Fuad Mirzayev MD, MPH

Laboratories, Diagnostics and Drug Resistance unit, WHO Global TB Programme

Global Forum of Xpert MTB/RIF implementers, 1 May 2014

Xpert MTB/RIF Implementation Manual: Xpert MTB/RIF Implementation Manual: Xpert MTB/RIF Implementation Manual: Xpert MTB/RIF Implementation Manual: selection of patients to test selection of patients to test selection of patients to test selection of patients to test and and and and interpretation of resultsinterpretation of resultsinterpretation of resultsinterpretation of results

May 5, 20142 |

�Expert Group Meeting – Veyrier-du-Lac, France

20-21 May 2013

�WHO commissioned three systematic reviews

� Xpert for the diagnosis of pulmonary TB and rifampicin

resistance in adults

� Xpert for the diagnosis of extrapulmonary TB

� Xpert for the diagnosis of TB in children

�Review of affordability and cost-effectiveness of Xpert

Evidence synthesis for utilityof Xpert MTB/RIF assay

May 5, 20143 |

� Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial

diagnostic test in adults suspected of having MDR-TB or HIV-associated TB (strong recommendation,

high-quality evidence).

� Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial

diagnostic test in children suspected of having MDR-TB or HIV-associated TB (strong

recommendation, very low-quality evidence).

� Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic

test in all adults suspected of having TB (conditional recommendation acknowledging resource

implications, high-quality evidence).

� Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic

test in all children suspected of having TB (conditional recommendation acknowledging resource

implications, very low-quality evidence).

� Xpert MTB/RIF may be used as a follow-on test to microscopy in adults suspected of having TB but

not at risk of MDR-TB or HIV associated TB, especially in further testing of smear-negative specimens

(conditional recommendation acknowledging resource implications, high-quality evidence).

Using Xpert MTB/RIF to diagnose pulmonary TB and rifampicin resistance in adults and children

Updated WHO policy

May 5, 20144 |

� First edition was based on the outcomes of a Global consultation on implementation

and scale-up of the Xpert MTB/RIF assay convened by WHO in December 2010. First

edition served a basis for the update

� New edition released in April 2014 reflects findings from the May 2013 Expert Group

Meeting and the experiences of early implementing countries and technical partners,

including those shared at the three annual Global Forums of implementers held by

WHO in 2011, 2012 and 2013.

� Draft reviewed by the large group of experts from Centers for Disease Control and

Prevention, United States, TB Supranational Reference Laboratories of Australia,

Belgium and Italy, Office of the United States Global AIDS Coordinator, United States,

KNCV, FIND, MSF, South Africa’s National Health Laboratory Service, Indian National

Institute of TB & Respiratory Diseases, Stop TB Partnership and WHO.

Xpert MTB/RIF implementation manual

Technical and operational ‘how-to’: practical considerations

May 5, 20145 |

WHO guidance

May 5, 20146 |

Topics included in the Implementation Manual

� Evidence baseEvidence baseEvidence baseEvidence base

� Positioning Positioning Positioning Positioning the the the the testtesttesttest

� Testing and managing Testing and managing Testing and managing Testing and managing patientspatientspatientspatients

� Selection of individuals to be Selection of individuals to be Selection of individuals to be Selection of individuals to be testedtestedtestedtested

� Interpreting results of Interpreting results of Interpreting results of Interpreting results of XpertXpertXpertXpert

� Case definitions and patient Case definitions and patient Case definitions and patient Case definitions and patient registration registration registration registration

� Practical considerationsPractical considerationsPractical considerationsPractical considerations

� Key prerequisites and actions Key prerequisites and actions Key prerequisites and actions Key prerequisites and actions

� Testing capacityTesting capacityTesting capacityTesting capacity

� Operation and storage Operation and storage Operation and storage Operation and storage conditionsconditionsconditionsconditions

� BiosafetyBiosafetyBiosafetyBiosafety

� Calibration and maintenanceCalibration and maintenanceCalibration and maintenanceCalibration and maintenance

� Quality assuranceQuality assuranceQuality assuranceQuality assurance

� Budgeting guidance Budgeting guidance Budgeting guidance Budgeting guidance

� Monitoring and evaluationMonitoring and evaluationMonitoring and evaluationMonitoring and evaluation

� SOPs for EP specimensSOPs for EP specimensSOPs for EP specimensSOPs for EP specimens

May 5, 20147 |D.

All individuals suspected of having TB(conditional recommendation)

Xpert MTB/RIFXpert MTB/RIFXpert MTB/RIFXpert MTB/RIF

Adults and children at risk of MDR-TB

(strong recommendation)A.

HIV (+) adults and children suspected of having TB

(strong recommendation) B.

Adults suspected of having TB but not at risk of MDR-TB or HIV-TB

(conditional recommendation)

Smear

microscopy

negative C.

Selection of individuals to test

� Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as theinitial diagnostic test in adults suspected of having MDR-TB or HIV-associated TB

(strong recommendation, high-quality evidence).

� Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as theinitial diagnostic test in children suspected of having MDR-TB or HIV-associated TB

(strong recommendation, very low-quality evidence).

� Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initialdiagnostic test in all adults suspected of having TB (conditional recommendationacknowledging resource implications, high-quality evidence).

� Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initialdiagnostic test in all children suspected of having TB (conditional recommendationacknowledging resource implications, very low-quality evidence).

� Xpert MTB/RIF may be used as a follow-on test to microscopy in adults suspected of having TBbut not at risk of MDR-TB or HIV associated TB, especially in further testing of smear-negativespecimens (conditional recommendation acknowledging resource implications, high-qualityevidence).

Xpert Xpert Xpert Xpert MTB/RIF MTB/RIF MTB/RIF MTB/RIF assayassayassayassay

MTB not MTB not MTB not MTB not detecteddetecteddetecteddetected

MTB MTB MTB MTB detected;detected;detected;detected;R sensitiveR sensitiveR sensitiveR sensitive

MTB MTB MTB MTB detected;detected;detected;detected;

R R R R sensitivesensitivesensitivesensitive

� WHO recommended WHO recommended WHO recommended WHO recommended regimen for MDRregimen for MDRregimen for MDRregimen for MDR----TB with TB with TB with TB with HHHH; ; ; ;

� Registration as RRRegistration as RRRegistration as RRRegistration as RR----TBTBTBTB

• WHO recommended WHO recommended WHO recommended WHO recommended firstfirstfirstfirst----line treatment; line treatment; line treatment; line treatment;

• Registration as Registration as Registration as Registration as bacteriologically bacteriologically bacteriologically bacteriologically confirmed TBconfirmed TBconfirmed TBconfirmed TB

If TB still suspectedIf TB still suspectedIf TB still suspectedIf TB still suspectedFurther investigation (CXR, Further investigation (CXR, Further investigation (CXR, Further investigation (CXR, repeat Xpert MTB/RIF, culture, repeat Xpert MTB/RIF, culture, repeat Xpert MTB/RIF, culture, repeat Xpert MTB/RIF, culture,

etc..)etc..)etc..)etc..)

DST to at least DST to at least DST to at least DST to at least R; H; R; H; R; H; R; H; Quinolones; SL Quinolones; SL Quinolones; SL Quinolones; SL injectableinjectableinjectableinjectable

MTB MTB MTB MTB detected;detected;detected;detected;R resistantR resistantR resistantR resistant

Repeat Repeat Repeat Repeat Xpert Xpert Xpert Xpert

MTB/RIF*MTB/RIF*MTB/RIF*MTB/RIF*

In groups with low In groups with low In groups with low In groups with low risk of MDRrisk of MDRrisk of MDRrisk of MDR----TBTBTBTB

MTB MTB MTB MTB detected;detected;detected;detected;R resistantR resistantR resistantR resistant

� Modify Modify Modify Modify MDRMDRMDRMDR----TB treatment TB treatment TB treatment TB treatment based on the DST results; based on the DST results; based on the DST results; based on the DST results;

� Update registrationUpdate registrationUpdate registrationUpdate registration

� WHO recommended regimen WHO recommended regimen WHO recommended regimen WHO recommended regimen for MDRfor MDRfor MDRfor MDR----TB with TB with TB with TB with HHHH; ; ; ;

� Registration as RRRegistration as RRRegistration as RRRegistration as RR----TBTBTBTB

DST to at least DST to at least DST to at least DST to at least H; Quinolones; H; Quinolones; H; Quinolones; H; Quinolones; SL SL SL SL injectableinjectableinjectableinjectable

In groups with high In groups with high In groups with high In groups with high risk of MDRrisk of MDRrisk of MDRrisk of MDR----TBTBTBTB

� Modify Modify Modify Modify MDR MDR MDR MDR ––––TB TB TB TB treatment treatment treatment treatment based on the based on the based on the based on the DST results; DST results; DST results; DST results;

� Update registrationUpdate registrationUpdate registrationUpdate registration

In case of discordance on In case of discordance on In case of discordance on In case of discordance on R result, refer R result, refer R result, refer R result, refer sample for sample for sample for sample for

sequencingsequencingsequencingsequencing

Interpretation of test results

* Done on a fresh sample. If LPA is available at the site and sample is smear positive, LPA can be used for the repeated testing

May 5, 20149 |

Linking parts of the algorithm

� Should be decided by Ministries of Health (MoH) within the context of national plans

for appropriate management of TB, MDR-TB and HIV associated TB, including the: � development of country-specific screening strategies,

� timely access to quality-assured first- and second-line anti-tuberculosis drugs, and

� appropriate care delivery mechanisms.

� The settings and algorithms for using Xpert MTB/RIF should be guided by: � country or region specific epidemiology (TB, HIV and MDR-TB),

� available resources,

� diagnostic tools available in the country and their characteristics and

� anticipated cost-effectiveness.

� Adoption of Xpert MTB/RIF does not eliminate the need for conventional TB

microscopy, culture and DST capacity.

� Microscopy and/or culture remain necessary for monitoring of treatment.

May 5, 201410 |

Fuad Mirzayev mirzayevf@who.int

Acknowledgements:

Laboratory Diagnostics and Drug Resistance unit at Global TB Programme, WHO

Karin Weyer, Fuad Mirzayev, Chris Gilpin, Wayne van Gemert, Jean Iragena, Diego Zallocco, Henriikka Weiss, Denisa Pohancanikova, Fraser Wares, Ernesto Jaramillo, Dennis Falzon, Vineet Bhatia, Linh Nguyen, Lynne Harrop