ACT4 Trial:Strengthening LTBI

Management for Household Contacts: Results and Reflections from the

ACT4 Trial

O L I V I A OX L ADE, P H D

O N B E H A L F O F T H E A C T 4 T R I A L T EA M

F E B R UARY 2 9 T H 2 0 2 0

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Conflict of interest•I have no conflict of interest to declare

•This trial was funded by the Canadian Institute of Health Research

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Overview• Background • Global epidemiology of LTBI

• Targets for Tuberculosis Preventive Treatment (TPT)

• ACT Trial• Trial objectives

• Results (Effectiveness and Cost)

• Reflections

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/

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In many LMIC many questions remain regarding how to best manage and implement TPT

How to find those most at

risk?

How to test them?

How to rule out active

TB? How to help people to

initiate treatment?

How to monitor for side effects?

Household contacts (HHC) who are 5 years and older are often not treated

In most LMIC persons living with HIV (PLHIV) and child household contacts under 5 years of age are prioritized for TPT

24% of population thought to be infected with M. Tuberculosis (Houben et al)

Epidemiology of TB infection and management worldwide

2018 UN High Level Meeting on TB

Declaration was made to scale up TB Preventive Treatment (TPT) to at least 30 million people globally by 2022

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• 6 million people living with HIV (PLHIV)• 4 million children <5 years of age who

are household contacts (HHC) of TB patients

• 20 million other household contacts.

How are we doing so far?

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WHO Global Tuberculosis Report 2019

Target group

Persons initiating TPT

2017 2018

PLHIV 1.0 million 1.8 million

Children under 5

292,182 349,487

Household contacts of other ages

103,344 79,195

How are we doing so far?

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WHO Global Tuberculosis Report 2019

Target group

PLHIV On track to meet targets

Children under 5 20% increase from 2017

Household contacts of other ages

30% decrease from 2017 (2% of UN target)

LTBI Cascade of Care

•Evidence is lacking on how best to expand and strengthen LTBI programs to efficiently initiate treatment for household contacts

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ACT4 Trial

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ACT4 trial objective

•To evaluate the effectiveness of a standardized public health intervention designed to evaluate and strengthen LTBI programs through local decision making

•We aimed to strengthen the LTBI cascade for all household contacts (not just under 5’s or PLHIV)

Study Outcomes:

1) Number of household contacts initiating LTBI treatment per newly diagnosed index patient

2) Costs and cost-effectiveness of the intervention

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Study Design and Population

•Pragmatic cluster-randomised controlled trial

•Randomization was at the level of the health unit (health facilities or groups of health facilities)

24 randomisation units across five countries◦ Canada

◦ Ghana

◦ Benin

◦ Vietnam

◦ Indonesia

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Study Design - Intervention

Included a standardized public health evaluation, local decision making and then strengthening – some of which was standardized (training) but mostly was flexible and tailored to sites based on solutions that each site selected in response to local barriers

1. Evaluation Phase- approximately 6 months

2. Decision Making Phase- approximately 4 months

3. Strengthening Phase- approximately 10 months

At control sites- standard of care for LTBI management

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Study Design I – Evaluation Phase13

Quantitative “LTBI cascade analysis”: ◦ “how many were being lost, at what

step?”

◦ Data collected at baseline from existing data sources retrospectively

Qualitative information about barriers: ◦ “why were the gaps or losses occurring?”

◦ standardised open-ended questionnaires were used to assess practices, knowledge, attitudes and beliefs regarding the key components of the LTBI management system

◦ Costs collected for research purposes (for Cost-effectiveness Analysis)

0%10%20%30%40%50%60%70%80%90%

100%

Expectedcontacts

Identifiedcontacts(STEP1)

CompletedInitial

Assessment(STEP2)

Completedmed eval(STEP3)

StartedLTBI Tx

(STEP4)*

Cu

mu

lati

ve p

erce

nt

(%)

Cumulative percentage of HHC retained in the cascade of care, at

each step

Study Design II - Decision Making Phase

•Information from cascade evaluation was used to identify the important barriers and solution were selected

•The following criteria were used to help select solutions to address barriers: ◦ efficacy from published studies

◦ feasibility and sustainability at participating health facilities

◦ acceptability by health care workers and patients

◦ affordability

•Local staff and stakeholders in each country selected the most appropriate solution(s) to implement at intervention health facilities.

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Flipchart for Health Care worker education

SMS Reminder

ACT4 Registry for in-service training

Non-monetary incentive

Solutions from Indonesia Site

Study Design III – Strengthening Phase

LTBI program strengthening was achieved in five steps:

1) initial clinical training

2) introduction of a paper based registry for contacts

3) ongoing in service training

4) implementation of solutions selected in decision making phase

5) repeat cascade evaluation based on data collected in new LTBI registry

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Registry for LTBI contacts in Brazil

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Analysis of outcomes

Primary outcome:

Calculated the number of household contacts (HHC) initiating treatment per 100 Index patients in each study phase, in Intervention and Control sites

Considered the difference in treatment initiation rates by study phase and between study arms (Rate difference: “difference of differences”)

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RESULTS

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Descriptive Analysis:Proportion of HHC initiating treatment

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Proportion of HHC initiating out of those eligible for

TPT (in strengthening phase)

Control Intervention

Overall (24 sites)

Total 0.28 0.35

Under age 5 0.64 0.68

Age 5 and over 0.12 0.28

Canada (4 sites)

Total 0.48 0.30

Under age 5 0.33 0.39

Age 5 and over 0.49 0.28

LMIC only (20 sites)

Total 0.25 0.36

Under age 5 0.64 0.75

Age 5 and over 0.04 0.28

Primary Study Outcome:Control Health Facilities

(n=12)Intervention Health Facilities

(n=12)

Phase 1 Phase 2Phase 1

Evaluation

Phase 2

Strengthening

Index TB patients 494 549 494 533

Total HHC (Household contacts) identified from Index patients

702 683 807 1672

Total HHC initiating treatment 226 147 122 487

Number of HHC initiating treatment/100 Index patients (95% CI)

30 (11,83) 18 (6, 52) 23 (8, 65) 83 (43, 162)

Rate Difference in number of

HHC initiating treatment/100

Index patients (95% CI)

-12 (-33,10) 60 (4,116)

Difference of differences (rate difference)/100 index patients (95% CI)

72 (10, 134) more HHC started LTBI tx per 100 new Index TB patients

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Results by LMIC Country: Number of HHC initiating treatmentper 100 Index TB patient and difference of differences

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Control Intervention

Adjusted

Difference of

differences per

100 index cases

(95% CI)Country

Phase 1 Phase 2Phase 1

Evaluation

Phase 2

Strengthening

LTBI treatment in Under 5s only

Benin 84 (72, 97) 40 (33, 48) 61 (48, 79) 94 (77, 114) 77 (49, 104)

Indonesia 0 (--, --) 0 (--, --) 3 (0, 17) 13 (4, 41) 11 (0, 22)

LTBI treatment in all ages during ACT4

Ghana 26 (14, 46) 56 (33, 95) 0 (--, --) 364 (292, 453) 333 (247, 419)

Vietnam 0 (--, --) 0 (--, --) 1 (0,26) 106 (50, 223) 104 (55, 154)

Results by Region: Number of HHC initiating treatment per 100 Index TB patient and difference of differences

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Control Intervention Difference of

differences per

100 index cases

(95% CI)CountryPhase 1 Phase 2

Phase 1

Evaluation

Phase 2

Strengthening

Canada 96 (39, 237) 100 (90,112) 73 (11, 547) 72 (35, 152) -11 (-148, 127)

All LMIC

combined

55(-10, 121) 35 (10, 60) 24 (-9, 57) 107(61, 154) 104 (31, 177)

• Number of Index TB patients identified did not differ over study phases

• Significant increase in the number of HHC identified

COST and COST EFFECTIVENESS

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Costing Objectives

To evaluate the costs and cost effectiveness of the "LTBI program evaluation & strengthening" intervention

Costed from the program perspective (ie. for those looking to implement the ACT4 package in other settings/health facilities)

Included costs associated with

1) Implementation of the intervention

2) Health system costs for increased clinical care associated with the intervention

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Cost- Personnel timeImplementation costs included time spent by staff that participated at all levels of strengthening (ie. hours contributed by NTP staff down to hours spent by clinical staff receiving training)

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0

50

100

150

200

250

Benin- Personnel time (hours) for implementation

PI and NTP management personnel time Health Centre- management staff (Jr and senior)

Health Centre- Clinical staff

Evaluation Phase Decision making Phase Strengthening Phase

Cost Effectiveness of intervention

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Total Cost

Cost per 100

Index patients

Additional Contacts

initiating treatment

per 100 index patients

(95% CI) ICER (Range)

Overall $517,422 $82,945 72 (10; 134) $1,348 ($724; $9,708)

LMIC only $315,799 $77,213 104 (31; 177) $742 ($436; $2,491)

ICER= Cost per additional contact initiating treatment

ICER= Cost per additional contact initiating treatment

All costs in 2017 Canadian Dollars

Reflections

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Reflections at LMIC sites

The intervention worked in LMIC and was relatively cost effective

Approach provides a logical framework for implementation that relies on local data and mobilizes key stakeholders

Significant time commitment from different administrative levels (NTP and health system)

Training (ie. In service training) is a long-term investment

Task shifting for clinical activities was seen in study and should be planned for in scale up

Reflections at Canadian sites

Intervention did not change the number of HHC initiating treatment

HHC are already considered a high priority in most high-income settings

It may take more time to make programmatic changes, and to change provider or patient behaviour.

Some programs may be reaching a ceiling for optimal retention rates

Example, if a clinic is achieving 90% retention at each LTBI cascade step, this would result in a cumulative initiation rate of 50% of those eligible

What aspects of the study are the most important for scale up in LMIC?

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Cascade analysis gave important information- identified major areas for improvement; effective for motivating and convincing people of specific and actionable problems

Meetings during decision making phase are essential to engage key stakeholders who will in turn support and prioritize strengthening activities

Registries were useful for reporting, training & surveillance but need to be integrated into existing reporting mechanisms

In-service training (ongoing) was felt to be key to success.

Understanding motivators for health care workers- meeting program indicators/targets, financial incentives, leadership

Study material available from

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https://www.mcgill.ca/tb/projects

Thanks to the ACT4 team!33

Montreal Coordinating Center: Dr. Dick Menzies, Dr. Olivia Oxlade, Dr. Federica Fregonese, Chantal Valiquette, Dr. Hannah Alsdurf

Benin: Dr. Menonli Adjobimey, Lydia Yaha

Canada: Dr. James Johnston, Dr. Victoria Cook, Dr. Dina Fisher, Dr. Richard Long, Dr. Faiz Khan, Dr Leila Barss, Kamilla Romanowski, Nancy Bedingfield and Catherine Paulsen

Ghana: Dr. Joseph Obeng, Daniel Boafo

Indonesia: Dr. Rovina Ruslami, Dr. Panji Hadisoemarto, Isni Aini

Vietnam: Dr. Greg Fox, Dr. Thu Anh Nguyen, Dr. Tran Buu

Brazil: Dr Anete Trajman, Dr Mayara Bastos