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Workshop on the development of National Strategic Plans for TB Control Divonne, France, February 18th 2014

Planning for the implementation of new

diagnostic tests

Dr Christopher Gilpin

Laboratories, Diagnostics & Drug Resistance

WHO Global TB Programme, Geneva

GLOBAL TB PROGRAMME

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Estimated number of cases

Estimated number of deaths

1.3 (1.0-1.6) million* • 74.000 in children

• 410.000 in women

8.6 (8.3-9.0) million • 0.5 m in children

• 2.9 m in women

450.000 (300k-600k)

All forms of TB

Multidrug-resistant TB

HIV-associated TB 1.1 (1.0-1.2) million (13%)

320,000 (300k-340k)

Source: WHO Global Tuberculosis Report 2013 * Including deaths attributed to HIV/TB

The Global Burden of TB -2012

170,000 (102k-242k)

3 million cases missed

Outline

• WHO requirements for evaluation of new TB diagnostics

• Diagnostic pipeline

• Levels of laboratory services

• Diagnostic tools – what is necessary?

• Forecasting and quantification based on country specific edpidemiology

• Maintenance

• Technical assistance

Phase 1

Research and Development

Phase 2 Evaluation and Demonstration

Phase 3

WHO evidence assessment

GRADE

Phase 4 Phased uptake and

collection of evidence for

scale-up

Phase 5 Scale-up and policy refinement

Evidence required for WHO review of diagnostics

Pipeline for new TB diagnostics

PROGRESS AT A GLANCE – 2013 Global Report

Molecular Detection MTB and drug resistance

Alere Q, Alere, USA B-SMART, LabCorp, USA Gendrive MTB/RIF ID, Epistem, UK LATE-PCR, Brandeis University, USA GeneXpert XDR cartridge, Cepheid, USA TruArray MDR-TB, Akkoni, USA INFINITIMTB Assay, AutoGenomics, USA

Nonmolecular technologies TB Rapid Screen, Global BioDiagnostics, USA TBDx, Signature Mapping Medical Sciences, USA

Culture-based technologies BNP Middlebrook, NanoLogix, USA MDR-XDR TB Color Test, FIND, Switzerland /

Imperial College, UK TREK Sensititre MYCOTB MIC plate, Trek

Diagnostic Systems/ Thermo Fisher Scientific, USA

Molecular Detection MTB and drug resistance

iCubate System, iCubate, USA TB drug resistance array, Capital Bio, China NATeasy TB Diagnostic kit, Ustar

Biotechnologies, China Truelab/Truenat MTB, Molbio/bigtec

Diagnostics, India

Molecular Detection MTB +/- drug resistance

TB LAMP, Eiken, Japan Genotype MTBDRsl, Hain Lifescience,

Germany

Volatile Organic Compounds BreathLink, Menssana Research, USA Prototype breathanalyzer device, Next

Dimensions Technology, USA

Nonmolecular technologies Alere Determine TB-LAM, Alere,

USA

Molecular Detection of MTB and drug resistance

Xpert MTB/RIF (pulmonary extrapulmonary and paediatric samples)

Lineprobe assays for the detection of MTB and rifampicin resistance conferring mutations in AFB smear positive sputum or MTB cultures Microscopy

Light and LED Microscopy Same-day -diagnosis

Culture-based technologies Commercial liquid culture systems and rapid

speciation Non-commercial culture and DST (MODS,

NRA, CRI)

Commercial serodiagnostics (ALL MANUFACTURERS)

Interferon-gamma release assays for the detection of active TB (ALL SETTINGS)

Technologies endorsed by WHO • MTB and drug resistance

Xpert MTB/RIF (pulmonary extrapulmonary and

paediatric samples)

Lineprobe assays for the detection of MTB and

rifampicin resistance conferring mutations in AFB smear

positive sputum or MTB cultures

• Microscopy

Light and LED Microscopy

Same-day -diagnosis

• Culture-based technologies

Commercial liquid culture systems and rapid speciation

Non-commercial culture and DST (MODS, NRA, CRI)

WHO recommended diagnostics for use at different levels of laboratory sophistication

*Available at: http://www.who.int/tb/dots/laboratory/policy/en

Biosafety Levels for

TB Laboratories

High TB risk precautions

•Culture, DST, LPA (cultures)

Moderate TB risk precautions

• liquifying (processing) samples

Low TB risk precautions

•Microscopy, Xpert

High TB Risk Precautions

TB containment laboratory

• Double door airlock

• Separate air inlet

• Venting of BSC via thimble

• Aerosol containment

• Negative pressure monitoring

• Uni-directional airflow

• PPE

• Autoclave for waste disposal

• Necessary for performing culture and DST

Why perform culture?

• Culture in Liquid media – up to six weeks – Reference method

• Culture on solid media – up to eight weeks

• Given the diagnostic delay – culture is NOT a good diagnostic tool

• Essential for performing DST to second-line drugs

• Necessary for monitoring patient response to treatment

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1. Liquefaction 2. Sample decanted 3. Decontamination NaOH 4. Vortex 5. Phosphate Buffer

Complexity of performing sputum culture and line probe assays

6. Centrifugation 7. Decant 8. Re-suspend 9. Inoculation

Why perform LPA?

• LPA can be used to detect rifampicin and isoniazid conferring mutations in

– AFB smear positive specimens

– Positive TB cultures

• Results can be available in 24 hrs

• Secondline LPA NOT recommended

• Needs sophisticated laboratory

• Needs good referral mechanisms

• Suitable for high throughput testing at

Central or Regional laboratory level

Additional infrastructure for LPA

1. Laboratory infrastructure to address biosafety and contamination control

1. Containment laboratory for DNA extraction

2. At least two additional rooms needed for DNA pre-amplification and post-amplification processes

2. Appropriately well train staff supervised by experience technologists in molecular biology

3. Multiple pieces of equipment

4. Stringent laboratory protocols needed

– SOPs, Internal QC, External QA,

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Why perform Xpert MTB/RIF

1. Laboratory infrastructure similar to that for microscopy is required

2. Can be de-centralised for testing at lower levels of the laboratory network

3. Suitable for the diagnosis of TB and rifampicin resistance in AFB smear-negative and smear-positive individuals

4. New WHO policy recommendations issued for use in adults children and extrapulmonary TB

Smear neg.

Co

nd

ition

al recom

men

datio

n

All individuals

presumed to have TB

Initial TB

diagnostic test

Smear

microscopy

Xpert MTB/RIF A.

B.

C.

Strong recommendation

All individuals at

risk of MDR-TB (TB

confirmed and TB

suspected)

Xpert MTB/RIF

Xpert MTB/RIF

Strong recommendation

HIV (+) individuals

(or HIV unknown in

high HIV settings)

suspected of

having TB

Conditional recommendation

Adults presumed to

have TB but not at

risk of MDR-TB or

HIV associated TB

Individuals to test using Xpert MTB/RIF

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

initial diagnostic test in adults presumed to have 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 presumed to have 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 presumed to have 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 presumed to have 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 presumed to have 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).

Xpert

MTB/RIF

assay

TB not

detected

TB

detected;

Rif

sensitive

TB

detected;

Rif

sensitive

WHO recommended

regimen for MDR-TB

with INH;

Registration as RR-TB

• WHO recommended

first-line treatment;

• Registration as

bacteriologically

confirmed TB

If TB still

suspected

Further investigation (CXR,

repeat Xpert MTB/RIF,

culture, etc..)

DST to at least RIF; INH;

Quinolones; SL injectable

TB

detected;

Rif

resistant

Repeat

Xpert

MTB/RIF

In groups with low

risk of MDR-TB

TB

detected;

Rif

resistant

Modify treatment based on

the DST results;

Update registration

WHO recommended

regimen for MDR-TB with

INH;

Registration as RR-TB

DST to at least INH;

Quinolones; SL injectable

In groups with high

risk of MDR-TB

Modify treatment

based on the DST

results;

Update registration

In case of discordance

on Rif result refer sample

for sequencing

Interpretation of test results

National strategy and objectives

Planning for infrastructure improvement

Planning for procurement of goods (shelf-life)

Quantifying and forecasting needs

Developing a supply chain (cold) for TB laboratories

Which diagnostics will be used?

At which level - peripheral, district, regional, central?

Which diagnostic algorithm will be

implemented?

What infrastructure needs to be established or

upgraded?

How many labs?

At which level?

Is a specimen transport and referral

system adapted to this new plan?

Procurement planning is directly linked to the

National TB Plan

WHO

TB Planning and budgeting tool

Ready-made framework for planning/budgeting for each component of TB control

Menu driven system

Summary tables and figures automatically produced

Choosing country via menu system selects correct set of epidemiology/ demographic/financial historical data, projections and default values

Guidance available within tool

Application options to enhance user-friendliness

Example: Pakistan

# MDR patients (projections)

What diagnostics are needed for

previously treated patients?

• Need estimates of the

number of previously

treated persons based on

case notifications.

• Need to estimate proportion

of rifampicin resistance

e.g Pakistan

• 14,000 previously treated

persons

• 30% Rifampicin resistance

among previously treated

• 3% Rif resistance among

new cases

14,000 persons require a rapid DST – Xpert MTB/RIF or LPA 4,200 persons (30% of 14,000)(MDR-TB patients) will require culture and DST for secondline drugs Each person will require additional cultures for monitoring response to therapy – up to 12 cultures per person or 50,400 cultures Need many more Xpert tests to detect 3% RIF resistance among new cases – aim for 20% by 2015

What diagnostics are needed for

previously treated patients?

• 14,000 persons require a rapid DST – Xpert MTB/RIF or LPA

• The structure of the laboratory network and referral

mechanism will determine which tests to use where.

• If network is well structured testing can be de-centralised and

test previously treated persons using Xpert

• If only the central level is strong a larger proportion of the

tests could be referred to the central level for testing by

LPA(where capacity already exists)

• A combination of specimen referral for LPA and de-

centralized Xpert testing can be used

What diagnostics are needed for

person with HIV? Indicator Source Remarks

a Annual projected number of

HIV positive (adult and

children) in care at a clinic,

(pre-ART and ART) based on a

baseline figure (2012)

National HIV program

(user entry)

HIV in care includes HIV treatment, i.e.

enrolment in the pre-ART register or in

the ART register once started on ART.

Projections are based on 2012 baseline

data.

b Assumption 1. 100 % of HIV

positive (adult and children) in

care at a clinic are screened

User can modify this

assumption based on

the coverage of TB

screening among PLHIV

The TB screening should be done based

on national TB/HIV guidelines.

c Assumption 2. 15% of HIV

positive (adult and children) in

care at a clinic screened and

with presumptive TB

Assumption based on

expert group decision

for the Spectrum model

This assumption is based on a premise of

rule-in TB in order to increase the

suspicion of having TB in PLHIV.

d Assumption 3. % coverage of

Xpert testing for the 15% HIV

positive presumed to have TB

User entry: based on the

capacity to scale up

Xpert testing

e Estimated number of HIV

positive patients tested with

Xpert

Calculated e= a*b*c*d Default formula appears in costing tool

What diagnostics are needed for

person with HIV?

• Annual projected of the number of HIV positive persons in care

• Assume: 100% screening

• Assume: 15% with presumptive

• Consider % coverage of Xpert

• e.g Africa context

• 100,000 PLHIV in care

• Need to test 20-30% have symptoms of TB

Up to 30,000 persons will require a rapid diagnostic test – Xpert MTB/RIF (depending on Xpert coverage) Assuming 3% MDR-TB among new cases of TB in PLHIV Up to 900 persons (MDR-TB patients) will require culture and DST for secondline drugs Each person will require additional cultures for monitoring response to therapy – up to 12 cultures per person or 10,800 cultures

Planning for facility maintenance

• Annual certification of BSC – Costs vary depending on setting

• Centrifuge maintenance

• GeneXpert module calibration

• Autoclave

• Monitoring integrity of ducted exhaust

• Building maintenance – Need to consider approx. 10% of facility cost needed for

annual maintenance

Technical Assistance

• Collaboration agreements

• Quality assurance

• Appropriate biosafety

• Diagnostic algorithms

• Functional networks

• Rational planning with laboratory experts

Acknowledgements Laboratory, Diagnostics and Drug Resistance unit in the WHO Global TB Programme: Karin Weyer, Fuad Mirzayev, Wayne van Gemert, Jean Iragena, Fraser Wares, Ernesto Jaramillo, Dennis Falzon, Vineet Bhatia, Henriikka Huttunen, Lynne Harrop, Diego Zallocco

gilpinc@who.int

Item Cost Comment

A

Equipment

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

C UPS $1,000.00 Local purchase, price depends on the market

and back up capacity of UPS

D Printer $200.00 Local purchase, price depends on the market,

optional

E Maintenance Annual calibration costs $1,800.00 Highest price if done in Cepheid Toulouse,

when web-based drops to 450USD

F

Consumables

Cost per cartridge $9.98 85% price reduction compared to EU

G Number of working days per

year 250 Number can vary depending on local context

H Average number of tests per

instrument /day 12

Number can vary depending on working

hours

I Number of tests/1 year/ full

load 1 instrument 3000 G*H

J

Losses due to

error/incorrect use (high

estimate 10%)

300 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 $19,700.00 A+B+C+D

N

Running costs

(annual, 1

instrument)

$34,734.00 E+F*(I+J)

O GRAND TOTAL $64,434.00 N+M+L+K

Xpert MTB/RIF – What is needed?