Xpert MTB/RIF: Evidence, WHO Policy Recommendations · PDF filemetal frame and leather on legs...
Transcript of Xpert MTB/RIF: Evidence, WHO Policy Recommendations · PDF filemetal frame and leather on legs...
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Elizabeth A Talbot MD
Assoc Prof, Dartmouth and Medical Scientist, FIND
Xpert MTB/RIF: Evidence, WHO Policy
Recommendations and Roadmap
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Disclosure
• I have no personal financial conflict of interest to disclose. However, I contract for FIND, which has a contractual relationship with Cepheid
• This agreement calls for FIND to support development work and undertake studies of Cepheid‟s TB diagnostic assay
• In turn, Cepheid is to provide their tests at favorable prices to the public sector in developing countries
• Thanks to C Boehme, CN Paramasivan, L Sundaram and M Perkins at FIND and K Weyer for slides
• Thanks to CORE Group
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TB: Major Cause of
Suffering and Death
• First human case 3400 BC
• Consumption, White Plague,
scrofula, King‟s Evil, pthisis
• England 1815: 1 in 4 deaths
• France 1918: 1 in 6 deaths
• During 20thC, TB killed ~100 million
• In 2009, estimated 9.4 million incident cases, and 1.68 million deaths
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Timothy Cratchit
aka Tiny Tim
• Tiny Tim known based on invalid
son of Dicken‟s friend
• 1997 Excavation at St. Andrew‟s
Church found 19C gravesite
• „„In Memory. Timothy Cratchit. 1839–1884, Beloved Husband of Julia, Father of Robert, and Son of Robert and Martha.‟‟
• Skeletal remains of 40yo man wearing metal frame and leather on legs and back
• PCR confirmed TB**CW Callahan. JID 1997;176:1653–4
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Evolution of TB
diagnostics in
the public
sector
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Evolution of TB
diagnostics in
the public
sector
Fundamental
diagnostic: 1882
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Evolution of TB
diagnostics in
the public
sector
Fundamental
diagnostic: 1882
Fundamental
diagnostic: 2010
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The Slow Road to Microscopy
Diagnosis of TB
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9
Vision is of a world where
everyone will have equitable
access to high quality
diagnosis
Mission is to drive the
development and
implementation of accurate and
affordable diagnostic tests that
are appropriate to patient care
in low-resource settings
About FIND
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Simple Standards for New TB
Diagnostics
• Higher sensitivity than microscopy
– >85% true positive rate
– Not impaired by HIV
• Comparable specificity to microscopy
– >95% true negative rate
• Limited additional workload
• Practicability of use in the field
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FIND‟s Focus in Value Chain
Liaise with funders,
pharmaceutical
and biotech companies,
research institutions, academia
Create network of public and private
partners to create effective tests and
demonstrate their success
Liaise with funders, multi-
lateral agencies, NGOs, health
ministries, and agencies like
GDF and GFATM
WHO policy, market access and distribution
Discovery and research
FIND‟s focusUpstream Downstream
Development Evaluation Demonstration
Development
Facilitate,co-fund,
co-develop
Evaluation
Regulatory-quality
lab & fieldtrials
Demonstration
Large-scaleprojects
measuring feasibility &impact on
disease control programs
Proof of
principle
Product
in box
Efficacy
Data
Effectiveness
Data
WHO
Policy
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TB Diagnostic Testing at Different
Levels of Health System
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New Technologies for Reference Level
• Automated liquid culture and DST
– WHO endorsement 2007
• Rapid species identification
– WHO endorsement 2007
• Line-probe assays for MDR TB
– WHO endorsement 2008
• Noncommercial culture and DST
– MODS and Colour Test
– WHO policy July 2010
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New Technologies for
Microscopy Level
• iLED fluorescent microscopy
– WHO endorsement 2009
– Policy July 2010
• Manual DNA detection
– LAMP (in evaluation)
• Automated DNA detection
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GeneXpert MTB/RIF
• Automated, real-time molecular diagnostic
– PCR technology
– Simultaneous detection of TB and rifampicin
resistance
• Simple process depends on acquiring sputum
• 100 min to result
• No need for biosafety cabinet• For use at district and sub-district
• Modular system– Cartridges for other diseases
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From Bench to Bedside
• WHO Expert Group assessment: 1 Sept 2010
• STAG-TB evaluation: 27 Sept 2010
• WHO Global Consultation: 30 Nov-2 Dec 2010
• WHO Policy announcement: 7 Dec 2010
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How Does Xpert MTB/RIF
Work in the Lab?
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19
5 20 80 500-1000Samples per shift
GeneXpert
Xpert
MTB/RIF
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21
Example of Rif-Sensitive Profile – 5 probes &
SPC show fluorescence
Xpert MTB/Rif Molecular Beacon Assay
Molecular
Beacon
Target
Hybrid
Each probe is labeled with a different fluorescent
dye, permitting simultaneous detection
The PCR target is the 81 bp region of the rpoB gene: 5 probes bind to wildtype, but not mutant target
SPC
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http://www.genexpertinfinity.com/video/video3.htm
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The Evidence for Xpert
MTB/RIF
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Multicenter Evaluation Study
INDIA
HIV 5%
TB (C+) 60%
MDR TB 67%
AZERBAIJAN
HIV 5%
TB (C+) 42%
MDR TB 31%
PERU
HIV 2%
TB (C+) 61%
MDR TB 7%
SOUTH
AFRICA
Cape
Town
Durban
HIV 77% 72%
TB (C+) 39% 13%
MDR TB 10% 9%
5 reference laboratories with high quality gold standard Geographically diverse populations1,730 patients suspected of pulmonary TB or MDR-TB (4,386 samples)
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Single, Direct Xpert: Performance Similar to Solid Culture
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Rifampicin Resistance Detection: Performance Similar to Phenotypic
Standard
Compared to sequencing: 99% sens, 100% spec
98% of RIF resistant cases were confirmed MDR-TB
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Implications of Rifampicin Resistance Testing According to Prevalence
% RMP Resist
TP FP FN TN PPV NPV
1% 9.5 19.8 0.5 970.2 32.4% 99.9%
5% 47.5 19 2.5 931 71.4% 99.8%
10% 95 18 5 882 84.1% 99.4%
15% 142.5 17 7.5 833 89.3% 99.1%
Due to high spec, NPV >99% in settings with both highand low RMP resistance In low RMP resistance settings, PPV is reduced Careful risk assessment in patients
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Operational Considerations of
Xpert MTB/RIF
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9 settings of intended use in 6 countries District/sub-district (3), microscopy centers (3), MDR screening/ER (3)
Diverse lab conditions (temp up to 42C, space, staff background) 7000 TB or MDR-TB suspected patients screened from diverse populations
Manila Philippines
HIV <1%
TB (C+) 20%
MDR TB 54%
Kampala Uganda
HIV 100%
TB (C+) 42%
MDR TB 2% Vellore India
HIV <1%
TB (C+) 10%
MDR TB 7%
Baku Azerbaijan
HIV 6%
TB (C+) 47%
MDR TB 22%
Cape Town South Africa
HIV 77% (K), 30% (P)
TB (C+) 26%
MDR TB 4%
Lima Peru
HIV 3%
TB (C+) 17%
MDR TB 8%
Multicenter Implementation Studies
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Partners and Study DesignLima, Peru INSNTP / DISA IV Lima Este Instituto A. v. Humboldt UPCH
Manila, Philippines Lung InstituteTDF CDC
Cape Town, South AfricaMOH / NTPNHLSMSFUCT
Patient management on Xpert
Vellore, IndiaCentral TB DivisionCommunity Health Dep.Christian Medical College
Kampala, UgandaNRLMakerere UniversityMulago HospitalUniversity of California
Baku, AzerbaijanMOHMOJSTI/Main Medical Dep.
Validation PhaseImplementation
PhaseContinuation
Phase
1 Xpert added to routine examinations;
Culture / DST added as reference standard;
Patient management on smear/culture;
Culture dropped
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Operational Performance and Robustness
Variable Performance / outcome
Indeterminate rate 2.5% and 0.3% after repetition. Culture indeterminate rate 4.7%
DNA contamination events None observed (swabs, neg controls)
Operating and short term storage temperature
High lab temperature = no effect on performance
Training needs 2 days for non-experienced lab techs
User appraisal Less difficult than microscopy; user friendly; user-independent read-out
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Considerations for Implementation
Variable Performance / outcome
Preventive maintenance Annual calibration (logistics and costs)
Storage 2-28°C; cartridges require substantial storage space
Electrical supply and back-up power power outage reported; uninterruptable power supply with UPS (400 VA) for 20 min. Serial car batteries tested
Biosafety requirements Same as smear microscopy*
Waste management As for sputum containers; additional waste volume compared to smear microscopy
*Banada PP., et al. Containment of bioaerosol infection risk by the Xpert MTB/RIF assay and its applicability to point-of-care settings. J Clin Microbiol 2010; 48 (10): 3551-7
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Current Temperature
Recommendations
• Recommended cartridge storage temp 2-28°C
• Max recommended operating temp 30°C
– If exceeds by 5-10°C
o Module becomes unavailable for use
o Any test in process is reported as ERROR
• Once temperature drops to recommended
returns to normal function
• Investigating extending temperatures
– Note similar or lower temperature requirements for
tests currently in use for other diseases
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Current Negotiated Prices for
~150 Countries
• Capital costs > microscopy lab but < culture lab
• GeneXpert GXIV-4 configuration $17,000-$17,500
• MTB/RIF test costs > than single microscopy test
– Per cartridge is $16.86
– Cost of culture/drug susceptibility testing similar to
Xpert MTB/RIF test
• Annual calibration and maintenance $1,400
• Xpert MTB/RIF implementation likely cost-
effective for NTPs*
– Prices < tests such as HIV viral load or CD4+ that
have been successfully rolled out
*Amsterdam Institute of Global
Health and Development
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Rapid Implementation and
Roll-out of Xpert MTB/RIF
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WHO Expert Group Review:Findings
Test accuracy high, single test detecting 91% of culture-confirmed TB patients (99% smear-pos and 80% smear-neg), unaffected by HIV. R resistance detected with 95% sensitivity and 98% specificity;
Time to detection <1day, compared to 17 days (liquid culture); >30 days (solid culture); >75 days (phenotypic DST). Smear-negative TB patients started Rx after 4 days vs 58 days when Xpert not used;
TB and MDR-TB case detection significantly increased, cost-comparison favourable to phenotypic culture and DST; cost-effectiveness highest when used as add-on to microscopy, but impact highest when used as initial diagnostic test in high-risk groups;
Operational findings confirmed robustness, safety, minimal training needs, high user satisfaction. Relatively stable power supply, security against theft, annual validation, adequate storage capacity and waste disposal management required.
Courtesy: Dr. Karin Weyer
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WHO Expert Group Meeting: Grade Summary
Courtesy: Dr. Karin Weyer
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WHO Expert Group Recommendations
Courtesy: Dr. Karin Weyer
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WHO Expert Group Recommendations (continued)
Courtesy: Dr. Karin Weyer
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Collecting Evidence for Scale up
1. Cost and cost-effectiveness of the algorithms in different epidemiological and risk settings 2. Additional yield, sensitivity, specificity, and predictive values3. Impact on treatment and patient management4. Impact on access to care by different socio-economic groups5. Performance of Xpert MTB/RIF in remote and peripheral settings 6. Performance of Xpert MTB/TB in extra-pulmonary and paediatric TB7. Models to engage the private sector and strengthen linkages with national TB programmes
Operational research agenda:
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Mission Accomplished?
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Does it Meet the Simple
Standards for New Diagnostic?
• “Higher sensitivity than microscopy”• For TB, performance similar to culture
• For RIF-res, sensitive and specific
• “Comparable specificity to microscopy”
• “Limited additional workload”
• “Practicability of use in the field”
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TB Diagnostic Testing at Different
Levels of Health System
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New Point-of-Care Technologies
• Antigen detection
– LAM
– Volatile organic compounds
• Antibody detection
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COMMUNITY BASED
Prioritize
problems
Co-invest with industry on existing technologies
Translate platforms into
Point-Of-Care solutions
Prioritize
solutions
Patient-centered approach
Prioritize
technologies
People-centered
approach
Identify / select platforms with potential for integration
Decentralize technologies at community level and institutionalize approach
paradigm shift
Integrated molecular platforms
60%
Disease-centered
approach
FIND Strategic Evolution
5%
35%
Liquid culture - DST
Line-probe assay
Automated molecular detection
Manual DNA amplification
COMMUNITY
• Smear positive
• Smear negative
• DST
• Latent TB infection
TB
viral
load
TB
malaria
HAT
EID/HIV
Leish
Health centers
District level
Regional lab
Reference lab
malaria HIV HAT TB STD M&Ccare
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Reference
Labs
Regional
Labs
R
D
T
R
e
f
e
r
r
a
l
HIV
RDT
HAT TB
sputum collectionSTD
RDT
Mother and child
protection
Pregnancy test
Malaria
RDT
HATScreening-Met
RDT
HIVSymptoms
RDT
+
Referral
Community
Level
District
Level
Second
Generation
RDTs
Positive
Control
Wells
TBSymptoms
Sputum collection
MALARIAR
D
TRx
R
e
f
e
r
r
a
l
• Surveillance
• Reference methods
• Network supervision
• Resolution testing (screening-test
negative, drug resistance)
• Detect/confirm and treat
• Resolution testing (screening-test
negative, drug resistance)
Screening +
primary care
Microscopy
Level
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Summary
• Improved TB diagnosis is cornerstone of
TB control
• Effective use of new technologies requires
– Demonstration at program level
– Implementation at appropriate level of
healthcare system
– Continued commitment toward people-
centered approach to reach those most in
need