43rd Union World Conference on Lung Health November 2012 J2J Lung Health Media Training

Hope in the Pipeline: Virtual Implementation to assess new diagnostic tools

Ivor Langley, Liverpool School of Tropical Medicine, UK Hsien-Ho Lin, National Taiwan University

Agenda
Background Tuberculosis diagnostics - Some challenges and opportunities - How can modelling help? Virtual implementation What is it? - Operational modelling - Transmission modelling - Linking operational and transmission models
Virtual Implementation Case Study from Tanzania Next Steps

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

TB diagnostics some challenges and opportunities

- the challenges for TB diagnosis ACCESS TO DIAGNOSIS Case detection is only around 45-80% in many parts of the world

McNerney R, and Daley P (2011), Towards a point-of-care test for active tuberculosis: obstacles and opportunities, March 2011 | Volume 9 www.nature.com/reviews/micro 3 Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

TB diagnostics some challenges and opportunities

- the challenges for TB diagnosis

SPEED OF DIAGNOSIS Many visits required to provide sputum samples, receive diagnosis, and commence treatment Leads to high diagnostic default rate MDR-TB diagnosis will take a lot longer ~2-4 months

At end of intermediate phases if smear Positive Test For Drug Resistance and put on MDR -TB Treatment if found

Treatment Monitoring

TB Diagnostic Centre

Home

Becomes Sick with cough

Home

Return Home

At end of intermediate phases if smear negative

TB Cure

Health Clinic
TB Suspect

Returning Every 2 wks for Medicines

TB Receive Treatment Diagnostic Medicine Centre

TB Diagnosed

Home

TB Provide Diagnostic Sputum Centre Sample 1

Smear Positive

TB Diagnostic Centre
Smear Negative

No TB Found

Return Home

Home

Home

Return Home

TB Diagnostic Centre
Receive Diagnosis

Home
Return Home

TB Diagnostic Centre
Provide Sputum Sample 2

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

TB diagnostics some challenges and opportunities

- the challenges for TB diagnosis ACCURACY OF DIAGNOSIS Sputum Smear Microscopy only detects around 30 70% of TB cases Accuracy is much worse for HIV+ patients (typically 40% of cases) Secondary techniques such as chest x-ray and short course antibiotics treatment are likely to have high false positive rate 25-50%

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

TB diagnostics some challenges and opportunities

- hope in the pipeline The introduction and scale-up of new tools for the diagnosis of Tuberculosis (TB) in developing countries has the potential to make a huge difference to the lives of millions of people particularly those living in poverty e.g.

Ziehl Neelsen Microscopy

Sensitivity 35-75% Specificity 99-100% Turnaround 24-48hrs Cost per test $1.50 Time per test ~60mins Extra Investment nil

LED Fluorescence Microscopy

Sensitivity 40-80% Specificity 99-100% Turnaround 24-48hrs Cost per test $1.50 Time per test ~55mins Extra Investment $1,250

GeneXpert MTB/RIF
Sensitivity 80-95% Specificity 98-99% Turnaround <12hrs Cost per test $10-$17 Time per test ~2hrs Extra Investment $9k-18k

Point of Care?
Sensitivity ? Specificity ? Turnaround <1hr Cost per test ? Time per test ? Extra Investment ?
6

Small PM, Pai M. (2010), Tuberculosis diagnosis - time for a game change. N Engl J Med. 2010; 363(11): 1070-1.
Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

TB diagnostics how modelling can help?

- the challenge for policy makers

to identify the most effective, sustainable, and appropriate TB diagnostic technology and algorithm for each individual context

. by projecting the impacts on patients, the health system, and the community.

Frank Cobelens, Susan van den Hof, Madhukar Pai, S. Bertel Squire, Andrew Ramsay, Michael E. Kimerling (2012); 7 Which New Diagnostics for Tuberculosis, and When?, National Taiwan of InfectiousNTLP Tanzania Liverpool School of Tropical Medicine, The Journal University, and Diseases, DOI: 10.1093/infdis/jis188

TB diagnostics how modelling can help?

- the projected impacts that policy makers want to understand

Impact Assessment Framework*

EFFICACY - How well does it work? EQUITY - Who benefits and why? HEALTH SYSTEM - Operational effects? SCALE-UP - Impacts of national rollout?

Patients
What is the increase in patients diagnosed and cured? Do HIV+ patients benefit? Will it benefit the poor? Will drug resistant patients benefit? Will it reduce patient visits and waiting time? How much quicker will patients be treated? How many patients will benefit if rolled out?

Health System
How many more TB treatments required? Will it reduce wastage false positive?

Community

How will staff be impacted?

How much will it cost? What is the affect on the number of samples collected? Will it overcome bottlenecks or just move them on? Where to place the new test in the diagnostic algorithm Where to start? How much will it cost? Is it cost effective? What will the impact be on TB incidence and prevalence? Will it contribute to achieving the 2015/ 2050 millennium development goals for TB?

HORIZON SCANNING - How does it compare to other technologies?

Will it mean more patients seek diagnosis?

What if? - New test performance changes, targeted differently, numbers grow or fall?

* Mann G, Squire SB, Bissell K, Eliseev P, Du Toit E, Hesseling A, et al. (2010), Beyond accuracy: creating a 8 comprehensiveevidence base for TB diagnostic tools. Int J University,Lung Dis. 2010; 14(12): 1518-24. Liverpool School of Tropical Medicine, National Taiwan Tuberc and NTLP Tanzania

TB diagnostics how modelling can help?

- complementing trials

Critical evidence is provided by : Laboratory Tests Demonstration Studies Explanatory Trials (Does it work?) Pragmatic Trials (Does it work in normal practice in a particular context?)

Modelling (Virtual Implementation) complements trials by applying the evidence to other contexts to predict impacts
Projecting patient effects across a wide spectrum of measures Projecting health system effects and costs Projecting impacts of scale-up Assessing cost effectiveness and sustainability Projecting TB incidence and other transmission impacts
SB. Squire, ARC. Ramsay, S. van den Hof, KA. Millington, I. Langley, G. Bello, A. Kritski, A. Detjen, R. Thomson, F. Cobelens, GH. Mann, Making innovations accessible to the poor through implementation research, INT J TUBERC LUNG DIS 15(7):862870, doi:10.5588/ijtld.11.0161 Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

Virtual implementation What is it?

- bringing together operational, transmission, and cost effectiveness modelling

OPERATIONAL MODEL Patient & Health System Effects

TRAMSMISSION MODEL Community & Disease Transmission Impacts

WITNESS simulation tool

Berkeley Madonna

Katsaliaki K, Mustafee N (2010), Applications of simulation within the healthcare context. Journal of the Operational 10 Research Society. 2010; doi:10.1057/ University, and NTLP Tanzania Liverpool School of Tropical Medicine, National Taiwanjors.2010.20mall PM,

Virtual implementation What is it?

- operational modelling
1. Individual becomes sick with TB symptoms and is referred to diagnostic centre Individuals home 2. Return for further samples, diagnosis, or first treatment

OPERATIONAL MODEL Patient & Health System Effects

X-Ray 4. Smear -ve sent for X-ray

8. Return for therapeutic monitoring

TB patients home

3. Further sample required or not TB D. Results B. Results A. Sputum sample for testing 5. Start TB treatment Sputum Collection and Diagnosis 9. Continuation of treatment

Central Reference Lab (CTRL)

Microscopy, culture and drug susceptibility testing

Diagnostic Centre Lab

Sample Preparation ZN or LED Microscopy Automated Nucleic Acid Amplification test (aNAAT)

DOTS training TB treatment dispensed

6. Return home with treatment 7. Return for next batch of medication LEGEND Solid Green Lines Individuals with suspected TB Dash/Dot Red Lines -.-.Patients being treated for TB Dash Blue Lines - - Sputum sample pathways

District Diagnostic Centre

C. Drug resistance expected, Transport samples to CTRL

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation What is it?

- operational modelling

OPERATIONAL MODEL Patient & Health System Effects

The operational component of virtual implementation is:A. B. C. D. E. Detailed - to take account of the complex interactions that affect outcomes, cause bottlenecks,
and limit capacity

Visual- to give a representation of the operation that enables non modellers (e.g. policy
makers) to engage with the modelling and assist in its validation not a black box.

Flexible- so the effects of many

new and existing diagnostics options and contexts can be modelled. Also enabling what if? questions to be addressed.

Output rich - so outcomes can be analysed using readily available database and statistical
tools e.g. matching the WHO output requirements for monitoring implementations of Xpert MTB/RIF

Powerful to enable many iterations of the process to be rapidly completed e.g. simulating 510 years of TB diagnosis in under an hour of real time

SB. Squire, ARC. Ramsay, S. van den Hof, KA. Millington, I. Langley, G. Bello, A. Kritski, A. Detjen, R. Thomson, F. Cobelens, GH. Mann, Making innovations accessible to the poor through implementation research, Int J Tuberc Ling Dis 12 Liverpool School 15(7):862870, doi:10.5588/ijtld.11.0161 NTLP Tanzania of Tropical Medicine, National Taiwan University, and

Virtual implementation What is it?

- example screen layout District diagnostic facility

OPERATIONAL MODEL Patient & Health System Effects

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation What is it?

- operational modelling entering input parameters

OPERATIONAL MODEL Patient & Health System Effects

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation What is it?

- example screen layout District diagnostic laboratory

OPERATIONAL MODEL Patient & Health System Effects

SET-UP

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation What is it?

- common features in transmission model

TRAMSMISSION MODEL Community & Disease Transmission Impacts

affect transmission

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation What is it?

- from diagnostic tool to diagnostic pathway

TRAMSMISSION MODEL Community & Disease Transmission Impacts

Diagnostic accuracy is only one step in the whole diagnostic pathway In order to understand the transmission impact of a new tool, we have to understand the operational context where it is implemented

Dowdy DW, Cattamanchi A, Steingart KR, Pai M (2011), Is Scale-Up Worth It? Challenges in Economic Analysis 17 of Diagnosticof Tropical Medicine, National Taiwan University, 8(7): e1001063 Liverpool School Tests for Tuberculosis. PLoS Med and NTLP Tanzania

Virtual implementation What is it?

-expanded transmission component

TRAMSMISSION MODEL Community & Disease Transmission Impacts

Sensitivity

Lin HH, Langley I, Mwenda R, et al. (2011), A modelling framework to support the selection and implementation of new 18 tuberculosis diagnostic tools. Int J Tuberc Lung Dis 15(8):9961004, doi:10.5588/ijtld.11.0062 Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

Virtual implementation What is it?

-transmission modelling -- what about HIV?

TRAMSMISSION MODEL Community & Disease Transmission Impacts

What will be the impact of new TB diagnostics on HIV epidemiology? -- Do we care? Better survival of TB-HIV co-infected patients Increased HIV prevalence Increased cost from expenditure on antiretroviral therapy?

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation What is it?

- incorporating HIV epidemiology

TRAMSMISSION MODEL Community & Disease Transmission Impacts

A Isp S Lf Ls Isn
TB disease States

HIV R

HIV + CD4>350
Test + will treat

Sick2

Sick1

Health center

Sputu m exam

Result s

Test +

Treat

LTFU

Test TB disease States

HIV + CD4<350 ART

HIV + CD4<350 No ART

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation What is it?

-transmission modelling -- overall summary

TRAMSMISSION MODEL Community & Disease Transmission Impacts

Country epidemiology data

TB/HIV natural history

TB/HIV model structure and parameters

Isp S F L Isn R

120 100 80 60 40

project

20 0 2010 2012 2014 2016 2018 2020

Characteristics of diagnostics
Health system context

TB/HIV epidemiology

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation What is it?

- bringing together operational, transmission, and cost effectiveness modelling

Output
OPERATIONAL MODEL Patient & Health System Effects

Time to start treatment Diagnostic default rate Incremental Costs

Input

TRANSMISSION MODEL Community & Disease Transmission Impacts

Input

TB Incidence rate Incremental DALYs averted

Output

Combining the outputs to calculate the Incremental Cost Effectiveness Ratio (ICER)
Lin HH, Langley I, et al. (2011), A modelling framework to support the selection and implementation of new tuberculosis 22 diagnostic tools. Int J TubercMedicine, National Taiwan University, and NTLP Tanzania Liverpool School of Tropical Lung Dis 15(8):9961004, doi:10.5588/ijtld.11.0062

Virtual implementation What is it?

-transmission modelling what models cannot do

Tell the future -- The future is molded by unpredictable events. -- Models seek to simplify a complex world. -- Comparisons are usually more useful than precise point estimates. Tell us which sets of assumptions are right -- Models can use different sets of assumptions to make different projections, but cannot tell which projections are the right ones. Make decisions for people -- Decision-making is a political process; models seek only to bring evidence into that process, and highlight where assumptions are being made.

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Courtesy of Dr. David Dowdy

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- example patient output impact on TB cases cured

ZN Microscopy

LED Fluorescence

LED Same Day New TB Cures Xpert for Sm- HIV+ & Retreat Retreat TB Cures MDR-TB

Xpert for Sm- HIV+ Known & Retreat

Treatment Fail
Xpert for HIV+ and retreat Untreated TB

Xpert for HIV+ known and retreat

Xpert full roll-out 0 10000 20000 30000 40000 50000

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- example patient output impact on time to start treatment

0.00 ZN Microscopy

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

LED Fluorescence

LED Same Day Complete Initial Diagnosis

Xpert for Sm- HIV+ & Retreat Xpert for Sm- HIV+ Known & Retreat Xpert for HIV+ and retreat Xpert for HIV+ known and retreat Xpert full roll-out

Start TB Treatment

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- example health system output impact on TB treatment
ZN Microscopy

LED Fluorescence

LED Same Day

Xpert for Sm- HIV+ & Retreat Test+ve TB Test-ve TB Xpert for Sm- HIV+ Known & Retreat MDR-TB

Xpert for HIV+ and retreat

Xpert for HIV+ known and retreat

Xpert full roll-out 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- example transmission output impact on TB incidence of Xpert vs. ZN microscopy

Decline in TB incidence

4.0% 2.4%

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- example output impact on TB cases over time taking into account transmission

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- example transmission output impact on HIV prevalence of Xpert vs. ZN microscopy
Incremental increase in HIV prevalence

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- example transmission output-impact on ART requirements of Xpert vs. ZN microscopy

16000 14000 12000 10000 8000

6000
4000 2000 0 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- calculating Disability adjusted life years (DALYs) averted

A summary measure of population health that combines:

Years of life lost from premature death (YLL): impact on mortality Years of life lost due to disability (YLD): impact on incidence/prevalence

DALY = YLL + YLD

Includes the health impact on both TB and HIV

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- calculating the Incremental Cost Effectiveness Ratio (ICER)

A measure of the cost effectiveness of a new intervention which enables interventions to be compared and prioritised. ICER = Incremental costs of the intervention Incremental DALYs averted

The ICER can be compared to the

o ICER of alternative interventions in TB diagnostics o ICER of other health interventions (e.g. in malaria diagnosis) o Willingness to pay threshold of countries e.g. some have proposed using the GDP per capita as a threshold (Tanzania $529)

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- Cost effectiveness and sustainability analysis
Incremental Cost Effectiveness Ratio (Cost Effective?)

$200
Xpert for Smknown HIV+
25720

$150
Xpert for known HIV+
32426

NOTE: The size of the circle and the number in the circle represent the benefits measured in DALY's averted per year of the new tool relative to LED fluorescence microscopy (Benefit)

$100

Xpert Sm- & HIV+ 46970

Xpert All HIV+

Xpert for all suspects

$50
LED

LED

Same Day LED

72098

161622

$0

60445

-$500,000

$500,000

$1,500,000

$2,500,000

$3,500,000

$4,500,000

-$50
Additional Annual Cost to Health Service (Sustainable?)

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual implementation Case Study Tanzania

- Summary Virtual implementation for TB diagnostics in Tanzania will help: guide where to implement Xpert MTB/RIF guide which algorithm to use with Xpert MTB/RIF guide which alternatives to Xpert to use in districts where Xpert rollout is currently unsustainable evaluate future tools for TB diagnostics as they become available.

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Virtual Implementation
the next steps Tanzania Finalise analysis of scale-up of the options including additional ART costs and sensitivity analysis Consider which centres should be priority for Xpert implementation and which algorithms Implement virtual implementation tool in the NTLP Wider Application Apply the models to other settings Develop models for MDR-TB diagnosis Publications Peer reviewed publication Brochure Treat TB Symposium 15th November- 5pm Conf Hall 1
Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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Acknowledgment
USAID Ya Diul Mukadi Tanzania NTLP Saidi Egwaga Basra Doulla Raymond Shirima Riziki Kisonga Malawi MOH Reuben Mwenda The Union (Treat-TB) I.D. Rusen Anne Detjen

Liverpool School of Tropical Medicine Bertie Squire Kerry Millington Harvard School of Public Health Ted Cohen Megan Murray Lanner Group Geoff Hook

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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ANY QUESTIONS?

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Virtual implementation What is it?

-what is modelling?
A model is a simplified representation of a complex system

The more realistic (complex) the better?

Liverpool School of Tropical Medicine, National Taiwan University, and NTLP Tanzania

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