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Xpert MTB/RIF Operational c onsiderations Workshop for Early Implementers Hotel Starling, Geneva, Switzerland 7 -

Xpert

MTB/RIF

Xpert MTB/RIF Operational c onsiderations Workshop for Early Implementers Hotel Starling, Geneva, Switzerland 7 - 8

Operational c onsiderations

Workshop for

Early Implementers

Hotel Starling, Geneva, Switzerland 7 - 8 April 2011

Christophe r Gilpin PhD MPH TB Diagnostics and Laboratory S trengthening Unit, Stop TB Department

7 - 8 April 2011 Christophe r Gilpin PhD MPH TB Diagnostics and Laboratory S trengthening

WHO policies 200 7-2011

WHO policies 200 7-2011
WHO policies 200 7-2011 a) early diagnosis & care; b) smea r-negative TB; c) rapid MDR/XDR
WHO policies 200 7-2011 a) early diagnosis & care; b) smea r-negative TB; c) rapid MDR/XDR
WHO policies 200 7-2011 a) early diagnosis & care; b) smea r-negative TB; c) rapid MDR/XDR
WHO policies 200 7-2011 a) early diagnosis & care; b) smea r-negative TB; c) rapid MDR/XDR

a) early diagnosis & care;

b) smea r-negative TB; c) rapid MDR/XDR

detection Sensitivity Year Technolo gy Turnaround time gain Before 2007 ZN microsc opy Solid cultu
detection
Sensitivity
Year
Technolo gy
Turnaround time
gain
Before 2007
ZN microsc opy
Solid cultu re
2-3 days
30-60 days
Baseline
2007
Liquid culture / DST
Rapid specia tion
15-30 days
+10% compared
to LJ
Line Probe A ssay
2008
2-4 days
(1st line, R &
H)
At this time for
S+ only
LED-based FM
1-2 days
2009
+10% compared
to ZN
Conditional
In-house D ST
(MODS, CRI, NRA)
15-30 days
1 st line only
2009
Endorsed
2010
Automated N AAT
(TB, R)
90 minutes
+40% compared
to ZN

Characteristics and labo ratory requirements of WHO-approved technol ogies

Diagnostic tool or method

Laboratory

Time to detection of MDR

Equipment

Consumables

Training

Infrastructure (Risk category)

service

needs

 

level

 
   

Direct

 

Indirect

       

Microscopy

Peripheral

n/a

 

n/a

+

+

Minimal

+

Intermediate

 

Central

Solid culture & DST

Central

n/a

9

- 12 weeks

+

++

Moderate

++

Intermediate

 

Commercial liquid culture & DST

Central

n/a

3 - 5 weeks

+++

+++

Extensive

+++

Intermediate

Non-commercial culture & DST MODS NRA

Central

           

Intermediate

2 – 21 days 6 – 9 days

3

– 4 weeks

++

++

Extensive

++

7

– 11 weeks

+

++

Moderate

++

CLI

n/a

3

– 5 weeks

+

++

Extensive

+++

(liquid culture) 7 – 10 weeks (solid culture)

Line probe

Central

   

+++

++

Moderate

 

assay

Intermediate

SM pos

24-48hrs

++

SM neg

n/a

3

– 5 weeks

+++

Adapted from: World Health Organization, Stop TB Partnership

Adapted from: World Health Organization, Stop TB Partnership

Retooling Task Force, Stop TB Partnership New Diagnostics

Retooling Task Force, Stop TB Partnership New Diagnostics

Working Group. New Laboratory Diagnostic Tools for Tuberculos is Control. 2009. Available at: http://www.stoptb.org/retooling.

Working Group. New Laboratory Diagnostic Tools for Tuberculos is Control. 2009. Available at: http://www.stoptb.org/retooling.

Positioning in tiered health sys tem

•Surveillance •Reference methods •Network supervision
•Surveillance
•Reference methods
•Network supervision
Resolution testing (screening-test negative drug resistance)
Resolution testing
(screening-test negative
drug resistance)
LC / DST 15d/ 30d SC / DST LC / DST 30d / 60d 15d
LC / DST
15d/ 30d
SC / DST
LC / DST
30d / 60d
15d / 30d

In house DST (MODS, NRA, CRI)

Special settings and conditions

Re ference

Lab s

LPA Rif / INH 2d

Regional

Labs

District Level •Screening •Passive case finding •Detect and treat SubDistrict ZN 2-3d Level Microscopy LED
District
Level
•Screening
•Passive case finding
•Detect and treat
SubDistrict
ZN 2-3d
Level
Microscopy
LED FM +10%
Level
•Clinical screening
•Primary care
Community
Level

Integrated NAAT +40% /2h

Level Microscopy LED FM +10% Level •Clinical screening •Primary care Community Level Integrated NAAT +40% /2h

Xpert MTB/RIF does not repl ace 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 co nfirmed by Xpert MTB/RIF and who have rifampicin su sceptible TB disease should be monitored during treatmen t with sputum smear microscopy

Patients with TB and rifampicin resist ance confirmed by Xpert MTB/RIF and placed on MDR-TB tre atment should be monitored by sputum smear and cultu re as per current WHO guidelines

Molecular tests, including Xpert MTB/ RIF, are not suitable for patient monitoring as these tests also detect DNA from non- viable bacilli.

Xpert MTB/ RIF, are not suitable for patient monitoring as these tests also detect DNA from
Xpert MTB/ RIF, are not suitable for patient monitoring as these tests also detect DNA from
Xpert MTB/ RIF, are not suitable for patient monitoring as these tests also detect DNA from

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Xpert MTB/ RIF, are not suitable for patient monitoring as these tests also detect DNA from
Practical consideration s: operational Storage requirements Packaging for cartridges is bulky Requires storage space for

Practical consideration s: operational

Storage requirements

Packaging for cartridges is bulky

Requires storage space for cartridg es (at 2-28C°), shelf life maximum 18 months

Packaging for cartridges is bulky Requires storage space for cartridg es (at 2-28C°), shelf life maximum

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Packaging for cartridges is bulky Requires storage space for cartridg es (at 2-28C°), shelf life maximum

Practical consideration s: operational

Sample preparation and testing

Testing capacity of 4 module system

per working day is 15-20 tests

(depending on working hours), each t est takes approx.2hr

(depending on working hours), each t est takes approx.2hr Mix with specimen. Incubate for 15 minutes
Mix with specimen. Incubate for 15 minutes at room temperature Transfer sample Insert the cartridge
Mix with specimen. Incubate
for 15 minutes at room
temperature
Transfer sample
Insert the cartridge and
start the test
Handling Time =
2 MINUTES

Once cartridge is ready, test sho uld be loaded within 30 minutes.

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and start the test Handling Time = 2 MINUTES Once cartridge is ready, test sho uld

Practical consideration s: operational

Stable electricity supply needs to b e established.

UPS devices 400V or battery pack

needs to b e established. UPS devices 400V or battery pack Can be provided by Cepheid

Can be provided by Cepheid fo r approx. USD 500

Local purchase may be better

Provides only an interim solutio n for short power cuts

A power solution is needed whi ch ensures the tests run until completed

solution is needed whi ch ensures the tests run until completed Generators may be additionally ne

Generators may be additionally ne eded

Fuel as needed

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solution is needed whi ch ensures the tests run until completed Generators may be additionally ne

Practical consideration s: operational

Infrastructure requirements

Xpert MTB/RIF testing require bio-saf ety conditions similar to the conventional sputum

smear microscopy sample processing testing

or

sputum smear microscopy sample processing testing or Has range of ambient operating tem peratures max. 30C°

Has range of ambient operating tem peratures max. 30C°

Consistent with other laboratory e quipment, computers etc.

Need a secure environment to guard against theft

max. 30C° Consistent with other laboratory e quipment, computers etc. Need a secure environment to guard

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max. 30C° Consistent with other laboratory e quipment, computers etc. Need a secure environment to guard

Practical consideration s: operational

Quality control measures (internal)

The sample processing control (SPC) con tains non-infectious spores in the form of a dry spore cake that is included in each cart ridge to verify adequate processing of MTB.

• Verifies that lysis of MTB has occurr ed if the organisms are present

• Verifies the specimen processing is adequate.

• Detects specimen associated inhibiti on of the real-time PCR assay.

• SPC should be positive in a negative

• SPC can be negative or positive in a positive sample.

• SPC passes if it meets assigned acc eptance criteria.

sample and

The Probe Check Control is a check under taken before the start of the PCR reaction. The system measures the fluorescence sign al from the probes to monitor bead rehydration, reaction-tube filling, probe integ rity and dye stability. PCC passes if it meets assigned acceptance criteria.

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reaction-tube filling, probe integ rity and dye stability. PCC passes if it meets assigned acceptance criteria.

Practical consideration s: operational

What testing capacity is necessary? One 4 module system per working day is 15-20 tests (depending on working hours)

5 20 80 500-1000
5 20
80
500-1000

Samples per shift

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One 4 module system per working day is 15-20 tests (depending on working hours) 5 20

Interpretation:

Xpert MTB/RIF - Positive result

Interpretation: Xpert MTB/RIF - Positive result 12
Interpretation: Xpert MTB/RIF - Positive result 12

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Interpretation: Xpert MTB/RIF - Positive result 12

Interpretation:

Xpert MTB/RIF - Positive result

Interpretation: Xpert MTB/RIF - Positive result 13

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Interpretation: Xpert MTB/RIF - Positive result 13

Interpretation:

Xpert MTB/RIF - Negative result

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Interpretation:

Xpert MTB/RIF - Invalid result

Interpretation: Xpert MTB/RIF - Invalid result 15
Interpretation: Xpert MTB/RIF - Invalid result 15

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Interpretation: Xpert MTB/RIF - Invalid result 15

Interpretation:

Xpert MTB/RIF Uninte rpretable results

INVALID

result indicates that the SPC failed . The sample was not properly processed or PCR was inhibited.

ERROR

was not properly processed or PCR was inhibited. ERROR result indicates that the Probe Che ck

result indicates that the Probe Che ck control failed and the assay was aborted possibly due to the reactio n tube being filled improperly, a reagent probe integrity problem was detect ed, or because the maximum pressure limits were exceeded or there was a GeneXpert module failure.

NO RESULT

indicates that insufficient data were stopped a test that was in progress

collected. For example, the operator

.

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RESULT indicates that insufficient data were stopped a test that was in progress collected. For example,

GeneXpert maintenanc e requirements

Maintenance at user level:

Manual Self-Test: Checks for ha rdware failure problems (as necessary).

Cartridge bay disinfection (onc e a month)

Module calibration

bay disinfection (onc e a month) Module calibration Must be performed once a year or every

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 perform s within a set of specifications.

Ensures reading at correct wav elength and temperature ramping are sufficient

Avoids costly repairs and wast ed cartridges

reading at correct wav elength and temperature ramping are sufficient Avoids costly repairs and wast ed

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GeneXpert maintenanc e:

Module calibration requ irements

GeneXpert maintenanc e: Module calibration requ irements 18
GeneXpert maintenanc e: Module calibration requ irements 18

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Xpert MTB/RIF training needs Minimal training is needed Xpert MTB/RIF is a complex yet us

Xpert MTB/RIF training needs

Minimal training is needed

Xpert MTB/RIF is a complex yet us er-friendly technology

Computer training support should be assessed at each implementation site

In-country technical support will b e available from distributors in large implementation sites such as Sout h Africa.

On-line technical support available through skype with the manufacturer

Video demonstrations

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such as Sout h Africa. On-line technical support available through skype with the manufacturer Video demonstrations
Xpert MTB/RIF – Qualit y Assurance What is needed? A panel of unknown samples to

Xpert MTB/RIF – Qualit y Assurance

What is needed?

A panel of unknown samples to be tested using the Xpert MTB/RIF

When should this be done?

At time of installation and follo wing module calibration

How many samples?

Panels should comprise approx . 5 unknown artifical sputum samples spiked with heat killed organisms.

Who will manufacture the QA mate rial?

One SRL will be supported to e stablish and validated panel stability and suitability for use i n the GeneXpert

How will users access the QA mate rial?

A panel set could be shipped w ith each instrument and or modules following calibration by the ma nufacturer

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rial? A panel set could be shipped w ith each instrument and or modules following calibration

Practical consideration s: preferential pricing and eligible countries*

Afghanistan Chile Ghana Libya P akistan Sudan, South
Afghanistan
Chile
Ghana
Libya
P akistan
Sudan, South

Albania

China

Grenada

Lithuania

P alau

Suriname

Algeria Colombia Guatemala Macedonia P anama Swaziland Angola Guinea Madagascar P apua New Guinea Syria
Algeria
Colombia
Guatemala
Macedonia
P anama
Swaziland
Angola
Guinea
Madagascar
P apua New Guinea
Syria
Antigua and
Barbuda
Comoros
Congo, Democratic
Republic of the
Congo, Republic of
the
Guinea-Bissau
Malawi
P araguay
Tajikistan
Argentina
Guinea, Equatorial Malaysia
P eru
Tanzania
Armenia
Costa Rica
Haiti
Maldives
P hilippines
Thailand
Azerbaijan
Cote d'Ivoire
Honduras
Mali
R
omania
Timor-Leste
Bangladesh
Croatia
India
Mauritania
R
ussia
Togo
Belarus
Cuba
Indonesia
Mauritius
R
wanda
Tonga
Belize
Djibouti
Iraq
Mexico
S aint Kitts and Nevis
Tunisia

Micronesia, Federated States of S aint Lucia S aint Vincent & the

GeneXpert System

Benin

Dominica

Jamaica

Turkmenistan

Bolivia Dominican Republic Jordan Moldova G renadines Tuvalu
Bolivia
Dominican Republic
Jordan
Moldova
G renadines
Tuvalu

Bosnia and

Herzegovina

Ecuador

Kazakhstan

Mongolia

S amoa

Uganda

4 module with desktop – 17’000 $ with laptop – 17’500 $

Botswana Egypt Kenya Montenegro S ao Tome and Principe Ukraine
Botswana
Egypt
Kenya
Montenegro
S ao Tome and Principe
Ukraine

Brazil

El Salvador

Kiribati

Morocco

S enegal

Uruguay

Bulgaria Eritrea Korea, North Mozambique S erbia Uzbekistan
Bulgaria
Eritrea
Korea, North
Mozambique
S erbia
Uzbekistan

Burkina Faso

Estonia

Kosovo

Myanmar (Burma)

S eychelles

Vanuatu

Cartridge – 16.86 $ Burundi Ethiopia Kyrgyzstan Namibia S ierra Leone Venezuela Cambodia Fiji Laos
Cartridge – 16.86 $
Burundi
Ethiopia
Kyrgyzstan
Namibia
S ierra Leone
Venezuela
Cambodia
Fiji
Laos
Nauru
S olomon Islands
Vietnam
Cameroon
Gabon
Latvia
Nepal
S omalia
Western Sahara

Cabo Verde

Gambia, The

Lebanon

Nicaragua

S outh Africa

Yemen

Central African Republic Gaza and West Bank Lesotho Niger S ri Lanka Zambia
Central African
Republic
Gaza and West Bank Lesotho
Niger
S ri Lanka
Zambia

Chad

Georgia

Liberia

Nigeria

S udan

Zimbabwe

*as of 19.02.2011

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Gaza and West Bank Lesotho Niger S ri Lanka Zambia Chad Georgia Liberia Nigeria S udan

Practical consideration s: installation and running costs

Sample annual itemized budget

Item Cost Comment A GeneXpert 4 module with laptop (Ex - Works price) $17,500.00 >60%
Item
Cost
Comment
A
GeneXpert 4 module with laptop (Ex -
Works price)
$17,500.00
>60% price reduction compared to EU/US
B
Shipment
$1,000.00
Depends on destination
Equipment
C
Uninterruptible Power Source
$500.00
Local purchase, depends on the market
D
Printer
$200.00
Local purchase, depends on the market
E
Maintenance
Annual calibration costs
$1,800.00
Highest price if done in Cepheid Toulouse
F
Cost per cartridge
$16.86
75% price reduction compared to EU
G
Number of working days per year
250
Number can vary depending on local context
Consumables
H
Average number of tests per
instrument /day
15
Number can vary depending on working hours
I
Number of tests/1 year/ full load 1
instrument
3750
G*H
J
Losses due to damage/incorrect use
(high estimate 10%)
375
10% of I
K
HR costs
Technician annual salary
$5,000.00
Country-specific
L
Training and TA
$5,000.00
Depends on the needs
M
Installation costs
$19,200.00
A+B+C+D
N
Running costs (annual,
1 instrument)
$71,347.50
E+F*(I+J)
O
GRAND TOTAL
$100,547.50
N+M+L+K
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Practical consideration s: operational Summary Doesn’t eliminate need for conventi onal smear, culture, DST Requires

Practical consideration s: operational

Summary

Doesn’t eliminate need for conventi onal smear, culture, DST

Requires stable electricity supply

Has range of ambient operating tem peratures max. 30C°(under revision)

Requires storage space for cartridg es (at 2-28C°), shelf life 18 months

Testing capacity of 4 module system

per working day is 15-20 tests

(depending on working hours, each te st 100 min.)

Requires annual calibration

Xpert MTB/RIF testing require bio-saf ety conditions similar to the conventional sputum smear microsco py sample processing or testing

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require bio-saf ety conditions similar to the conventional sputum smear microsco py sample processing or testing