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Cepheid Xpert Flu Validated in ER Setting as Firm Targets Rapidly Crowding Flu MDx Market

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NEW YORK (GenomeWeb) — Researchers at Johns Hopkins University have performed the first validation of the Cepheid Xpert Flu assay in a population of emergency room patients with acute undifferentiated respiratory illness.

Cepheid's Xpert Flu is one of many rapid molecular influenza tests currently available or in development, and clinical validation may be an important factor influencing test uptake.

The results of the prospective study, which was partially sponsored by Cepheid, were published last week in the Journal of Clinical Microbiology. It compared Xpert Flu, a US Food and Drug Administration-cleared real-time PCR-based assay, to another FDA-cleared qPCR test, Hologic's Prodesse ProFlu+ assay.

In an assessment of nasopharyngeal swabs from 281 adults with suspected influenza infection in an inner-city clinic's ER, Xpert Flu test had an overall sensitivity of about 95 percent, and was about 99 percent specific. Restricting the comparison to 126 patients with high acuity illness requiring hospital admission, Xpert Flu was 100 percent specific and sensitive for both influenza A and B.

Andrea Dugas, lead author on the JCM article and an assistant professor in the department of emergency medicine at JHU, said she undertook her study to address an unmet need for tools to guide treatment in the ER, particularly with respect to US Centers for Disease Control and Prevention antiviral prescribing guidelines.

"In my own practice, it was really hard for me to decide who I should be giving antivirals to. I wanted to do what the CDC was recommending, but that was very challenging because I didn't know who had influenza. This is something that I really struggled with," she told PCR Insider in an interview this week.

Dugas' dilemma stemmed from the fact that rapid influenza antigen tests have notoriously low sensitivity, while traditional batch-processed PCR for flu "doesn't turn around in the time frame of an emergency department visit," she said. And with only one class of antivirals currently recommended against influenza, indiscriminate prescribing could drive resistance in the virus.

Xpert Flu is part of a family of tests that run on Cepheid's GeneXpert platform, and is designed to simultaneously detect and differentiate flu A, flu B, and 2009 H1N1 flu virus. At the JP Morgan Healthcare Conference in January Cepheid CFO Andrew Miller said that by the end of this year the firm expects to have a total of 18 GeneXpert tests available in the US and 25 available in Europe, up from 14 in the US and 15 in Europe as of the end of 2013.

JHU had already adopted GeneXpert to test for methicillin-resistant Staphylococcus aureus in operating rooms and Group B Streptococcus in the obstetrics department. "I'd heard about the Cepheid product," Dugas said, "so I asked them if they would give me test kits for my work."

The roughly 80-minute turnaround time, coupled with the high sensitivity of the test, was appealing to Dugas, she said, because it would allow her to make a treatment decision based on the Xpert test result as opposed to only her clinical opinion. "I had some real, reliable data that I could use to make a decision," she said, "and I got that reliable data in a time frame that would not delay care to the patient, which has been shown in previous studies to lead to worse outcomes."

Dugas had previously performed a cost-effectiveness modeling analysis of rapid PCR-based influenza testing. In that work, published in the Annals of Emergency Medicine, she and her co-authors showed that the economic benefit of incorporating rapid molecular flu testing into treatment practice depends on flu prevalence, and is most cost-effective at lower prevalences.

The JCB study was completed two flu seasons ago, and since then Dugas has been continuing her evaluations and studies with Xpert Flu, with a current study involving giving test results to providers to guide treatment in the ER. Validation in a real-world setting is important, she said. "Sometimes tests might look really good in very controlled situations, but when you put them into a real population they don't do quite as well," she explained. "I thought the Xpert did exactly as I had hoped it would do."

With a growing number of point-of-care molecular flu tests now available to clinicians, validation studies like Dugas' are critical for companies to distinguish their platforms and encourage uptake. For example, a group at Stanford compared Xpert Flu to antigen tests, finding Xpert had sensitivities of 97 percent and 100 percent compared with traditional PCR for influenza A and B, respectively. The commercial rapid antigen tests had much lower sensitivities of about 70 percent or less. That study was also funded by an investigator-initiated grant from Cepheid.

Cepheid recently received CE marking for Xpert Flu/RSV XC, a test that detects and differentiates influenza A, influenza B, and respiratory syncytial virus infection. The company expects to submit the assay soon to the FDA.

The crowding flu space

There are currently about two-dozen nucleic acid-based tests of influenza cleared or approved by the FDA. These include a handful that could be considered rapid point-of-care tests.

In June, Alere received FDA clearance for a new influenza test that can both detect and discriminate influenza A and influenza B. The test takes 15 minutes and uses an isothermal duplex amplification, eliminating the need for a thermal cycler and making the assay suitable for use at the point of care. It runs on the Alere i platform, and the company expects the test to cost around $80 with the list price for the platform itself around $8,500. The assay boasts sensitivities and specificities of approximately 99 percent. Alere also offers a rapid immunoassay for influenza called BinaxNOW.

This week, Alere announced that it had entered into a $12.9M, three-and-a-half year contract with the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority to develop diagnostic countermeasures for pandemic influenza. That contract also covers the creation of a next generation Alere i platform and flu test.

Focus Diagnostics, a Quest Diagnostics subsidiary, makes Simplexa Flu A/B & RSV Direct, which was cleared by the FDA to run single samples on a 3M thermal cycler. BARDA awarded a $5.9 million contract for that test's development in 2012.

Researchers in Rochester compared Simplexa Flu A/B & RSV to Prodessa ProFlu+ last year and found the tests comparable. The test was also recently validated by a group in Sweden on respiratory samples collected in saline, and was further found by a group at Yale to be more sensitive than a direct fluorescent-antibody assay, but less sensitive than an in-house RT-PCR test.

Quidel markets an influenza A/B assay on its Lyra platform. After extraction, the test takes 75 minutes and can be run on Thermo Fisher Scientific's Applied Biosystems 7500 Fast Dx or QuantStudio Dx real-time PCR instrument, and the Cepheid SmartCycler II. Quidel also offers an influenza immunoassay called Sofia.

Finally, Becton Dickinson offers a Flu A/B test on its random-access BD Max platform.

Other companies, meanwhile, are contracting out flu test development for already-existing rapid molecular platforms.

Qiagen contracted with IMDx last year to make, among other assays, a flu test for its QiaSymphony platform.

IMDx has also gotten licensure in Canada for sale and distribution of its own molecular tests for qualitative detection of flu A/B and RSV. The tests run on the Abbott m2000 platform under a multi-year test development agreement signed in 2011. IMDx said in August that it has been placing "significant focus" on obtaining international licenses to globally distribute and sell these products.

Finally, there are other molecular flu tests that will likely enter the US market in the future.

InDevr recently signed a $14.7 million contract with BARDA to finish the development of the FluChip-8Ga. That assay is based on simultaneous amplification of eight genes followed by hybridization to a microarray with sequence-specific targets, and includes automated image analysis and automated results interpretation, according to the company website.

Earlier this year, Roche acquired Marlboro, Mass.-based Iquum and its laboratory-in-a-tube system, an FDA 510(k)-cleared and CE-marked point-of-care molecular testing system, in a bid to quickly enter the near-patient MDx market. As covered in PCR Insider, this also brought on board a molecular assay for influenza A and B that is "ready to go" and will be for sale by the company this coming flu season.

Other companies reported to be developing point-of-care rapid molecular tests for flu include Mesa Tech, Sony Micronics, Enigma Diagnostics, Luminex, and GE Global research.

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