Antiviral Agents
In the United States, 4 prescription antiviral drugs (oseltamivir, zanamivir, amantadine, rimantadine) are approved for treatment and chemoprophylaxis of influenza. Since January 2006, only the neuraminidase inhibitors (oseltamivir, zanamivir) have been recommended because of widespread resistance to the adamantanes (amantadine, rimantadine) among influenza A (H3N2) virus strains. The neuraminidase inhibitors have activity against influenza A and B viruses (including H1N1), while the adamantanes have activity against influenza A viruses only.
Oseltamivir (Tamiflu) resistance emerged in the United States during the 2008-2009 influenza season. In 2007-2008, a significant increase in the prevalence of oseltamivir resistance was reported among influenza A (H1N1) viruses worldwide. During the 2007-2008 influenza season, 10.9% of H1N1 viruses tested in the United States were resistant to oseltamivir.
Oseltamivir is taken orally (75 mg bid), and zanamivir [Relenza] is taken via an inhalation apparatus (10 mg bid for 5 d). Multiple studies have demonstrated their efficacy. These agents work by inhibiting influenza virus neuraminidase, a glycoprotein spike that protrudes from the virus envelope; this spike is needed for successful cellular release of virus and transmission within the body.
To be effective, these agents must be administered within 40 hours of symptom onset. For critically ill patients with H5N1 infection, evidence suggests that initiation of oseltamivir up to 6-8 days from onset of symptoms may reduce the mortality rate.[44]
Studies also demonstrate the efficacy of these agents in preventing influenza A and B. The prophylactic dose is one half the acute treatment dose.
In a study of 445 patients by the Management of Influenza in the Southern Hemisphere Trialists (MIST) group 1, zanamivir reduced the duration and severity of illness.[45] Zanamivir was administered to one half of patients and placebo to the others within 36 hours of symptom onset. Duration of the flu was reduced by 1.5 days in normal-risk groups and 2.5 days in high-risk groups. A significant decrease in the severity of illness in patients treated with zanamivir allowed them to resume normal activities much sooner.
A placebo-controlled study of oseltamivir by Treanor et al demonstrated the ability of that agent to decrease the duration and severity of influenza.[46] This analysis included patients with laboratory-based diagnoses of influenza and those with clinical diagnosis based on symptoms. The 629 patients were enrolled and randomized into 1 of 3 treatment arms: (1) standard-dose oseltamivir, (2) high-dose oseltamivir, and (3) placebo. In both oseltamivir groups, the mean illness duration was reduced from 103 to 70 hours. The symptom severity decreased in the treated group by 40%.
Additional studies have demonstrated the benefit of neuraminidase inhibitors both in acute disease and in prevention. In a study of 837 relatives of family members infected with influenza, 20% of those treated with placebo became ill, compared with only 4% of those who received prophylactic zanamivir.[47] In addition, this study provided treatment to the index case family member, resulting in a 2.5-day reduction in illness over placebo. Recombinant DNA viral sequences were performed in this study, and no resistant influenza strains developed.
A novel study documented the prophylactic and therapeutic effects of oseltamivir in experimentally induced influenza in humans.[48] In a controlled laboratory environment, volunteers were inoculated intranasally with influenza A/Texas/36/91 (H1N1). In the prophylaxis arm of the study, subjects received either oseltamivir or placebo 26 hours before virus inoculation; in the treatment arm, subjects received oseltamivir or placebo 28 hours after inoculation.
In the prophylactic group, 38% of patients developed influenza, versus which 67% in the placebo group. In the treatment group, oseltamivir reduced the duration of illness from 95 to 53 hours and reduced the severity reduced by 50%, compared with placebo.[48]
Hayden et al also documented the prophylactic efficacy of oseltamivir. In this study, 1559 healthy nonimmunized patients were treated with either placebo or oseltamivir for 6 weeks; at the end of the period, 4.8% of the placebo group had laboratory-confirmed influenza, compared with only 1.2% of the oseltamivir group.[49]
In a randomized, double-blind, placebo-controlled trial of children aged 1-3 years (n=408) with influenza A or B, Heinonen et al found that oseltamivir decreased the incidence of acute otitis media by 85% when treatment began within 12 hours of symptom onset. When treatment began within 24 hours of symptom onset, no significant reduction in incidence of acute otitis media was observed.[50]
When oseltamivir treatment started within 24 hours for children with influenza A, the median time to resolution of illness was decreased by 3.5 days in all children and reduced parental work absenteeism by 3 days. Efficacy was not demonstrated against influenza B infections.[50]
Prompt use of antiviral drugs during the 2009 H1N1 influenza pandemic improved survival among severely ill pregnant women. The CDC examined reports of severe flu (resulting in death or ICU admission) in 347 pregnant women during the pandemic, including 272 who were admitted to the ICU and survived and 75 who died. Severely ill postpartum women (n=15), including 9 who died, also were reported.
Of the 307 pregnant women for whom information regarding the presence of underlying medical conditions was available, half had underlying conditions such as asthma, diabetes, or hypertension. Among those who died, 86.1% received antiviral treatment with oseltamivir or zanamivir, compared with 94.8% of survivors. Time to initiate treatment from symptom onset was significantly different for women who died, compared with those who survived (P < .01). Only 4 women (7%) of those who died received an antiviral within 2 days of symptom onset, compared with 41% of survivors.
This analysis reaffirms the importance of prevention (ie, vaccination of pregnant women regardless of trimester) and prompt treatment with a neuraminidase inhibitor (ie, within 2 d of symptom onset) if influenza occurs during pregnancy.[51]
Lam et al suggested that cases of suspected severe influenza infection should be treated early and aggressively, even before diagnostic tests can be confirmed.[52] In their study, a higher dose of oseltamivir and nonconventional methods of ventilation improved outcome in patients with pandemic H1N1 2009 infection.
A large meta-analysis of treatment of pandemic H1N1 found that neuraminidase inhibitors reduced the death rate in hospitalized patients by 63% when given within 48 hours of symptom onset.[53]
Whether to prescribe one of the newer neuraminidase inhibitors should depend on the patient, the probable type of influenza involved (A or B), and the potential benefit. Advantages for prescribing these agents include significantly reducing illness severity and duration. In elderly and high-risk patients who receive these agents, the secondary complications of influenza are also decreased.
Disadvantages include potential adverse effects and costs. Some patients may be willing to pay $100 to have a less severe episode of the flu. Adverse effects include potential bronchospasm with inhaled zanamivir and nausea, vomiting, and headache from oseltamivir. The bronchospasm associated with zanamivir has received attention from national media. Until more data are available, physicians should not prescribe zanamivir to patients prone to bronchospasm.
Although oseltamivir is approved for use up to 48 hours after the initiation of symptoms, one study suggested that the most significant effect occurs when taken within 6 hours of symptom onset and only limited effects when therapy is begun more than 24 hours after symptom onset.
Probenecid, a uricosuric, approximately doubles the effective dose of oseltamivir by disrupting renal excretion of the drug and may have a role in a pandemic or in severe infections.[54] No studies have yet been performed to confirm the appropriate dosing regimen in this situation.
Antiviral drug recommendations
The CDC has made the following recommendations regarding the use of antiviral drugs in influenza[43] :
· Antiviral treatment is recommended as soon as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness or who require hospitalization
· Antiviral treatment is recommended as soon as possible for outpatients with confirmed or suspected influenza who are at higher risk for influenza complications on the basis of their age or underlying medical conditions; clinical judgment should be an important component of outpatient treatment decisions
· Recommended antiviral medications include oseltamivir and zanamivir
· Oseltamivir may be used for treatment of influenza in children aged 2 weeks or older, and for chemoprophylaxis in children aged 1 year or older
· Antiviral treatment also may be considered on the basis of clinical judgment for any outpatient with confirmed or suspected influenza who does not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset.
· Because antiviral resistance patterns can change over time, clinicians should monitor local antiviral resistance surveillance data
Investigational antiviral agents
Investigational antiviral agents for influenza include laninamivir octanoate and peramivir. In a double-blind, randomized controlled trial, the median time to illness alleviation with a 40-mg dose of laninamivir octanoate was similar to that with oseltamivir. A single inhalation of laninamivir octanoate is effective for the treatment of seasonal influenza, including that caused by oseltamivir-resistant virus, in adults.[55]
A single intravenous dose of peramivir, a sialic acid analogue and a selective inhibitor of neuraminidases produced by influenza A and B viruses, is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection. At both 300 mg and 600 mg, time to alleviation of symptoms was significantly reduced compared with that of placebo.[56]
Treatment of avian influenza
H7N9
The CDC has issued interim guidance for antiviral treatment of human infections with avian influenza A (H7N9).[57, 58]
In uncomplicated cases, oseltavivir is recommended for all ages and inhaled zanamivir is recommended for children aged 7 and older.[57] For outpatients with the absence of fever and nearly resolved symptoms, decisions to treat should be based on clinical judgment. The CDC recommends that hospitalized patients with severe or complicated illness receive longer treatment with oral oseltavivir because of the lack of data available for inhaled zanamivir. IV zanamivir should be considered for patients who cannot tolerate oral oseltamivir.
While no data are available regarding early neuraminidase inhibitor treatment of persons infected with H7N9 virus, laboratory testing with functional assays indicates that H7N9 viruses are susceptible to neuraminidase inhibitors (oseltamivir and zanamivir), but resistant to adamantanes (amantadine and rimantadine). Therefore, amantadine and rimantadine are not recommended for treatment of H7N9 virus infection.
Because of the potential severity of illness associated with H7N9 virus infection, it is recommended that all confirmed cases, probable cases, and cases under investigation receive antiviral treatment with a neuraminidase inhibitor as early as possible. Treatment should be initiated even if it is more than 48 hours after onset of illness. For uncomplicated illness, the recommended treatment duration is 5 days.
For hospitalized patients and patients with severe or complicated illness, treat with oral oseltamivir (and not inhaled zanamivir). Longer courses of treatment should be considered for severely ill hospitalized. Inhaled zanamivir also should not be administered to individuals with underlying airway disease (eg, asthma, COPD).
Laboratory testing and initiation of antiviral treatment should occur simultaneously; treatment should not be delayed for laboratory confirmation of influenza or H7N9 infection.
For hospitalized patients who cannot tolerate or absorb oral oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding, intravenous (IV) zanamivir should be considered.
H5N1
Administration of neuraminidase inhibitors is currently the only specific therapy for human H5N1 disease. Early administration agent appears to be critical for clinical benefit. Because diagnostic uncertainty is likely, management may include the administration of broad-spectrum antibiotics and aggressive fluid resuscitation to manage clinical signs of sepsis.
Guidelines from the World Health Organization (WHO) from 2007 recommend therapy regimens with a neuraminidase inhibitor, preferably oseltamivir.[59] Studies are ongoing as to the relative effectiveness of high-dose and/or prolonged courses of therapy with oseltamivir.[39] If high-dose regimens prove to be more effective, the availability of antiviral medication in the event of a massive outbreak, as well as treatment considerations for mildly versus severely ill people, would be affected.
Although most H5N1 influenza cases are resistant to amantadine or rimantadine (reflecting mutations in the M2 gene segment[15] ), combination therapy is recommended unless the patient was exposed in an area known to contain virus strains resistant to the other antiviral agents. Treatment failures due to resistance to single-drug oseltamivir regimens have been reported.[39]
Zanamivir has not yet been tested in people with H5N1 disease, but animal studies are promising and the resistance mutations to oseltamivir do not cause cross-resistance. Some researchers have recommended dual therapy with both existing neuraminidase inhibitors. One concern is that inhaled zanamivir is unlikely to reach distal airways in severe disease.[39]
Two experimental drugs exist; arbidol is available in China and Russia, and peramivir is still being studied. Neither is yet available in the United States.
Steroids have not been shown to be beneficial, except perhaps in the setting of septic shock with adrenal insufficiency.[39]
Supportive care such as oxygen therapy, intravenous fluids, and parenteral nutrition may be needed. Severe cases may require ventilatory support with intubation and low-volume (high-frequency) ventilation.
Infection control and prevention of transmission to other patients and health care workers are important. Droplet precautions should be used, including eye protection. No evidence shows that airborne spread is possible, but if fine aerosols are expected because of specific procedures, a particulate respirator should be properly fitted and used.
Adults and children older than 12 years require 1 week of infection-control precautions, from the initial onset of symptoms. Children younger than 12 years may shed high titers of human influenza virus for up to 21 days after the illness onset, and the World Health Organization (WHO) recommends the same duration for avian influenza precautions.[39]
If proper handling of biologic specimens can be ensured, repeat studies of the viral load, susceptibilities, and drug levels can be used to monitor the response to therapy.
Activity Modification
Patients with influenza generally benefit from bed rest.
Most patients with influenza recover in 3 days; however, malaise may persist for weeks.
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