Interim Guidance on the Use of Antiviral Agents for Treatment of Human Infections with Avian Influenza A (H7N9) Virus
This document replaces “Interim Guidance on the Use of Antiviral Agents for Treatment of Human Infections with Avian Influenza A (H7N9) Virus” posted on April 18, 2013. Since that date, a Health Advisory with updated recommendations for testing and updated case definitions for H7N9 virus infection were released to reflect current epidemiology of H7N9 cases and risk assessment for infection. This guidance on antiviral treatment has been updated to be consistent with current CDC and World Health Organization recommendations, and provides updated recommendations for antiviral treatment of confirmed cases and probable cases of human infection with avian influenza A (H7N9), as well as cases under investigation for human infection with avian influenza A (H7N9) virus in the United States.
The previous guidance recommended antiviral treatment for all confirmed cases, probable cases, and cases of H7N9 under investigation. The new guidance continues to recommend treatment for all hospitalized H7N9 cases, and for confirmed and probable outpatient H7N9 cases. The primary change in the new guidance is that outpatient cases under investigation who have had recent close contact with a confirmed H7N9 case should receive antiviral treatment, whereas outpatients meeting only the travel exposure criteria for a case under investigation are not recommended to receive antiviral treatment (see Interim Guidance on Case Definitions to be Used for Novel Influenza A (H7N9) Case Investigations in the United States). For guidance on investigation of close contacts of confirmed or probable cases, see new Interim Guidance on the Use of Antiviral Medications for Chemoprophylaxis of Close Contacts of Persons with Avian Influenza A (H7N9) Virus Infection).
These recommendations are based upon expert opinion and available published and unpublished data on the treatment of other influenza viruses, including seasonal, pandemic, and zoonotic viruses. This guidance will continue to be updated as additional information on H7N9 virus transmissibility, epidemiology, and antiviral susceptibility patterns becomes available.
Summary and Background
Randomized controlled trials have demonstrated decreased time to symptom improvement when currently approved antiviral agents are used to treat healthy persons with acute uncomplicated influenza caused by circulating seasonal influenza viruses within the first few days of illness [1-9]. On the basis of these trials and additional pooled analyses and observational studies [10-12], most experts believe that when antiviral agents are given early in the course of uncomplicated influenza illness, both the duration of symptoms and the likelihood of complications are reduced. Clinical benefit is greatest when antiviral treatment is administered early, especially within 48 hours of influenza illness onset [1-16]. Among patients hospitalized with seasonal influenza A (including 2009 H1N1) or B, or avian influenza A (H5N1) virus infections, observational studies suggest that early treatment reduces disease severity and mortality [17-26]. Although earlier antiviral treatment results in greater clinical benefit, observational studies support the use of antiviral treatment in hospitalized patients even when started after 48 hours of illness [25, 27-33]. Antiviral agents have been used for treatment of persons infected with the H7N9 virus, although the effectiveness of early neuraminidase inhibitor treatment has not yet been determined [34-37]. Laboratory testing indicates that most H7N9 viruses are susceptible to the neuraminidase inhibitors (oseltamivir and zanamivir), but similar to seasonal influenza viruses, they are resistant to the adamantanes (amantadine and rimantadine). Therefore, amantadine and rimantadine are not recommended for treatment of H7N9 virus infection
- Initiation of antiviral treatment with a neuraminidase inhibitor is recommended as early as possible for hospitalized patients who are confirmed cases, probable cases, or H7N9 cases under investigation, even if more than 48 hours has elapsed since illness onset.
- For hospitalized patients and patients with severe or complicated illness, treatment with oral or enterically administered oseltamivir is recommended. Inhaled zanamivir is not recommended because of the lack of data for use in patients with severe influenza disease.
- Laboratory testing and initiation of antiviral treatment should occur simultaneously; treatment should not be delayed while waiting for laboratory testing results. (For information regarding collection and laboratory testing, please see Interim Guidance for Specimen Collection, Processing, and Testing for Patients Who May Be Infected with Avian Influenza A (H7N9) Virus.)
- The recommended treatment course for uncomplicated influenza is two doses per day of a neuraminidase inhibitor medication for 5 days; however, the optimal duration and dose are uncertain for severe or complicated influenza. Pending further data, longer courses of treatment (e.g., 10 days of treatment) should be considered for severely ill hospitalized H7N9 patients.
- Clinical judgment and virologic testing of lower respiratory tract specimens by rRT-PCR should guide decisions to consider treatment regimens longer than 5 days for patients with severe and prolonged illness, until clearance of viral shedding. For patients with lower respiratory tract disease, lower respiratory tract specimens, such as bronchoalveolar lavage or endotracheal aspirate, are preferred; an oropharyngeal (throat) swab may be collected if lower respiratory specimens are not available.
- Longer treatment regimens might be necessary in immunosuppressed persons who may have prolonged viral replication and also are at risk of developing antiviral-resistant virus.
- A higher dose of oseltamivir has been recommended by some experts (e.g., 150 mg twice daily in adults with normal renal function) for treatment of influenza in immunocompromised patients and in severely ill hospitalized patients, although it is unknown if this provides clinical benefit [38-40].
- Although oral or enterically delivered oseltamivir is well absorbed in critically ill influenza patients [41-45], for patients who cannot tolerate or absorb oral oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding, the use of investigational intravenous (IV) zanamivir should be considered. IV zanamivir is an investigational parenterally administered neuraminidase inhibitor product available by enrollment in a clinical trial or compassionate use under an emergency investigational new drug (EIND) request to the manufacturer. An IV zanamivir compassionate use request may be made by contacting the GSK Clinical Support Help Desk via email (gskclinicalsupportHD@gsk.com) or by calling 1-877-626-8019 or 1-866-341-9160. The GSK Clinical Support Help Desk will provide information and instructions on obtaining IV zanamivir, assess eligibility for clinical trials, and provide the EIND form that needs to be completed to obtain FDA approval of release of the drug.
- It is possible that some H7N9 viruses may rapidly become oseltamivir-resistant and remain zanamivir-susceptible . If a hospitalized patient treated with oseltamivir manifests progressive lower respiratory symptoms, resistant virus should be considered, and, after consultation with the CDC Influenza Division, investigation for antiviral resistance should be performed and oseltamivir should be stopped when IV zanamivir can be initiated.
- Any questions regarding arranging testing for antiviral resistance, or regarding appropriate clinical management if antiviral resistance is a concern, should be directed to the CDC Influenza Division via the CDC Emergency Operations Center (770-488-7100).
Uncomplicated Illness in Outpatients
- Initiation of antiviral treatment with a neuraminidase inhibitor is recommended as early as possible for outpatients who are confirmed cases, probable cases, or cases under investigation based on exposure criteria consisting of contact with a confirmed human H7N9 case. Treatment is not currently recommended for outpatients whose exposure criteria consists only of travel to an area with H7N9 cases (see Interim Guidance on Case Definitions to be Used for Novel Influenza A (H7N9) Case Investigations in the United States).
- When warranted, antiviral treatment should be initiated as early as possible, even if more than 48 hours has elapsed since illness onset. For H7N9, treatment is recommended even for otherwise healthy persons, but is especially important for those at higher risk of influenza complications: this includes children <5 years, with highest risk for those aged <2 years old, adults aged >65 years, pregnant women, and persons with certain underlying medical conditions. Please see link for complete list of people considered to be at higher risk for influenza complications at Influenza Antiviral Medications: Summary for Clinicians.
- For outpatients with uncomplicated disease in whom fever is absent and symptoms are nearly resolved, decisions to initiate antiviral treatment should be based on clinical judgment. Persons who are not treated with antiviral medications should be monitored for progression of illness.
- Recommended duration of treatment for uncomplicated illness is 5 days.
- Inhaled zanamivir is not recommended for persons with underlying airway disease (e.g., asthma or chronic obstructive pulmonary disease).
For additional guidance on the use of influenza antiviral agents, including dosage recommendations for treatment by age group, please see Guidance on the Use of Influenza Antiviral Agents: Dosage.
Oral oseltamivir is approved by the FDA for treatment of acute uncomplicated influenza in persons >14 days old. Although use of oral oseltamivir for treatment of influenza in infants less than 14 days old is not part of the FDA-approved indication, it is recommended by the CDC and the American Academy of Pediatrics. Inhaled zanamivir is approved for treatment of acute uncomplicated influenza in persons aged 7 years and older. Clinicians may refer to the manufacturer’s package inserts for additional information regarding dosing, limitations of populations studied, contraindications, and adverse events. Please see FDA Approved Drugs for Influenza.
CDC will continue to evaluate new information as it becomes available and will update this guidance as needed. Updated information will be provided on the CDC website at Avian Influenza A (H7N9) Virus).
Table. Antiviral treatment recommendations according to case definition category.
|Case category||Definition||Antiviral treatment1|
|Confirmed case||Avian influenza A (H7N9) virus infection in a patient that is confirmed by CDC’s Influenza Laboratory or a CDC certified public health laboratory using methods agreed upon by the CDC and the Council of State and Territorial Epidemiologists. Confirmation of avian influenza A (H7N9) viruses may be made by public health laboratories following CDC-approved protocols for detection of avian influenza A (H7N9) virus, or by laboratories using an FDA-authorized test specific for detection of avian influenza A (H7N9) virus.||Recommended for hospitalized patients and outpatients|
|Probable case||Illness compatible with influenza in a patient meeting any of the exposure criteria below and for whom laboratory diagnostic testing is positive for influenza A, negative for H1, negative for H1pdm09, and negative for H3 by real-time reverse transcription polymerase chain reaction (RT-PCR) and therefore unsubtypeable.||Recommended for hospitalized patients and outpatients|
|Case under investigation||Illness compatible with influenza in a patient meeting any of the exposure criteria below and for whom laboratory confirmation is not known or pending or for whom test results do not provide a sufficient level of detail to confirm avian influenza A (H7N9) virus infection.|
Exposed during travel
|Patients with recent travel (within <10 days of illness onset) to areas where human cases of avian influenza A (H7N9) virus infection have become infected or to areas where avian influenza A (H7N9) viruses are known to be circulating in animals. 2||Recommended for hospitalized patients|
Exposed to confirmed case
|Patients who have had recent close contact (within <10 days of illness onset) with confirmed cases of human infection with avian influenza A (H7N9) virus. Close contact may be regarded as coming within about 6 feet (2 meters) of a confirmed case while the case was ill (beginning 1 day prior to illness onset and continuing until resolution of illness). This includes healthcare personnel providing care for a confirmed case, family members of a confirmed case, persons who lived with or stayed overnight with a confirmed case, and others who have had similar close physical contact. 3||Recommended for hospitalized patients and outpatients|
1 For specific guidance on medications recommended for treatment of H7N9 infections, see Interim Guidance on the Use of Antiviral Agents for Treatment of Human Infections with Avian Influenza A (H7N9) Virus – September 30, 2013. For specific dosage recommendations for treatment by age group, please see Guidance on the Use of Influenza Antiviral Agents: Dosage.
2 As of September 30, 2013, China was the only country where avian influenza A (H7N9) viruses were known to be circulating in animals or where human cases have become infected. For more information, including updates on countries affected, please see the CDC Avian Influenza A (H7N9) Virus information page.
3 Limited data are available for avian influenza A (H7N9); however, limited person-to-person transmission of avian influenza A (H5N1) virus has been demonstrated only with close, prolonged physical contact.
1. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Lancet 1998; 352(9144): 1877-81.
2. 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. The Pediatric infectious disease journal 2000; 19(5): 410-7.
3. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections. The Journal of infectious diseases 1999; 180(2): 254-61.
4. Monto AS, Webster A, Keene O. Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis. The Journal of antimicrobial chemotherapy 1999; 44 Suppl B: 23-9.
5. 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 2000; 355(9218): 1845-50.
6. 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 : the journal of the American Medical Association 2000; 283(8): 1016-24.
8. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. The New England journal of medicine 1997; 337(13): 874-80.
9. Heinonen S, Silvennoinen H, Lehtinen P, et al. Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010; 51(8): 887-94.
10. Hernan MA, Lipsitch M. Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2011; 53(3): 277-9.
11. Lalezari J, Campion K, Keene O, Silagy C. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Archives of internal medicine 2001; 161(2): 212-7.
12. Yu H, Liao Q, Yuan Y, et al. Effectiveness of oseltamivir on disease progression and viral RNA shedding in patients with mild pandemic 2009 influenza A H1N1: opportunistic retrospective study of medical charts in China. Bmj 2010; 341: c4779.
14. Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. The Journal of clinical investigation 1998; 101(3): 643-9.
15. Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA : the journal of the American Medical Association 1999; 282(13): 1240-6.
17. Chemaly RF, Vigil KJ, Saad M, et al. A multicenter study of pandemic influenza A (H1N1) infection in patients with solid tumors in 3 countries: early therapy improves outcomes. Cancer 2012; 118(18): 4627-33.
18. Hiba V, Chowers M, Levi-Vinograd I, Rubinovitch B, Leibovici L, Paul M. Benefit of early treatment with oseltamivir in hospitalized patients with documented 2009 influenza A (H1N1): retrospective cohort study. The Journal of antimicrobial chemotherapy 2011; 66(5): 1150-5.
22. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2012; 55(9): 1198-204.
23. Muthuri SG, Myles PR, Venkatesan S, Leonardi-Bee J, Nguyen-Van-Tam JS. Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-2010 influenza A(H1N1) pandemic: a systematic review and meta-analysis in hospitalized patients. The Journal of infectious diseases 2013; 207(4): 553-63.
24. Rodriguez A, Diaz E, Martin-Loeches I, et al. Impact of early oseltamivir treatment on outcome in critically ill patients with 2009 pandemic influenza A. The Journal of antimicrobial chemotherapy 2011; 66(5): 1140-9.
25. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA : the journal of the American Medical Association 2010; 303(15): 1517-25.
26. Yu H, Feng Z, Uyeki TM, et al. Risk factors for severe illness with 2009 pandemic influenza A (H1N1) virus infection in China. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2011; 52(4): 457-65.
27. Chemaly RF, Torres HA, Aguilera EA, et al. Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2007; 44(7): 964-7.
28. Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, Boeckh M. Differences in clinical outcomes after 2009 influenza A/H1N1 and seasonal influenza among hematopoietic cell transplant recipients. Blood 2011; 117(19): 5050-6.
29. Kumar D, Michaels MG, Morris MI, et al. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. The Lancet infectious diseases 2010; 10(8): 521-6.
30. Lee EH, Wu C, Lee EU, et al. Fatalities associated with the 2009 H1N1 influenza A virus in New York city. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010; 50(11): 1498-504.
32. Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2008; 46(8): 1323-4.
33. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2007; 45(12): 1568-75.
35. Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 2013; 381(9881): 1916-25.
37. Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet 2013.
38. Kumar D, Morris MI, Kotton CN, et al. Guidance on novel influenza A/H1N1 in solid organ transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2010; 10(1): 18-25.
39. Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza AV, Abdel-Ghafar AN, Chotpitayasunondh T, et al. Update on avian influenza A (H5N1) virus infection in humans. The New England journal of medicine 2008; 358(3): 261-73.
40. South East Asia Infectious Disease Clinical Research N. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. Bmj 2013; 346: f3039.
41. Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2010; 182(4): 357-63.
42. Eyler RF, Heung M, Pleva M, et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharmacotherapy 2012; 32(12): 1061-9.
43. Giraud C, Manceau S, Oualha M, et al. High levels and safety of oseltamivir carboxylate plasma concentrations after nasogastric administration in critically ill children in a pediatric intensive care unit. Antimicrobial agents and chemotherapy 2011; 55(1): 433-5.
44. Mulla H, Peek GJ, Harvey C, Westrope C, Kidy Z, Ramaiah R. Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support. Anaesthesia and intensive care 2013; 41(1): 66-73.
46. Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet 2013; 381(9885): 2273-9.
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- Page last updated: September 30, 2013
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