments. Since the 1950s, researchers have been able to isolate influenza viruses in cell culture and to identify more precisely the changing subtypes that have circulated
From the Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. Address correspondence to Charles G. Prober, MD, Infectious Diseases Division, Department of Pediatrics, Stanford University School of Medicine, G312, 300 Pasteur Dr, Stanford, CA 94305. Copyright 2002, Elsevier Science (USA). All rights reserved. 1045-1870/02/1301-0007$35.00/0 doi:10.1053/spid.2002.29755
in the human population. The surface membrane proteins, HA and NA, are critical components of the virion envelope and form spikes on the virion surface. HA is responsible for virus attachment to cells, which allows the virus to enter respiratory epithelial cells and initiate infection; it was identified by its capacity to agglutinate red blood cells. The internal proteins of the virus are the nucleoprotein, matrix (M) proteins 1 and 2, 3 viral polymerases, and the nonstructural proteins (NS1 and NS2) of unknown function. HA contains major protective epitopes against which the host immune response is directed. NA may help the virus to move through mucous, and this protein functions to promote the release and spread of newly synthesized virions from infected cells. Protective immunity also is elicited against epitopes of influenza NA. The M1 and M2 proteins are involved at various steps in the assembly and maturation of the virus particles. Changes in the M2 protein mediate the resistance of influenza A virus to amantadine. Influenza C viruses, which rarely are infectious in humans, differ from influenza A and B viruses by having only 7 RNA genome segments and by the absence of an NA gene. New influenza viruses that have RNA mutations encoding variants of the HA protein emerge annually or every few years. Variation in HA is a key factor for immune evasion by influenza and may occur separately or in conjuction with changes in NA. Each new influenza isolate is classified according to its subtype, which may be A, B, or C; by the geographic source of the isolate; and by the year of isolation (eg, influenza A/Syndney/97). Influenza A strains are subtyped as H1N1, H2N3, or H3N2 influenza, according to the antigenic characteristics of their HA and NA proteins. The introduction of new influenza strains into the human population is thought to result from transmission from infected birds, which are a natural reservoir for influenza viruses; birds are infected with other viral subtypes, most of which are not directly infectious for humans but may be a source of genetic mutations that are transferred into human strains. Influenza viruses replicate in the intestinal tract of domestic and wild fowl, which permits their wide dissemination in the environment and allows transfer to other
Seminars in Pediatric Infectious Diseases, Vol 13, No 1 ( January), 2002: pp 31-39
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species, including swine, a potential intermediate host, and, in some cases, to people. How efficiently these novel viruses spread appears to depend upon poorly understood virulence factors that enhance infectivity for nonavian species. Antigenic drift is the first and more common type of viral mutation. Under these conditions, the HA and NA proteins change slowly, owing to the accumulation of single nucleotide changes in the respective genes that encode these proteins. As a result, anti-HA and anti-NA antibodies acquired during previous infections provide limited or no protection against the new strain. The second kind of antigenic variation in influenza strains is antigenic shift.3 The segmented genome of influenza viruses permits recombination, in which viral genes from 1 strain are introduced into another virus. When antigenic shift occurs, the HA protein is changed, with or without alterations in NA. The result is a truly new strain, which cannot be inhibited by the host response to strains that circulated earlier. When such strains emerge, widespread epidemics or pandemics ensue.
Epidemiology and Transmission Influenza A and B viruses emerge and spread annually within the global human population, with representatives of the influenza A subtypes and influenza B groups being recovered from infected individuals each year. During most annual epidemics, infections with either influenza A or influenza B are more common. Some information about the epidemiology of influenza viruses is available for most of the 20th century, as shown in Fig 1.3 Influenza A viruses that have been prevalent since the late 1960s belong to the H1N1 or H3N2 subtypes; the occurrence of H2N2 epidemics before this time suggest that the 3 subtypes of influenza A viruses may exhibit cycles of predominance. The emergence of the H3N2 strain in 1968 is an example of antigenic shift, resulting in the Hong Kong flu pandemic. The degree to which an influenza virus strain spreads also depends on how many susceptible patients are present in the population. In contrast to outbreaks of influenza A and B, influenza C outbreaks usually are limited geographically, and children and young adults are infected most often. During influenza infection, infected epithelial cells are disrupted and progeny virions are released into respiratory secretions. The concentration of infectious virions in respi-
Figure 1. The historic pattern of influenza A epidemics. Data from reference 3.
ratory secretions of individuals with acute influenza A or B infection often is 104 to 105 tissue culture infectious dose per milliliter. The high concentrations of infectious virions facilitates transmission to susceptible contacts, which may occur by aerosolization of infectious particles in respiratory secretions or by self-inoculation of the virus by hand after direct contact with infected surfaces or fomites. The physiology of sneezing is such that aerosolized particles travel at 100 feet per second and for distances of 2 to 5 feet. Therefore, close exposure to an infected individual is highly likely to result in inoculation with infectious virions. Whether influenza-related disease follows depends on whether the exposed contact has immunity to the infecting virus or to strains that are antigenically very similar. During primary infection in children, influenza viruses persist at respiratory mucosal sites for up to 10 to 14 days. The individual becomes less contagious over time from onset because the infectious virus content in respiratory secretions peaks within 1 to 3 days and then declines rapidly.
Clinical Manifestations of Influenza Infection Illnesses caused by influenza A and B viruses cannot be differentiated clinically.4 After inoculation of the respiratory mucosa, influenza viruses begin to replicate in the columnar epithelial cells. As infection progresses, production of proinflammatory cytokines is induced and the nasal epithelium becomes edematous. Localized edema and inflammation of the nasal epithelium usually develops within 48 to 72 hours and results in symptoms of congestion and obstruction of sinus and middle ear passages. The onset of influenza illness is associated typically with fever of 38 to 40°C and sudden onset of sore throat, cough, headache, and myalgias. How influenza viruses cause nonrespiratory symptoms has not been explained, but release of cytokines, such as interferon ␣/, is presumed to be the mechanism. In most cases, fever persists for 1 to 5 days and other respiratory and systemic symptoms last for up to a week. Most often, a persistent dry cough is the only prolonged symptom of influenza. The clinical course of uncomplicated influenza is agerelated and varies depending on whether the individual has any cross-reactive immunity from previous infections with similar strains. Primary infection of the naive host with influenza A or B viruses is associated with a more prolonged illness and with the highest risk of lower respiratory infection. Although infection may be asymptomatic in older individuals, most infections in children younger than 5 years old cause some signs of illness. Serious morbidity and influenza-related mortality in children is highest in this age group and is comparable to the risks associated with influenza in the elderly (Fig 2).5 More severe upper respiratory symptoms, such as laryngeotracheobronchitis and influenza pneumonia, are most common in young children who are encountering influenza A or B for the first time. Pneumonia, whether diagnosed clinically or by chest radiograph, is described in 10 to 50 percent of these cases. Nevertheless,
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Antiviral Therapy for Influenza
Figure 4. Recovery of respiratory viruses from middle ear fluid in children with otitis media. Data from reference 7. Figure 2. Age-related differences in morbidity and mortality caused by influenza. Data from reference 5.
influenza pneumonia in the healthy child usually is selflimited and resolves rapidly without sequelae. In the youngest age group, small airway size may enhance morbidity, resulting in bronchiolitis, and in the newborn period, influenza may cause a sepsis-like syndrome with minimal respiratory signs. Many children receive antibiotics for influenza during the annual epidemics (Fig 3).6 However, much of the symptomatology of influenza is a consequence of viral infection. For example, influenza A or B viruses were recovered from middle ear fluid in 40 percent of children and were third, after respiratory syncytial virus and parainfluenza viruses, in frequency of isolation from children with otitis media (Fig 4).7 For the most part, influenza replication is limited to the respiratory mucosa. Many children experience vomiting, diarrhea, and abdominal pain, but these signs do not indicate viral replication in the gastrointestinal tract. Myocarditis, myositis, and encephalitis are serious complications of uncertain cause. Influenza is associated with a risk of bacterial superinfection. The destruction of mucosal epithelial cells by the virus compromises ciliary function and probably facilitates secondary bacterial infections of the upper or lower respi-
ratory tract. Although influenza may cause otitis, bacterial otitis media is the most common secondary infection. Staphylococcal and pneumococcal pneumonia are the most significant secondary bacterial complications and account for most hospitalizations and fatal illnesses during the annual influenza epidemics (Table 1).8 The host response eliminates influenza by destroying infected cells and by releasing cytokines that protect adjacent uninfected cells. The lysis of infected cells is mediated by antibodies against HA in combination with complement, antibody-mediated cytotoxicity, and cytotoxic T cells. Because the healthy host has all of these defense mechanisms, which one is most important for resolution of infection is not clear. However, influenza virus persists longer in children with deficiencies of cellular immunity, indicating an important role for cytotoxic T cell clearance. In some immunocompromised patients, such as bone marrow transplant recipients, influenza is life-threatening.4 Cell-mediated responses may be particularly useful because they are directed against conserved proteins, such as the matrix and nucleoproteins, and mediate immunity that is cross-reactive against a broad range of influenza subtypes. Antiinfluenza IgG and mucosal IgA antibodies are made against the HA and NA proteins, and their neutralizing activity is considered the most important defense against reinfection with related subtypes.
Diagnosis The laboratory diagnosis of acute influenza has improved dramatically in recent years.2 Direct virus detection meth-
Table 1. Association of Influenza and Pneumococcal Pneumonia in Children
Figure 3. Office visits and antibiotic use in children with influenza infections: events per 100 children. Data from reference 6.
Event
Odds Ratio
Influenza-like illness before admission Influenza-like illness in family H1N1 seroconversion
12.4 (1.7-306) 2.6 (1.0-6.3) 3.7 (1.0-18.1)
Data from reference 7.
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Charles G. Prober
Table 2: Antiviral Drugs or the Prevention and Treatment of Influenza Infections Agent
Indication
Amantadine (Symmetrel, Endo Therapy for type A Pharmaceutical, Inc, influenza infections Chaddsford, PA) Prevention of type A influenza infection Rimantadine (Flumadine, Therapy for type A Forest Pharmaceutical, St. influenza infections Louis, MO) Prevention of type A influenza infections Oseltamivir (Tamiflu, Roche Therapy for type A & B Pharmaceuticals, Nutley, NJ) influenza infections Prevention of type A & B influenza infections Zanamivir (Relenza, Therapy for type A & B GlaxoWellcome, Research influenza infections Triangle Park, NC)
ods and viral culture have replaced serologic testing for a 4-fold rise in anti-HA antibody titers between acute and convalescent sera. The sensitivity of direct detection and viral culture methods is optimal when specimens are obtained within the first 24 to 72 hours after onset of typical influenza symptoms because the peak titer of virus is present in respiratory secretions during this time interval. Rapid tests of nasal or throat swab specimens are sensitive and specific when compared with viral culture, which is the standard for unequivocal proof of an influenza infection. Infected epithelial cells from swab specimens can be detected by staining and by immunofluorescence microscopy examination. Enzyme immunoassays identify viral proteins in respiratory secretion specimens, providing a diagnosis within 15 to 20 minutes. These methods differentiate between influenza A and B, which is important when antiviral therapy is considered because amantadine is effective against only influenza A strains. Molecular methods, such as polymerase chain reaction or in situ hybridization, rarely are needed but can be useful when the specimen is negative by viral culture or to test tissue specimens for influenzainfected cells. Serologic assays can be used to assess anti-HA antibodies to determine whether an individual is likely to be susceptible to a new influenza strain. However, such serologic testing is complex and rarely practical because the serum must be tested for antibodies that will bind to the new variant or novel HA protein or neutralize the circulating influenza strain.
Antiviral Agents for the Prevention and Treatment of Influenza Virus Infections Under ideal circumstances, infections caused by influenza viruses should be prevented by immunization. However, the current inactivated vaccine is recommended only for adults older than 50 years of age and adults and children at high-risk of developing serious infection caused by influenza
Age
Daily Dosage
ⱖ1 yr
5 mg/kg in 1-2 doses; 100-200 mg for adults for 5 days ⱖ1 yr 5 mg/kg in 1-2 doses; 100-200 mg for adults for ⱖ4 weeks ⱖ18 yr 5 mg/kg in 1 dose; 100-200 mg for adults for 5 days ⱖ1 yr 5 mg/kg in 1 dose; 100-200 mg for adults for ⱖ4 weeks ⱖ1 yr 4 mg/kg in 2 doses; 150 mg for adults for 5 days ⱖ13 yr 4 mg/kg in 2 doses; 150 mg for adults for 6 weeks ⱖ7 yr 20 mg in 2 doses for 5 days
Cost (for Adults) $2-$10 for 5 days
$20 for 5 days
$53 for 5 days
$44 for 5 days
viruses. Antiviral chemotherapy may be useful for those who did not receive a vaccination, have impaired immunologic responses, or contract infection despite immunization. Two classes of antivirals are licensed for the prevention and treatment of infections caused by influenza viruses (Table 2). One class includes amantadine and rimantadine, which are closely related symmetric tricyclic amines that are active against only type A influenza viruses. The second class includes the recently licensed neuraminidase inhibitors, zinamivir and oseltamivir, which are active against both type A and type B influenza viruses. Widespread vaccination and optimal use of available antiviral drugs should lead to declines in physician visits, hospitalizations, and deaths attributable to influenza infection.9
Amantadine and Rimantadine Amantadine (Symmetrel) and rimantadine (Flumadine) are symmetric tricyclic amines that are closely related structurally. Approved by the Food and Drug Administration in 1966, amantadine has the distinction of being the first antiviral agent licensed for systemic use in the United States. Rimantadine was approved for use in the United States more than a quarter of a century later (1993).
Antiviral Action and Drug Resistance The activity of amantadine and that of rimantadine are limited to influenza A viruses. Rimantadine is 4- to 10-fold more active than is amantadine; inhibitory concentrations of susceptible influenza A isolates range from 0.1 to 0.4 g/mL for amantadine and from 0.01 to 0.1 g/mL for rimantadine.10,11 The target of the inhibitory action for both of these antivirals is the influenza A virus M2 protein. The M2 protein forms a channel that spans the viral membrane, allowing the penetration of hydrogen ions into the interstices of the viral particle.12 The drop in pH accompanying the hydrogen flux facilitates the dissociation of the M1
Antiviral Therapy for Influenza protein from the ribonucleoprotein complexes so that the ribonucleoprotein can enter the cell nucleus and initiate replication.13 Blocking the flow of hydrogen ions inhibits viral replication.14 Resistance to amantadine and rimantadine results from a point mutation in the RNA sequence encoding for the M2 protein transmembrane domain.15 Resistance typically appears in the treated subject within 2 to 3 days of initiating therapy; 25 to 35 percent of treated patients shed resistant strains by the fifth day of treatment.16 The clinical significance of isolating resistant strains from the treated subject is not clear; infection and illness in immunocompetent people infected with a drug-resistant virus are similar to those in patients infected with viral strains who are susceptible to the drugs.17,18 However, transmission of resistant strains to household contacts can occur, and failure of drug prophylaxis can result. Therefore, contact between treated patients and susceptible high-risk patients should be avoided.19
Pharmacokinetics and Dosage Both amantadine and rimantadine are well absorbed after oral administration, and food does not interfere with absorption of either drug.20,21 More than 90 percent of a dose of amantadine is excreted unchanged in the urine, whereas rimantadine is metabolized extensively, with less than 15 percent of the drug excreted unchanged in the urine. Peak serum concentrations of both drugs range from 0.4 to 0.8 g/mL after 100-mg oral doses. The time to attain peak concentrations varies from 2 to 6 hours. Concentrations of amantadine and rimantadine in nasal secretions are 50 to 100 percent of those attained in serum, and limited data suggest that adequate penetration into pulmonary tissue of infants occurs.22 The half-life of amantadine (12 to 18 hours) is approximately half that of rimantadine (24 to 36 hours). Because most of the dose of amantadine is excreted unchanged in the urine, whereas rimantadine is substantially metabolized, compromised renal function more markedly affects the elimination half-life of amantadine than that of rimantadine. Therefore, major dose adjustments of amantadine are necessary in persons with creatinine clearances of less than 80 mL/min/1.73 m2, but dose adjustments for rimantadine are not necessary unless the creatinine clearance is less than 10 mL/min/1.73 m2.23 Amantadine is approved for prophylactic and therapeutic use for adults and children older than 1 year of age. Rimantadine also is approved for prophylactic and therapeutic use for adults but is approved for prophylaxis only (not therapy) for children older than 1 year of age. The usual dose of amantadine in children with normal renal function is 5 mg/kg/d given in 1 to 2 divided doses. The dose of rimantadine also is 5 mg/kg/d, but it is administered as a single daily dose. The dose of both drugs for adults is 100 to 200 mg/d; the lower dose is for the elderly. The cost of a 5-day course of amantadine ranges from approximately $2.00 to $10.00 (lower cost for generic formulation), and the cost for a 5-day course of rimantadine is about $20.00.9
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Adverse Effects Although the types of adverse reactions associated with both amantadine and rimantadine are qualitatively similar, they are less frequent and less severe with rimantadine 9 because amantadine stimulates the release of cathecholamines, whereas rimantadine does not. The most common complaints associated with the administration of both drugs are dose-related gastrointestinal and central nervous system symptoms.24 Gastrointestinal complaints include nausea, vomiting, and dyspepsia. Approximately 10 percent of amantadine recipients and 2 percent of rimantadine recipients experience 1 or more symptoms of central nervous system disturbances, including anxiety, depression, insomnia, difficulty concentrating, or confusion. High concentrations of plasma may cause hallucinations or seizures. Patients with chronic seizure disorders can have increased frequency of seizures associated with either amantadine or rimantadine therapy. Long-term amantadine therapy can cause vision loss, hypotension, urinary retention, peripheral edema, and congestive heart failure. In a study involving children, the incidence of side effects among rimantadine recipients was the same as that among placebo recipients.25
Clinical Indications Prophylaxis with either amantadine or rimantadine prevents approximately 50 to 60 percent of infections and 70 to 90 percent of clinical illnesses caused by type A influenza virus.9,25-28 This degree of prophylactic effectiveness is similar to that of inactivated influenza vaccine. Although vaccine administration would be more convenient, prophylaxis of high-risk hosts throughout the influenza virus season is recommended for those who cannot tolerate the vaccine because of toxicity or allergies and those in whom the vaccine is unlikely to induce protective immunity because of severe immunosuppression.29 Prophylaxis also is indicated if the vaccine may be ineffective because the epidemic strain differs substantially from the vaccine strain of influenza A and for the 2 weeks after vaccination if influenza A already is active in the community.29 Seasonal prophylaxis should be initiated as soon as influenza is identified in the community and continued throughout the epidemic period. Amantadine and rimantadine also have been used to control outbreaks of infection occurring within households, schools, nursing homes, and hospitals.9,26,27,30 Under these circumstances, prophylactic therapy of contacts is started as soon as the index patients are recognized and continued for 4 to 8 weeks. Amantadine and rimantadine also have been shown to be effective in the treatment of influenza A infections in adults and children if treatment is initiated within 48 hours of the onset of symptoms.31,32 Compared with placebo, drug therapy results in reduced duration of viral excretion, fever, and other systemic complaints, as well as an earlier resumption of normal activities. In general, the duration of illness is shortened by about 1 day. In a direct comparison of the 2 drugs in college students, efficacy was similar.32
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Oseltamivir and Zanamivir Oseltamivir (Tamiflu) and Zanamivir (Relenza) are recently licensed agents with activity against both influenza A and B viral strains. Both drugs have pediatric indications approved by the Food and Drug Administration.
Oseltamivir Antiviral Action and Drug Resistance. Oseltamivir is an ethyl ester prodrug that is hydrolyzed by hepatic esterases to the biologically active compound, oseltamivir carboxylate. The mechanism of action for this class of compounds is the specific inhibition of the influenza NA, a highly conserved enzyme, common to type A H1N1, type A H2N2, type A H3N2, type A H5N1, and type B influenza viruses. Structurally, NA inhibitors are analogues of Nacetylneuraminic acid, a component of mucoproteins in respiratory secretions. During infection, virus binds to the mucus but is eluted by the action of NA, facilitating the penetration of the virus to the surface of the respiratory cells. Inhibition of NA prevents penetration of the virus to the cell surface. In addition, NA is necessary for the optimal release of progeny virus from infected cells; inhibition of this process decreases the spread of virus and the intensity of infection. Antiviral resistance has been generated in the laboratory by passaging virus in the presence of increasing concentrations of oseltamivir carboxylate. In addition, 3 percent of posttreatment influenza isolates in human challenge studies developed resistance to oseltamivir. A specific mutation in the active site of the NA molecule of the resistant strain, as compared to the challenge virus, appeared to confer the resistance. In studies of the treatment of naturally occurring influenza infection, approximately 1.5 percent of posttreatment influenza isolates show reduced susceptibility to oseltamivir.33 Accurate estimation of the risk of emergence of oseltamivir resistance in the clinical setting will be determined only by careful phase IV postlicensure monitoring. Pharmacokinetic and Dosage. Approximately 75 percent of the orally administered drug reaches the systemic circulation in the form of oseltamivir carboxylate. The maximum plasma concentration of active compound after the twice-daily administration of multiple, 75-mg doses is approximately 350 ng/mL. Co-administration with food has no significant effect on bioavailability. More than 90 percent of oseltamivir is metabolized to oseltamivir carboxylate. Oseltamivir carboxylate is not further metabolized, but it is almost entirely eliminated by renal excretion by glomerular filtration and tubular secretion. The half-life of oseltamivir carboxylate is 6 to 10 hours.34 Serum concentrations of drug increase in the presence of declining renal function, and dose adjustment is recommended for patients with a creatinine clearance level less than 30 mL per minute. Oseltamivir has been approved for the treatment of children older than 1 year of age. It is licensed for the prevention of influenza infection in those older than 13 years. The pediatric dose of suspension is 2 mg/kg, admin-
istered twice daily. The recommended adult dose (and maximum dose for children) is 75 mg, given twice daily. When used for therapy of active infection, administration of the drug should begin within 2 days of onset of symptoms of influenza and continue for a total of 5 days. The approximate cost of 5 days of therapy for an adult is $53.00. Adverse Effects. The most common side effect reported with oseltamivir use is nausea, with or without vomiting. In controlled clinical trials, approximately 10 percent of patients reported nausea without vomiting, and an additional 10 percent experienced vomiting. The nausea and vomiting episodes generally were of mild to moderate degree and usually occurred on the first 2 days of therapy. Fewer than 1 percent of study subjects discontinued participation in the clinical trials because of nausea or vomiting. Food may help to alleviate the gastrointestinal side effects. Insomnia and vertigo also occur occasionally in oseltamivir recipients. Clinical Indications. Compared with placebo, oseltamivir administered for 6 weeks during the peak of influenza season significantly reduced the risk of contracting influenza.35 The rate of infection was reduced approximately 50 percent, and the rate of illness was reduced more than 80 percent. These rates are comparable with that achievable with amantadine and rimantadine for influenza A virus infections. Influenza infection was prevented in 89 percent of families in which oseltamivir was given to all family members older than 12 years of age who were exposed to influenza in their households.36 In another study, in which oseltamivir was given to nursing home residents for 6 weeks, most of whom had been vaccinated, the rate of influenza infection was reduced by 92 percent.37 Oseltamivir also is effective in the therapy for influenza infections, if initiated soon after the onset of symptoms. Efficacy initially was established as the result of 2 large studies, one conducted at 60 centers throughout the United States and the other conducted at 63 centers in Europe, Canada, and China.37,38 The studies were performed during the 1998 influenza season, and they used identical designs. There were 1,355 patients enrolled in the 2 trials; 849 (63%) had confirmed influenza virus infections. Ninety-five percent of the infections were caused by influenza A. Study inclusion criteria included temperature of at least 100°F, with 1 or more respiratory symptoms, including cough, sore throat, and rhinorrhea, and 1 or more constitutional symptoms, including headache, malaise, myalgia, sweats, and chills. Enrollment had to occur within 36 hours of onset of symptoms. Duration of illness among oseltamivir recipients was reduced by 1 to 1.5 days in both studies compared with the duration of illness among placebo recipients.37,38 The effect was greatest for patients treated within 24 hours of onset of symptoms.38 When evaluated, the clinical benefits observed were associated with reductions in the duration or quantity of virus in patients’ secretions.37 The frequency of physician-diagnosed secondary complications leading to the need for antibiotic prescriptions also was reduced among oseltamivir recipients.38 The efficacy, safety, and tolerability of osetamivir also has been evaluated in a recently published, randomized, double-blind, placebo-controlled trial conducted in children
Antiviral Therapy for Influenza 1 through 12 years of age.39 Six hundred and ninety-five children with fever (ⱖ38°C) and a history of cough or coryza for less than 48 hours duration received oseltamivir or placebo for 5 days. Sixty-five percent (452) of the subjects had confirmed infection caused by influenza virus. The duration of illness was reduced by an average of 1.5 days in patients treated with oseltamivir compared with placebo recipients. In addition, new diagnoses of otitis media were reduced by 44 percent among antiviral recipients, and the incidence of the need for physician-prescribed antibiotics was significantly lower in influenza-infected patients treated with oseltamivir than in placebo recipients (31% vs 41%, respectively).39
Zanamivir Antiviral Action and Drug Resistance. Zanamivir also interferes with the function of the influenza NA enzyme. The in vitro activity of zanamivir against influenza A and influenza B strains is similar to that of oseltamivir. Antiviral resistance can be induced in vitro by passaging virus in the presence of increasing concentrations of zanamivir. Decreased susceptibility to zanamivir is associated with mutations resulting in amino acid changes in the viral NA and/or HA. Resistance also has been documented in clinical specimens isolated from a zanamivir recipient. After undergoing 2 weeks of therapy with zanamivir, an immunocompromised patient infected with influenza B shed a resistant isolate that was shown to have mutations in both the viral HA and the viral NA.40 The NA mutation resulted in a 1,000-fold reduction in enzyme activity. Cross-resistance between zanamivir and oseltamivir has been observed. Pharmacokinetics and Dosage. Zanamivir has poor oral bioavailability and, therefore, is administered by oral inhalation. More than 75 percent of an orally inhaled dose of zanamivir is deposited in the oropharynx, and most of it is swallowed. Approximately 13 percent of the dose distributes to the airways and lungs, although the actual amount delivered depends on patient factors such as inspiratory flow.41 Local respiratory mucosal concentrations of zanamivir exceed 1,000 ng/mL in sputum for 6 hours after inhalation, greatly exceeding the amount of drug needed to inhibit influenza A and B viruses.41,42 Approximately 10 percent of an inhaled dose of zanamivir is absorbed systemically; peak serum concentrations range from 17 to 142 ng/mL within 2 hours of administration of a 10 mg dose.41 The plasma half-life of zanamivir ranges from 2.5 to 5 hours.41 No metabolites of zanamivir have been identified; all absorbed drug is excreted unchanged in the urine. Although serum zanamivir concentrations increase with decreasing creatinine clearance, no adjustment in dosing is necessary for renal insufficiency because of the limited amount of systemically absorbed drug. Zanamivir has been approved by the Food and Drug Administration for the treatment of influenza infections in patients older than 7 years of age. The recommended dose for children and adults is 10 mg (given in 2 inhalations of 5 mg each), administered twice daily for 5 days. Two doses should be taken on the first day of treatment whenever
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possible, with at least 2 hours between doses. On subsequent days, the doses should be approximately 12 hours apart. The approximate cost of a 5-day course of therapy is $44.00.9 Adverse Effects. Zanamivir is well-tolerated. Respiratory distress is the most serious adverse event associated with its use. In some patients with underlying airway disease, a decline in pulmonary function and bronchospasm have been reported.43 Although influenza itself can cause these symptoms, zanamivir is not recommended for treatment of patients with underlying airways disease because of the risk of adverse events and lack of proven efficacy in this population. Zanamivir should be discontinued in any patient who develops bronchospasm or decline in respiratory function. Clinical Indications. Inhaled zanamivir, administered for 4 weeks as seasonal prophylaxis, reduces the likelihood of laboratory confirmed influenza infection by 30 percent, influenza disease by 67 percent, and influenza disease with fever by 84 percent.44 Short-term (5 days) prophylaxis with zanamivir, after presumed exposure to influenza in the community, also has been shown to reduce the rate of secondary infection from 6 percent among placebo recipients to 2 to 3 percent among antiviral recipients.45 Prophylaxis within households also is effective. When zanamivir was given for 5 days to both the index patient and exposed family members older than 5 years of age within 24 hours of the index patient becoming ill, a 79 percent reduction in the proportion of families with at least 1 affected contact was observed.46 Protection was observed against both influenza A and influenza B virus infections. The efficacy of zanamivir in the treatment of influenza A and B virus infections has been shown in several placebo controlled studies conducted in adults 47-50 and 1 study conducted in 471 children, 5 to 12 years of age.51 Patients received zanamivir 10 mg inhaled twice daily versus placebo inhaled twice daily. On average, the zanamivir-treated patients improved 1.0 to 2.5 days faster than did the placebo recipients. Combined analysis of these trials indicates that zanamivir reduces the duration of symptoms by approximately 1.5 days. In the pediatric study, a 1.25-day reduction occurred in clinically significant symptoms attributed to influenza, compared with only a 0.5-day reduction of symptoms in the intent-to-treat analysis.52 Zanamivir therapy also appears to reduce the frequency of secondary respiratory complications of influenza infections requiring antibiotic prescription.
Summary Infections caused by influenza viruses are a major source of morbidity and mortality worldwide. Recent data underscore the potential seriousness of influenza infections in children, especially infants and toddlers. Four antiviral agents are licensed for the treatment and prevention of influenza virus infections. Two of the agents (amantadine and rimantadine) are active against only type A strains and 2 (oseltamivir and zanamivir) are active
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against both type A and type B strains. Historically, amantadine and rimantadine have not been used widely in children, and experience with the newer agents is quite limited. Considering the small degree of therapeutic gain observed with these antivirals, cost effectiveness considerations will help physicians decide their role, if any, in the treatment of healthy children and adults with suspected or proven influenza infections. The role of antiviral agents in the prevention of influenza infections is secondary to that of vaccination. Although an effective inactivated vaccine is available for those at increased risk for developing serious infections caused by influenza viruses, the vaccine is underused, not effective under all circumstances (eg, hosts with compromised immunity), and not recommended for routine use in children. Therefore, under certain circumstances, control of community and household spread of influenza infections may be augmented by use of chemotherapy.
References 1. Lamb RA, Krug RM: Orthomyxoviridae: The viruses and their replication, in Fields BN, Knipe DM, Howley PM, (eds): Fields Virology. Philadelphia, PA, Lippincott-Raven, 1996 2. Ziegler T, Cox N: Influenza viruses, in Murray PR, Baron EJ, Pfaller MA, Tenover PC, Yolken RH (eds): Manual of Clinical Microbiology ed. 7. Washington, DC, American Society for Microbiology, 1999, p 928-935 3. Murphy BR, Webster R: Orthomyxoviruses, in Field BN (ed): Virology. Raven, 1990 4. Gruber W: Influenza Viruses, in Long S, Prober C, Pickering L (eds): Principles and Practices of Pediatric Infectious Diseases. Phildelphia, PA, Lippincott, 1997, p 1267-1271 5. Glezen WP: Emerging Infections: Pandemic influenza. Epidemiol Rev 18:64-76, 1996 6. Neuzil KM, Mellen BG, Wright PF, et al: The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 342:225-231, 2000 7. Heikkinen T, Thint M, Chonmaitree T: Prevalence of various respiratory viruses in the middle ear during acute otitis media. New Engl J Med 340:260-264, 1999 8. O’Brien KL, Walters MI, Sellman J, et al: Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection. Clin Infect Dis 30:784-789, 2000 9. Couch RB: Prevention and treatment of influenza. N Engl J Med 343:1778-1787, 2000 10. Browne MJ, Moss M, Boyd MR: Comparative activity of amantadine and ribavirin against influenza virus in vitro: Possible clinical relevance. Antimicrob Agents Chemother 23:503-505, 1983 11. Valette M, Allard JP, Aymard M, et al: Susceptibilities to rimantadine of influenza A/H1N1 and A/H3N2 viruses isolated during the epidemics of 1988 to 1989 and 1989 to 1990. Antimicrob Agents Chemother 37:2239-2240, 1993 12. Pinto LH, Holsinger LJ, Lamb RA: Influenza virus M2 protein has ion channel activity. Cell 69:517-528, 1992 13. Bui M, Whittaker C, Helenius A: Effect of M1 protein and low pH on nuclear transport of influenza virus ribonucleoproteins. J Virol 70:8391-8401, 1996 14. Tosteson MT, Pinto LH, Holsinger LJ, et al: Reconstitution of the influenza virus M2 ion channel in lipid bilayers. J Membrane Biol 142:117-126, 1994
15. Hayden FG, Couch RB: Clinical and epidemiologic importance of influenza A viruses resistant to amantadine and rimantadine. Rev Med Virol 2:89-96, 1992 16. Hayden FG, Belshe RB, Clover RD, et al: Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med 321:1696-702, 1989 17. Monto AS, Arden NH: Implications of viral resistance to amantadine in control of influenza A. Clin Infect Dis 15:368-369, 1992 18. Hayden FG, Sperber SJ, Belshe RB, et al: Recovery of drugresistant influenza A virus during therapeutic use of rimantadine. Antimicrob Agents Chemother 35:1741-1747, 1991 19. Hayden FG, Couch RB: Clinical and epidemiologic importance of influenza A viruses resistant to amantadine and rimantadine. Rev Med Virol 2:89-96, 1992 20. Aoki FY, Sitar DS: Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet 14:35-51, 1985 21. Capparelli EV, Stevens RC, Chow MSS: Rimantadine pharmacokinetics in healthy subjects and patients with end stage renal failure. Clin Pharmacol Ther 43:536-541, 1988 22. Fishaut M, Mostow S: Amantadine for severe influenza A pneumonia in infancy. Am J Dis Child 134:321-323, 1980 23. Horadam VW, Sharp JG, Smilack JD, et al: Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function. Ann Intern Med 94:454-458, 1981 24. Dolin R, Reichman RC, Madore HP, et al: A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 307:580-584, 1982 25. Clover RD, Crawford SA, Abell TD, et al: Effectiveness of rimantadine prophylaxis of children within families. Am J Dis Child 140:706-709, 1986 26. Douglas RG: Prophylaxis and treatment of influenza. N Engl J Med 322:443-450, 1990 27. Crawford SA, Clover RD, Abell TD et al: Rimantadine prophylaxis in children: A follow-up study. Pediatr Infect Dis J 7:379383, 1988 28. Demicheli V, Jefferson T, Rivetti D, et al: Prevention and early treatment of influenza in healthy adults. Vaccine 18:957-1030, 2000 29. Immunization Practices Advisory Committee: Prevention and control of influenza. MMWR Morb Morbal Wkly Rep 41:1-14, 1992 30. World Health Organization: Current status of amantadine and rimantadine as anti-influenza-A agents. Bull World Health Organ 63:51-56, 1985 31. Hall CB, Dolin R, Gala CL, et al: Children with influenza A infection: Treatment with rimantadine. Pediatrics 80:275-282, 1987 32. Van Voris LP, Betts RF, Hayden FG, et al: Successful treatment of naturally occurring influenza A/USSR/77 H1N1. JAMA 245:1128-1131, 1981 33. Covington E, Mendel DB, Escarpe PA, et al: Phenotypic and genotypic assay of influenza virus neuraminidase indicates a low incidence of viral drug resistance during treatment with oseltamivir. II International Symposium on Influenza and Other Respiratory Viruses, Grand Cayman, December 10-12, 1999 (abstr) 34. Wood ND, Aitken M, Sharp S, et al: Tolerability and pharmacokinetics of the influenza neuraminidase inhibitor Ro-64-0802 (GS4071) following oral administration of the prodrug Ro-640796 (GS4104) to health male volunteers. Presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997 (abstr A-123)
Antiviral Therapy for Influenza 35. Hayden FG, Atmar RL, Schilling M, et al: Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 341:1336-1343, 1999 36. Munoz FM, Galasso GJ, Gwaltney JM Jr, et al: Current research on influenza and other respiratory viruses: II International Symposium. Antiviral Res 46:91-124, 2000 37. Treanor JJ, Hayden FG, Vrooman PS, et al: Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: A randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 283:1016-1024, 2000 38. Nicholson KG, Aoki FY, Osterhaus AD, et al: Efficacy and safety of oseltamivir in treatment of acute influenza: A randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet 355:1845-1850, 2000 39. Whitley RJ, Hayden FG, Reisinger KS, et al: Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20:127133, 2001 40. Gubareva LV, Matrosovich MN, Brenner MK, et al: Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 178:1257-1262, 1998 41. Cass LM, Brown J, Pickford M, et al: Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinetics 36: 21-31, 1999 (suppl 1) 42. Calfee DP, Peng AW, Hussey EK, et al: Safety and efficacy of once daily intransal zanamivir in preventing experimental human influenza A infection. Antiviral Ther 4:143-149, 1999 43. Cass LM, Gunawardena KA, Macmahon MM, et al: Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir. Respir Med 94:166-173, 2000
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44. Monto AS, Robinson DP, Herlocher L, et al: Zanamivir in the prevention of influenza among healthy adults. JAMA 282:3136, 1999 45. Kaiser L, Henry D, Flack NP, et al: Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study. Clinical Infect Dis 30:587-589, 2000 46. Hayden FG, Gubareva LV, Monto A, et al: Inhaled zanamivir for the prevention of influenza A in families. N Engl J Med 343:1282-1289, 2000 47. Management of Influenza in the Southern Hemisphere Trialists Study Group: Randomized trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 352:1877-1881, 1998 48. Makela MJ, Pauksens K, Rostila T, et al: Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: A randomized, double-blind, placebo-controlled European study. J Infection 40:42-48, 2000 49. Lalezari J, Klein T, Stapleton JT, et al: The efficacy and safety of inhaled zanamivir in the treatment of influenza in otherwise healthy and “high risk” individuals in North America. J Antimicrob Chemother 44:42, 1999 (abstr) 50. Hayden FG, Osterhaus ADME, Treanor JJ, et al: Efficacy and safety of the neuraminadase inhibitor zanamivir in the treatment of influenzavirus infections. N Engl J Med 337:874-880, 1997 51. Hedrick JA, Barzilai A, Behre U, et al: Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J 19:410-417, 2000 52. Gubareva LV, Kaiser L, Hayden FG: Influenza virus neuraminidase inhibitors. Lancet 355:827-835, 2000
he influenza viruses consist of the influenza A and the influenza B subgroups.1,2 These viruses are ubiquitous human pathogens that cause annual epidemics because of their distinctive capacity to undergo frequent antigenic changes in the viral hemagglutinin (HA) and neuraminidase (NA) proteins that mediate infectivity. Influenza infections almost always are limited to the respiratory tract, and most serious morbidity and influenza-associated mortality results from influenza pneumonia or secondary bacterial pneumonia. Reinfection is a common occurrence because alterations in the major viral proteins allow influenza A and B viruses to escape the adaptive immune responses acquired during previous infections. Antiviral drugs that are available for the treatment of influenza in children and adolescents include amantadine, which was one of the first drugs used to treat viral infection, and the new neuraminidase inhibitors, zanimivir and oseltamivir.
T
The Virus Influenza A and B viruses are enveloped, single-stranded RNA viruses that contain a segmented genome.1,2 Eight RNA segments, each of which encodes 1 or 2 viral proteins, exist; the complete virion is composed of 5 internal and 3 membrane proteins. Although both influenza A and B viruses have the 8-component, negative-sense RNA genome, major differences are identified in the genes encoded by 2 of the 8 segments. Since the 1950s, researchers have been able to isolate influenza viruses in cell culture and to identify more precisely the changing subtypes that have circulated
From the Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. Address correspondence to Charles G. Prober, MD, Infectious Diseases Division, Department of Pediatrics, Stanford University School of Medicine, G312, 300 Pasteur Dr, Stanford, CA 94305. Copyright 2002, Elsevier Science (USA). All rights reserved. 1045-1870/02/1301-0007$35.00/0 doi:10.1053/spid.2002.29755
in the human population. The surface membrane proteins, HA and NA, are critical components of the virion envelope and form spikes on the virion surface. HA is responsible for virus attachment to cells, which allows the virus to enter respiratory epithelial cells and initiate infection; it was identified by its capacity to agglutinate red blood cells. The internal proteins of the virus are the nucleoprotein, matrix (M) proteins 1 and 2, 3 viral polymerases, and the nonstructural proteins (NS1 and NS2) of unknown function. HA contains major protective epitopes against which the host immune response is directed. NA may help the virus to move through mucous, and this protein functions to promote the release and spread of newly synthesized virions from infected cells. Protective immunity also is elicited against epitopes of influenza NA. The M1 and M2 proteins are involved at various steps in the assembly and maturation of the virus particles. Changes in the M2 protein mediate the resistance of influenza A virus to amantadine. Influenza C viruses, which rarely are infectious in humans, differ from influenza A and B viruses by having only 7 RNA genome segments and by the absence of an NA gene. New influenza viruses that have RNA mutations encoding variants of the HA protein emerge annually or every few years. Variation in HA is a key factor for immune evasion by influenza and may occur separately or in conjuction with changes in NA. Each new influenza isolate is classified according to its subtype, which may be A, B, or C; by the geographic source of the isolate; and by the year of isolation (eg, influenza A/Syndney/97). Influenza A strains are subtyped as H1N1, H2N3, or H3N2 influenza, according to the antigenic characteristics of their HA and NA proteins. The introduction of new influenza strains into the human population is thought to result from transmission from infected birds, which are a natural reservoir for influenza viruses; birds are infected with other viral subtypes, most of which are not directly infectious for humans but may be a source of genetic mutations that are transferred into human strains. Influenza viruses replicate in the intestinal tract of domestic and wild fowl, which permits their wide dissemination in the environment and allows transfer to other
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species, including swine, a potential intermediate host, and, in some cases, to people. How efficiently these novel viruses spread appears to depend upon poorly understood virulence factors that enhance infectivity for nonavian species. Antigenic drift is the first and more common type of viral mutation. Under these conditions, the HA and NA proteins change slowly, owing to the accumulation of single nucleotide changes in the respective genes that encode these proteins. As a result, anti-HA and anti-NA antibodies acquired during previous infections provide limited or no protection against the new strain. The second kind of antigenic variation in influenza strains is antigenic shift.3 The segmented genome of influenza viruses permits recombination, in which viral genes from 1 strain are introduced into another virus. When antigenic shift occurs, the HA protein is changed, with or without alterations in NA. The result is a truly new strain, which cannot be inhibited by the host response to strains that circulated earlier. When such strains emerge, widespread epidemics or pandemics ensue.
Epidemiology and Transmission Influenza A and B viruses emerge and spread annually within the global human population, with representatives of the influenza A subtypes and influenza B groups being recovered from infected individuals each year. During most annual epidemics, infections with either influenza A or influenza B are more common. Some information about the epidemiology of influenza viruses is available for most of the 20th century, as shown in Fig 1.3 Influenza A viruses that have been prevalent since the late 1960s belong to the H1N1 or H3N2 subtypes; the occurrence of H2N2 epidemics before this time suggest that the 3 subtypes of influenza A viruses may exhibit cycles of predominance. The emergence of the H3N2 strain in 1968 is an example of antigenic shift, resulting in the Hong Kong flu pandemic. The degree to which an influenza virus strain spreads also depends on how many susceptible patients are present in the population. In contrast to outbreaks of influenza A and B, influenza C outbreaks usually are limited geographically, and children and young adults are infected most often. During influenza infection, infected epithelial cells are disrupted and progeny virions are released into respiratory secretions. The concentration of infectious virions in respi-
Figure 1. The historic pattern of influenza A epidemics. Data from reference 3.
ratory secretions of individuals with acute influenza A or B infection often is 104 to 105 tissue culture infectious dose per milliliter. The high concentrations of infectious virions facilitates transmission to susceptible contacts, which may occur by aerosolization of infectious particles in respiratory secretions or by self-inoculation of the virus by hand after direct contact with infected surfaces or fomites. The physiology of sneezing is such that aerosolized particles travel at 100 feet per second and for distances of 2 to 5 feet. Therefore, close exposure to an infected individual is highly likely to result in inoculation with infectious virions. Whether influenza-related disease follows depends on whether the exposed contact has immunity to the infecting virus or to strains that are antigenically very similar. During primary infection in children, influenza viruses persist at respiratory mucosal sites for up to 10 to 14 days. The individual becomes less contagious over time from onset because the infectious virus content in respiratory secretions peaks within 1 to 3 days and then declines rapidly.
Clinical Manifestations of Influenza Infection Illnesses caused by influenza A and B viruses cannot be differentiated clinically.4 After inoculation of the respiratory mucosa, influenza viruses begin to replicate in the columnar epithelial cells. As infection progresses, production of proinflammatory cytokines is induced and the nasal epithelium becomes edematous. Localized edema and inflammation of the nasal epithelium usually develops within 48 to 72 hours and results in symptoms of congestion and obstruction of sinus and middle ear passages. The onset of influenza illness is associated typically with fever of 38 to 40°C and sudden onset of sore throat, cough, headache, and myalgias. How influenza viruses cause nonrespiratory symptoms has not been explained, but release of cytokines, such as interferon ␣/, is presumed to be the mechanism. In most cases, fever persists for 1 to 5 days and other respiratory and systemic symptoms last for up to a week. Most often, a persistent dry cough is the only prolonged symptom of influenza. The clinical course of uncomplicated influenza is agerelated and varies depending on whether the individual has any cross-reactive immunity from previous infections with similar strains. Primary infection of the naive host with influenza A or B viruses is associated with a more prolonged illness and with the highest risk of lower respiratory infection. Although infection may be asymptomatic in older individuals, most infections in children younger than 5 years old cause some signs of illness. Serious morbidity and influenza-related mortality in children is highest in this age group and is comparable to the risks associated with influenza in the elderly (Fig 2).5 More severe upper respiratory symptoms, such as laryngeotracheobronchitis and influenza pneumonia, are most common in young children who are encountering influenza A or B for the first time. Pneumonia, whether diagnosed clinically or by chest radiograph, is described in 10 to 50 percent of these cases. Nevertheless,
33
Antiviral Therapy for Influenza
Figure 4. Recovery of respiratory viruses from middle ear fluid in children with otitis media. Data from reference 7. Figure 2. Age-related differences in morbidity and mortality caused by influenza. Data from reference 5.
influenza pneumonia in the healthy child usually is selflimited and resolves rapidly without sequelae. In the youngest age group, small airway size may enhance morbidity, resulting in bronchiolitis, and in the newborn period, influenza may cause a sepsis-like syndrome with minimal respiratory signs. Many children receive antibiotics for influenza during the annual epidemics (Fig 3).6 However, much of the symptomatology of influenza is a consequence of viral infection. For example, influenza A or B viruses were recovered from middle ear fluid in 40 percent of children and were third, after respiratory syncytial virus and parainfluenza viruses, in frequency of isolation from children with otitis media (Fig 4).7 For the most part, influenza replication is limited to the respiratory mucosa. Many children experience vomiting, diarrhea, and abdominal pain, but these signs do not indicate viral replication in the gastrointestinal tract. Myocarditis, myositis, and encephalitis are serious complications of uncertain cause. Influenza is associated with a risk of bacterial superinfection. The destruction of mucosal epithelial cells by the virus compromises ciliary function and probably facilitates secondary bacterial infections of the upper or lower respi-
ratory tract. Although influenza may cause otitis, bacterial otitis media is the most common secondary infection. Staphylococcal and pneumococcal pneumonia are the most significant secondary bacterial complications and account for most hospitalizations and fatal illnesses during the annual influenza epidemics (Table 1).8 The host response eliminates influenza by destroying infected cells and by releasing cytokines that protect adjacent uninfected cells. The lysis of infected cells is mediated by antibodies against HA in combination with complement, antibody-mediated cytotoxicity, and cytotoxic T cells. Because the healthy host has all of these defense mechanisms, which one is most important for resolution of infection is not clear. However, influenza virus persists longer in children with deficiencies of cellular immunity, indicating an important role for cytotoxic T cell clearance. In some immunocompromised patients, such as bone marrow transplant recipients, influenza is life-threatening.4 Cell-mediated responses may be particularly useful because they are directed against conserved proteins, such as the matrix and nucleoproteins, and mediate immunity that is cross-reactive against a broad range of influenza subtypes. Antiinfluenza IgG and mucosal IgA antibodies are made against the HA and NA proteins, and their neutralizing activity is considered the most important defense against reinfection with related subtypes.
Diagnosis The laboratory diagnosis of acute influenza has improved dramatically in recent years.2 Direct virus detection meth-
Table 1. Association of Influenza and Pneumococcal Pneumonia in Children
Figure 3. Office visits and antibiotic use in children with influenza infections: events per 100 children. Data from reference 6.
Event
Odds Ratio
Influenza-like illness before admission Influenza-like illness in family H1N1 seroconversion
12.4 (1.7-306) 2.6 (1.0-6.3) 3.7 (1.0-18.1)
Data from reference 7.
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Table 2: Antiviral Drugs or the Prevention and Treatment of Influenza Infections Agent
Indication
Amantadine (Symmetrel, Endo Therapy for type A Pharmaceutical, Inc, influenza infections Chaddsford, PA) Prevention of type A influenza infection Rimantadine (Flumadine, Therapy for type A Forest Pharmaceutical, St. influenza infections Louis, MO) Prevention of type A influenza infections Oseltamivir (Tamiflu, Roche Therapy for type A & B Pharmaceuticals, Nutley, NJ) influenza infections Prevention of type A & B influenza infections Zanamivir (Relenza, Therapy for type A & B GlaxoWellcome, Research influenza infections Triangle Park, NC)
ods and viral culture have replaced serologic testing for a 4-fold rise in anti-HA antibody titers between acute and convalescent sera. The sensitivity of direct detection and viral culture methods is optimal when specimens are obtained within the first 24 to 72 hours after onset of typical influenza symptoms because the peak titer of virus is present in respiratory secretions during this time interval. Rapid tests of nasal or throat swab specimens are sensitive and specific when compared with viral culture, which is the standard for unequivocal proof of an influenza infection. Infected epithelial cells from swab specimens can be detected by staining and by immunofluorescence microscopy examination. Enzyme immunoassays identify viral proteins in respiratory secretion specimens, providing a diagnosis within 15 to 20 minutes. These methods differentiate between influenza A and B, which is important when antiviral therapy is considered because amantadine is effective against only influenza A strains. Molecular methods, such as polymerase chain reaction or in situ hybridization, rarely are needed but can be useful when the specimen is negative by viral culture or to test tissue specimens for influenzainfected cells. Serologic assays can be used to assess anti-HA antibodies to determine whether an individual is likely to be susceptible to a new influenza strain. However, such serologic testing is complex and rarely practical because the serum must be tested for antibodies that will bind to the new variant or novel HA protein or neutralize the circulating influenza strain.
Antiviral Agents for the Prevention and Treatment of Influenza Virus Infections Under ideal circumstances, infections caused by influenza viruses should be prevented by immunization. However, the current inactivated vaccine is recommended only for adults older than 50 years of age and adults and children at high-risk of developing serious infection caused by influenza
Age
Daily Dosage
ⱖ1 yr
5 mg/kg in 1-2 doses; 100-200 mg for adults for 5 days ⱖ1 yr 5 mg/kg in 1-2 doses; 100-200 mg for adults for ⱖ4 weeks ⱖ18 yr 5 mg/kg in 1 dose; 100-200 mg for adults for 5 days ⱖ1 yr 5 mg/kg in 1 dose; 100-200 mg for adults for ⱖ4 weeks ⱖ1 yr 4 mg/kg in 2 doses; 150 mg for adults for 5 days ⱖ13 yr 4 mg/kg in 2 doses; 150 mg for adults for 6 weeks ⱖ7 yr 20 mg in 2 doses for 5 days
Cost (for Adults) $2-$10 for 5 days
$20 for 5 days
$53 for 5 days
$44 for 5 days
viruses. Antiviral chemotherapy may be useful for those who did not receive a vaccination, have impaired immunologic responses, or contract infection despite immunization. Two classes of antivirals are licensed for the prevention and treatment of infections caused by influenza viruses (Table 2). One class includes amantadine and rimantadine, which are closely related symmetric tricyclic amines that are active against only type A influenza viruses. The second class includes the recently licensed neuraminidase inhibitors, zinamivir and oseltamivir, which are active against both type A and type B influenza viruses. Widespread vaccination and optimal use of available antiviral drugs should lead to declines in physician visits, hospitalizations, and deaths attributable to influenza infection.9
Amantadine and Rimantadine Amantadine (Symmetrel) and rimantadine (Flumadine) are symmetric tricyclic amines that are closely related structurally. Approved by the Food and Drug Administration in 1966, amantadine has the distinction of being the first antiviral agent licensed for systemic use in the United States. Rimantadine was approved for use in the United States more than a quarter of a century later (1993).
Antiviral Action and Drug Resistance The activity of amantadine and that of rimantadine are limited to influenza A viruses. Rimantadine is 4- to 10-fold more active than is amantadine; inhibitory concentrations of susceptible influenza A isolates range from 0.1 to 0.4 g/mL for amantadine and from 0.01 to 0.1 g/mL for rimantadine.10,11 The target of the inhibitory action for both of these antivirals is the influenza A virus M2 protein. The M2 protein forms a channel that spans the viral membrane, allowing the penetration of hydrogen ions into the interstices of the viral particle.12 The drop in pH accompanying the hydrogen flux facilitates the dissociation of the M1
Antiviral Therapy for Influenza protein from the ribonucleoprotein complexes so that the ribonucleoprotein can enter the cell nucleus and initiate replication.13 Blocking the flow of hydrogen ions inhibits viral replication.14 Resistance to amantadine and rimantadine results from a point mutation in the RNA sequence encoding for the M2 protein transmembrane domain.15 Resistance typically appears in the treated subject within 2 to 3 days of initiating therapy; 25 to 35 percent of treated patients shed resistant strains by the fifth day of treatment.16 The clinical significance of isolating resistant strains from the treated subject is not clear; infection and illness in immunocompetent people infected with a drug-resistant virus are similar to those in patients infected with viral strains who are susceptible to the drugs.17,18 However, transmission of resistant strains to household contacts can occur, and failure of drug prophylaxis can result. Therefore, contact between treated patients and susceptible high-risk patients should be avoided.19
Pharmacokinetics and Dosage Both amantadine and rimantadine are well absorbed after oral administration, and food does not interfere with absorption of either drug.20,21 More than 90 percent of a dose of amantadine is excreted unchanged in the urine, whereas rimantadine is metabolized extensively, with less than 15 percent of the drug excreted unchanged in the urine. Peak serum concentrations of both drugs range from 0.4 to 0.8 g/mL after 100-mg oral doses. The time to attain peak concentrations varies from 2 to 6 hours. Concentrations of amantadine and rimantadine in nasal secretions are 50 to 100 percent of those attained in serum, and limited data suggest that adequate penetration into pulmonary tissue of infants occurs.22 The half-life of amantadine (12 to 18 hours) is approximately half that of rimantadine (24 to 36 hours). Because most of the dose of amantadine is excreted unchanged in the urine, whereas rimantadine is substantially metabolized, compromised renal function more markedly affects the elimination half-life of amantadine than that of rimantadine. Therefore, major dose adjustments of amantadine are necessary in persons with creatinine clearances of less than 80 mL/min/1.73 m2, but dose adjustments for rimantadine are not necessary unless the creatinine clearance is less than 10 mL/min/1.73 m2.23 Amantadine is approved for prophylactic and therapeutic use for adults and children older than 1 year of age. Rimantadine also is approved for prophylactic and therapeutic use for adults but is approved for prophylaxis only (not therapy) for children older than 1 year of age. The usual dose of amantadine in children with normal renal function is 5 mg/kg/d given in 1 to 2 divided doses. The dose of rimantadine also is 5 mg/kg/d, but it is administered as a single daily dose. The dose of both drugs for adults is 100 to 200 mg/d; the lower dose is for the elderly. The cost of a 5-day course of amantadine ranges from approximately $2.00 to $10.00 (lower cost for generic formulation), and the cost for a 5-day course of rimantadine is about $20.00.9
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Adverse Effects Although the types of adverse reactions associated with both amantadine and rimantadine are qualitatively similar, they are less frequent and less severe with rimantadine 9 because amantadine stimulates the release of cathecholamines, whereas rimantadine does not. The most common complaints associated with the administration of both drugs are dose-related gastrointestinal and central nervous system symptoms.24 Gastrointestinal complaints include nausea, vomiting, and dyspepsia. Approximately 10 percent of amantadine recipients and 2 percent of rimantadine recipients experience 1 or more symptoms of central nervous system disturbances, including anxiety, depression, insomnia, difficulty concentrating, or confusion. High concentrations of plasma may cause hallucinations or seizures. Patients with chronic seizure disorders can have increased frequency of seizures associated with either amantadine or rimantadine therapy. Long-term amantadine therapy can cause vision loss, hypotension, urinary retention, peripheral edema, and congestive heart failure. In a study involving children, the incidence of side effects among rimantadine recipients was the same as that among placebo recipients.25
Clinical Indications Prophylaxis with either amantadine or rimantadine prevents approximately 50 to 60 percent of infections and 70 to 90 percent of clinical illnesses caused by type A influenza virus.9,25-28 This degree of prophylactic effectiveness is similar to that of inactivated influenza vaccine. Although vaccine administration would be more convenient, prophylaxis of high-risk hosts throughout the influenza virus season is recommended for those who cannot tolerate the vaccine because of toxicity or allergies and those in whom the vaccine is unlikely to induce protective immunity because of severe immunosuppression.29 Prophylaxis also is indicated if the vaccine may be ineffective because the epidemic strain differs substantially from the vaccine strain of influenza A and for the 2 weeks after vaccination if influenza A already is active in the community.29 Seasonal prophylaxis should be initiated as soon as influenza is identified in the community and continued throughout the epidemic period. Amantadine and rimantadine also have been used to control outbreaks of infection occurring within households, schools, nursing homes, and hospitals.9,26,27,30 Under these circumstances, prophylactic therapy of contacts is started as soon as the index patients are recognized and continued for 4 to 8 weeks. Amantadine and rimantadine also have been shown to be effective in the treatment of influenza A infections in adults and children if treatment is initiated within 48 hours of the onset of symptoms.31,32 Compared with placebo, drug therapy results in reduced duration of viral excretion, fever, and other systemic complaints, as well as an earlier resumption of normal activities. In general, the duration of illness is shortened by about 1 day. In a direct comparison of the 2 drugs in college students, efficacy was similar.32
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Charles G. Prober
Oseltamivir and Zanamivir Oseltamivir (Tamiflu) and Zanamivir (Relenza) are recently licensed agents with activity against both influenza A and B viral strains. Both drugs have pediatric indications approved by the Food and Drug Administration.
Oseltamivir Antiviral Action and Drug Resistance. Oseltamivir is an ethyl ester prodrug that is hydrolyzed by hepatic esterases to the biologically active compound, oseltamivir carboxylate. The mechanism of action for this class of compounds is the specific inhibition of the influenza NA, a highly conserved enzyme, common to type A H1N1, type A H2N2, type A H3N2, type A H5N1, and type B influenza viruses. Structurally, NA inhibitors are analogues of Nacetylneuraminic acid, a component of mucoproteins in respiratory secretions. During infection, virus binds to the mucus but is eluted by the action of NA, facilitating the penetration of the virus to the surface of the respiratory cells. Inhibition of NA prevents penetration of the virus to the cell surface. In addition, NA is necessary for the optimal release of progeny virus from infected cells; inhibition of this process decreases the spread of virus and the intensity of infection. Antiviral resistance has been generated in the laboratory by passaging virus in the presence of increasing concentrations of oseltamivir carboxylate. In addition, 3 percent of posttreatment influenza isolates in human challenge studies developed resistance to oseltamivir. A specific mutation in the active site of the NA molecule of the resistant strain, as compared to the challenge virus, appeared to confer the resistance. In studies of the treatment of naturally occurring influenza infection, approximately 1.5 percent of posttreatment influenza isolates show reduced susceptibility to oseltamivir.33 Accurate estimation of the risk of emergence of oseltamivir resistance in the clinical setting will be determined only by careful phase IV postlicensure monitoring. Pharmacokinetic and Dosage. Approximately 75 percent of the orally administered drug reaches the systemic circulation in the form of oseltamivir carboxylate. The maximum plasma concentration of active compound after the twice-daily administration of multiple, 75-mg doses is approximately 350 ng/mL. Co-administration with food has no significant effect on bioavailability. More than 90 percent of oseltamivir is metabolized to oseltamivir carboxylate. Oseltamivir carboxylate is not further metabolized, but it is almost entirely eliminated by renal excretion by glomerular filtration and tubular secretion. The half-life of oseltamivir carboxylate is 6 to 10 hours.34 Serum concentrations of drug increase in the presence of declining renal function, and dose adjustment is recommended for patients with a creatinine clearance level less than 30 mL per minute. Oseltamivir has been approved for the treatment of children older than 1 year of age. It is licensed for the prevention of influenza infection in those older than 13 years. The pediatric dose of suspension is 2 mg/kg, admin-
istered twice daily. The recommended adult dose (and maximum dose for children) is 75 mg, given twice daily. When used for therapy of active infection, administration of the drug should begin within 2 days of onset of symptoms of influenza and continue for a total of 5 days. The approximate cost of 5 days of therapy for an adult is $53.00. Adverse Effects. The most common side effect reported with oseltamivir use is nausea, with or without vomiting. In controlled clinical trials, approximately 10 percent of patients reported nausea without vomiting, and an additional 10 percent experienced vomiting. The nausea and vomiting episodes generally were of mild to moderate degree and usually occurred on the first 2 days of therapy. Fewer than 1 percent of study subjects discontinued participation in the clinical trials because of nausea or vomiting. Food may help to alleviate the gastrointestinal side effects. Insomnia and vertigo also occur occasionally in oseltamivir recipients. Clinical Indications. Compared with placebo, oseltamivir administered for 6 weeks during the peak of influenza season significantly reduced the risk of contracting influenza.35 The rate of infection was reduced approximately 50 percent, and the rate of illness was reduced more than 80 percent. These rates are comparable with that achievable with amantadine and rimantadine for influenza A virus infections. Influenza infection was prevented in 89 percent of families in which oseltamivir was given to all family members older than 12 years of age who were exposed to influenza in their households.36 In another study, in which oseltamivir was given to nursing home residents for 6 weeks, most of whom had been vaccinated, the rate of influenza infection was reduced by 92 percent.37 Oseltamivir also is effective in the therapy for influenza infections, if initiated soon after the onset of symptoms. Efficacy initially was established as the result of 2 large studies, one conducted at 60 centers throughout the United States and the other conducted at 63 centers in Europe, Canada, and China.37,38 The studies were performed during the 1998 influenza season, and they used identical designs. There were 1,355 patients enrolled in the 2 trials; 849 (63%) had confirmed influenza virus infections. Ninety-five percent of the infections were caused by influenza A. Study inclusion criteria included temperature of at least 100°F, with 1 or more respiratory symptoms, including cough, sore throat, and rhinorrhea, and 1 or more constitutional symptoms, including headache, malaise, myalgia, sweats, and chills. Enrollment had to occur within 36 hours of onset of symptoms. Duration of illness among oseltamivir recipients was reduced by 1 to 1.5 days in both studies compared with the duration of illness among placebo recipients.37,38 The effect was greatest for patients treated within 24 hours of onset of symptoms.38 When evaluated, the clinical benefits observed were associated with reductions in the duration or quantity of virus in patients’ secretions.37 The frequency of physician-diagnosed secondary complications leading to the need for antibiotic prescriptions also was reduced among oseltamivir recipients.38 The efficacy, safety, and tolerability of osetamivir also has been evaluated in a recently published, randomized, double-blind, placebo-controlled trial conducted in children
Antiviral Therapy for Influenza 1 through 12 years of age.39 Six hundred and ninety-five children with fever (ⱖ38°C) and a history of cough or coryza for less than 48 hours duration received oseltamivir or placebo for 5 days. Sixty-five percent (452) of the subjects had confirmed infection caused by influenza virus. The duration of illness was reduced by an average of 1.5 days in patients treated with oseltamivir compared with placebo recipients. In addition, new diagnoses of otitis media were reduced by 44 percent among antiviral recipients, and the incidence of the need for physician-prescribed antibiotics was significantly lower in influenza-infected patients treated with oseltamivir than in placebo recipients (31% vs 41%, respectively).39
Zanamivir Antiviral Action and Drug Resistance. Zanamivir also interferes with the function of the influenza NA enzyme. The in vitro activity of zanamivir against influenza A and influenza B strains is similar to that of oseltamivir. Antiviral resistance can be induced in vitro by passaging virus in the presence of increasing concentrations of zanamivir. Decreased susceptibility to zanamivir is associated with mutations resulting in amino acid changes in the viral NA and/or HA. Resistance also has been documented in clinical specimens isolated from a zanamivir recipient. After undergoing 2 weeks of therapy with zanamivir, an immunocompromised patient infected with influenza B shed a resistant isolate that was shown to have mutations in both the viral HA and the viral NA.40 The NA mutation resulted in a 1,000-fold reduction in enzyme activity. Cross-resistance between zanamivir and oseltamivir has been observed. Pharmacokinetics and Dosage. Zanamivir has poor oral bioavailability and, therefore, is administered by oral inhalation. More than 75 percent of an orally inhaled dose of zanamivir is deposited in the oropharynx, and most of it is swallowed. Approximately 13 percent of the dose distributes to the airways and lungs, although the actual amount delivered depends on patient factors such as inspiratory flow.41 Local respiratory mucosal concentrations of zanamivir exceed 1,000 ng/mL in sputum for 6 hours after inhalation, greatly exceeding the amount of drug needed to inhibit influenza A and B viruses.41,42 Approximately 10 percent of an inhaled dose of zanamivir is absorbed systemically; peak serum concentrations range from 17 to 142 ng/mL within 2 hours of administration of a 10 mg dose.41 The plasma half-life of zanamivir ranges from 2.5 to 5 hours.41 No metabolites of zanamivir have been identified; all absorbed drug is excreted unchanged in the urine. Although serum zanamivir concentrations increase with decreasing creatinine clearance, no adjustment in dosing is necessary for renal insufficiency because of the limited amount of systemically absorbed drug. Zanamivir has been approved by the Food and Drug Administration for the treatment of influenza infections in patients older than 7 years of age. The recommended dose for children and adults is 10 mg (given in 2 inhalations of 5 mg each), administered twice daily for 5 days. Two doses should be taken on the first day of treatment whenever
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possible, with at least 2 hours between doses. On subsequent days, the doses should be approximately 12 hours apart. The approximate cost of a 5-day course of therapy is $44.00.9 Adverse Effects. Zanamivir is well-tolerated. Respiratory distress is the most serious adverse event associated with its use. In some patients with underlying airway disease, a decline in pulmonary function and bronchospasm have been reported.43 Although influenza itself can cause these symptoms, zanamivir is not recommended for treatment of patients with underlying airways disease because of the risk of adverse events and lack of proven efficacy in this population. Zanamivir should be discontinued in any patient who develops bronchospasm or decline in respiratory function. Clinical Indications. Inhaled zanamivir, administered for 4 weeks as seasonal prophylaxis, reduces the likelihood of laboratory confirmed influenza infection by 30 percent, influenza disease by 67 percent, and influenza disease with fever by 84 percent.44 Short-term (5 days) prophylaxis with zanamivir, after presumed exposure to influenza in the community, also has been shown to reduce the rate of secondary infection from 6 percent among placebo recipients to 2 to 3 percent among antiviral recipients.45 Prophylaxis within households also is effective. When zanamivir was given for 5 days to both the index patient and exposed family members older than 5 years of age within 24 hours of the index patient becoming ill, a 79 percent reduction in the proportion of families with at least 1 affected contact was observed.46 Protection was observed against both influenza A and influenza B virus infections. The efficacy of zanamivir in the treatment of influenza A and B virus infections has been shown in several placebo controlled studies conducted in adults 47-50 and 1 study conducted in 471 children, 5 to 12 years of age.51 Patients received zanamivir 10 mg inhaled twice daily versus placebo inhaled twice daily. On average, the zanamivir-treated patients improved 1.0 to 2.5 days faster than did the placebo recipients. Combined analysis of these trials indicates that zanamivir reduces the duration of symptoms by approximately 1.5 days. In the pediatric study, a 1.25-day reduction occurred in clinically significant symptoms attributed to influenza, compared with only a 0.5-day reduction of symptoms in the intent-to-treat analysis.52 Zanamivir therapy also appears to reduce the frequency of secondary respiratory complications of influenza infections requiring antibiotic prescription.
Summary Infections caused by influenza viruses are a major source of morbidity and mortality worldwide. Recent data underscore the potential seriousness of influenza infections in children, especially infants and toddlers. Four antiviral agents are licensed for the treatment and prevention of influenza virus infections. Two of the agents (amantadine and rimantadine) are active against only type A strains and 2 (oseltamivir and zanamivir) are active
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Charles G. Prober
against both type A and type B strains. Historically, amantadine and rimantadine have not been used widely in children, and experience with the newer agents is quite limited. Considering the small degree of therapeutic gain observed with these antivirals, cost effectiveness considerations will help physicians decide their role, if any, in the treatment of healthy children and adults with suspected or proven influenza infections. The role of antiviral agents in the prevention of influenza infections is secondary to that of vaccination. Although an effective inactivated vaccine is available for those at increased risk for developing serious infections caused by influenza viruses, the vaccine is underused, not effective under all circumstances (eg, hosts with compromised immunity), and not recommended for routine use in children. Therefore, under certain circumstances, control of community and household spread of influenza infections may be augmented by use of chemotherapy.
References 1. Lamb RA, Krug RM: Orthomyxoviridae: The viruses and their replication, in Fields BN, Knipe DM, Howley PM, (eds): Fields Virology. Philadelphia, PA, Lippincott-Raven, 1996 2. Ziegler T, Cox N: Influenza viruses, in Murray PR, Baron EJ, Pfaller MA, Tenover PC, Yolken RH (eds): Manual of Clinical Microbiology ed. 7. Washington, DC, American Society for Microbiology, 1999, p 928-935 3. Murphy BR, Webster R: Orthomyxoviruses, in Field BN (ed): Virology. Raven, 1990 4. Gruber W: Influenza Viruses, in Long S, Prober C, Pickering L (eds): Principles and Practices of Pediatric Infectious Diseases. Phildelphia, PA, Lippincott, 1997, p 1267-1271 5. Glezen WP: Emerging Infections: Pandemic influenza. Epidemiol Rev 18:64-76, 1996 6. Neuzil KM, Mellen BG, Wright PF, et al: The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 342:225-231, 2000 7. Heikkinen T, Thint M, Chonmaitree T: Prevalence of various respiratory viruses in the middle ear during acute otitis media. New Engl J Med 340:260-264, 1999 8. O’Brien KL, Walters MI, Sellman J, et al: Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection. Clin Infect Dis 30:784-789, 2000 9. Couch RB: Prevention and treatment of influenza. N Engl J Med 343:1778-1787, 2000 10. Browne MJ, Moss M, Boyd MR: Comparative activity of amantadine and ribavirin against influenza virus in vitro: Possible clinical relevance. Antimicrob Agents Chemother 23:503-505, 1983 11. Valette M, Allard JP, Aymard M, et al: Susceptibilities to rimantadine of influenza A/H1N1 and A/H3N2 viruses isolated during the epidemics of 1988 to 1989 and 1989 to 1990. Antimicrob Agents Chemother 37:2239-2240, 1993 12. Pinto LH, Holsinger LJ, Lamb RA: Influenza virus M2 protein has ion channel activity. Cell 69:517-528, 1992 13. Bui M, Whittaker C, Helenius A: Effect of M1 protein and low pH on nuclear transport of influenza virus ribonucleoproteins. J Virol 70:8391-8401, 1996 14. Tosteson MT, Pinto LH, Holsinger LJ, et al: Reconstitution of the influenza virus M2 ion channel in lipid bilayers. J Membrane Biol 142:117-126, 1994
15. Hayden FG, Couch RB: Clinical and epidemiologic importance of influenza A viruses resistant to amantadine and rimantadine. Rev Med Virol 2:89-96, 1992 16. Hayden FG, Belshe RB, Clover RD, et al: Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med 321:1696-702, 1989 17. Monto AS, Arden NH: Implications of viral resistance to amantadine in control of influenza A. Clin Infect Dis 15:368-369, 1992 18. Hayden FG, Sperber SJ, Belshe RB, et al: Recovery of drugresistant influenza A virus during therapeutic use of rimantadine. Antimicrob Agents Chemother 35:1741-1747, 1991 19. Hayden FG, Couch RB: Clinical and epidemiologic importance of influenza A viruses resistant to amantadine and rimantadine. Rev Med Virol 2:89-96, 1992 20. Aoki FY, Sitar DS: Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet 14:35-51, 1985 21. Capparelli EV, Stevens RC, Chow MSS: Rimantadine pharmacokinetics in healthy subjects and patients with end stage renal failure. Clin Pharmacol Ther 43:536-541, 1988 22. Fishaut M, Mostow S: Amantadine for severe influenza A pneumonia in infancy. Am J Dis Child 134:321-323, 1980 23. Horadam VW, Sharp JG, Smilack JD, et al: Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function. Ann Intern Med 94:454-458, 1981 24. Dolin R, Reichman RC, Madore HP, et al: A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 307:580-584, 1982 25. Clover RD, Crawford SA, Abell TD, et al: Effectiveness of rimantadine prophylaxis of children within families. Am J Dis Child 140:706-709, 1986 26. Douglas RG: Prophylaxis and treatment of influenza. N Engl J Med 322:443-450, 1990 27. Crawford SA, Clover RD, Abell TD et al: Rimantadine prophylaxis in children: A follow-up study. Pediatr Infect Dis J 7:379383, 1988 28. Demicheli V, Jefferson T, Rivetti D, et al: Prevention and early treatment of influenza in healthy adults. Vaccine 18:957-1030, 2000 29. Immunization Practices Advisory Committee: Prevention and control of influenza. MMWR Morb Morbal Wkly Rep 41:1-14, 1992 30. World Health Organization: Current status of amantadine and rimantadine as anti-influenza-A agents. Bull World Health Organ 63:51-56, 1985 31. Hall CB, Dolin R, Gala CL, et al: Children with influenza A infection: Treatment with rimantadine. Pediatrics 80:275-282, 1987 32. Van Voris LP, Betts RF, Hayden FG, et al: Successful treatment of naturally occurring influenza A/USSR/77 H1N1. JAMA 245:1128-1131, 1981 33. Covington E, Mendel DB, Escarpe PA, et al: Phenotypic and genotypic assay of influenza virus neuraminidase indicates a low incidence of viral drug resistance during treatment with oseltamivir. II International Symposium on Influenza and Other Respiratory Viruses, Grand Cayman, December 10-12, 1999 (abstr) 34. Wood ND, Aitken M, Sharp S, et al: Tolerability and pharmacokinetics of the influenza neuraminidase inhibitor Ro-64-0802 (GS4071) following oral administration of the prodrug Ro-640796 (GS4104) to health male volunteers. Presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997 (abstr A-123)
Antiviral Therapy for Influenza 35. Hayden FG, Atmar RL, Schilling M, et al: Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 341:1336-1343, 1999 36. Munoz FM, Galasso GJ, Gwaltney JM Jr, et al: Current research on influenza and other respiratory viruses: II International Symposium. Antiviral Res 46:91-124, 2000 37. Treanor JJ, Hayden FG, Vrooman PS, et al: Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: A randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 283:1016-1024, 2000 38. Nicholson KG, Aoki FY, Osterhaus AD, et al: Efficacy and safety of oseltamivir in treatment of acute influenza: A randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet 355:1845-1850, 2000 39. Whitley RJ, Hayden FG, Reisinger KS, et al: Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20:127133, 2001 40. Gubareva LV, Matrosovich MN, Brenner MK, et al: Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 178:1257-1262, 1998 41. Cass LM, Brown J, Pickford M, et al: Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinetics 36: 21-31, 1999 (suppl 1) 42. Calfee DP, Peng AW, Hussey EK, et al: Safety and efficacy of once daily intransal zanamivir in preventing experimental human influenza A infection. Antiviral Ther 4:143-149, 1999 43. Cass LM, Gunawardena KA, Macmahon MM, et al: Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir. Respir Med 94:166-173, 2000
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44. Monto AS, Robinson DP, Herlocher L, et al: Zanamivir in the prevention of influenza among healthy adults. JAMA 282:3136, 1999 45. Kaiser L, Henry D, Flack NP, et al: Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study. Clinical Infect Dis 30:587-589, 2000 46. Hayden FG, Gubareva LV, Monto A, et al: Inhaled zanamivir for the prevention of influenza A in families. N Engl J Med 343:1282-1289, 2000 47. Management of Influenza in the Southern Hemisphere Trialists Study Group: Randomized trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 352:1877-1881, 1998 48. Makela MJ, Pauksens K, Rostila T, et al: Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: A randomized, double-blind, placebo-controlled European study. J Infection 40:42-48, 2000 49. Lalezari J, Klein T, Stapleton JT, et al: The efficacy and safety of inhaled zanamivir in the treatment of influenza in otherwise healthy and “high risk” individuals in North America. J Antimicrob Chemother 44:42, 1999 (abstr) 50. Hayden FG, Osterhaus ADME, Treanor JJ, et al: Efficacy and safety of the neuraminadase inhibitor zanamivir in the treatment of influenzavirus infections. N Engl J Med 337:874-880, 1997 51. Hedrick JA, Barzilai A, Behre U, et al: Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J 19:410-417, 2000 52. Gubareva LV, Kaiser L, Hayden FG: Influenza virus neuraminidase inhibitors. Lancet 355:827-835, 2000