Pharmacotherapy for novel influenza A (H1N1)

Novel influenza A (H1N1) is a new influenza virus of swine origin and was first described in April of 2009. This virus is a genetic hybrid of swine influenza, avian influenza and human influenza.

As of June 1, 2009, 10,053 laboratory-confirmed cases in all 50 states, including 17 deaths, had been confirmed by the CDC. As little immunity to this novel virus is likely to occur in the population, it is likely that infection rates with influenza A (H1N1) will increase. As of press time, seasonal influenza A (H1N1, H3N2) and influenza B continued to circulate in the United States. This month’s column will review drug therapy in children for this novel respiratory virus.

Pharmacotherapy decisions

Should all children with suspected or confirmed infection with novel influenza A (H1N1) be treated with antiviral pharmacotherapy? If a child is not in a high-risk group or is not hospitalized, CDC guidelines recommend using clinical judgment to guide treatment decisions. A child with mild disease, who is not in a high-risk group may not significantly benefit from drug therapy, especially if pharmacotherapy is not initiated early.

Risk factors for complications and increased disease morbidity from novel influenza A (H1N1) are similar to infection and disease from seasonal influenza. Children younger than 5, and especially children younger than 2, are at higher risk of complications. Concomitant diseases that increase risk of complications from novel influenza A (H1N1) include immune suppression, HIV/AIDS, chronic kidney disease, heart disease, diabetes mellitus, pregnancy, asthma/pulmonary disorders, hematologic disorders (including sickle cell), neurologic disorders affecting respiratory function, metabolic disorders (those unable to tolerate prolonged fasting) and children receiving long-term aspirin therapy.

Only two antiviral agents are recommended by the CDC for treatment of novel influenza A (H1N1) disease – oseltamivir (Tamiflu, Roche) and zanamivir (Relenza, GlaxoSmithKline). These two agents are both neuraminidase inhibitors. The neuraminidase inhibitors prevent the release of newly-produced virus from host cell membranes. The viral enzyme neuraminidase functions to detach newly-produced virus from the host cell, preventing its release to infect other cells. This drug’s mechanism of action explains why these agents are most effective when given early in the disease process when viral replication is high.

Oseltamivir is labeled for treatment and prophylaxis for people age 1 year and older when symptomatic for 48 hours or less. Oseltamivir is available as an oral capsule and as a fruit-flavored suspension.

As disease with novel influenza A (H1N1) may result in increased morbidity in children younger than 1 year, the use of oseltamivir in this age group has been granted approval by the FDA under an Emergency Use Authorization (EUA). This authorization additionally grants authority for use of oseltamivir beyond the time period of 48 hours post- symptom onset and in those ill enough to require hospitalization (ie, not with “uncomplicated acute illness”).

By granting an EUA, this extends FDA-approval for use of oseltamivir beyond the normal use labeling. Labeled treatment and prophylaxis dosing for oseltamivir are weight-based for 1 year and older (Table). Dosing under the EUA is listed in the table. Under the EUA granted for oseltamivir, chemoprophylaxis in infants younger than 3 months is not recommended unless the clinical situation is judged to be critical, as limited data are available for this age group. Although safety data are limited for oseltamivir use in infants younger than 1, no data indicate an increased risk of adverse effects or toxicity in this age group.

Zanamivir is available as an inhalation disk. It is labeled for treatment use in children ages 7 years and older when symptomatic for 48 hours or less and in ages 5 years and older for prophylaxis. When used for seasonal influenza, zanamivir should not be used for children with underlying airway disease, including asthma, due to risk of serious bronchospasm. An EUA for zanamivir has also been granted by the FDA for zanamivir use at later time points (ie, beyond 48 hours of having symptoms) and for individuals ill enough to require hospitalization.

As discussed above, oseltamivir and zanamivir are most effective when initiated within 48 hours of symptom onset, and most studies have evaluated the efficacy of these agents for seasonal influenza when begun within this time period.

Guidelines

Guidelines on the treatment of novel influenza A (H1N1) from the CDC state that some studies of hospitalized patients with seasonal influenza given oseltamivir when first initiated beyond 48 hours of symptom onset have demonstrated reductions in duration of hospitalization or mortality. However, it is important to consider that evidence for the benefit of oseltamivir and zanamivir for seasonal influenza is based primarily on studies of ambulatory patients with uncomplicated disease.

These studies have shown that when these medications are initiated within 48 hours of symptom onset, illness duration is reduced by approximately one day compared with placebo. When pharmacotherapy was begun greater than 48 hours after symptom onset for seasonal influenza, minimal or no benefit was reported in these studies.

Aoki and colleagues investigated the relationship between initiation of therapy with oseltamivir and time since symptom onset. Study patients (aged 12-70) presenting within 48 hours of symptom onset were evaluated in an open-label manner. Of 1,426 patients evaluated, 958 had laboratory-confirmed influenza disease. Earlier intervention was significantly associated with shorter illness duration (P <.05). Initiation of oseltamivir within 12 hours of symptom onset reduced illness duration by 3.1 days as compared with treatment initiation at 48 hours. For every six hours earlier that treatment was initiated, a corresponding benefit of 10 hours of shorter illness duration was realized.

Either oseltamivir or zanamivir can be used for prophylaxis of novel influenza A (H1N1). Treatment duration is 10 days after the last known exposure for post-exposure prophylaxis. Consideration for prophylactic pharmacotherapy can be given for close contacts of cases that are at high-risk for complications of influenza.

For more information:

• CDC. Interim guidance on antiviral recommendations for patients with novel influenza A (H1N1) virus infection and their close contacts. www.cdc.gov/h1n1flu/recommendations.htm
• CDC. Interim guidance for clinicians on the prevention and treatment of novel influenza A (H1N1) influenza virus infection in infants and children. www.cdc.gov/h1n1flu/childrentreatment.htm
• Aoki FY. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chem. 2003;51:123-9
• CDC. Prevention and control of influenza. MMWR.2008;57(RR07):1-60
• Committee on Infectious Diseases. Antiviral therapy and prophylaxis for influenza in children. Pediatrics.2007;119:852-60