Xpert

Operational considerations
Workshop for Early Implementers
Hotel Starling, Geneva, Switzerland
7 - 8 April 2011
Christopher Gilpin PhD MPH
TB Diagnostics and Laboratory Strengthening Unit, Stop TB Department
Xpert MTB/RIF
Operational considerations
Workshop for Early Implementers
Hotel Starling, Geneva, Switzerland
8 April 2011
Christopher Gilpin PhD MPH
TB Diagnostics and Laboratory Strengthening Unit, Stop TB Department
WHO policies 2007
Year Technology
Before 2007
ZN microscopy
Solid culture
a) early diagnosis & care; b) smear
detection
2007
Liquid culture / DST
Rapid speciation
2008
Line Probe Assay
(1st line, R & H)
2009
LED-based FM
Conditional
2009
In-house DST
(MODS, CRI, NRA)
Endorsed
2010
Automated NAAT
(TB, R)
2007-2011
Technology Turnaround time
Sensitivity
gain
microscopy
culture
2-3 days
30-60 days
Baseline
early diagnosis & care; b) smear-negative TB; c) rapid MDR/XDR
culture / DST
speciation
15-30 days
+10% compared
to LJ
Assay
(1st line, R & H)
2-4 days
At this time for
S+ only
based FM 1-2 days
+10% compared
to ZN
house DST
(MODS, CRI, NRA)
15-30 days 1
st
line only
NAAT
90 minutes
+40% compared
to ZN
Characteristics and laboratory requirements of
WHO-approved technologies
Diagnostic tool
or method
Laboratory
service
level
Time to detection of MDR
Direct Indirect
Microscopy Peripheral
Intermediate
Central
n/a n/a
Solid culture &
DST
Central
Intermediate
n/a 9 - 12 weeks
Commercial Central n/a 3 - 5 weeks
liquid culture &
DST
Intermediate
Non-commercial
culture & DST
MODS
NRA
CLI
Central
Intermediate
2 21 days
6 9 days
n/a
3 4 weeks
7 11 weeks
3 5 weeks
(liquid culture)
7 10 weeks
(solid culture)
Line probe
assay
SM pos
SM neg
Central
Intermediate
24-48hrs
n/a 3 5 weeks
Adapted from: World Health Organization, Stop TB Partnership Retooling Task Force, Stop TB Partnership New Diagnostics
Working Group. New Laboratory Diagnostic Tools for Tuberculosis Control
Adapted from: World Health Organization, Stop TB Partnership Retooling Task Force, Stop TB Partnership New Diagnostics
Working Group. New Laboratory Diagnostic Tools for Tuberculosis Control
Characteristics and laboratory requirements of
approved technologies
Equipment Consumables Training
needs
Infrastructure
(Risk category)
+ + Minimal +
+ ++ Moderate ++
+++ +++ Extensive +++
++
+
+
++
++
++
Extensive
Moderate
Extensive
++
++
+++
+++ ++ Moderate
++
+++
Adapted from: World Health Organization, Stop TB Partnership Retooling Task Force, Stop TB Partnership New Diagnostics
New Laboratory Diagnostic Tools for Tuberculosis Control. 2009. Available at: http://www.stoptb.org/retooling.
Adapted from: World Health Organization, Stop TB Partnership Retooling Task Force, Stop TB Partnership New Diagnostics
New Laboratory Diagnostic Tools for Tuberculosis Control. 2009. Available at: http://www.stoptb.org/retooling.
Positioning in tiered health system
Reference
Labs
Regional
Labs
District
Surveillance
Reference methods
Network supervision
Resolution testing
(screening-test negative
drug resistance)
SubDistrict
Level
Microscopy
Level
Community
Level
District
Level
Screening
Passive case finding
Detect and treat
Clinical screening
Primary care
Positioning in tiered health system
Reference
Labs
LC / DST
15d/ 30d
LPA Rif / INH 2d SC / DST
30d / 60d
LC / DST
15d / 30d
In house DST
(MODS, NRA, CRI)
Special settings and
conditions
Integrated NAAT +40% /2h
LED FM +10%
ZN 2-3d
Xpert MTB/RIF does not replace the need for
conventional smear, culture and DST
Conventional smear, culture, DST will still be required
Required to perform culture and DST for drugs other than
rifampicin
Patients whose diagnosis of TB is confirmed by Patients whose diagnosis of TB is confirmed by
MTB/RIF and who have rifampicin susceptible TB disease
should be monitored during treatment with
microscopy
Patients with TB and rifampicin resistance
MTB/RIF and placed on MDR-TB treatment should be
monitored by sputum smear and culture
guidelines
Molecular tests, including Xpert MTB/RIF, are not suitable for
patient monitoring as these tests also detect DNA from non
viable bacilli.
MTB/RIF does not replace the need for
conventional smear, culture and DST
Conventional smear, culture, DST will still be required
Required to perform culture and DST for drugs other than
is confirmed by Xpert is confirmed by Xpert
susceptible TB disease
should be monitored during treatment with sputum smear
resistance confirmed by Xpert
TB treatment should be
sputum smear and culture as per current WHO
MTB/RIF, are not suitable for
patient monitoring as these tests also detect DNA from non-
5
Practical considerations: operational
Storage requirements
Packaging for cartridges is bulky
Requires storage space for cartridges
months
Practical considerations: operational
storage space for cartridges (at 2-28C), shelf life maximum 18
6
Practical considerations: operational
Sample preparation and testing
Testing capacity of 4 module system per working day is 15
(depending on working hours), each test takes approx.2hr
Mix with specimen. Incubate
for 15 minutes at room
temperature
Transfer sample
Once cartridge is ready, test should be loaded within 30 minutes.
Handling Time = 2 MINUTES
temperature
Practical considerations: operational
of 4 module system per working day is 15-20 tests
(depending on working hours), each test takes approx.2hr
Insert the cartridge and
start the test
7
Once cartridge is ready, test should be loaded within 30 minutes.
Handling Time = 2 MINUTES
Practical considerations: operational
Stable electricity supply needs to be established.
UPS devices 400V or battery pack
Can be provided by Cepheid for approx. USD 500
Local purchase may be better
Provides only an interim solution for short power cuts Provides only an interim solution for short power cuts
A power solution is needed which ensures the tests run until
completed
Generators may be additionally needed
Fuel as needed
Practical considerations: operational
needs to be established.
Can be provided by Cepheid for approx. USD 500
Provides only an interim solution for short power cuts Provides only an interim solution for short power cuts
A power solution is needed which ensures the tests run until
may be additionally needed
8
Practical considerations: operational
Infrastructure requirements
Xpert MTB/RIF testing require bio-safety
conditions similar to the conventional sputum
smear microscopy sample processing or
testing
Has range of ambient operating temperatures Has range of ambient operating temperatures
max. 30C
Consistent with other laboratory equipment,
computers etc.
Need a secure environment to guard against
theft
Practical considerations: operational
safety
conditions similar to the conventional sputum
smear microscopy sample processing or
operating temperatures operating temperatures
Consistent with other laboratory equipment,
Need a secure environment to guard against
9
Practical considerations: operational
Quality control measures (internal)
The sample processing control (SPC) contains non
a dry spore cake that is included in each cartridge to verify adequate processing of
MTB.
Verifies that lysis of MTB has occurred if the organisms are present
Verifies the specimen processing is adequate. Verifies the specimen processing is adequate.
Detects specimen associated inhibition of the real
SPC should be positive in a negative sample and
SPC can be negative or positive in a positive sample.
SPC passes if it meets assigned acceptance criteria.
The Probe Check Control is a check undert
The system measures the fluorescence signal from the probes to monitor bead
rehydration, reaction-tube filling, probe integrity and dye stability.
PCC passes if it meets assigned acceptance criteria.
Practical considerations: operational
contains non-infectious spores in the form of
a dry spore cake that is included in each cartridge to verify adequate processing of
of MTB has occurred if the organisms are present
Verifies the specimen processing is adequate. Verifies the specimen processing is adequate.
Detects specimen associated inhibition of the real-time PCR assay.
SPC should be positive in a negative sample and
SPC can be negative or positive in a positive sample.
SPC passes if it meets assigned acceptance criteria.
ertaken before the start of the PCR reaction.
The system measures the fluorescence signal from the probes to monitor bead
tube filling, probe integrity and dye stability.
PCC passes if it meets assigned acceptance criteria.
10
Practical considerations: operational
What testing capacity is necessary?
One 4 module system per working day is 15
5 20 80
Samples per shift
Practical considerations: operational
4 module system per working day is 15-20 tests (depending on working hours)
11
500-1000
Samples per shift
Interpretation:
Xpert MTB/RIF - Positive result Positive result
12
Interpretation:
Xpert MTB/RIF - Positive result Positive result
13
Interpretation:
Xpert MTB/RIF - Negative result Negative result
14
Interpretation:
Xpert MTB/RIF - Invalid result Invalid result
15
Interpretation:
Xpert MTB/RIF Uninterpretable
INVALID
result indicates that the SPC failed. The sample was not properly
processed or PCR was inhibited.
ERROR
result indicates that the Probe Check control failed and the assay was result indicates that the Probe Check control failed and the assay was
aborted possibly due to the reaction tube being filled improperly, a reagent
probe integrity problem was detected, or because the maximum pressure
limits were exceeded or there was a
NO RESULT
indicates that insufficient data were collected. For example, the operator
stopped a test that was in progress
Uninterpretable results
result indicates that the SPC failed. The sample was not properly
result indicates that the Probe Check control failed and the assay was
16
result indicates that the Probe Check control failed and the assay was
aborted possibly due to the reaction tube being filled improperly, a reagent
probe integrity problem was detected, or because the maximum pressure
limits were exceeded or there was a GeneXpert module failure.
indicates that insufficient data were collected. For example, the operator
stopped a test that was in progress.
GeneXpert maintenance requirements
Maintenance at user level:
Cartridge bay disinfection (once a month)
Manual Self-Test: Checks for hardware failure problems (as
necessary).
Module calibration
Must be performed once a year or every 2000 module runs
Calibration must be performed remotely by manufacturer
Performs a thermal and optical calibration of the module
Why calibration?
Verifies that the system performs within a set of specifications.
Ensures reading at correct wavelength and temperature ramping
are sufficient
Avoids costly repairs and wasted cartridges
maintenance requirements
Cartridge bay disinfection (once a month)
Test: Checks for hardware failure problems (as
Must be performed once a year or every 2000 module runs
Calibration must be performed remotely by manufacturer
Performs a thermal and optical calibration of the module
Verifies that the system performs within a set of specifications.
Ensures reading at correct wavelength and temperature ramping
Avoids costly repairs and wasted cartridges
17
GeneXpert maintenance:
Module calibration requirements
maintenance:
Module calibration requirements
18
Xpert MTB/RIF training needs
Minimal training is needed
Xpert MTB/RIF is a complex yet user
Computer training support should be assessed at each
implementation site
In-country technical support will be In-country technical support will be
implementation sites such as South Africa.
On-line technical support available through
manufacturer
Video demonstrations
MTB/RIF training needs
complex yet user-friendly technology
should be assessed at each
be available from distributors in large be available from distributors in large
implementation sites such as South Africa.
available through skype with the
19
Xpert MTB/RIF Quality Assurance
What is needed?
A panel of unknown samples to be tested using the
When should this be done?
At time of installation and following module calibration
How many samples? How many samples?
Panels should comprise approx. 5 unknown
samples spiked with heat killed organisms.
Who will manufacture the QA material?
One SRL will be supported to establish and validated panel
stability and suitability for use in the
How will users access the QA material?
A panel set could be shipped wi
following calibration by the manufacturer
Quality Assurance
A panel of unknown samples to be tested using the Xpert MTB/RIF
At time of installation and following module calibration
Panels should comprise approx. 5 unknown artifical sputum
samples spiked with heat killed organisms.
Who will manufacture the QA material?
One SRL will be supported to establish and validated panel
stability and suitability for use in the GeneXpert
How will users access the QA material?
with each instrument and or modules
following calibration by the manufacturer
20
Practical considerations: preferential pricing
and eligible countries*
Afghanistan Chile Ghana Libya Pakistan
Albania China Grenada Lithuania Palau
Algeria Colombia Guatemala Macedonia Panama
Angola Comoros Guinea Madagascar Papua New Guinea
Antigua and
Barbuda
Congo, Democratic
Republic of the Guinea-Bissau Malawi Paraguay
Argentina
Congo, Republic of
the Guinea, Equatorial Malaysia Peru
Armenia Costa Rica Haiti Maldives Philippines
Azerbaijan Cote d'Ivoire Honduras Mali Romania
Bangladesh Croatia India Mauritania Russia
Belarus Cuba Indonesia Mauritius Rwanda Belarus Cuba Indonesia Mauritius Rwanda
Belize Djibouti Iraq Mexico Saint Kitts and Nevis
Benin Dominica Jamaica
Micronesia,
Federated States of Saint Lucia
Bolivia Dominican Republic Jordan Moldova
Saint Vincent & the
Grenadines
Bosnia and
Herzegovina Ecuador Kazakhstan Mongolia Samoa
Botswana Egypt Kenya Montenegro Sao Tome and Principe
Brazil El Salvador Kiribati Morocco Senegal
Bulgaria Eritrea Korea, North Mozambique Serbia
Burkina Faso Estonia Kosovo Myanmar (Burma) Seychelles
Burundi Ethiopia Kyrgyzstan Namibia Sierra Leone
Cambodia Fiji Laos Nauru Solomon Islands
Cameroon Gabon Latvia Nepal Somalia
Cabo Verde Gambia, The Lebanon Nicaragua South Africa
Central African
Republic Gaza and West Bank Lesotho Niger Sri Lanka
Chad Georgia Liberia Nigeria Sudan
Practical considerations: preferential pricing
Pakistan Sudan, South
Palau Suriname
Panama Swaziland
Papua New Guinea Syria
Paraguay Tajikistan
Peru Tanzania
Philippines Thailand
Romania Timor-Leste
Russia Togo
Rwanda Tonga Rwanda Tonga
Saint Kitts and Nevis Tunisia
Saint Lucia Turkmenistan
Saint Vincent & the
Grenadines Tuvalu
Samoa Uganda
Sao Tome and Principe Ukraine
Senegal Uruguay
Serbia Uzbekistan
Seychelles Vanuatu
Sierra Leone Venezuela
Solomon Islands Vietnam
Somalia Western Sahara
South Africa Yemen
Sri Lanka Zambia
Sudan Zimbabwe
GeneXpert System
4 module
with desktop 17000 $
with laptop 17500 $
Cartridge 16.86 $
21
*as of 19.02.2011
Practical considerations: installation and
running costs
Sample annual itemized budget
Item
A
Equipment
GeneXpert 4 module with laptop (Ex
Works price)
B Shipment
C Uninterruptible Power Source
D Printer
E Maintenance Annual calibration costs
F Cost per cartridge F
Consumables
Cost per cartridge
G Number of working days per year
H
Average number of tests per
instrument /day
I
Number of tests/1 year/ full load 1
instrument
J
Losses due to damage/incorrect use
(high estimate 10%)
K HR costs Technician annual salary
L Training and TA
M Installation costs
N
Running costs (annual,
1 instrument)
O GRAND TOTAL
Practical considerations: installation and
Cost Comment
GeneXpert 4 module with laptop (Ex-
$17,500.00
>60% price reduction compared to EU/US
$1,000.00
Depends on destination
$500.00
Local purchase, depends on the market
$200.00
Local purchase, depends on the market
$1,800.00 Highest price if done in Cepheid Toulouse
$16.86
75% price reduction compared to EU
$16.86
75% price reduction compared to EU
250 Number can vary depending on local context
15
Number can vary depending on working hours
Number of tests/1 year/ full load 1
3750
G*H
Losses due to damage/incorrect use
375
10% of I
$5,000.00
Country-specific
$5,000.00
Depends on the needs
$19,200.00 A+B+C+D
$71,347.50 E+F*(I+J)
$100,547.50 N+M+L+K
22
Practical considerations: operational
Summary
Doesnt eliminate need for conventional smear, culture, DST
Requires stable electricity supply
Has range of ambient operating temperatures
Requires storage space for cartridges Requires storage space for cartridges
Testing capacity of 4 module system per working day is 15
(depending on working hours, each test 100 min.)
Requires annual calibration
Xpert MTB/RIF testing require bio-safety
conventional sputum smear microscopy sample processing or testing
Practical considerations: operational
need for conventional smear, culture, DST
operating temperatures max. 30C(under revision)
storage space for cartridges (at 2-28C), shelf life 18 months storage space for cartridges (at 2-28C), shelf life 18 months
of 4 module system per working day is 15-20 tests
(depending on working hours, each test 100 min.)
safety conditions similar to the
conventional sputum smear microscopy sample processing or testing
23