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Study Shows Cepheid Xpert Assay Viable for Diagnosing TB Meningitis in High-Burden Settings

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A South African research team this week published a study demonstrating the accuracy of Cepheid's quantitative PCR-based Xpert MTB/RIF test for diagnosing tuberculosis meningitis, or TBM, in HIV-infected patients in a high-burden setting.

Specifically, the team showed that Xpert MTB/RIF had an overall sensitivity of 62 percent and specificity of 95 percent compared to conventional methods and when using raw cerebrospinal fluid samples. However, the test's sensitivity increased to approximately 80 percent — considerably better than demonstrated for other molecular assays — when the samples had undergone a centrifugation step prior to testing.

Cepheid's Xpert MTB/RIF — a nested real-time PCR-based assay that simultaneously detects Mycobacterium tuberculosis and rifampicin resistance in about two hours — and the benchtop GeneXpert system on which the assay runs has seen significant uptake in resource-poor areas of the world for diagnosis of TB and drug resistance.

This uptake has been aided by multiple peer-reviewed studies demonstrating that the assay has equivalent or superior sensitivity and specificity to traditional culture-based methods for detecting M. tuberculosis and rifampicin resistance, as well as a 2010 endorsement from the World Health Organization to make Xpert MTB/RIF the initial test in suspected multidrug-resistant or HIV-associated TB cases.

Cepheid has also inked a series of agreements with various government agencies and non-profit global health organizations to buy down the price of the Xpert MTB/RIF cartridge to approximately $10 in order to help drive widespread adoption (PCR Insider 8/9/12 and 12/6/12).

Although tests like Xpert MTB/RIF are helping to curb TB incidence, the epidemic still rages in much of the developing world — especially in sub-Saharan Africa and in patients co-infected with HIV.

Further complicating the problem, up to 40 percent of those co-infected patients have extrapulmonary TB, and about 10 percent of those patients have TBM. These patients require prolonged clinic admission and have high morbidity and mortality rates, and as such TBM consumes a disproportionate amount of healthcare resources.

To address this issue, the South African team — comprising researchers primarily from University of KwaZulu-Natal, University of Cape Town — decided to evaluate the use of Xpert MTB/RIF as a fast "rule-in, rule-out" test for TBM.

In their study, published this week in PLOS Medicine, the scientists evaluated the accuracy of Cepheid's test to diagnose TBM using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid samples from 235 South African patients suspected of having the disease.

Of 204 evaluable patients, of whom 87 percent were HIV-infected, 59 were determined to have definite TBM, 64 probable TBM, and 81 non-TBM using a clinical score derived using basic clinical and laboratory information.

The Xpert MTB/RIF test demonstrated a sensitivity of 62 percent and specificity of 95 percent using uncentrifuged samples. This sensitivity was significantly better than that of smear microscopy (12 percent) and of the clinical scoring method (30 percent).

Xpert MTB/RIF sensitivity was higher — 82 percent — when centrifuged samples were used, as compared to 47 percent for uncentrifuged samples. The Cepheid assay was not useful in identifying TBM in HIV-free individuals, although the sample size was small.

The results led the researchers to conclude that Xpert MTB/RIF may be a good "rule-in test" for diagnosing TBM in HIV-infected individuals in TB-endemic settings.

However, they also believe that more detailed studies, using validated scoring systems, are needed in non-HIV-endemic setting to evaluate the impact of the assay on diagnostic accuracy, morbidity, and mortality in TBM patients.

In an accompanying perspective article in PLOS Medicine, University of Minnesota researcher David Boulware, who was not involved in the study, took a similarly cautiously optimistic tack.

"Although two commercial TB PCR tests previously existed, the innovation is that the GeneXpert platform is fully automated and is being rolled out in low- and middle-income countries," Boulware wrote. "Thus, GeneXpert is an actual technology that can be — and is being — widely used globally. However, immediate implementation of a $10 Xpert MTB/RIF assay for all cases of meningitis is unwise and unsustainable. Further research is needed on how best to incorporate the Xpert MTB/RIF test into diagnostic testing for meningitis, to ensure that it is a cost-effective intervention that improves health and does not waste resources."

Cepheid is indeed finding a meaningful market for Xpert MTB/RIF in the developing world — areas that it refers to as high-burden developing countries, or HBDCs.

The PLOS Medicine study was published a week after Cepheid released its third quarter earnings. The firm reported a 24 percent increase in year-over-year revenues boosted in part by record revenues from its HBDC program, through which it sells GeneXpert systems and Xpert MTB/RIF cartridges.

In the quarter, the company installed a total of 133 GeneXpert systems as part of its commercial clinical business, and 441 systems as part of the HBDC program. Total commercial sales were $79.8 million in the third quarter, while HBDC sales totaled $20.3 million. Based on these results, but offset by an expected 1 percent drop in commercial clinical sales, Cepheid increased its full-year revenue guidance to a range of $389 to $391 million.

More on Cepheid's overall Q3 financial results can be found here.

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