Southern Africa out of control

Swaziland

South Africa

Namibia

Botswana

Zimbabwe

Lesotho

Zambia

1990 2007

400

800

1200

P. Godfrey-Faussett, H. Ayles, N. Beyers

Southern Africa

Map Source: Google Earth October 2007

Zambia

Western Cape

Western Cape0 30 Km15

Zambia

0 400 Km

200

A community randomized trial of two interventions delivered to ~1,000,000 people while strengthening the existing health systems

Enhanced Case finding (ECF)

Community Mobilization and sputum collection

School intervention Open Access at the clinic Guiding Principles

▪ Every person able to give sputum within 30 min walk▪ Sputum smear results within 48 hours

Household Intervention (HH)

Using a TB patient as the Gateway to a household at risk of TB and HIV

3 visits (0,2, completion TB treatment)

Group education TB/HIV TB screening HIV testing (group,

couple, individual) Counselling and referral

for care

Actual Trial

Total Population 962,655 6 communities per arm Primary endpoint:

Prevalence of TB ● Enhanced case finding

(ECF) Vs no ECF● Household Intervention

(HH) Vs no HH

Secondary Endpoint: Community level: TB

transmission

TB/HIV at the clinic: 257,698

Enhanced Case Finding: 148,090

Household: 257,729

ECF & Household: 299,138

Prevalence surveys Random sample of adults living in

each of 24 communities Geographically based clustered

sample used Every adult equal chance of being

picked

Respiratory sample collected from every consenting adult and cultured on MGIT

Household enumerated48,395

Eligible Individuals 123,790

No consent from household7,055

Individual Consent90,601

Questionnaire Respiratory sample

Individuals not found or no

consent33,189

Household visited 55,450

HIV test, blood sugar

Field work Flow

Laboratory methods

Sample receipt Samples transported to 5 laboratories (furthest site 800 km) Each sample inoculated on two manual MGIT tubes

● Reduce proportion of contaminated samples● Increase yield

QA: Each batch of samples processed with one positive and negative control

Each laboratory working at maximum capacity (100 per day in each mini-lab, 200 per day in centralised lab)

Isolate identification ZN stain MPB 64 Ag test 16s rRNA gene sequencing done on samples

that were either ZN stain positive or MPB64 positive

Evaluable Culture 64,430

M.tb (16S)884

No TB63,546

Both cultures Contaminated

9,461

Consented 90,601

Batch rejected due to QA failure

16,710

Laboratory Flow

Prevalence of TB

Zambian sites▪ Prevalence 542/100,000 adults (SD 263)▪ Community range 221-1,096/100,000

South African sites▪ Prevalence 2,319/100,000 adults (SD 487)▪ Community range 1489-3054/100,000

TB/HIV @ clinic

770/100,000

(ref)

ECF

1,010/100,000

aRR 1.03   [0.71-1.50]

Household

700/100,000

aRR 0.77  [0.53-1.13]

ECF & Household

880/100,000

aRR 0.89  [0.61-1.29]

TB/HIV @ clinic

ECF

Household

ECF & Household

Prevalence 880/100,00 (Ref)

Prevalence 780/100,000 Adj RR 0.82 (0.64-1.05) P=0.07

TB/HIV @ clinic

ECF

Household

ECF & Household

Prevalence 730/100,00 (Ref)Prevalence 940/100,000 Adj RR 1.09

(0.85-1.40) P=0.48

Transmission endpoint

Longitudinal design

Direct measure of incidence of tuberculous infection

Follow children TST negative at baseline and measure rate of TST conversion

Advantage over repeated cross sectional design in that cumulative incidence would be acquired throughout child’s life and not just for the duration of the interventions

Trial outcome, so favour specificity over sensitivity

2nd TST Survey results

12,075 children seen, assented, injected and read at 2nd survey.

8809 negative at baseline.

Median follow-up period was 4 years (IQR: 3.5-4.7)

.

Enrolle

d at b

asel

ine

Enrolle

d at 2

nd Surv

ey

Cohort

TST conve

rsio

ns0

5000

10000

15000

20000

25000

21,393

12,075

8,809

733

TST conversion rate (per 100 person-years) against baseline prevalence of TB infection in 6-11 year olds

02

46

8T

ST

con

vers

ion

rate

0 5 10 15 20 25Prevalence of TST1 induration 15mm or above (%)

ZA, HH No ZA, HH YesSA, HH No SA, HH Yes

0.13 0.25 0.50 1.00 2.00 4.00 8.00 16.00

Series1

Series1

Series1

Series1 HH impact on prevalence

HH impact on transmission

ECF impact on prevalence

ECF impact on transmission

Risk ratios (for prevalence) and Rate ratios (for transmission)

Risk and Rate ratios for intervention effect at the community level, comparing communities with intervention to those without

Summary

Community randomized trial conducted in 24 communities in Zambia and Western Cape SA

Great need for interventions to reduce TB and HIV

HH intervention reduced the prevalence of culture positive TB by 18%

HH intervention also associated with an important reduction in incidence of tuberculous infection in children

No effect seen from ECF intervention

Future Directions

ZAMSTAR has built a huge team involving researchers, communities and health systems

Platform for the PopART (HPTN 071) study Builds on ZAMSTAR household counselling

intervention to deliver universal coverage of combination prevention and test and treat

Lessons for impact evaluations

Heterogeneity of communities▪ Opportunity for interventions▪ Challenge for trial design▪ TB>HIV

Herd effects▪ TB and HIV intervention trials need to be huge▪ Need to understand transmission networks

HIV incidence similar to TB incidence rates▪ TB and HIV intervention trials need to be huge

ZAMSTAR Team; Communities; Participants; Zambian Ministry of Health; Western Cape Provincial and South African National Department of Heath; CREATE; Bill and Melinda Gates Foundation (Grant No. 19790.01)