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Antiviral Drugs
The decision to prescribe an antiviral drug for the prevention or treatment of influenza must be based on
proof or a strong probability that a person will be exposed to or has an influenzavirus infection. Proof that an epidemic is under way is best provided by virologic surveillance of ill people.
2,
5 The use of a rapid diagnostic test can facilitate decisions regarding treatment for individual patients as well as decisions regarding prophylaxis during institutional outbreaks. Several diagnostic kits are commercially available; their sensitivity for the detection of influenza is high (approximately 90 percent) for acutely ill hospitalized children but only moderate to low for adults and people with less severe illness.
55,
56 Only the reverse-transcriptase–polymerase-chain-reaction assay has a sensitivity similar to that of viral culture, but the method is not yet available commercially.
56 Rapid tests should be used for all patients hospitalized with an acute respiratory illness during the epidemic period. A positive test provides a diagnosis and data that can be used to control the infection in hospitals, that guides therapy, and that helps determine the prognosis for a given patient. The use of a rapid diagnostic test in the clinic is not necessary for initiating antiviral drug therapy in patients with typical cases of febrile influenza during the epidemic period, but it can provide reassurance that such therapy is appropriate for patients with other acute respiratory syndromes. An additional advantage of obtaining a rapid, specific diagnosis is that it permits physicians to withhold antibiotics with confidence.
Amantadine and Rimantadine
Amantadine and rimantadine are related antiviral drugs, with a similar mechanism of action.
Both are effective against influenza A viruses only (
Table 4).
Antiviral Action
Both amantadine and rimantadine
inhibit the growth of influenza A virus in vitro at concentrations of less than 1 µg per milliliter, and both are effective for the prevention and treatment of type A influenza in animals.
58,
59,
60,
61 They are not effective against influenza B. These drugs act by blocking an ion channel formed by the M2 protein that spans the viral membrane.
62 During the initial stage of viral replication, virus is taken into endocytotic vesicles, in which the pH falls as hydrogen ions enter. The hydrogen ions pass through the M2 channel into the interstices of the viral particle and promote the dissociation of the M1 protein from the ribonucleoprotein complexes so that the ribonucleoprotein can enter the cell nucleus and initiate replication.
63 Both amantadine and rimantadine enter the ion channel and block the penetration by the hydrogen ions that is necessary for the dissociation of M1 and ribonucleoprotein.
64,
65 Pharmacokinetics
Amantadine is absorbed rapidly and nearly completely, and it takes approximately two hours for the peak plasma concentration to be reached; the peak plasma concentration is 50 percent higher in elderly people than in younger adults.
58 Most of the amantadine is excreted in the urine, and the half-life in younger adults is about half that in elderly people (
Table 5). Rimantadine is also nearly completely absorbed after an oral dose, but its absorption is slower than that of amantadine.
58 The time to the peak plasma concentration is about twice that of amantadine, and the peak concentration is about half that of amantadine. Rimantadine is metabolized and excreted in the urine, with a half-life of about 30 hours in both young and elderly adults.
Adverse Effects
Amantadine stimulates the release of catecholamines, whereas rimantadine does not, which presumably accounts for the prominent central nervous system side effects of amantadine.
66 It causes anxiety, depression, insomnia, and other central nervous system side effects in about 10 percent of normal subjects; high plasma concentrations may induce hallucinations and seizures.
58,
67,
68 About 2 percent of people who are given rimantadine report central nervous system side effects. Both amantadine and rimantadine occasionally cause nausea, vomiting, and dyspepsia.
67,
69 The adverse effects of both drugs are correlated with their plasma concentrations and disappear when therapy is discontinued. In a study involving college students, central nervous system symptoms were reported in 4 percent of those given placebo, 6 percent of those given rimantadine, and 13 percent of those given amantadine.
68 In a study involving children, the incidence of adverse effects in the group given rimantadine was similar to that in the group given placebo.
70 Efficacy
Both amantadine and rimantadine are effective for the prevention of influenza A infection and illness (
Table 4).
The rate of protection against influenzavirus infection has ranged from 0 to 90 percent, and the rate of protection against influenza illness has ranged from 0 to 100 percent, but prophylaxis with either drug usually prevents about 50 percent of infections and 70 to 90 percent of illnesses.58 Thus, for prevention, these antiviral drugs are about as effective as inactivated vaccine when given daily throughout the period of exposure. In a recent review the average effectiveness of amantadine and rimantadine for the prevention of confirmed influenza illness was 61 percent and 72 percent, respectively.
71 Amantadine and rimantadine are effective for the treatment of influenza A, provided that administration of the drug is started during the first two days of illness.67,
69 All but 1 of 25 studies of treatment involving healthy adults and children reported beneficial effects on the symptoms and signs of influenza, and in most studies there was an accompanying reduction in the amount of virus present in secretions.
58 In a direct comparison in college students, the efficacy of the two antiviral drugs was similar.
72 In general, illnesses are shortened by about one day in patients treated with amantadine or rimantadine. Dosage
Amantadine and rimantadine are available only as tablets or syrup for oral administration. The recommended daily doses may be given once or divided in two (
Table 5). The dose of amantadine should be reduced in patients with any renal insufficiency, but that of rimantadine need be reduced only in patients with a creatinine clearance of 10 ml per minute or less.
7,
67,
69 Drug Resistance Mutations leading to an amino acid change in the M2 channel of the virus may lead to resistance to amantadine and rimantadine.64,
65 Strains that develop a resistance to either drug are also fully resistant to the other drug. Such strains develop rapidly during treatment and have been recognized in about 25 to 35 percent of treated patients.73 Immunocompetent people who are infected with a drug-resistant virus do not have either a prolonged illness or a rebound of illness, and both the infection and the illness are similar to those in patients infected by viral strains susceptible to the drugs.
73,
74 Although it has not been demonstrated, it seems likely that drug-resistant virus could become dominant in a localized outbreak.
Each new influenzavirus that appears is considered to have arisen from a single source. The likelihood that one of these new viruses would have acquired its M2 gene segment from a resistant virus is currently remote. Strains with drug-induced resistance that emerge during a season should progressively disappear as they are replaced with new sensitive viruses.
75 Nevertheless,
the potential for emergence of resistance naturally exists, since resistance has been detected in some naturally occurring H1N1 isolates collected between 1933 and 1945, long before the introduction of amantadine (Bean WJ: personal communication). Also, 16 of 2017 isolates from 43 countries and territories were resistant, and the resistance of 8 of these isolates was not attributable to treatment with amantadine or rimantadine or exposure to treated persons.
76 Zanamivir and Oseltamivir
Zanamivir and oseltamivir are related antiviral drugs with a similar mechanism of action and a similar rate of effectiveness against both influenza A and B viruses (
Table 4).
77,
78,
79,
80,
81 Both are neuraminidase inhibitors; as such they are analogues of
N-acetylneuraminic acid (the cell-surface receptor for influenzaviruses), and their design was based on knowledge of the tertiary structure of the virion neuraminidase.
77,
78,
82 Antiviral Action N-acetylneuraminic acid is a component of mucoproteins in respiratory secretions; virus binds to the mucus, but elution caused by the activity of neuraminidase permits the virus to penetrate to the surfaces of cells.
83 Inhibition of the neuraminidase prevents infection. Neuraminidase is also necessary for the optimal release of virus from infected cells, an action that increases the spread of virus and the intensity of the infection.
83 Inhibition of neuraminidase decreases the likelihood that illness will occur and reduces the severity of any illness that does develop. Pharmacokinetics
Zanamivir is inhaled through the mouth at a high flow rate (
Table 5).
84 Scintigraphic studies indicate that 78 percent of a dose of zanamivir is deposited in the oropharynx, whereas only 15 percent reaches the tracheobronchial passages and the lungs.
84 About 10 to 20 percent of the inhaled dose is bioavailable.
85 Although the 90 percent inhibitory concentration in cell-culture assays ranged from 0.05 to more than 100 µM, the concentration in secretions should exceed that needed for the inhibition of most strains of influenzavirus.
86 Absorbed drug is excreted unchanged in the urine.
85
Oseltamivir is given orally; an estimated 75 percent of the dose enters the systemic circulation as oseltamivir carboxylate after it has been converted by hepatic enzymes.
87 Reductions in the dose are recommended for people with a creatinine clearance of less than 30 ml per minute, but precise guidelines for use in people with renal insufficiency are not yet available.
87 Currently, no other adjustments of the dose are recommended.
Adverse Effects
Several minor side effects were reported in less than 5 percent of persons who were given zanamivir, but the frequencies were similar in groups who were given placebo.
86 In 11 patients with mild-to-moderate asthma, zanamivir did not reduce pulmonary function or increase airway responsiveness to methacholine, but zanamivir should be used cautiously in patients with chronic respiratory disease because it can cause bronchospasm and reductions in airflow.
86,
88
Oseltamivir has caused nausea and vomiting in about 10 percent of treated persons; nevertheless, most continued taking the drug.
87,
89,
90 When oseltamivir is taken with food, the incidence of gastrointestinal side effects is reduced and the pharmacokinetics are not altered.
87,
91 No other adverse effects have been attributed to oseltamivir, and no drug interactions have been identified for either zanamivir or oseltamivir.
Efficacy Both zanamivir and oseltamivir are approved for the treatment of influenza only in persons who have been symptomatic for less than two days.86,
87 Overall, the symptoms of influenza disappeared 1 to 1.5 days sooner in the drug-treated groups than in the placebo groups, and
the clinical benefit was associated with reductions in the duration or quantity of virus in the patients' secretions.79,
80,
81,
90,
92 In some studies the frequency of complications such as sinusitis, purulent bronchitis, otitis media, and other infections requiring antibiotic therapy was reduced in both healthy and high-risk persons, but the frequency of pneumonia was too low to be evaluated meaningfully.
79,
80,
81,
90 Zanamivir in a dose of 10 mg once daily and oseltamivir in a dose of 75 mg once daily also prevented influenza when given before exposure during a community epidemic.89,
93 The two drugs had similar rates of effectiveness in the
prevention of infection (30 percent and 50 percent, respectively) and in the prevention of illness (67 percent and 84 percent, respectively). In a study in which oseltamivir was given to exposed family members 12 years old or older, influenza was prevented in 89 percent of families
94; in another study, in which zanamivir was given to both the index patient and exposed family members 5 years old or older, new cases were prevented in 79 percent.
95 In a study in which oseltamivir was given to nursing home residents for six weeks, the reduction in influenza infection in those given the drug was 92 percent.
94 Since almost all the nursing home residents had been vaccinated, the benefit was in addition to that of vaccine.
Drug Resistance Resistance to the neuraminidase inhibitors may develop because of a resistance to the binding of the drug and the inhibition of neuraminidase activity or because of a reduction in the hemagglutinin-receptor binding affinity so that neuraminidase activity has no effect on the release of virus from infected cells.86,
87,
94,
96,
97,
98 Mutations leading to resistance of the neuraminidase to oseltamivir have occurred in about 1.5 percent of treated persons, but resistance mutations were not detected in the trials of zanamivir.
86,
87,
94,
95 However, mutations in both the hemagglutinin and the neuraminidase occurred in an immunocompromised patient with an influenza B infection who was treated for two weeks with zanamivir.
98 The recovery of immunocompetent patients in whom resistant strains developed was similar to that of other treated patients, and studies in animals have suggested that resistant strains are somewhat attenuated.
94,
97 Recommendations for Use of Antiviral Drugs
Recommendations for the use of antiviral drugs are given in
Table 6. The highest priority is for prophylaxis in people who are at high risk of serious complications but who have not been vaccinated. People with immunodeficiency should be vaccinated, but because of poor immune responses, they should also be given an antiviral drug during the epidemic period. Prophylaxis in vaccinated members of high-risk groups, particularly elderly people, should be considered, because the combination of vaccine and an antiviral drug increases protection against influenza.
94,
99 Prophylaxis for those exposed in their homes should also be considered because of the high efficacy of prophylaxis in these persons.
94,
95
All members of a high-risk group in whom clinical influenza develops should be treated, regardless of their vaccination status.
Treatment has been proved to be effective only when it is begun during the first two days after the onset of symptoms, but because of the increased risk of complications, which may be reduced by treatment with zanamivir or oseltamivir,79,80,81,90 it is reasonable to consider treating people at high risk who present with febrile influenza on the third or fourth day of their illness. A potential benefit of treating people with influenza is a
reduction in transmission; such a reduction occurred in a family study in which only the index patient was treated with amantadine or rimantadine.4 Selection of an Antiviral Drug Only amantadine and rimantadine are approved for prophylaxis, and they are effective only for protection against influenza A. The efficacy and the risk of drug resistance are similar with the two drugs. When they are approved for prophylaxis, zanamivir and oseltamivir will provide more options; however, unless their prices are lowered, the cost of prolonged administration will be great, and there is no clear advantage to their use for influenza A epidemics. These drugs, however, are the only option for the prevention of influenza B.
Because the development of drug-resistant virus has not been a problem among persons receiving amantadine or rimantadine for prophylaxis, because their efficacy is similar to that of zanamivir and oseltamivir, and because their cost is substantially lower,
amantadine and rimantadine are preferred for prophylaxis against influenza A. Rimantadine is the safer of the two, but amantadine costs less. For influenza B, either zanamivir or oseltamivir may be given. Oseltamivir is easier to administer, since the administration of zanamivir requires good physical coordination, good lung function, and an understanding of the required inhalation techniques. Direct comparative studies of the various antiviral drugs in terms of safety and effectiveness could alter these recommendations.
For treatment, amantadine is approved for adults and for children who are at least one year old. Rimantadine is approved only for adults, but it can also be given safely in children one year old or older; zanamivir is approved for adults and for children seven years old or older, but oseltamivir is currently approved only for adults. Although zanamivir and oseltamivir cost more than amantadine and rimantidine, they are preferred for treatment because of their effectiveness against influenza B, because data suggest that they have lower complication rates, and because they are associated with a lower risk of drug resistance. The development of resistance to amantadine or rimantadine and the transmission of resistant virus to other people have been demonstrated in families and long-term care facilities.
73,
74,
100 If neuraminidase-inhibitor–resistant strains that emerge during treatment are transmissible and capable of inducing illness, prophylaxis with amantadine or rimantadine will still be effective against influenza A strains. There are no data suggesting that treatment for more than five days is beneficial, and the risk of drug-resistant virus increases with time, particularly among immunocompromised people. Treatment should therefore probably not exceed 10 to 14 days, regardless of the patient's clinical status.
Long-Term Care Facilities
Outbreaks in long-term care facilities can involve 20 to 70 percent of residents, with high mortality rates.
47 The primary method for prevention is annual vaccination, but many frail elderly people have a poor response to vaccine, and outbreaks still occur.
21 Vaccination of the staff of these facilities is important because facilities with high rates of vaccination among staff members have lower mortality rates among residents than facilities with lower rates, regardless of the vaccination status of the residents.
45,
46 Although vaccination is the most important tool for the prevention of influenza, antiviral drugs are useful when outbreaks occur. The antiviral drug should be given to all residents, regardless of their vaccination status, and to all unvaccinated staff members. For outbreaks of influenza A, rimantadine is preferable because it is associated with fewer adverse effects than amantadine, but amantadine is acceptable and cheaper. Zanamivir has been demonstrated to control outbreaks, but oseltamivir should also be effective.
94,
101 Prophylaxis for 14 days or until 7 days after the onset of the last confirmed case of influenza appears to be adequate.
102 Restricting the number of visitors to the facility, decreasing contact among the residents, requiring sick staff members to stay home, and isolating ill residents are recommended practices, all of which may contribute to the control of outbreaks.
103 
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Resistencia al oseltamivir de los virus de la influenza estacional A (H1N1) durante la temporada 2008-2009.pdf
