Scale-up of Xpert MTB/RIF: SA rollout

Reality Check: 2 years later and over 1.45 million tests!

Sebaka Molapo, Dr Leigh Berrie

On behalf of the GeneXpert Team

TB and TB-HIV burden 2011 • ~500,000 new cases and 25,000 deaths

due to TB.

• TB incidence continues to rise (~incidence 993 per 100,000)

• Fuelled by HIV epidemic (largest burden of HIV-infected individuals worldwide (5.6 million in 2011).

• >65% of new TB cases coinfected with HIV

• TB leading cause of death among HIV infected

• High risk populations

– Mining populations 4000/100,000

– Correctional Services 4500/100,0000

• Increasingly smear negative (8-10% positivity prior Xpert), diagnosis made too

late to avert mortality. (Lawn. JID 2011, Corbett,

2003, Holmes, JAIDS 2006

Urgent interventions are needed, one of which has been the need for rapid diagnosis of MTB technology.

TB

TB-HIV WHO Global Tuberculosis Report 2012. Geneva, World Health Organization, 2012 www.who.int/tb/publications/global_report/en/. Accessed on 29 October 2012

•WHO’s Strong Recommendation in December 2010

“The new automated DNA test for TB should be used as the initial diagnostic test in individuals suspected of MDR-TB or HIV/TB” (i.e.Most TB suspects in SA)

•In March 2011, South Africa developed and initiated a National Plan for phased implementation of the technology, as a replacement for microscopy as the initial diagnostic screen for TB suspects

•Using existing microscopy centres facilitated rapid implementation (244 centres)

•Significant support from CDC, Global fund, BMGF, UNITAID, amongst others

•Performed over 1,301 517 tests to date (April 2013), across all 9 provinces

•Significant increase in case detection in suspects (8 to16%) in first year, second year: 14%

•Significant increase in detection of drug resistance (7%)

•Expanded access to correctional services inmates and miners

•Several SA research studies emerging confirm the increase in laboratory detection, reduced time to diagnosis and treatment initiation and a possible reduction in empiric treatment

Background to South Africa’s GeneXpert’s Program

Monthly monitoring

•Data analysis

•Utilization •Errors

Meetings

•Bi-weekly meetings with team and supplier

•Monthly NHLS EXCo

•Quarterly NDoH

•Model review

Commence testing at

sites

•Manage assay version change(Dec2011)

•Manage stock-out in August

•Remote calibration

•Remote connectivity

Initiate sites: 95 to date

125 planned

•LIS installation

•Instrument installation

•Verify instruments

•On-site training /test witness

•Parallel clinic training

Require R&D

•Training material

•SOP •Verification program

•Instrument interface

•Paediatrics •EPTB •POC •Smear negative

Funders engage

•Phase II Instruments

•kit orders •Forecasting •Supplier negotiation

•Clinical algorithm

•Impact study planned

Formed advisory

team (NPP)

•Pilot I (March 2011)

•Phased plan developed

•Algorithm •NTCM model

Discuss with

partners

•Funders •Supplier •Laboratory •Clinical •Economists

NDoH/ NHLS

engage

WHO Dec 2010

South Africa’s implementation process: January 2011: one National Plan

Coordinate efforts, define

priorities

Develop implementation plan, documents

Prepare sites

Build capacity for training (lab

+clinic), support resources

Support data collection and

impact evaluation

USG technical approach for Xpert roll-out only published 28 August 2012

Phased implementation of GeneXpert in SA One National Plan

• Three phases of implementation in microscopy centres

• Phase I: Pilot in high burden districts in 9 provinces

• Phase II: Completion of high burden districts a. Full capacitation of Phase I labs

b. Full capacitation of high burden districts

• Phase III: XTEND Study (Aurum: BMGF funded, RCT) a. Intervention arm

b. Control arm.

c/d. Completion of all sites

• Full financial commitment attained for the National Program originally described, treasury support for test till 2016

• Now Program to be expanded for mines and correctional services with aspects of both surveillance, screening and case finding and Xpert to be used as front-line

Phased implementation Progress Where are we now?

• Phases 1-3b completed; Phases 3c 85%; Phase 3d 53%

• 175 testing centres established (~76% coverage) • 242 instruments: GX4 : 65; GX16-8: 1: GX16 : 135; GX48: 1: GX80-48: 1 • Placement of 7 infinities (Steve Biko, CHB, Leratong, Tshepong, Pelonomi,

Greenpoint, PE): 6 month production time

• 80% coverage except for key populations

• Train-the-Trainer courses conducted

• 100 centres actively reporting on the Remote Connectivity website

• Remote calibration active from November 2012

Courtesy NPP, NHLS

SA: >1.3 million tests, excl. private sector 288 purchased: 3060 modules 50% of global usage

http://who.int/tb/laboratory/GeneXpert_rollout_large.jpg

Current GeneXpert Placements in National Health Laboratory Service (NHLS)

Testing centres: 175 Analysers: 242 Clinic placements: 20 Gx4: 77 Gx16-8: 1 Gx16: 162 GX48: 1 GX80-48: 1

Phase 2

Phase 3

268 labs 244 Microscopy centres 16 DST/LPA

Rollout of GeneXpert sites, with all NDOH Health facilities

GeneXpert Summary 01 March 2011 – 31 May 2013

1,451,361 assays to date nationally (4500-5000/day) 13.94% MTB positive cumulative (started out at 17%) Results demonstrating a downward trend Geographical variation

Decline in TB cases: • improved diagnosis and less empirical treatment • ARV coverage?, • Adequate reporting from clinical side? • Too early to tell?

Province MTB DetectedMTB Not Detecte Test Unsuccessful Total % MTB DetectedEastern Cape 35 083 200 611 6 811 242 505 14.47 Free State 20 192 139 846 710 160 748 12.56 Gauteng 23 354 156 940 5 560 185 854 12.57 Kwa-Zulu Natal 53 709 288 757 13 823 356 289 15.07 Limpopo 11 220 103 165 3 239 117 624 9.54 Mpumalanga 9 220 49 017 2 888 61 125 15.08 North West 12 865 74 021 4 275 91 161 14.11 Northern Cape 10 500 59 372 3 002 72 874 14.41 Western Cape 26 212 135 079 1 890 163 181 16.06 TOTAL 202 355 1 206 808 42 198 1 451 361 13.94

Test Volume Comparisons: 2011 to 2013

Jan Feb Mar Apr May Jun Jul Aug Oct Nov Dec Sept2011 3016 12823 15873 17879 19512 24196 32750 32684 24031 267592012 31547 36897 45356 37443 49297 53602 50747 58226 84821 93277 61769 643712013 90410 98374 116252 119559

0

20000

40000

60000

80000

100000

120000

140000

Num

ber o

f Tes

ts

Rollout to be completed in October 2013; slowed due to management of cartridge supply

Rif Resistance in MTB positive samples Stable RIF resistance rates geographical variation

Current MDR register requires culture confirmation: Will change to include R-R TB

Province Inconclusive Resistant Sensitive No Rif Result Total % Rif ResistantEastern Cape 565 2 452 31 781 285 35 083 6.99 Free State 325 1 207 18 626 34 20 192 5.98 Gauteng 333 1 548 21 383 90 23 354 6.63 Kwa-Zulu Natal 859 4 502 47 810 538 53 709 8.38 Limpopo 163 746 10 174 137 11 220 6.65 Mpumalanga 130 919 8 074 97 9 220 9.97 North West 185 958 11 676 46 12 865 7.45 Northern Cape 150 631 9 422 297 10 500 6.01 Western Cape 348 1 304 24 557 3 26 212 4.97 TOTAL 3 058 14 267 183 503 1 527 202 355 7.05

National Error Rates

-

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

20.00

3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5

2011 2012 2013

% E

RR

% Error Rate: GeneXpert

% RIF Concordance by LPA or DST n=9549 (March 2011-March 2013)

Concordance for Rif Resistance now reaching 90%: Beyong questioning accuracy • Algorithm adherence concerns: ~ 20-30% • Although small numbers E. Cape now deferring to LPA. • Western Cape is our role model: 87% adherence to algorithm, Rif Concordance 96-100% • (only difference: two sputums collected upfront: 1 Xpert, reflex testing done by lab) • KZN and W Cape: greatest number of confirmations: INH positivity: KZN (87.4% INH

resistance); W.Cape: (82%)

Probabilistic matching: No unique identifier for patients in SA

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10

20

30

40

50

60

70

80

90

100

3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4

2011 2012 2013

%NPP GeneXpert Monthly TAT

% Same Day % Next Day % TAT: Same Day or Next Day

% Same Day: Percentage of Xpert samples tested on the day of receipt % Next Day: Percentage of Xpert samples tested a day after receipt % TAT: Same Day of Next Day: Total percentage of Xpert samples resulted either on the same or next day of receipt

Implementation of TRAK(LIS) More remote sites

80-90% result returned in ,48 hours

Summary of country activities: ongoing and new

• Remote connectivity

• Remote calibration

• EQA production

• Publications

• Early impact studies:

– Time to diagnosis

– Time to treatment

• New impact studies

• Costing model

• Algorithm review

• Paediatrics and EPTB

• Formalized Brazil-South Africa-Mozambique collaboration

Cepheid/NHLS Remote Connectivity project

• Operational dashboard for real-time monitoring of results, errors, resistance and positivity rates

• Pre-configured on all newly installed GeneXperts

User Workshop held 5-9th November to improve usability and facilitate design changes, Johannesburg

Audit indicators Module trends: • identify module outliers from

same instrument, same lab over time.

User trends and training needs: • Users with increased rates of

positivity • Users with increased error

rates

Training needs and managing staff turnover

Higher error rates

at first testing

High staff turnover and staff task shifting

Module failure at March 2013

Cepheid remote monitoring tool.

• # tests analysed =348 645

• # modules = 1 335 – Max number results/module = 1 424

– Median number results/module = 197

– Max number errors/module = 137

– Number of errors/day/module = 7

– Problem modules = 101

(>7% error rate)

0%

20%

40%

60%

80%

100%

120%

0 200 400 600 800 1000 1200 1400 1600

Erro

r Rat

e

Number of tests

# Tests vs # Errors

Higher the test number = lower module failure

Problem modules

0-100, 21, 14%

100-200, 41, 27%

200-300, 51, 34%

300-400, 12, 8%

400-500, 11, 7%

500-700, 14, 10%

0-100

100-200

200-300

300-400

400-500

500-700

# days

Time and number of module failure

Total No. of Modules 1888 No of Modules Replaced 150 % Replaced within 2 Yrs. (n=150) 7.94 % Replaced within 1 Yr. (n=125) 6.62

Ẋ Time to Failure 278 Median Time to Failure 219 Max 699 Min 2

NHLS LIS

Overcoming hurdles to rollout Remote Calibration NHLS collaboration with Cepheid

• Calibration cartridges as opposed to swap-out module. • Run cartridge as a normal Xpert assay (21minutes) • Software calibration is performed once the calibration file has been

verified by Cepheid • Calibration key = barcode to be scanned in the calibration software

to activate the calibration. • Phase 1 (June 2012) and 2 (August 2012) study completed • Operational in SA in Nov 2012 • Original annual costs: R58,140,00(quoted costs + travel costs

for current instrument load):R 14,076,000. • MASSIVE SAVINGS

User runs calibration software & loads the calibration cartridges

Cepheid analyzes data

Activation code is provided to user to update calibration

Certificate issued

Customer Service notified for follow-up

Data sent by internet or by CD

Courtesy FIND 201

5 cartridges

Ensuring on-going quality testing

• Verification – Once off or upon instrument placement,

maintenance / module swap-out

– Prove the instrument is “fit-for-purpose”

– Every module tested

• EQA – Proficiency testing of the laboratory staff

– Assurance of instrument performance

– 3 x per annum/per instrument, cost?

• Continuous monitoring through remote connectivity

Verification using DCS

Gous N, Scott L, Prieur R, Kana B, Stevens W, 3rd SA TB Conference, June 2012, South Africa

Manufacture of bulk culture: single cell suspension

Inactivation in Xpert SR buffer (2 hrs), confirmation by MGIT

Quantitfy using flow cytometry: small particle counting (1um)

Calculate bacterial events/ul

Spot onto Whatman paper cards

Send to sites for Gx testing

How do you do verification and EQA with this modular format? No available EQA at time of initiation?

Novel approach using Dried Culture Spots

Scott LE, et al. Dried Culture Spots for Xpert MTB/RIF External Quality Assessment: Results of phase 1 pilot study from South Africa. J Clin Microbiol. 2011 Dec;49(12):4356-60

Expanded to: Kenya, Malawi, Mozambique, Zimbabwe and with AIDS Clinical Trials Group (ACTG) to Brazil, Peru and USA.

Global interest in DCS product

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SD o

f Pro

be A

Number of modules verified

DCS variabiity per batch

average SD for probe A (2.73) across all modules tested

• # modules verified using DCS to date= 1665

• Average SD for probe A Ct = 2.7 • Total number errors = 31 (1.86%)

A multi-centre feasibility study to assess five EQA panels for Xpert in South Africa

First pilot using DCS rolled out in SA (3 panels in 2013)

Collaborative project, NHLS, GLI, FIND, CDC, 2012/2013

Results under review by collaborators

Panel Vircell CDC MMQCI GLI DCS

Qualitative analysis (n=11) Correct result 0 1 0 1 1

Instrument error related to volume 1 1 0 0 0 Cold chain and special packaging

required 1 1 0 1 1

Extra consumables required 1 1 0 0 0 Questionnaire (n=10)

Received in good condition 1 1 1 1 1 SOP clarity 0 1 0 1 1

Easy to open 1 0 1 1 0 Easy to handle 0 0 1 1 1

Easy to rehydrate and dissolves fully 1 1 1* 1* 1 Easy to transfer to Xpert cartridge 1 1 0 1 1

Quantitative analysis

Increased probe Ct SD above pool 1 0 1 0 1 PCR inhibition 1 1 1 1 1

Subtotal 9 9 6 9 9

Scoring System: up for modifications and suggestions

0.0

1.0

2.0

3.0

MTB detected, RIF sensitive (SD across probes and panels)

Vircell

CDC

MMQCI

GLI

DCS

0.01.02.03.04.05.06.0

MTB detected, RIF resistant, across probes and panels

Vircell

CDC

CDC

MMQCI

GLI

DCS

Interest in Ct variability for ensuring Rif call rates

Potential for expanding DCS for other EQA programs like LPA testing Objective: to determine the value of DCS as a potential EQA format for the Hain Line probe assay

N=48 DCS tested

Resuspended in 2ml PBS for 15 minutes

Panel composition x24 MTB Rif resistant and

x24 NTM strains •x8 M.intracellulare

•x8 M.kansasii •x8 M.fortuitum

1ml used for DNA extraction: Genolyse kit

(Hain Lifesciences)

Hain MTBDrplus v2.0 testing

All n=24 correctly identified as M.tb positive,

Rifampicin resistant

1ml residual for repeat testing if required

All N=24 M.tb negative by Hain v2.0

x6 M.intracellulare correctly identified x6 M.kansasii correctly identified x6 M.fortuitum correctly identified

Further Hain CM testing

Automated Platform for Xpert MTB/RIF Verification and EQA data management: www.tbgxmonitor.com

• TBGxMonitor™ was developed to assist in the automated report generation for GeneXpert (MTB/RIF) Verification and EQA programmes.

• EQA Provider Neutral – samples barcoded by expected result for cross compatibility and standardized reporting.

• Currently supports • 200 sites (laboratories and clinics) • 266 instruments • 14 countries (Botswana, Brazil, Haiti, India, Kenya, Malawi, Mozambique, Peru, South Africa, Tanzania, Thailand, USA, Zambia, Zimbabwe

Upload results from laboratory

Central review and release of reports Can be automated fully

New feature: bar-code labels for scanning contains result and panel details.

Cunningham B, Scott L, Molapo S, Gous N, Erasmus L, Stevens W, 3rd SA TB Conference, June 2012, South Africa

TBGxMonitor EQA reports

Summary of country activities: Publications

Summary of country activities: Early impact studies

New impact studies

– XTEND: Aurum/BMGF funded/NHLS: cluster randomized trial Xpert testing sites with/out Xpert to review cost-effectiveness and impact.

– X-Phactor: Xpert MTB/RIF for people attending HIV care: interventional cohort study to guide rational implementation.

– EXIT-RIF: UNC, NC/RTC/WITS/NIH funded/NHLS: Observation study: Rif resistant patients identified arm 1 by culture, arm 2 by Xpert

MSF: Implementing Xpert MTB/RIF in Zimbabwe (S. Van Den Broucke, IAS 2012): •Xpert doubled detection rate; •Increased the no. of lab confirmed TB cases- less empiric diagnosis of TB; •Triples/quadruples the number of MDR –TB diagnosed

RTC in central Karoo region (T,van den Handel: personal communication):

•Xpert increased case detection •Pre-Xpert: 22% cases treated were smear negative, culture negative vs 1% post Xpert . •Pre-Xpert 21% patients initiated in 5 days, post expert 95% initiated in 5 days.

Summary of country activities: Costing models

Significant algorithm simplification required?

Costs of current algorithm for HIV+ Xpert - TB suspects • In 2014, with full implementation of current

Xpert algorithm

– 436,025 TB cases will be notified

– 20,714 will be Xpert- HIV+, culture+ PTB (<5%)

– To diagnose these 20,714 PTB cases, we will do 1,668,607 cultures

– R3,674 per TB diagnosis (overall), R6,885 per TB case diagnosed by culture

• What if we restrict culture testing for those still symptomatic after antibiotics?

– assume 62% still symptomatic at 2nd visit

– 434,928 TB cases notified (missed TB in <1% of cases)

– R2,942 per TB diagnosis (20% reduction)

– annual saving of R322 million

K. Bistline and W. Stevens

Complicated algorithm one of the problems for Linkage to Care

Xpert performance in paediatric TB: Better than smear but not good enough using sputum!

Johannesburg study: Gous N, Scott LE; Khan S; Reubenson G; Coovadia A; Cunningham B; Stevens W. CROI 2012,

Reality of Xpert MTB/RIF at POC for Diagnosing Childhood TB using Raw Sputum

• 67% specimens had below required volume for Xpert testing.

• Sensitivity vs culture = 40%, versus MTB confirmed =66.7%

Rachow et al. 2012

Baseline characteristics Nr of

participants Median

age HIV

infection Specimens

Nicol et al, Lancet ID

2011

452 1.6 years 24% Induced

Rachow et al, CID 2012

164 5.8 years 51% Induced and spontaneous

Zar et al, CID, 2012

535 1.7 years 22% Nasopharyngeal aspirate

Sensitivity and specificity for pediatric TB detection

Sensitivity in C+ (95 CI)

Specificity in C- (95 CI)

Nicol et al, Lancet ID 2011

76% [64-87]

99% [98 - 100]

Rachow et al, CID 2012*

75% [55-89]

100% [99 - 100]

Zar et al, CID, 2012

65%

[53-77]

99%

[98-100]

Sensitivity

FIND, 2012

Miscellaneous (sample types <5)

1%

Miscellaneous (sample types <30)

2% Blood

1%

Tissue 2%

Ascitic fluid 2%

Pus 4%

Fluid 5%

Aspirate 9%

Pleural fluid 10%

FNA 27%

Cerebrospinal fluid 37%

EPTB specimen types received in a high throughput central laboratory, n=6112 received in 6 months (April 2012-Jan 2013

• Median time to diagnosis: lymph node TB – 5 days microscopy – 31 days culture DST

• Median time to treatment initiation – 1 day using Xpert

• Median time for Rif resistance diagnosis – 1 day using Xpert – 47 days using culture/MTBDRplus

EPTB specimens: Xpert Validation, preliminary results (Aug – Jan2013):

(Elizabeth Prentice, Lesley Scott, Gloria Nkuna, Natalie Beylis, Wendy Stevens)

EPTB Findings • Overall sensitivity of Xpert compared to

MGIT=55.9% (CI 48.8; 62.8)

• Absolute number: 159 new cases (18% of total referrals)

3 5 6 13

21 25

39

68

3 6 3

20 14

32 28

96

1 1 0 7 7 11 15

28

0

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60

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100

120

MGIT and Xpert positivity per specimen type

Xpert positive (incl culture contaminated) Culture pos Cul contam

3 6 3 20 14

32 28

96

3 4 6

12 20 22 32

60

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40

60

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100

120

140

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Xpert positivty of MGIT

Cul pos Xpert pos

38%

53% 41%

59%

38%

67% 40% 50%

Cost-effectiveness doesn’t equal

affordability or uptake: linkage to care!

(Clouse, K et al, SAMJ 2012)

• Feasibility and impact of Gx at POC (~2hr test result). – Concerns: Expanding Xpert to POC could result in important patient

benefits but requires substantial strengthening of primary care facilities and investment in human resources (a minimum of two full-time staff required to supervise sputum collection, process sputum, perform assays, document and communicate results for an average of 15 TB suspects daily). Some patients did not receive same day treatment due to specimen preparation times.

Proposed Linkage to Care Project: Possible Laboratory contribution

• We now have a similar situation to HIV program where patients loss to follow up in wellness clinics is high: 40% do not return for CD4 results

• First focus on MDR cases, then drug-sensitive PTB • Development of an m-Health solution from the point where the first

diagnosis is made: sms to clinic sms printer, to clinic co-ordinator, to MDR referral site and weekly results sent to provincial MDR co-ordinator. Can be rules-based output from laboratory system. Additional phone queue from laboratory system

• Assessment of gaps in current system linking diagnosis to patient and then to edr.net network

• Improve training outputs

FITS WITH WHO THINKING ON ADHERENCE AND SMS STRATEGIES

Current Challenges

• Global shortages of cartridges – Situation resolving with deliveries of backorders currently underway – Remains a concern as other countries come on- line – See Cepheid web-site which provides an explanation

• Phased implementation: Incomplete access to testing: two algorithms

in place (smear & GXP) – Becoming less of an issue as access improves

• Non-adherence to algorithm / confusion regarding test requests

– No confirmatory testing for Rif resistant (from 20-30%) – Multiple tests requested on one form – Simplification required – Underestimated training requirements at clinical level on algorithm

• Under-estimated awareness campaign costs • Change in requisition forms, reporting structures • Linkage to Care • R&D requirements: Paediatric Testing, Extra-pulmonary samples

Solutions and Action needed…

• Clinical algorithm: requires urgent review

• Training of both laboratory and clinical staff- massive ramping up required

• Monitor stock situation constantly

• Rolling out of remote connectivity system for instrument performance and continuous quality monitoring to sites

• Finalization of EQA plan: First national EQA pilot gone out

• Remote calibration performance reviewed and acceptable

• Need for electricity, sensitive to huge temperature fluctuations

• HEALTH SYSTEM STRENGTHENING NEEDED: FIRST STEP IN CONTINUUM OF CARE

Most recent NDoH Campaign…Rotary International…..CDC funded vehicle on the move

Xpert MTB/RIF field testing for NDoH campaign and using DCS to verify mobile Gx units.

Acknowledgements • Honorable Minister of Health: Dr Motsoaledi

• NHLS National Priority Program staff : Prof Wendy Stevens

• NDoH: Drs Mametje, Pillay, Mvusi, Barron. Mabope, Nshuti

• Centre for Tuberculosis: Drs N. Ismail. L.Erasmus

• CDC for funding and support

• HERO team, G. Meyer –Rath, K. Bistline, Prof S.Rosen, Dr Billl Macleod

• Right to care: Prof Ian Sanne

• MM&H: Prof Scott, N. Gous, B. Cunningham, Dr E.Prentice

• Centre for TB excellence: Dr Bavesh Khana

• NHLS TB Expert working group: Dr A Whitelaw, Prof M.Nichol

• USAID, South Africa

• FIND: new work on EQA, R&D projects: Heidi Albert, Dr Boehme

• Aurum Institute: Prof G Churchyard, XTEND study and staff

• Bill and Melinda Gates foundation

• Cepheid for new collaboration: regarding remote calibrations and connectivity

• Arnoud and Alex de Nooy: supported my projects over a 15 year period