NEW YORK (360Dx) – The Foundation for Innovative New Diagnostics (FIND), a Swiss nonprofit, is looking for partners to assess the performance of a new, point-of-care urine test for diagnosing tuberculosis in people infected with HIV.
Developers claim the immunochromatographic assay has advantages over other tests on the market for diagnosing TB in HIV patients, as well as the conventional approach, culture. The assay, called Silvamp TB LAM, was co-developed with Tokyo-based Fujifilm. It is capable of detecting low concentrations of the antigen lipoarabinomannan (LAM), a compound produced by TB, in the urine of people co-infected with TB and HIV.
The Global Health Innovative Technology Fund (GHIT), a public-private funding organization headquartered in Japan, as well as the German Federal Ministry of Education and Research have pledged JPÂ¥422 million ($3.8 million) to support evaluations of the test at different sites, obtain regulatory approval for it, and scale up manufacturing of the assay.
The ultimate aim is to generate a submission to the World Health Organization that could lead to the WHO recommending the use of the test for diagnosing TB in HIV-positive individuals. Sites that wish to participate in the trial should submit proposals to FIND by the end of January 2019.
Tobias Broger, senior technical officer at Geneva-based FIND, said that the organization works with industry to develop new tests for poverty-related diseases such as TB, and has produced 20 new tests since it was established in 2003. Its work with Fujifilm on the Silvamp TB LAM test was an outgrowth of its mission to address an unmet need in the marketplace.
In this case, it was a need for a test to diagnose TB early in HIV patients in developing countries. The need was particularly acute, Broger said, because TB is one of the most common causes of death for people living with HIV, and current tests diagnose TB on the basis of sputum analysis. As HIV can impair patients' ability to cough, collecting sputum from them can be a challenge.
"Many patients have difficulties in producing sputum," said Broger, "so, we were looking for a urine-based test." He noted that "an existing test" showed promise to detect the LAM marker in urine and is recommended by the WHO, but it is not sensitive enough to detect very low concentrations of the biomarker and therefore is only recommended for severe HIV-positive patients. “We were scouting for something more sensitive, something that could measure LAM in the low picomolar or even femtomolar range" he said.
Though he did not name the test, he was most likely referring to Alere's Determine test, which the WHO has recommended for field use since 2010. Alere did not respond to a request for comment.
Before deciding to partner with Fujifilm, FIND and its partners surveyed roughly a hundred technologies in a quest to identify a simple, point-of-care test that could measure low concentrations of LAM in urine. The assay makes use of Fujifilm's silver halide amplification technology, originally used by the Japanese firm for the development of photographic film.
By employing the amplification approach in an immune-chromatography process, it's possible to amplify the test band intensity and low LAM concentrations can be detected by the human eye. The entire assay can be carried out in about an hour and requires no instrument, making it ideal for field testing. Fujifilm originally developed the method for a point-of-care influenza test, which it launched in 2011. Developers liken the platform to a pregnancy test.
"The Fujifilm test targets the POC setting, places with limited infrastructure and not necessarily a stable power supply, said Broger. "The goal is that people with minimal training can use the test and FIND will evaluate this as part of the planned trials."
In addition to Fujifilm, FIND worked with researchers at Rutgers, the State University of New Jersey; the University of Alberta in Canada; Otsuka Pharmaceutical in Japan; and the University of Cape Town in South Africa to develop the test. GHIT pledged $2.2 million in 2015 to support the effort, and several international donors like the governments of the Netherlands, Australia, the UK, and Germany, as well as the Bill & Melinda Gates Foundation have also supported R&D for the test over the past decade.
Test developers have already concluded preliminary work on frozen urine samples from three cohorts of HIV-positive patients in South Africa. Broger said the results were positive and that they will be published in the future.
According to Broger, as part of the new trial, participants will undertake a review of retrospective data generated from frozen urine specimens from HIV-positive patients by May 2019. A comprehensive review of data from the prospective studies funded as part of the trial will follow once that data becomes available.
"So far, we have the product, we have tested it on samples, and those results will be published soon, but I think what we still need to do is to test it in relevant settings in fresh samples in prospective studies, in the hands of the end user," said Broger. "This is ultimately what is important for WHO policy," he said. "This is why we are organizing relatively large multi-country studies in Asia and Africa, and also South America, just to get a broad understanding of the clinical and operational performance of the test."
Assuming the trial goes well, Fujifilm will have to scale up manufacturing of the test, Broger noted. The company will also have to seek regulatory approval, beginning with a CE-IVD marking in Europe. While the test will most likely not be used within Europe, Broger said that the CE-IVD mark is recognized in many of the countries where the test would be deployed. "Ultimately, I think Fujifilm would market the test," he said.
Fujifilm in a statement last month said it was committed to achieving recommendation from the WHO related to the test, and said it would take the test through CE-IVD certification in Europe, as well as help support the large clinical evaluations taking place in developing countries under the new trial.
However, a timeline for when the test could become available has not been set, and Broger reiterated that the partners remain cautious in terms of setting dates.
Teruo Takahashi, a business development manager within Fujifilm's in vitro diagnostics and medical systems division, said that the new test is a unique addition to Fujifilm's menu, as it relies on manual amplification, as opposed to the automated amplification that is employed to process its other test kits using instruments, such as Fujifilm's DRI-CHEM IMMUNO AG1 analyzer. "The TB one is going to be the first manual amplification model," said Takahashi, "simply, because we would like to deliver amplified sensitivity to patients in limited resource settings — even [with] unstable electricity and with minimally trained medical staff."
He said that in the future, Fujifilm might add manual amplification versions its legacy respiratory disease tests, if it sees "sizable demand" for such kits. "No viable plan," exists for such an endeavor yet.
As the new kit is being funded through GHIT, Takahashi said that it is being brought to market on a "no gain, no loss" basis. Fujifilm anticipates that its kits will be most widely used in "sub-Saharan countries, where there are a large number of people living with HIV."
He said that the project might not significantly contribute to Fujifilm's revenues, but in the long run, it believes its experience working with FIND, the WHO, and other global stakeholders will raise awareness of the firm's technologies and will "indirectly make positive contributions to our business growth overall."Â Â Â
Other preliminary work on the test was published recently in the Journal of Clinical Microbiology. The paper described the evaluation of 100 monoclonal antibody pairs using Meso Scale Diagnostics' electrochemiluminescence platform. Not only did the sensitivity for LAM detection in HIV-positive patients have a sensitivity and sensitivity of 93 percent and 97 percent, respectively, in HIV-negative, it achieved sensitivity of 80 percent, a multitude higher than competitive techniques.
"We tried to get our hands on every particle antibody and screened them directly with samples," said Broger of the JCM paper. "The paper is quite significant because it shows a clear way forward for this biomarker, especially since, so far, people didn't really know if LAM was detectable in HIV-negative patients," he said. "In principle, we would like a test that works in all patients and the paper shows clear a pathway toward such a test;" he said.
He noted that the work was done on the Meso Scale platform in a central laboratory and had not been replicated in a POC setting.