NEW YORK (GenomeWeb) – The World Health Organization has awarded prequalification to two CE-marked qualitative HIV tests, enabling them to be procured in certain countries with global health donations earmarked for diagnostics.
The Alere q HIV-1/2 Detect assay and the Cepheid Xpert HIV-1 Qual are both qualitative tests for HIV nucleic acids. The Alere q HIV-1/2 Detect was CE marked in 2015. The Cepheid Xpert HIV-1 Qual was also CE marked that year. Unlike the other dozen nucleic acid-based in vitro diagnostics awarded WHO prequalification since 2011, the Alere and Cepheid tests are considered more decentralizable.
While prequalification now unlocks certain markets for the companies, they may now also compete to pioneer the near-patient and point-of-care spaces for HIV testing, particularly early infant testing in sub-Saharan Africa.
Infants and children, who can contract HIV from their mothers, respond quite well to anti-retroviral therapy (ART) but get access to it much less often. In 2013, only about 40 percent of HIV-exposed infants in sub-Saharan Africa were tested within two months of birth, according to the Elizabeth Glaser Pediatric Aids Foundation (EGPAF). "Diagnosing children living with HIV as early as possible is critical for their survival," EGPAF notes on its website. Without a diagnostic test children aren't treated, and half will subsequently die by age two.
Indeed, "The biggest bottleneck in getting access to therapy is getting a diagnosis," Duncan Blair, director of public health initiatives at Alere, told GenomeWeb in an interview. Lab testing is available, but even when infants are tested it is not always possible to find them and get them the results weeks to months later. Thus, rapid near-patient and point-of-care options could be incredibly beneficial.
Alere has other non-molecular diagnostics products that are already prequalified, but this one is "a milestone," both for the company's business and for the public health community, particularly the patients, Blair said.
David Persing, chief medical officer at Cepheid, noted in a separate interview that the prequalifications awarded to Cepheid and Alere mark "the first decentralized options" for molecular HIV testing.
Philippe Jacon, director of emerging markets at Cepheid, added that a number of countries ask for WHO prequalification before they can purchase and procure a product.
"In turn, that becomes almost mandatory for us, not from the funding organization standpoint, because the global funders can buy based on CE-IVD, but the countries themselves ask for companies to get [it] before the product can be procured," Jacon explained.
Alere's Blair said that many ministries have been "waiting for this effective green light from the WHO to minimize their risk in terms of the quality and suitability." There are also countries that may implement national programs using the Alere test, as previously reported. While he couldn't speak for those countries per se, Blair said Mozambique, Kenya, Tanzania, Uganda, Zambia, Zimbabwe, and Cote d'Ivoire are the main ones where EGPAF is working. Other countries like Swaziland, Lesotho, and Malawi have begun pilots and are interested in moving towards scale, Blair said.
Prequalification was initially designed as a mechanism to help prevent ineffective drugs from being sold in low- and middle-income countries. The WHO branched out into prequalifying in vitro diagnostics in 2010, with the first HIV tests, RealTime HIV-1 assays from Abbott Molecular, awarded prequalification the following year.
"This prequalification can give programs a green light, and the certainty that they need to be sure that global donors are happy and that the quality assurance and performance is there," Blair said. "It opens up access to a whole lot of markets that are funded by external global donors."
Prequalification was also designed to fill a regulatory framework gap in countries that don't have agencies akin to the US Food and Drug Administration or mechanisms similar to CE-IVD marking. However, Cepheid's Jacon noted that, while it is theoretically an excellent strategy to protect patients, it may also be somewhat redundant and time consuming for the diagnostics industry.
"Whether you get a stringent regulatory authority having reviewed your product or not — like FDA or CE-IVD — doesn't make a difference; [the WHO] asks companies to go again through their prequalification system," Jacon said.
The system involves multiple stages, including an inspection of the manufacturing facilities, and in Cephied's case it took 17 months, according to Jacon. "From a commendable idea in the beginning, I think it is becoming a bit of a hurdle ... it is disheartening if WHO becomes an organization that is slowing down access," he said.
Nevertheless, prequalification is essential to unlock certain large caches of funds that are prohibited from being used to purchase non-WHO prequalified diagnostics. Procurement usually happens via a mechanism where countries get funds from donors, and then procure the tests directly from companies.
Alere's Blair noted that there are a number of non-governmental funding agencies that prefer prequalified purchases. UNITAID, for example, is an organization that recently provided around $200 million in funds earmarked for piloting, implementing, and scaling point-of-care HIV molecular testing to agencies such as EGPAF, the Clinton Health Initiative, and Médecins Sans Frontières (MSF).
In particular, EGPAF was awarded $63 million for a four-year project to scale up point-of-care testing for early infant diagnosis in nine countries.
Furthermore, other procurement programs, like the United States President's Emergency Plan for AIDS Relief, or PEPFAR, and the US Centers for Disease Control and Prevention are a bit "at the mercy of what the country-specific policies are," Persing said. "They like to be able to work with the countries to be able to bring in prequalified technologies."
Blair also added that the US CDC Global Aids Program worked with the WHO on the current prequalification, "so we are also aware that the CDC is in the process of issuing a memo to the field — to embassies and CDC offices around the world — also indicating that this product is eligible for procurement," he said. This specifically frees up US funds, such as from USAID and PEPFAR, Blair said.
Cepheid is already selling the product in countries that do not require WHO prequalification, Jacon said. Among those that do require prequalification, some will now also require a local evaluation to ensure the test has the same performance characteristics with their local conditions.
Alere, meanwhile, has been anticipating the prequalification for some time, Blair said, and the firm has been scaling up its sales and marketing team for many months.
"Perhaps more importantly, we've been scaling up our teams in terms of support, so we have pretty unparalleled levels of infrastructure in sub-Saharan Africa for a major diagnostic company," Blair said, including staff for training and troubleshooting. "This helps us market a solution rather than simply a product."
Competing at the point of care
Although prequalification has already been awarded to tests from firms like Abbott, BioMérieux, Siemens, and Roche, these are all lab-based tests that require trained personnel to operate them.
The Alere and Cepheid tests are novel because they can be used outside of a lab and can be operated by non-experts. Each test offers its own advantages for the sub-Saharan region, however.
The Alere test is "the first, and currently the only, true point-of-care molecular test for diagnosing HIV," Blair said. The primary application will be for diagnosing HIV in infants, whose small blood volume make standard testing with venous blood samples a challenge.
"Our assay is fully decentralizable, really down to the lowest level of the healthcare system, because we don't require continuous power, water, or trained lab technicians, [and] there is zero sample preparation that needs to be done with this test — it is sample in, result out," Blair said.
The test takes 52 minutes, and the firm has some internal evidence already that the Alere q has a "huge impact on retention in care and initiation of ART" in infants, Blair said. The test can also be run by "lay healthcare professionals" after a half day of training, and "it can be taken out where the kids are being born."
Blair said the Cepheid system is also good, but is not as decentralizable, requires more training of technicians to run the tests, and requires a computer. "If you have [the Cepheid] system in a lab, unless you happen to be born next door, then you don't really get the advantages that the point-of-care brings, and even then, the turn-around time is substantially slower."
The Cepheid test, meanwhile, may have some advantages in installed base. Persing further noted, "In terms of Alere versus Cepheid, if you look at the package inserts and claims posted by the WHO it's pretty clear that there are some performance advantages of our assay — it is much more sensitive, it covers more HIV-1 subtypes — and there are operational advantages in terms of being able to work with dried blood spots, which are kind of standard practice in neonatal testing."
Cepheid claims about 5,000 Xpert systems in low- and middle-income countries are running the firm's TB assay, many with available capacity to run additional tests. Many of these systems are located in HIV hospitals where TB is managed, Persing said. He was not sure how many of these were in maternal-child hospitals, but he said there is need for rapid molecular technology is all settings, and that the firm's expanding menu may also be attractive to potential customers.
"We also see a need for a fast follow-on WHO PQ viral load assay which can be done in the same settings, and that's what we are hoping for as well."
Persing also said that having healthcare personnel available, as well as testing tied to locations which can also dispense treatment, could be linked to meaningful impact on patient care. "It really comes down to the definition of point of impact versus point of care," he said, adding that a totally decentralized system may be useful for active case finding, but will not necessarily lead to immediate treatment unless they are in an appropriate setting.
That said, Jacon added that the Cepheid technology "is already well decentralized, and goes beyond the clinic — we have a lot of systems that have been put in vans that go around, groups like MSF have them under the tents in their small mobile hospitals, and so on." The test is also "high on the list" for being ported onto the firm's smaller platform, the Omni, which is in development.
Regardless of the outcome, Persing said that, along with FDA clearance, prequalification could be a good predictor of test performance three to five years down the road. "They are both independent evaluations, and they both serve as third-party assessments of performance that most people discern to be objective," he said. "Not all CE-IVD marked, self-declared technologies can really survive that long, and many of them are self-declared on the basis of minimal data," Persing added.
Cepheid's MTB/RIF tuberculosis assay, for example, is "living up to its claims of five years ago," Persing said, but also noted that assay was endorsed, rather than prequalified, by the WHO.
Both firms are also developing whole blood quantitative, as opposed to qualitative, tests, as well as ones that will require plasma, meaning they will need to be run in a lab. "We recognize that our instrument has utility at all levels of the healthcare system, from centralized through to fully decentralized, to mobile, in a canoe, on a bike, et cetera," Alere's Blair said.