irony is that when WHO gave its recommendation to Xpert MTB/RIF, it did not
seem to be expecting that the earliest implementer would be moving his entire
nation from one diagnostic platform to the new diagnostic platform in the space
of three years.
Reading between the lines of the recommendations on
GeneXpert, it seemed that WHO was painfully aware that cost was going to make
it difficult for many countries to take advantage of what its own review of the
evidence showed to be a major advance in TB diagnostics. Consequently, the
scope of the recommendation was rather limited.
1) Xpert MTB/RIF should be used as the
initial diagnostic test in individuals suspected of having MDR-TB or HIV-associated
TB. (Strong recommendation.)
“The selection of individuals to test [with Xpert]
would be based on a risk assessment,” said Dr Christopher Gilpin of the Global
Laboratory Initiative, explaining the policy at the New Diagnostics Working
Group Meeting before the Union World Conference on Lung Health last October in
Lille. For instance, he said that anyone diagnosed with, or suspected of having
TB, is someone who might be at risk of MDR-TB; or people with symptoms of TB
who are known to be HIV-positive, or who are of unknown status in a setting
with a high burden of HIV, should also be targeted for GeneXpert testing. And
as a secondary consideration, one might also target HIV-negative individuals,
not believed to be at risk of MDR-TB but who have either an abnormal chest X-ray, or
who are still suspected of having TB despite having a negative sputum smear.
2) Xpert MTB/RIF may be considered as
a follow-on test to microscopy in settings where MDR-TB or HIV is of lesser
concern, especially in further testing of smear-negative specimens. (Conditional recommendation acknowledging
major resource implications.)
In other words, WHO was saying that Xpert MTB/RIF might cost
too much to use in every TB suspect as the initial test, and that, unless there
was a lot of MDR-TB or HIV, programmes should continue to use microscopy to
diagnose the easy smear-positive cases, and then use Xpert MTB/RIF to mop up
Bistline said this was considered in South Africa, before
they chose to offer the test to any TB suspect for reasons of equity.
Another question was whether GeneXpert would be situated
within existing laboratory facilities or placed within the facility so that
point-of-care testing would be available?
“Currently testing is using a more centralised model, but significant
efforts are being invested in appropriate point-of care testing as an extension
of the laboratory network,” Sagie Pillay of the NHLS said at the South African
AIDS Conference in 2011. But for the GeneXpert to be placed into the health
facility, a number of issues would need to be addressed in that context,
- Assay validation
- Quality control material and practices
- Patient, clinician acceptance
- LIS (laboratory information system) interface
with centralised monitoring
- Simplified standard operating
Dr Lesley Scott of NHLS presented on the challenges of
getting various point-of-care test equipment (including a GeneXpert) to work
well together in a primary care clinic, and to report data back to LIS. For
example, the machines each required their own dedicated phone line. Achieving a
similar level of connectivity between various pieces of equipment and the
Laboratory Information System may prove more challenging at primary care
Because many of the benefits of the GeneXpert technology are
driven by its ability to provide rapid diagnosis, Bistline said that South
Africa also considered whether the appropriate placement was at the labs or whether it should be at point of treatment.
“Unfortunately now, the point of care is too expensive”, said Bistline. “It would cost three times as
much to purchase the instruments. That’s because there’s 3800 health facilities
in South Africa that would’ve required a GeneXpert. If we look at an average
clinic placement, it would be a tiny GeneXpert 1 with only one module, and the
clinic would do less than two tests per day, whereas in a laboratory placement
where we’re purchasing GeneXpert 16s, we
would do on average 59 tests per day. This lower volume also drives a higher
cost per test. So not only would the initial investment be more for South
Africa, but the ongoing cost of doing tests for South Africa would be more
MTB/RIF for smear-negative TB in primary health care
Nevertheless, having a GeneXpert on site offers significant
advantages, according to a presentation by Dr Jean Bassett of Witkoppen Health
and Welfare Center, a busy primary care clinic in Johannesburg. In particular
it may have a role in quickly diagnosing TB in smear-negative cases.
The clinic used a different model than the South African
Xpert roll-out. Instead, they followed WHO’s advice, using Xpert MTB/RIF only
after two negative smears on microscopy.
Several components were key to their approach. First, expert
patient-assistants helped patients to locate the various service points within
the clinic. Previously these people had been community volunteers.
Second, to enhance TB infection control, TB sputum was
collected in an outside private TB booth, which allowed maximum sunlight and
air ventilation. The buffer for the Xpert MTB/RIF was added to the sputum
sample outside, and then the test was done on site. This did not require a
highly educated health professional, the person who did it for them had
completed high school and had no formal training. Then the results were reviewed by a team of
clinicians on site.
There were about 200 participants, 72% of whom were HIV-positive,
and 69% of those were on ART. They were screened for symptoms of TB (weight
loss, fever, night sweats, and cough (in this study for two weeks). Two sputa were
collected for smear at the first clinic visit, and the patient was treated with
antibiotics. They were sent for chest x-rays if clinically indicated.
Patients were asked to return about five to seven days
later, for the smear results — because that’s how long the turnaround time
at the microscopy site was at the time. Then, if both smears were negative the
patient was enrolled into the study and further sputum was collected: one for microscopy;
one sputum for culture; and one for Xpert MTB/RIF.
Seven participants were smear positive, 15 were liquid
culture positive, and 16 patients tested positive by Xpert MTB/RIF. Of those
patients who were sent for X-ray about half had symptoms and signs suggestive
of TB. Note, 65% of the patients had sustained symptoms of TB despite
Twenty out of 21 cases of TB were diagnosed, depending on
whether one can have a diagnosis with an Xpert MTB/RIF-positive and culture-negative
Out of the 20 or 21 TB cases, 15 or 16 were diagnosed by a
single positive Xpert, the remainder by culture. Many of the cultures were contaminated or
their results lost. Dr Bassett noticed that the Xpert-positive, culture-negative
patients did not respond to the antibiotics, but 2 out of 5 culture-positive,
Xpert-negative patients did. But these numbers were too small to be
“Xpert available at point-of-care allowed healthcare
workers, at a primary healthcare level, to diagnose TB in smear-negative
patients with 76% sensitivity,” said Dr Bassett, who went on to add that even
though culture was more sensitive if performed correctly, “there are problems
in that turnaround time is long. And in our study 6% of cultures were
contaminated, and 13% of results never arrived at the clinic.”
“I would like to suggest that a targeted approach for the
use of Xpert at point-of-care should be explored further — especially for
highly resource-constrained settings. Specifically we should consider non-resolution of TB symptoms, after a
course of antibiotics; HIV infection; and recent exposure of a patient to TB as
reasons to perform an Xpert,” Dr Basset concluded.
How much would a targeted
Bistline presented an analysis of the costs of using
GeneXpert as a second-line tool to diagnose smear-negative TB.
"We wanted to look at an Xpert algorithm, where we
would use Xpert as a second-line diagnosis after smear-microscopy, and our
standard practice, which is a third sputum smear-microscopy combined with
liquid culture and line-probe assay as needed. In South Africa, if somebody is
culture-positive, we identify whether it is m.TB or non-tuberculous
mycobacteria by using line-probe assay,” she said.
The study compared the cost of the Xpert practice, to
standard practice per outcome – looking at the cost per TB suspect; the cost
per TB case diagnosed; and the cost per patient initiated onto TB treatment.
Liquid culture only costs about $12 a test, so at first it
might appear that GeneXpert will be at a disadvantage.
One disadvantage of culture, however, is that if it does
turn out positive, patients need to be traced to be provided their results, and
to get them on to treatment. Another problem is that 19 of the patients’
specimens were contaminated, or missing.
“This means that 19% of the patients did not receive the
laboratory diagnosis under the standard practice,” said Bistline.
Another issue was the number of active TB cases who received
TB treatment, and when. Fifteen of the 16 Xpert-positive patients started
treatment on the same day they received their results, with the remaining
patient starting treatment the following day.
On the other hand, of the five patients who were
Xpert-negative, but culture-positive, only one started TB treatment within the
course of this study.
“That’s 20% initiation — or 80% lost to initiation, 80%
primary default,” said Bistline. “Is it special to this study? We don’t think
so. Although our numbers were small we had done a baseline study at the same
site. And in the baseline study there was a 72% loss to initiation for
smear-negative, culture-positive. It is
just a fact that when you have to wait four to six weeks to get your culture
results, often times, the patients are not coming back to get onto treatment.”
The cost breakdown:
- Per smear-negative TB suspect, per person
tested, the Xpert MTB/RIF is 87% more expensive.
- Per diagnosed patient: Because of the large
number of missing and contaminated cultures, standard practice doesn’t perform
as well, compared to Xpert MTB/RIF — and so the cost per diagnosed patient is only 51%
more than the standard practice.
- Per TB case diagnosed: Standard practice and Xpert MTB/RIF algorithm
diagnosed very similar numbers of patients, and therefore the costs are similar
to just the number of people tested, with Xpert MTB/RIF being 75% more expensive.
- However, considering one of the more important outcomes, the cost
per smear-negative TB case initiated on to TB treatment, Xpert MTB/RIF here is 65% less
expensive per patient initiated because of the high loss to initiation under
the standard practice.
Bistline then drew the audience’s attention to the WHO’s
conditional recommendation to do smears first, in order to reduce the number of
Xperts. But, “Only 10% of TB
suspects in South Africa are smear-positive – 90% of people are either truly
smear-negative i.e. they don’t have TB or they have smear-negative TB. So 90%
of the people would come through as smear-microscopy screening, into Xpert,”
said Bistline. “Two smears are 80% less expensive than Xpert. So we would save some money by doing smear microscopy
first before Xpert. But you’re only saving it on 10% of the patients.”
“We also have to look at what it costs to save this money
per patient: At what cost to the clinical outcome, and to TB contacts
and increased transmission? It shouldn’t be, in theory, a large cost because
smear doesn’t take a very long time to do — we should have a turnaround time of
24 to 72 hours for smear microscopy. But as we heard in the earlier
presentation, the patients aren’t coming
back, and we’ve seen a median time from first smear to Xpert of 16 days, and
that was those who came back. We didn’t trace in this study all those who
perhaps had a negative smear but didn’t return to the clinic for further
testing,” she said.
But as she mentioned earlier, having this expensive
equipment at a site doesn’t make much sense either. Running just a couple of
tests a day was not a very cost-effective way to use this expensive equipment.
The higher volume run per day, the cheaper the tests become.
“So it may be that rather than using
smear-microscopy as a screening test, if we need to reduce the cost of Xpert MTB/RIF,
and we need to look at making sure enough scale and enough volume of tests are
performed on these instruments. Then we can actually save the same amount of
money, as we would by reducing the number of patients who are using Xpert,” she
“But in conclusion,
the long provider delays in waiting for culture results means that most
smear-negative TB patients are lost to follow-up, prior to TB treatment
initiation under standard practice. The Xpert algorithm does have a higher cost
than standard practice, per suspect tested.
But the Xpert algorithm has a lower cost per TB patient initiated onto
treatment,” she concluded.