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Measuring endpoints in

ZAMSTAR - the Zambian South

African TB and AIDS Reduction

trial

ZAMBART, UNZA

Centre for TB Research, Univ Stellenbosch

CBOH, Zambia

LDHMT, Zambia

City of Cape Town, SA

LSHTM, UK

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Estimated TB incidence

(per 100,000 population)

1000

800

600

400

200

0

TB incidence closely correlated with HIV

prevalence in Africa

0 10 20 30 40

HIV prevalence, adults 15-49y

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DOTS and HIV-Related TB

• DOTS is a critically important strategy for

effective management of TB

• DOTS increases cure rates, reduces

mortality and prevents emergence of drug

resistance

• In the setting of HIV prevalence, DOTS

alone is not sufficient to control TB

incidence

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Gates Foundation Press Briefing on TB and

HIV at the Bangkok AIDS Conference

July 15, 2004

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CREATE Objectives

• Design, implement and evaluate a portfolio of

community-level trials of new strategies

designed to reduce TB incidence in communities

with high HIV prevalence.

• Transform global policies for HIV-related TB

through evidence-based advocacy.

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ZAMSTAR

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ZAMSTAR Study Design

4-arm Community Randomised Trial

• Facility based TB/HIV activities (DOTS,

ProTEST)

– Improved standard of care

• Enhanced Tuberculosis Case Finding (ECF)

– Community level intervention

• Household level TB and HIV combined activities

(HH)

– Household intervention

• Both ECF and HH

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Study embedded in district health

system

• All 24 Communities will have

– DOTS strengthening

– TB/HIV Combined Activities (ProTEST)

– Reporting to Study and National TB Control

• All study communities will have enhanced

monitoring and evaluation using standard

indicators (TB; HIV; TB/HIV) and targets by

evaluation team.

• All interventions will be conducted by study staff

embedded in the district health system working

as additional TB/HIV coordinators

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Household counselling to improve TB

and HIV care and prevention

Household HIV/TB Intervention

1. All TB patients

recruited

2. Asked for

consent and to

ask household for

consent

Visits month

0,1,2,6/8

1. Household members

documented and consent

2. TB and HIV group

education and counselling

3. All HH members

screened for TB

4. HIV+ and children

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Enhancing case-finding by removing

barriers and empowering communities

ECF

Open Access lab

School Intervention

Outreach

1. Recruit additional

microscopists

2. Develop IEC

3. Establish ECF

register

4. QA

1. Develop school

TB/HIV curriculum

2. Twice yearly

intervention in all

schools in intervention

area

3. Establish ECF

register

4. QA

1. Develop

IEC/Outreach activities

2. Weekly Outreach

activities

3. Establish ECF

register

4. QA

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6 TB/HIV

6 ECF

Clinic &

VCT

Clinic &

VCT

HH Vs No HH

Clinic &

VCT

Clinic &

VCT

6 HH

6 ECF+HH

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6 TB/HIV

6 ECF

Clinic &

VCT

Clinic &

VCT

ECF Vs.No ECF

Clinic &

VCT

Clinic &

VCT

6 HH

6 ECF+HH

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Tuberculosis endpoints considered

• Disease

– Notification

– Incidence

–Prevalence

• Infection

–Prevalence

• Age-adjusted

• ARI

– Incidence

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Endpoints chosen

• Primary endpoint – prevalence of culture

positive tuberculosis

– 5000 adults per community sampled to determine the

prevalence after 3 years of the intervention

(n=120,000)

• Secondary endpoints

– Risk of tuberculous infection (measured by TST

conversion) (n=20,000)

– HIV and TB Incidence in households (using blood

spots collected at baseline and year 3) (n=10,000)

– TB, HIV TC & IPT uptake and outcomes

(Standardised, adapted registers used in all sites to

compare uptake, adherence and TB outcomes)

– Stigma (measured among household members)

• Economic evaluation

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Methods – Biostatistical Considerations

• Randomisation

– unmatched

– stratified according to country and age-standardised

prevalence of tuberculin positivity

– constrained according to baseline social surveys,

geography and estimated HIV prevalence

• Analytic Plan

– stratified community randomised study, with factorial

design

– primary outcome will be TB prevalence after 3 years

– odds ratios for interventions versus standard will be

estimated allowing for the community-randomised design.

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Methods – Study Timeline

Year 1 2 3 4 5 6

Site Preparation

Piloting interventions

Baseline TST surveys

Pilot prevalence surveys

Enhanced case-finding

Household Intervention

Monitoring and Evaluation X X X X X X X X X

Household Cohort Measurements X X

Endpoint Prevalence Surveys

Repeat TST surveys

Analysis and Dissemination

17 Mar 2006

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Objectives of prevalence surveys

• Estimate prevalence to check sample size

• Streamline methodology to improve primary

endpoint measurement

• Determine relationship between prevalence, HIV

and health-seeking behaviour

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Prevalence survey sites

South Africa Study

Areas

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Methods 1

• Sampling N=20,000

– Enumeration areas mapped and random order

for sampling generated

• Recruitment

– All households in EA visited and all consenting

adults recruited

• Data collection

– Questionnaire

– Sputum sample (1)

– Oral fluid for HIV (Z only)

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Methods 2

• Positive samples

– All positive samples are traced to the

individual

– The individual is revisited and asked to

produce 2 further sputum samples (spot

and morning)

– CXR is taken on all individuals

• Decision making is according to a

standard algorithm

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Case study 1

MB Linda compound

24 F, coughing >6 months, SOB, fever,

sweating, weight loss & chest pain.

Not been to the clinic.

MGIT +ve after 8 days incubation

Smear 3+, 2 further smears 3+

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Objectives of TST surveys

• Data for randomisation

• Identification of uninfected children

•Liaison with schools

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• Sampling

Methods

– All grade 1 and 2 children (sometimes

grade 3)

– Schools closest to TB Treatment Centre

• Preparation of Schools

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• Fears, Satanism

• Absenteeism

•Line-up

Challenges

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Methods

• Data collection

–Name

– Address (challenge)

–BCG

– Mantoux size

• Final visit

– Letter home with children

– Negative Mantoux – no action

– Positive Mantoux – refer to clinic

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TST frequency distribution differs between

Zambia and South Africa

Zambian mode is

15mm,

South African mode is

17mm

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Using a 15mm cut-off – estimated ARI in South

Africa is >2% while Zambia is

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Age-standardised prevalence of TST

positivity correlates with notification rates in

the 24 communities (R 2 = 0.53)

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Lessons Learned

• About 6-9 meetings are needed in a

community before the TST survey can

start in the schools – very time consuming

• Parent meetings often at night.

• Distribution curves indicate small effect of

BCG and NTM

• Difference between BCG vs. no BCG 1.6%

(12.52% vs. 10.89%; p=0.003)

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Challenge

– How to keep track of 19,804 school

children to measure incidence of

infection for secondary outcome

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Communities -Zambia

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Tuberculosis endpoints considered

• Disease

– Notification – dependent on poorly functioning health

system

– Incidence – hard to measure, sub-clinical or paucisymptomatic

patients, health seeking behaviour

– Prevalence – labour intensive, objective

• Infection

–Prevalence

• Age-adjusted – interpretation of TST difficult

• ARI – sample size even larger

– Incidence – interpretation of TST difficult

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Interferon-based assays

• Do we have a field-friendly, accurate, cheap test

for infection

• Elispot – too laboratory intensive

• Quantiferon 3g intube – declined by funders

(thought to be too expensive and not validated

sufficiently for large studies)

• Is there still a window of opportunity for large

longitudinal studies