Oseltamivir-Resistant 2009 Pandemic Influenza A (H1N1) Virus Infection in Two Summer Campers Receiving Prophylaxis --- North Carolina, 2009

Initial testing of the 2009 pandemic influenza A (H1N1) virus found it susceptible to neuraminidase inhibitors (oseltamivir and zanamivir) and resistant to adamantanes (amantadine and rimantadine) (1). Neuraminidase inhibitors have been used widely for treatment and chemoprophylaxis of 2009 pandemic influenza A (H1N1); however, sporadic cases of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection have been reported worldwide (2), including nine U.S. cases identified as of September 4.* On July 14, CDC was contacted by a physician at a summer camp in North Carolina regarding two cases of influenza-like illness (ILI) in adolescent girls receiving oseltamivir chemoprophylaxis during an ILI outbreak that had begun June 18. The two girls stayed in the same cabin, and both received oseltamivir during a mass chemoprophylaxis program in which approximately 600 campers and staff members received oseltamivir or zanamivir. On July 20 and July 22, the North Carolina State Laboratory of Public Health confirmed pandemic H1N1 virus infection in respiratory specimens from both girls. On August 14 and August 19, CDC detected the H275Y mutation (N1 numbering) in neuraminidase from both specimens by pyrosequencing (3,4). The H275Y mutation is associated with resistance to oseltamivir; zanamivir susceptibility is retained. A second mutation (I223V) in neuraminidase also was detected in both specimens. This is the first report of oseltamivir resistance in pandemic H1N1 cases with an epidemiologic link. Health-care providers should be aware that antiviral resistance can develop during chemoprophylaxis or treatment with subtherapeutic dosages and should follow published recommendations for antiviral medications (5).

The summer camp offered two 4-week sessions. The first session was conducted from June 14 to July 10, followed by a weekend break, July 11--12, before the start of the second session on July 13. Approximately 650 campers and 350 staff members participated in the first session, and 350 campers and 300 staff members participated in the second session. An outbreak of ILI began on June 18, soon after the start of the first session; the last case was diagnosed on July 22. All ill persons were grouped in isolation until 7 days after symptom onset and until well. All but one of the 61 ill campers and four ill staff members received treatment with either oseltamivir or zanamivir. Also, beginning on June 18, medical staff members conducted a mass program of antiviral chemoprophylaxis in which prophylactic oseltamivir or zanamivir was administered to all persons who had an ill sibling at the camp and to all persons who lived in a cabin with an ill person. Chemoprophylaxis was administered daily by camp staff members to ensure compliance. Over the two sessions, a total of 418 campers and 189 staff members received 10 days of chemoprophylaxis with either oseltamivir (75 mg or appropriate weight-based dosing, once daily) or zanamivir (two 5 mg inhalations, once daily). The camp medical staff continued the program until July 24.

Case Reports

Patient A. One of the campers, a previously healthy adolescent girl, received oseltamivir prophylaxis at an appropriate prophylactic dose of 75 mg daily during June 26--July 5, despite having no reported exposure to an ill person. After completing the initial course of oseltamivir on July 5, she was exposed to an ill cabin mate (patient C) and administered a second 10-day course of chemoprophylaxis at the same dosage beginning on July 7. On July 8, she experienced cough and headache without fever, and on July 9 she experienced chills, worsening headache, and loose stools. Despite these symptoms, her oseltamivir dose was not increased to a therapeutic treatment dose. On July 10, the last day of the first camp session, she traveled away from camp with three family members while ill, returning on July 12, afebrile and with a cough, to attend the second session. On July 12, a rapid influenza detection test was positive for influenza A. The family declined treatment with zanamivir because of concern over side effects, and the patient's oseltamivir dose was doubled to 75 mg, twice daily, an appropriate therapeutic treatment dose. Patient A was isolated with other ill campers and staff members until July 16, and she recovered uneventfully. The camp physician observed that the camper became ill while taking prophylaxis and became concerned that antiviral resistance might have occurred. Therefore, a nasopharyngeal swab specimen was obtained on July 14 and sent to the state laboratory for testing. On July 22, the laboratory confirmed the presence of 2009 pandemic influenza A (H1N1) virus by real-time reverse transcription--polymerase chain reaction (rRT-PCR). On August 19, CDC testing of the same clinical specimen detected the H275Y (3,4) and I223V mutations (6). Because viral isolation was unsuccessful, a neuraminidase inhibition assay was not performed. No illness was reported among her family members.

Patient B. A second previously healthy adolescent girl, who resided in the same cabin as patient A, began oseltamivir chemoprophylaxis at a dose of 75 mg daily on July 7 after exposure to patient C. On July 10, patient B left camp for a home visit during the break between camp sessions. The next day, while at home, she experienced onset of fever (101.9ºF [38.8ºC]), sore throat, and cough. She continued to engage in normal activities while ill, including visiting a shopping mall and movie theater. She returned to camp for the second session on July 12 with fever, headache, cough, malaise, and myalgias. On July 12, a rapid influenza detection test was positive for influenza A. Oseltamivir was discontinued, and zanamivir treatment (two 5 mg inhalations, twice daily) was begun. A nasopharyngeal swab specimen was obtained July 14 and sent to the state laboratory for testing. On July 20, the presence of 2009 pandemic influenza A (H1N1) virus was confirmed by rRT-PCR. On August 14, CDC testing of viral RNA detected H275Y and I223V mutations (3,4,6). Viral isolation was unsuccessful, and a neuraminidase inhibition assay was not performed. Patient B was isolated at the camp during July 12--18. Her fever resolved by July 14, and by July 17 she was asymptomatic. No illnesses were identified among close contacts potentially exposed during her weekend home visit.

Further Transmission Investigation

After identification of the oseltamivir-resistant pandemic H1N1 virus, the state health department and local health departments interviewed the families of the two campers and reviewed camp medical records to determine whether the campers might have transmitted virus to others. Retrospective review of camp records revealed that, during June 26--July 22, six other campers were diagnosed with illness while on oseltamivir chemoprophylaxis (75 mg once daily for 10 days). A single specimen from one of these six campers (not patient C) was obtained July 14 and sent to the state laboratory for testing by rRT-PCR, but no influenza virus was isolated. No evidence of pandemic H1N1 virus infection outside the camp linked to either patient A or patient B was found. CDC tested by pyrosequencing 59 specimens of pandemic H1N1 virus, collected during June 29--August 14 as part of routine surveillance conducted by sentinel sites throughout North Carolina. None of the 59 specimens had the H275Y or I223V mutations.

Reported by: M Garrison, Buncombe County Health Center; L Weldon, Henderson County Dept of Public Health; P Brantley, L Wolf, PhD, M Davies, MD, J-M Maillard, MD, Z Moore, MD, North Carolina Dept of Health and Human Svcs. T Sheu, V Deyde, PhD, L Gubareva, PhD, AM Fry, MD, Influenza Div, National Center for Immunization and Respiratory Diseases; A Fleischauer, PhD, Career Epidemiology Field Officer Program, Coordinating Office for Terrorism Preparedness and Emergency Response; NJ Dailey, MD, EIS Officer, CDC.

Editorial Note:

This report describes confirmed oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two previously healthy adolescents who were cabin mates and recipients of oseltamivir in a mass chemoprophylaxis program during an outbreak of ILI at a summer camp. This is the first report of oseltamivir resistance in symptomatic close contacts with confirmed infection. Two possible mechanisms of transmission seem most likely. One possibility is that oseltamivir-resistant virus was transmitted from patient A to patient B. The onset of illness for patient B occurred 4 days after the onset of illness for patient A, consistent with reported intervals for secondary transmission among household members with seasonal influenza (7). Alternatively, both patient A and patient B might have acquired oseltamivir-resistant virus infection from exposure to another ill person (e.g., an unknown camper or staff member, or patient C), or each might have developed oseltamivir resistance independently. Whether the H275Y and I223V mutations occurred independently, or whether virus with one or both of these mutations circulated more widely in the camp could not be determined.

Although six other persons had illness while receiving oseltamivir chemoprophylaxis, aside from the specimens collected from patients A and B, only one specimen was obtained from any other ill person, and the pandemic H1N1 virus was not detected in that specimen. Neither mutation was found in 59 surveillance specimens from sentinel sites in the state, suggesting that the mutations were not widespread in North Carolina. The H275Y mutation has been characterized previously among seasonal influenza A (H1N1) viruses and is associated with resistance to oseltamivir (3). The I223V mutation has not been reported previously in 2009 pandemic influenza A (H1N1); because the neuraminidase inhibition assay could not be performed, the mutation's functional significance is unknown.

These cases highlight a potentially adverse outcome from oseltamivir chemoprophylaxis. In two randomized clinical trials (with 962 and 812 participants, respectively), the efficacy of oseltamivir chemoprophylaxis for preventing clinical seasonal influenza among persons within households ranged from 68% (for laboratory-confirmed infection that included serologic outcomes of infection) to 89% (for laboratory-confirmed clinical influenza) (8,9). No evidence of oseltamivir-resistant virus was reported in these studies. However, the World Health Organization has reported multiple instances of oseltamivir-resistant 2009 pandemic influenza A (H1N1) viruses being isolated from persons who developed pandemic H1N1 infection while receiving oseltamivir chemoprophylaxis (2). Resistance to oseltamivir also might develop during subtherapeutic dosing. In this report, patient A was symptomatic while on a chemoprophylaxis dose of oseltamivir for 4 days. One possibility is that she developed resistance while on a subtherapeutic dosage of 75 mg once a day for chemoprophylaxis, rather than the appropriate treatment dose of 75 mg twice a day.

CDC recommendations regarding use of antivirals during the H1N1 pandemic were updated on September 8. Use of antiviral medications for postexposure chemoprophylaxis should be reserved for persons at higher risk for influenza-related complications who have had contact with someone likely to have been infected with influenza. An emphasis on early treatment once a patient has developed symptoms, rather than chemoprophylaxis, should reduce opportunities for development of oseltamivir resistance (5). Chemoprophylaxis should not be used for prevention of illness among healthy persons after exposures in community settings. Persons who are taking antiviral medications for prevention should be instructed to contact a health-care provider if illness develops. Persons under antiviral treatment should be instructed to contact a health-care provider if symptoms worsen. Other preventative measures (e.g., hand hygiene and cough etiquette) can reduce the risk for influenza virus transmission (5).

Chemoprophylaxis failure is known to occur even without antiviral resistance (8,9). Accordingly, not all failures need to be accompanied by testing for resistance; testing should be considered for individual cases in consultation with the state health department. However, if symptoms develop during chemoprophylaxis, providers should consider the possibility of antiviral resistance and consider alternate treatment options. Because the 2009 pandemic influenza A (H1N1) virus is resistant to adamantanes (1), limited treatment options will be available if widespread oseltamivir resistance develops. Zanamivir is not licensed for treatment of children aged <7 years and is contraindicated among persons with underlying airway disease.

References

1. CDC. Drug susceptibility of swine-origin influenza A (H1N1) viruses, April 2009. MMWR 2009;58:433--5.
2. World Health Organization. Pandemic (H1N1) 2009: update 60. Geneva, Switzerland: World Health Organization; 2009. Available at http://www.who.int/csr/don/2009_08_04/en/index.html.
3. Deyde VM, Gubareva LV. Influenza genome analysis using pyrosequencing method: current applications for a moving target. Expert Rev Mol Diagn 2009;9:493--509.
4. World Health Organization. Influenza A (H1N1) NA-H274 detailed pyrosequencing protocol for antiviral susceptibility testing. Geneva, Switzerland: World Health Organization; 2009. Available at http://www.who.int/csr/resources/publications/swineflu/NA_DetailedPyrosequencing_20090513.pdf.
5. CDC. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009--2010 season. Atlanta, GA: CDC; September 8, 2009. Available at http://www.cdc.gov/h1n1flu/recommendations.htm.
6. Garten RJ, Davis CT, Russell CA, et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 2009;325:197--201.
7. Cowling BJ, Fang VJ, Riley S, Malik Peiris JS, Leung GM. Estimation of the serial interval of influenza. Epidemiology 2009;20:344--7.
8. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 2001;285:748--54.
9. Hayden FG, Belshe R, Villanueva C, et al. Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004;189:440--9.

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Date last reviewed: 9/9/2009