Why an ancient disease has brought the world to a modern-day crossroads,
and how improved diagnostics could head off the tuberculosis epidemic.
By Paul Nicolaus
March 23, 2017 | It’s an ancient sickness. Traces can be found in mummies, and
the Greeks called it phthisis, meaning “a wasting away”. Well into the 20th
century consumption remained the common term because of the way the disease consumes
victims. Although its origins date back thousands of years, tuberculosis (TB) continues
to plague humanity today.
Recent figures indicate that roughly ten million people
continue to fall ill each year, and the disease ranks as one of the top
10 causes of death worldwide. Remarkably, estimates suggest that roughly one-third
of the world’s population is infected with latent TB. While not sick or able to
transmit, these carriers could develop an active form of the disease at any
time.
Once active, symptoms do emerge. Perhaps a nagging cough or
weight loss, maybe a fever or night sweats. But TB shares symptoms with plenty
of other diseases, and these supposed red flags can be mild initially, leading
to delays in seeking care. Meanwhile, sing a song, laugh at a joke, cough, spit,
or sneeze and the Mycobacterium tuberculosis (MTB) bug goes airborne.
Detection Dilemma
Progress
has been made. The incidence rate has fallen by an average of 1.5% per year
since 2000, and nearly 50 million lives were saved through diagnosis and
treatment between 2000 and 2015, but detection
remains a major problem. The most recent World Health Organization (WHO) report
estimated that approximately 4 million people with infectious TB are either not
diagnosed, diagnosed too late, or are not known to the control program.
The
rise of multidrug-resistant tuberculosis (MDR-TB), a form of the disease
resistant to frontline drugs, and extensively drug-resistant tuberculosis
(XDR-TB), which also resists some second-line drugs, has only added to the
challenges. Without
early, accurate diagnosis, it is difficult if not impossible to control. And without attention and action, 75 million
people could die from the illness by 2050, according to a KPMG report, at an
estimated global economic cost of $16.7 trillion.
“I
think it’s one of the great tragedies of TB that we haven’t eliminated it yet
when it has been detectable, preventable, and curable for a very long time
now,” said Erica Lessem, director of Treatment
Action Group’s (TAG) TB/HIV Project. And
while all the dire statistics ought to alarm the global community, when Lessem
looks around she sees complacency settling in.
“I think
that it hasn’t been treated with the sense of urgency and real terror, I think,
that the disease can provoke to individuals, to societies, and to economies.”
It’s a dynamic that may be contributing to a
lack of investment in new diagnostic technologies. According to a TAG analysis of the funding
landscape for TB R&D,
only US$62.8 million was devoted to this area in 2015 out of an estimated need
of $364 million. This shortage
of resources has resulted in imperfect tools.
The microscope is the oldest and still the most widely
used form of detection. Although
this is a relatively quick and easy method, it misses many cases and relies on a
sputum (coughed up mucus) sample, which is a challenge for many patients to
produce and cannot be used for detecting extrapulmonary TB. (While the disease is most
commonly found in the lungs, it can attack almost any area of the body, such as
the brain, spine, or kidneys.)
Even culture—considered the
gold standard—has clear drawbacks. The turnaround time (roughly two weeks for
liquid and up to two months for solid samples) means results are often received
too late to inform important treatment decisions.
Game Changer
It was the
introduction of Cepheid’s GeneXpert, a test device platform launched by Cepheid
in 2004, that shook up the diagnostic landscape. Although polymerase chain
reaction (PCR) technology is not new, it never took off in low- and middle-income countries (LMIC)
due to high costs and the need for sophisticated lab infrastructure as well as
highly skilled workers, explained Madhukar
Pai, director of McGill University’s Global Health Programs and associate
director of the McGill International TB Centre.
The Xpert
MTB/RIF, based on the GeneXpert platform and endorsed by WHO in 2010, changed
all that by automating the entire PCR process and making it user-friendly in a
simple, cartridge based format that removed the need for several rooms and
fancy labs. The tool can accurately
detect TB and resistance to the drug rifampicin in about 90 minutes and has
gone on to become the most scaled up new test. Along
the way, it attracted international attention and encouraged other
product developers to enter the market, which has since spurred a revitalized
diagnostics pipeline.
The results of this awakening are being realized. In 2015, for example, WHO approved
Alere’s TB lipoarabinomannan (LAM) test for those with HIV who have very low
CD4 counts, a welcome development considering the vulnerability of this
particular population—those with HIV are 20 to 30 times more likely to develop
active TB. Alere’s dipstick urine test can detect the
disease in about 25 minutes at a cost of just $2.
More
recently, WHO recommended a rapid diagnostics test with the goal of speeding up detection and
improving treatment outcomes for MDR-TB. The
line probe assay (LPA) test, called MTBDRsl and made by Hain Lifesciences, a
German company, identifies genetic mutations in MDR-TB strains and can detect
resistance to some fluoroquinolones, all second-line injectables, and ethambutol.
Results are obtained within
just 24 to 48 hours, which means MDR-TB patients with additional resistance are
diagnosed more quickly and can be placed on appropriate second-line treatments
faster as a result. The MTBDRsl test is also important for identifying MDR-TB
patients who are eligible for a newly recommended regimen that can be completed
in half the time (9-12 months as opposed to 18-24) and at a lower cost than
conventional options while avoiding putting those with resistance to second-line
drugs on this regimen, which could wind up encouraging the development of XDR-TB.
Diagnostics Pipeline
The current diagnostics landscape, detailed in TAG’s 2016 TB/HIV Pipeline Report, is
most developed for molecular technology looking to become even simpler to use than
the GeneXpert machine in decentralized settings, and there have been some promising strides made since last year. “I think the test
that everybody is really waiting for is the GeneXpert Omni,” Lessem said. While
the existing system requires electricity and temperature controls, the new
iteration promises to be a smaller, more rugged handheld device that runs on
battery or solar power and looks “like a little coffee maker.” The anticipated
release is Q3 2017.
Cepheid is also working on two cartridges that
are relatively close to completion. The Ultra is expected to have
improved sensitivity and detection of resistance to rifampicin, and the XDR
cartridge would be able to detect isoniazid and second-line drug resistance in
just two hours. “This would be a great advance for being able to rapidly
understand exactly what kind of TB a patient has and get them started on the
right treatment right away and potentially do it at the point of care level if
the Omni is introduced,” she said.
Cepheid was acquired in late 2016 by Danaher
Corporation but has indicated that development of these products will continue,
although additional funding is needed to speed along the XDR. Competitors
are working on similar tests, such as Molbio’s TrueNAT, but have not yet
received WHO approval, Lessem noted.
With the help of funding from the Bill & Melinda Gates
Foundation, QuantuMDx, a company headquartered in the UK, hopes its Q-POC device will
become one solution to the TB problem. The company’s molecular diagnostic
platform for rapid, low cost detection and drug susceptibility testing is being
developed for introduction into peripheral microscopy centers, clinics, and
hospitals in high burden countries.
The company has developed a technology that can “fish out”
low numbers of cells in sputum samples, explained Chief Scientific Officer Jonathan
O’Halloran. The vision is that patients will provide their samples right at home.
Once the cap on the container is shut, a reagent is released and a thinning
process occurs until the sample is handed over to a clinic.
“So literally you just push it in, put the flow cell into the
device, and press go,” he said. “What happens during this process is the
thinned sputum is then pushed over electrodes that capture the cells,
specifically the MTB cells, in the electric field and the rest of the sample
flows away.” A first diagnosis can be made using a microscope or the camera on
the device, and from there it is possible to look at drug resistance markers as
well.
At the moment, the Q-POC is the size of a laptop, although
O’Halloran said the goal is to reduce that size by the time the alpha version
comes out in October. The device will cost roughly US$2,000, and the disposable
assay is expected to come in at under $5. He and his colleagues believe it is
shaping up to be a promising technology, but they are also well aware that “the
proof is in the data.” Clinical trials are planned for early 2018, and if all
goes well, product rollout is expected later that year.
Sluggish Uptake
Even though new technologies in existence and under
development show promise, it can be a frustrating wait when dealing with a
global epidemic. “When GeneXpert came out in 2010, everybody thought there were
going to be a ton of what they call fast followers at the time,” Lessem said.
There were plenty of competitors developing tests, and there was plenty of hope
that this added competition would help drive prices down.
“A
lot of what we thought would be fast followers have actually been quite slow to
kind of come through the market in the way that everybody was hoping,” she
added. The even bigger
disappointment, however, is that programs aren’t doing more with what is
available right now. The Xpert
MTB/RIF isn’t used as widely as it ought to be. No
country has begun to implement Alere’s LAM test, and few countries are using
Hain’s MTBDRsl test.
“I
think what we’re seeing is the aftermath of a long period of neglect of the TB
field as a whole and the lack of awareness of the importance of it,” Lessem
explained. The field became accustomed to doing things in a specific and
old-fashioned way, and it has taken a lot to get programs to adopt these new
technologies.
Economics
is part of the story, too, of course. Even though microscopy may be
old-fashioned, it is the less expensive route. While countries have been spending less than a dollar for sputum
smears for decades, many are unwilling or unable to pay $10 for the Xpert MTB/RIF. Some countries,
primarily South Africa, have bucked this trend and rolled it out across the
country, Pai noted, and both India and Brazil are slowly stepping up as well.
Meanwhile, countries lacking in
financial resources continue to bear the burden of the disease as more than nine out of 10 TB-related deaths occur in LMIC. “This is a real
violation of human rights,” Lessem said, “both in terms of the right to health
and the right to the benefits of scientific progress.”
Aggressive Response
Needed
Many of the gaps in prioritized diagnostics
will simply not be filled by the current pipeline, which leans heavily toward
molecular smear replacement and drug susceptibility testing but not true
point-of-care (POC) tests, Pai and colleagues explained in a 2016
paper published in Microbiology Spectrum (doi:10.1128/microbiolspec.TBTB2-0019-2016). Ideally, he would like to see the emergence of a non-sputum,
biomarker-based, rapid test that can be handled easily at the POC.
HIV has an excellent rapid test that can be used at home, for example,
and a finger prick blood sample is all that is needed to diagnose malaria
accurately within 20 minutes. “So to have this biomarker-based test that we can
do with a finger prick sample, for example, would be the holy grail in TB,” he
said, “and as of today we don’t have one.”
There
are plenty of hurdles that stand in the way. A blood sample can reveal
antibodies that correlate well with the presence or absence of HIV, but
antibodies are not a good correlate of TB. Some are trying to look for more
complex biosignatures such as serum transcriptomics profiles. “Although there
are some proof of concept early studies, nothing has ever reached the level
that it can actually go into a kit in a box,” Pai said. “We are still waiting for the basic science to help us target
the best biosignature to use.”
Detecting
TB early relies on going to the places where people first start presenting
themselves. Waiting for them to come all the way to a city and end up in a large
hospital or tertiary center is already too late because they have infected others
by then. If the type of test that he envisions comes to fruition, it would be
less expensive, it wouldn’t require labs, and it could be decentralized even to
community health workers out in the field. “You could even do them under a
tree, so to speak,” he said.
But these
new and improved technologies will only go so far, he warned. As we’ve already
seen in the last decade, operational weaknesses and underfunded programs tend
to hinder uptake in countries with high burdens. National TB programs need to find
ways to scale up the best diagnostics available to achieve the biggest impact
possible.
And this
needs to be handled swiftly. “Everything we delay
doing now is going to have major implications on our ability to fight the
disease later on,” Lessem said. “It’s just going to get worse and worse over
time if we’re not mounting a very robust and aggressive response right now.”
Paul Nicolaus is a freelance writer
specializing in health and medicine. Learn more at www.nicolauswriting.com.