Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
From the Centers for Disease Control and Prevention |

Update: Drug Susceptibility of Swine-Origin Influenza A (H1N1) Viruses, April 2009 FREE

JAMA. 2009;301(20):2086-2087. doi:.
Text Size: A A A
Published online

MMWR. 2009;58:433-435

2 tables omitted

On April 28, this report was posted as an MMWR Dispatch on the MMWR website (http://www.cdc.gov/mmwr).

Since April 21, 2009, CDC has reported cases of respiratory infection with a swine-origin influenza A (H1N1) virus (S-OIV) that is being spread via human-to-human transmission.1 As of April 28, the total number of confirmed S-OIV cases in the United States was 64; these cases occurred in California (10 cases), Kansas (two), New York (45), Ohio (one), and Texas (six). The viruses contain a unique combination of gene segments that had not been reported previously among swine or human influenza viruses in the United States or elsewhere.1 Viruses from 13 (20%) of 64 patients have been tested for resistance to antiviral medications. To date, all tested viruses are resistant to amantadine and rimantadine but are susceptible to oseltamivir and zanamivir. The purpose of this report is to provide detailed information on the drug susceptibility of the newly detected S-OIVs, which will aid in making recommendations for treatment and prophylaxis for swine influenza A (H1N1) infection. These data also will contribute to antiviral-resistance monitoring and diagnostic test development.

Adamantane susceptibility was assessed by conventional sequencing or pyrosequencing assay2 with modifications,3 using viral RNA extracted from original clinical specimens and/or virus isolates. Susceptibility of virus isolates to the neuraminidase inhibitors (NAIs), including oseltamivir and zanamivir and two investigative NAIs (peramivir and A-315675), was assessed by chemiluminescent neuraminidase inhibition assay using the NAStar Kit (Applied Biosystems, Foster City, California).4 The generated IC50 values (ie, drug concentration needed to inhibit 50% of neuraminidase enzyme activity) of test viruses were compared with those of sensitive seasonal control viruses. In addition, because H274Y is the most commonly detected mutation in oseltamivir-resistant viruses,4,5 a set of new primers for pyrosequencing of the N1 gene was designed to monitor a residue of the neuraminidase protein at 274 (275 in N1 numbering) in viruses of swine origin.6,7

All 13 specimens tested contained the S31N mutation in the M2 protein, which confers cross-resistance to the adamantane class of anti-influenza drugs. In addition, a partial sequence deduced from the M2 pyrograms revealed changes characteristic for the M gene of S-OIVs. Existing primers used for the detection of adamantane resistance in seasonal viruses do not work with all tested S-OIVs. Optimized primers have been designed and are currently being validated. All 13 tested virus isolates exhibited IC50 values characteristic of oseltamivir- and zanamivir-sensitive influenza viruses. A/Georgia/17/2006 (H1N1), which is a seasonal virus, was used as a control. The IC50 for oseltamivir ranged from 0.28 nM to 1.41 nM, whereas those for zanamivir ranged from 0.30 nM to 1.34 nM. All tested viruses also were susceptible to peramivir and A-315675. A subset of viruses (n=2) tested in the fluorescent neuraminidase inhibition assay showed IC50 for oseltamivir and zanamivir ranging from 1.50 nM to 2.40 nM, similar to the sensitive control. Among the 36 specimens tested to date with pyrosequencing for the H274Y mutation in N1, none had mutations at residue 274.


L Gubareva, PhD, M Okomo-Adhiambo, PhD, V Deyde, PhD, AM Fry, MD, TG Sheu, R Garten, PhD, C Smith, J Barnes, A Myrick, M Hillman, M Shaw, PhD, C Bridges, MD, A Klimov, PhD, N Cox, PhD, Influenza Div, National Center for Infectious and Respiratory Diseases, Coordinating Center for Infectious Diseases, CDC.


In the United States, two classes of antiviral drugs are approved by the Food and Drug Administration (FDA) for use in treating or preventing influenza virus infections: M2 ion channel blockers and NAIs. The M2 blockers (adamantanes) are effective against influenza A viruses, but not influenza B viruses, which lack the M2 protein.8 However, use of the M2 blockers has been associated with the rapid emergence of drug-resistance mutations of the M2 protein among human influenza A viruses of H3N2 subtype, and in H1N1 subtype viruses circulating in certain geographic areas.2,3,9 Adamantane resistance also has been detected in A (H5N1) viruses in Southeast Asia.10,11 In addition, adamantane resistance has been reported for swine viruses in Eurasia12-14 but not in North America. This rapid increase in resistance has reduced the usefulness of this class of drugs for the management of influenza A infections, and since 2005, CDC has not recommended their use,15 although the emergence of resistance to oseltamivir in seasonal influenza viruses circulating during the 2008-09 season led to changes in CDC recommendations.*

Two NAIs, oseltamivir (Tamiflu [Hoffman-La Roche, Ltd, Basel, Switzerland]) and zanamivir (Relenza [GlaxoSmith Kline, Stevenage, United Kingdom]) are FDA-approved drugs for use against type A and type B influenza infections.16 The two drugs differ structurally, resulting in oseltamivir being orally bioavailable, whereas zanamivir is not and must be inhaled.17,18 A third NAI, peramivir (Bio Cryst, Inc., Birmingham, Alabama), is formulated for intravenous administration and is undergoing clinical trials, and a fourth, called A-315675 (Abbott Laboratories, Abbott Park, Illinois) has only been investigated in preclinical studies.

Compared with M2 blockers, NAIs previously exhibited lower frequency of antiviral resistance during therapeutic use.16,19 However, during the 2007-08 influenza season, emergence and transmission of oseltamivir-resistant A (H1N1) viruses, with a H274Y mutation in the neuraminidase protein, was simultaneously detected in several countries in the Northern Hemisphere4,20-22 and spread globally.7,9,23 As of April 2009, similar trends have been observed in the 2008-09 influenza season, with many countries reporting up to 100% oseltamivir resistance in A (H1N1) viruses. As a result, the World Health Organization Global Influenza Surveillance Network (GISN) and CDC have emphasized the urgent need for close monitoring of resistance to NAIs. Current interim antiviral recommendations for treatment and chemoprophylaxis of swine influenza A (H1N1) viruses include the use of either zanamivir or oseltamivir and are available at http://www.cdc.gov/swineflu/recommendations.htm.


23 Available.




Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.


Some tools below are only available to our subscribers or users with an online account.

1 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles