H1N1 Influenza: Prevention and Treatment-How and for Whom

September 30, 2009

Not all patients in whom infection with the H1N1 influenza virus is suspected or confirmed need to be treated. Many patients with mild disease can forgo pharmacotherapy. In fact, in many cases, it may even be prudent to discourage such patients from coming into their health care provider's office, in the interest of infection control. However, all patients with severe disease and those considered at high risk for complications from seasonal influenza should be offered therapy with antiviral agents.

Not all patients in whom infection with the H1N1 influenza virus is suspected or confirmed need to be treated. Many patients with mild disease can forgo pharmacotherapy. In fact, in many cases, it may even be prudent to discourage such patients from coming into their health care provider's office, in the interest of infection control. However, all patients with severe disease and those considered at high risk for complications from seasonal influenza should be offered therapy with antiviral agents.

Specific recommendations for therapy and infection control are summarized here. Clinicians are also advised to consult the CDC Web site (http://www.cdc.gov/h1n1flu/clinicians/), since the guidance is continuously updated. The World Health Organization (WHO) has also recently provided guidance for clinicians on the pharmacotherapy of the H1N1 virus and other influenza viruses. This is available on the WHO Web site.1SUPPORTIVE CARE

Nonspecific supportive measures include attention to hydration, use of cough medications, use of non-aspirin–containing analgesics, management of concurrent medical problems, and encouragement to avoid smoking and secondhand smoke, if possible. These measures are recommended for all patients with confirmed, probable, or suspected H1N1 influenza. More information on caring for ill persons and controlling the spread of infection in a home setting is available at http://www.cdc.gov/h1n1flu/guidance_homecare.htm.

ANTIVIRAL THERAPY

Who should be treated? Anti-viral treatment is currently recommended for all hospitalized patients and in patients considered at high risk for complications (Table 1). For patients in these categories, clinicians are strongly advised to urgently institute antiviral therapy for H1N1 influenza without waiting for test results. Conversely, clinicians are advised to consider refraining from using antiviral therapy in other patients who present with mild disease and can either self-monitor their status or be followed up on an outpatient basis during their illness. Indiscriminate use of antivirals for influenza-either when influenza is not high in the differential diagnosis or when there is no clear indication for treatment-may lead to drug resistance. Such practice patterns could result tragically in the compromise of supplies of antiviral drugs, thereby making them unavailable for others in need of treatment. This has already occurred in communities where some persons hoarded supplies for presumed later use.

Which drugs to use. Two classes of drugs are used for anti-influenza therapy; each of these consists of 2 commonly used agents. The neuraminidase inhibitors (NAIs) include oseltamivir (Tamiflu) and zanamivir (Relenza). The NAIs are the mainstay of therapy for currently circulating pandemic novel H1N1 viral infection. Because oseltamivir is administered orally, it is easier to take than zanamivir, which is inhaled. Thus, of these 2 drugs, oseltamivir is the preferred agent. The other classes of drugs, the adamantanes (ADs), or M2 ion channel blockers, include amantadine (Symmetrel) and rimantadine (Flumadine).

Common adverse effects of drugs in the NAI class include nausea and vomiting for oseltamivir (because of the higher systemic levels associated with this agent) and bronchospasm for zanamivir (because it is inhaled; inhalation results in lower systemic levels). With drugs in the AD class, GI and CNS adverse effects are most common. Infectious Diseases Society of America has published seasonal influenza treatment guidelines that contain detailed information on these agents. These guidelines are available at http://www.journals.uchicago.edu/doi/full/10.1086/598513.

The problem of drug resistance.
Resistance to antiviral drugs is a relatively recent phenomenon, and the reasons for its propagation are not well understood. Examples of such resistance include the resistance of H3N2 strains to the AD class of drugs and the resistance of the 2008-2009 seasonal influenza H1N1 virus (not the novel pandemic strain) to oseltamivir (but not zanamivir).

The novel H1N1 virus is now sensitive to both agents in the NAI class but resistant to those in the AD class. There have been only a few cases worldwide of patients infected with an oseltamivir-resistant novel H1N1 strain; no infections were observed among contacts of the patients infected with this drug-resistant strain.2 This resistance has been associated with an H275Y mutation in the neuraminidase gene.3 In those communities where a pattern of oseltamivir resistance in the seasonal H1N1 virus has been established, it is recommended that patients infected with the outbreak H1N1 viral strain receive zanamivir instead. If a patient in this situation cannot tolerate zanamivir, clinicians have been encouraged to add one of the two AD agents to oseltamivir as empiric treatment.4How to use. Antiviral medications are best used singly and within the first 48 hours of illness, when they tend to have the maximum benefit. Initial clinical trials demonstrated that timely antiviral therapy reduces symptom duration by about half a day, with a maximum reduction of 1 to 2 days. There is some evidence of benefit in hospitalized patients treated for seasonal influenza even when antiviral therapy is started more than 48 hours after illness onset. There are data to indicate that NAIs reduce the rate of complications, duration of viral shedding, and perhaps even mortality (although these effects have not been demonstrated in a systematic trial).5,6 Prescribing information for oseltamivir and zanamivir is summarized in Table 2.
 

Treatment
(5 days)                    

75-mg capsule bid  

 < 15 kg            

30 mg bid30 mg/d

 > 15 - 23 kg     

45 mg bid45 mg/d
 >60 mg bid60 mg/d
 > 40 kg75 mg bid75 mg/d
Adults Two 5-mg inhalations (10 mg total) bid   Two 5-mg inhalations (10 mg total)/d  
 Children Two 5-mg inhalations (10 mg total) bid (age, 7 y or older)Two 5-mg inhalations (10 mg total)/d (age, 5 y or older)
Body weightRecommended dosage for treatment (5 days)  

Recommended dosage for chemoprophylaxis (10 days)

 < 15 kg 2.5 mL bid 2.5 mL/d
 > 15 - 23 kg 3.8 mL bid 3.8 mL/d
 > 23 - 40 kg 5.0 mL bid 5.0 mL/d
 > 40 kg 6.2 mL bid 6.2 mL/d


According to the WHO guidelines, based on clinical response, some patients with severe or progressive illness could be considered appropriate candidates for higher doses of oseltamivir (150 mg bid) and longer durations of therapy. Such decisions are best made in the context of an infectious disease consultation. If oseltamivir is unavailable or cannot be used, or if oseltamivir resistance is suspected or confirmed, the alternate drug, zanamivir, should be used in severely ill patients.

Patients who are recovering from an influenza-like illness (ILI) caused by the H1N1 virus should be considered contagious from 1 day before symptom onset to 7 days after-regardless of whether they received antiviral drugs. If ill persons such as children or immunosuppressed patients, who shed virus for longer periods, continue to have symptoms beyond 7 days, they should be considered potentially contagious. To help prevent further spread of infection, advise patients to stay home for at least 24 hours after fever has abated (without the use of antipyretics).7ANTIVIRAL CHEMOPROPHYLAXIS

Antivirals have been shown to be quite effective for chemoprophylaxis. Either oseltamivir or zanamivir is recommended for antiviral chemoprophylaxis in persons who have been exposed (actually or potentially) to a patient infected with the novel H1N1 virus. The duration of postexposure chemoprophylaxis is 10 days after the last known exposure to an ill person with confirmed H1N1 influenza. Chemopreventive therapy may also be given during a period of potential exposure-and then continued for 10 days beyond the last known exposure to H1N1.

Whether for known preexposure coverage or postexposure, chemoprophylaxis with oseltamivir or zanamivir is recommended in the following settings:

•When household contacts are at relatively high risk for influenza-related complications-eg, they include persons with specific chronic medical conditions, persons older than 65 years, children younger than 5 years, or pregnant women.
•In health care workers who did not use appropriate personal protective equipment during risk-prone patient encounters.

In addition, chemopreventive therapy can be considered for the following populations:

•Persons in the categories of household contacts listed above who are at relatively high risk for influenza-related complications.
•Children in day care or in school.
•Health care workers and first responders at high risk for influenza-related complications.



TREATMENT AND CHEMOPROPHYLAXIS IN SPECIAL PATIENT POPULATIONSPregnant patients. Pregnant women infected with the H1N1virus usually present with an ILI and may have a self-limited bout of uncomplicated influenza illness. However, maternal illness maybe more severe, with rapid progression of symptoms or secondary bacterial complications and fetal distress. It is therefore prudent to test pregnant patients with ILI for H1N1 by obtaining specimens for a real-time polymerase chain reaction test, as outlined in "Diagnostic Testing for H1N1 Flu: When and How."

If a pregnant woman meets criteria for a confirmed, probable, or suspected case of H1N1 influenza, she should receive empiric oseltamivir as soon as possible, preferably within 48 hours of symptom onset-or even after this window, if she is hospitalized.

Both NAI agents-oseltamivir and zanamivir-are designated "Pregnancy Category C" medications (ie, no clinical studies have been conducted to assess their safety in pregnant women). However, if the benefit outweighs any perceived risk of teratogenicity, therapy for H1N1 infection should be given. Oseltamivir and zanamivir treatment and chemoprophylaxis regimens recommended for pregnant women are the same as those recommended for adults who have seasonal influenza. Recommended duration of treatment is 5 days, and recommended duration of chemoprophylaxis is 10 days.

If a pregnant woman experiences any degree of hyperthermia, the risk of neural tube defects and adverse outcomes almost doubles. As in normothermic pregnant women, multivitamins that contain folic acid would likely lessen such risks; it is also reasonable to suggest non-aspirin–containing antipyretics (ie, acetaminophen), which obviate the possibility of Reye syndrome and other complications. Fever during the intrapartum period is also associated with negative outcomes for the infant and thus should be treated expeditiously.

A number of nonpharmacological interventions, including the use of strict infection control practices, can be very helpful in preventing H1N1 infection in pregnant women. More information about the care of pregnant women who have H1N1 infection or who may be exposed to the virus can be found in the CDC guideline, "Pregnant Women and Novel Influenza A (H1N1) Virus: Considerations for Clinicians." This is available at http://www.cdc.gov/h1n1flu/clinician_pregnant.htm.

Infants. Oseltamivir has not been approved for use in children younger than 1 year. However, because infants with influenza experience high rates of morbidity and mortality, an Emergency Use Authorization has been issued by the FDA permitting the use of oseltamivir in infants with novel H1N1 influenza virus infection.9

Dosages for antiviral treatment in this age-group are 12 mg bid in infants younger than 3 months, 20 mg bid in those aged 3 to 5 months, and 25 mg bid in those aged 6 to 11 months. For chemoprophylaxis in the last two of these age-groups, simply administer once a day (instead of twice daily); chemoprevention is not recommended at all for infants younger than 3 months unless special considerations warrant it. Dosing recommendations from the CDC for treatment and chemoprophylaxis in infants are summarized in Tables 3 and 4.10 Specific antiviral dosing regimens for infants are available at the CDC Web site.10



When considering oseltamivir use in a seriously ill infant with confirmed or suspected H1N1 influenza, keep in mind the lack of data on safety and dosing for patients this age. Monitor all treated infants carefully for adverse events.

H1N1 VACCINE UPDATE


Fortunately, public health officials were able to identify and isolate the H1N1 virus in the earliest phase of this pandemic so that a seed stock of the virus would be available for vaccine development. The US Department of Health and Human Services has allocated almost $1 billion for H1N1 vaccine clinical trials and candidate vaccine mass production in 2009. Currently, 5 US manufacturers are working to ensure that vaccine supplies are sufficient.

The FDA and the WHO have identified A/California/07/2009 (H1N1) as the vaccine strain, with plans to have available for distribution both live, attenuated and inactivated influenza A(H1N1) 2009 monovalent vaccine formulations. Thus far, as in the case of seasonal influenza vaccine, neither formulation will contain adjuvants.11

Although details are pending, plans are under way to have supplies distributed initially around mid-October. Should the amount of vaccine available in the required time frame be insufficient, the major consequence would be suboptimal protection of certain groups against H1N1 infection.12

Seasonal influenza vaccine will most likely be administered with one of two H1N1 doses. Detailed guidance on the exact number of doses, timing, and the simultaneous administration of the seasonal influenza vaccine is forthcoming. Clinicians are referred to the CDC Web site for upcoming Morbidity and Mortality Weekly Reports monographs (http://www.cdc.gov/mmwr) or other new guidance (http://www.cdc.gov/flu).

Experts anticipate seasonal influenza strains to emerge-including A-H1N1, A-H3N2 and influenza B-for all of which seasonal influenza vaccine (2009-2010) should be an effective preventive measure. Detailed guidance has already been published on seasonal influenza vaccine for the upcoming 2009-2010 season.13 Vaccines will be administered by health departments, clinics, offices, and other entities.

Currently, the following 5 groups are being prioritized at the highest level to receive the vaccine:

•Pregnant women.
•Household contacts and caregivers of children younger than 6 months.
•Health care workers and first responders.
•Persons aged 6 months to 24 years.
•Persons aged 25 to 64 years who are at increased risk for influenza-related complications.14

Depending on vaccine supplies, the US government and the public health community are committed to eventually making the H1N1 vaccine  even more widely available.

With regard to the safety of the H1N1 vaccine-a cautionary and realistic note: although predistribution efforts will be made to ensure the safety of the vaccine-including oversight, meticulous safety reviews, and good clinical practice in ongoing and planned clinical H1N1 vaccine trials-it may take field experience involving larger populations to identify some potential vaccine-related adverse events. Informed clinicians and citizens will need to make individual decisions based on the best evidence and guidance available. Based on the 1976 swine influenza vaccine deployment efforts and the incidence of Guillain-Barr syndrome among those vaccinated, it would require that between half a million and a million persons receive the H1N1 vaccine to detect a risk similar to that associated with the 1976 vaccine.

Seasonal influenza vaccine has not thus far provided cross-protection against H1N1 influenza and is unlikely to do so. Finally, the Advisory Committee on Immunization Practices strongly recommends pneumococcal vaccine for persons older than 65 years and those between ages 2 and 64 years who have high-risk conditions.15

References:

REFERENCES:


1.

World Health Organization. WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. August 20, 2009.

http://www.who.int/csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/index.html

. Accessed September 9, 2009.

2.

Centers for Disease Control and Prevention. Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients-Seattle, Washington, 2009.

MMWR.

2009;58:893-896.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0814a1.htm

. Accessed August 26, 2009.

3.

World Health Organization. Pandemic (H1N1) 2009-update 60. Laboratory-confirmed cases of pandemic (H1N1) 2009 as officially reported to WHO by States Parties to the IHR (2005) as 31 July 2009.

http://www.who.int/csr/don/2009_08_04/en/index.html

. Accessed August 26, 2009.

4.

Centers for Disease Control and Prevention. Interim guidance on antiviral recommendations for patients with novel influenza A (H1N1) virus infection and their close contacts.

http://www.cdc.gov/h1n1flu/recommendations.htm

. Accessed May 24, 2009.

5.

McGreer AJ. Diagnostic testing or empirica therapy for patients hospitalized with suspected influenza: what to do?

Clin Infect Dis.

2009;48(suppl 1):S14-S19.

6.

McGreer AJ, Green KA, Plevneshi A, et al; for the Toronto Invasive Bacterial Diseases Network. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada.

Clin Infect Dis.

2007;45:1568-1575.

7.

Centers for Disease Control and Prevention. Questions & Answers-2009 H1N1 flu (swine flu) and you. August 5, 2009.

http://www.cdc.gov/h1n1flu/qa.htm

. Accessed September 9, 2009.

8.

Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008.

MMWR Recomm Rep.

2008;57(RR-7):1Ð60.

9.

Centers for Disease Control and Prevention. Interim guidance for clinicians on the prevention and treatment of novel influenza A (H1N1) influenza virus infection in infants and children. May 13, 2009.

http://www.cdc.gov/h1n1flu/childrentreatment.htm

. Accessed September 12, 2009.

10.

Centers for Disease Control and Prevention. Interim guidance on antiviral recommendations for patients with novel influenza A(H1N1) virus infection and their close contacts. May 6, 2009.

http://cdc.gov/h1n1flu/recommendations.htm

. Accessed September 6, 2009.

11.

Centers for Disease Control and Prevention. Use of influenza A (H1N1) 2009 monovalent vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009.

MMWR.

2009;59(RR-10):1-8.

http://cdc.gov/mmwr/preview/mmwrhtml/rr58e0821a1.htm

. Accessed September 9, 2009.

12.

Schnirring L. Officials lower expectations for size of first novel flu vaccine deliveries. Centers for Infectious Disease Research and Policy (CIDRAP) News.

http://www.cidrap.umn.edu/cidrap/content/influenza/swineflu/news/aug1409vaccine.html

. Accessed August 26, 2009.

13.

Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009.

MMWR.

2009;58(RR-8):1-52.

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5808a1.htm

. Accessed September 9, 2009.

14.

Centers for Disease Control and Prevention. H1N1 Flu Vaccination Resources.

http://www.cdc.gov/h1n1flu/vaccination

. Accessed August 26, 2009.

15.

Centers for Disease Control and Prevention. Interim guidance for use of 23-valent pneumococcal polysaccharide vaccine during novel influenza A (H1N1) outbreak.

http://www.cdc.gov/h1n1flu/guidance/ppsv_h1n1.htm

. Accessed August 26, 2009.

16.

Centers for Disease Control and Prevention. Novel influenza A (H1N1) virus infections in three pregnant women-United States, April-May 2009.

MMWR.

2009;58:497-500.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0512a1.htm

. Accessed August 26, 2009.

17.

Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children-diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America.

Clin Infect Dis.

2009;48:1003-1032.

http://journals.uchicago.edu/doi/full/10.1086/598513

. Accessed August 26, 2009.