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Tamiflu Resistant Pandemic H1N1 in Washington State
Recombinomics Commentary 03:20
August 15, 2009

On June 1, the patient was enrolled in an influenza antiviral treatment study and he began a 10-day course of oseltamivir.

A novel influenza A (H1N1) virus isolate from a specimen collected on May 31 was identified as susceptible to oseltamivir by pyrosequencing at CDC, but viruses isolated from specimens collected on June 11 and July 14 had the H275Y mutation, indicating oseltamivir resistance.

Antiviral treatment with high-dose oseltamivir (150 mg orally, twice a day) and rimantadine (100 mg orally, twice a day) was administered during June 26--July 1.

On August 10, CDC received other previously collected virus isolates from this patient for testing, and pyrosequencing of a virus isolated from a specimen collected on July 14 had the H275Y mutation, confirming oseltamivir resistance.

The above comments are from today's MMWR dispatch describing two immune-suppressed patients, who represent the first two confirmed cases of oseltamivir resistance in H1N1 pandemic swine flu in the United States.  Both patients were from King County in Washington State and initial isolates from both patients were sensitive.  In one patient, virus with H274Y was first detected in a sample collected 10 days after the start of treatment, while in the other patient, resistance was detected in a sample collected 18 days after the start of treatment. Because these patients were symptomatic at the start of treatment, the date of detectable resistance is unknown, in contrast to earlier patients who were asymptomatic at the start of prophylactic treatment and became symptomatic 5-6 days later.  In the patients treated prophylatically, the appearance of symptoms in the short time frame after the start of treatment suggests the resistant virus was present as a minor population, and the treatment led to detection.

In the two immune-suppressed patients it is harder to draw a conclusion because of the longer time period between the start of treatment and confirmation of resistance.  However, the report of two patients from the same area, who began treatment in June, raises concerns that H1N1 with H274Y is silently circulating.  In patients who are not immune-compromised, virus is usually cleared with or without Tamiflu treatment and therefore minor populations with H274Y would go undetected.  In immuno-compromised patients, as well as those who are on prophylactic Tamiflu, detections of resistance is more common because of the development of symptoms in patients who were previously asymptomatic, or in patients treated with Tamiflu over and extended time frame.

The report on these two patients follow reports of resistance in Hong Kong this week, as well as Singapore, China, and Thailand last week, in addition to media reports last week of resistance in patients in Texas at widely separated locations along the Mexican border, as well as comments from WHO on reports of resistance in an undisclosed number of patients at undisclosed locations.

These continuing reports of resistance at the same genetic position, H274Y, continue to increase concern of widespread resistance silently circulating as a minor population which is not discovered until patients are treated with oseltamivir.

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