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)