PopART: Cluster randomised trial of the impact of a combination prevention package
including early antiretroviral treatment on population-level HIV incidence in Zambia and
South Africa
Rationale
HIV prevalence and incidence remain at a very high level in many parts of Southern Africa and
there is an urgent need for more effective prevention measures. Mathematical models have
shown that universal voluntary HIV counselling and testing, with the offer of immediate
antiretroviral treatment for those testing HIV-positive, has the potential to achieve substantial
reductions in HIV incidence at population level. Testing the effectiveness of this strategy, in
combination with proven preventive interventions, is a key global health priority.
Study design
A cluster randomised trial will be conducted in 24 clusters in Zambia and South Africa, both
countries with severe generalised HIV epidemics. The cluster will be a community with a total
population of at least 25,000, defined as the catchment area of specified health facilities through
which services can be delivered. Of the 24 clusters, 8 will be randomly allocated to receive the
PopART HIV combination prevention programme (Arm A, see below for details); 8 will receive
the PopART programme but with treatment only offered to those already eligible according to
national guidelines (Arm B); and the remaining 8 will continue to receive current standard of
care and act as comparison communities (Arm C), to control for secular changes in HIV
incidence.
The 24 communities used for this trial will be the ZAMSTAR trial communities. These
communities have been working with us for the past 6 years and we have good community
relationships, active community advisory boards and the necessary infrastructure in place or
readily developed. In addition we have unique community level estimates of HIV prevalence,
HIV testing uptake, ART uptake and circumcision data for each community and this will allow
us to match communities to reduce the inter-cluster variation. We also have comparable
estimates of HIV incidence in a selected group of households (households of newly diagnosed
TB cases) in each of these communities.
A random sample of 2,500 adults will be selected from the general population of each cluster (a
total of 60,000 across all 24 clusters) and followed up for 2 years to measure the impact of the
intervention on HIV incidence.
PopART intervention
This will consist of:
 Intensive programme of HIV VCT, involving house-to-house visits and testing in the home
or at special mobile units. Testing will be repeated at annual intervals.
 Offer of male circumcision (MC) to all HIV-negative men who come forward for testing
(MC will also be provided to any HIV-infected men who request it).
 Counselling on risk reduction and condom provision will be provided as part of the VCT
programme.
 Offer of immediate ART to all those testing HIV-positive either through the mass testing
programme or through any other testing service (PICT, ANC, stand-alone VCT services
etc.).
We recognise that there are concerns about the feasibility of universal ART and its additional
benefit over combination prevention, which is why we would include a third arm (Arm B)
which would include all of the above combination package but with provision of ART according
to prevailing national guidelines in Zambia and South Africa (currently defined as CD4 count <
350 cells/mm3 or WHO stage 3 or 4).
In the control arm (Arm C) HIV testing will be conducted as is current standard of care in that
community so will consist of a combination of PICT, ANC and stand-alone VCT approaches.
Individuals who are found to be HIV positive will be referred for care according to national
guidelines and HIV-negative men will be encouraged to access male circumcision again
according to national guidelines. PMTCT services will be strengthened in all three study arms.
Impact evaluation
To measure the impact of the intervention, a population cohort consisting of a random sample of
2,500 adults aged 18-44 years will be selected from the general population of each cluster (a
total of 60,000 across all clusters). A baseline survey of the cohort will be carried out at the time
the intervention is initiated in the intervention clusters, to check the comparability of the
intervention and control arms. Follow-up surveys of the cohort will be carried out after 1 and 2
years and used to measure the impact of the intervention on HIV incidence and other outcomes.
In Arms A and B, a patient cohort, consisting of a sample of HIV-infected individuals who are
detected through the testing programme, will also be followed up to measure process and other
variables.
Primary and secondary outcomes
The primary outcome will be HIV incidence over 2 years in members of the population
cohort who are HIV-negative at baseline, and will be compared in the intervention and
control clusters to measure the population-level effectiveness of the PopART intervention.
Secondary outcomes will also be measured in the population cohort and compared between
the intervention (Arms A and B) and control (Arm C) clusters. These will include:
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Reported sexual risk behaviour, to test for potential risk disinhibition and to help fit
mathematical models
Measures of HIV-related stigma carried out as part of the qualitative research
Community viral load, obtained by measuring HIV plasma viral load in cohort members
who are HIV-positive at the follow-up survey
Proportion of pregnant women who receive effective PMTCT services
We will also measure the incidence of active TB through clinic-based surveillance; and
clinical events including adverse events and other treatment outcomes Additional data will be
examined on health facility workload across the different arms of the study using enhanced
clinic registers.
Process variables to be measured in the intervention clusters will include:
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Proportion accepting HIV testing and re-testing
Proportional uptake of male circumcision among men testing HIV-negative
Proportion of those testing HIV-positive started on ART within 3 months
Proportion of those commencing ART retained on treatment and virally suppressed after
12 months
Proportion of those patients not virally suppressed after 12 months who have genotypic
evidence of drug resistance
Sample size
Preliminary mathematical modelling has shown that the full intervention can be expected to
reduce HIV incidence in adults by 50-60% over two years. With 8 matched triplets of clusters
and a cohort of 2,500 adults in each cluster followed up for 2 years, assuming a baseline HIV
prevalence of 15%, loss to follow-up over 2 years of 20%, and a between-cluster coefficient
of variation of 0.20, the trial will have 98% power of detecting a 50% impact and 88% power
of detecting a 40% impact, if HIV incidence is 1.0/100py . There will also be 87% power of
detecting a difference between Arms A and B, if immediate initiation of ART increases the
impact from 30% to 60%.
Other research components
Qualitative research will be carried out to examine the acceptability of the intervention and
effects on behaviour and community-level HIV-associated stigma. At the end of the testing
campaign in each community, random samples of individuals who accept or decline testing
will be interviewed to explore the reasons for their decisions. Similarly random samples of
HIV-positive patients who are offered immediate ART and who accept or decline treatment
will be interviewed to explore the reasons for their decisions. Finally, we will interview
random samples of patients with good or poor adherence to ART.
Data from the trial will be used to fit mathematical models that will estimate the contribution
of different components of the package, and project the impact of PopART and other
combination packages in a range of settings.
Detailed costing studies will also be carried out in both intervention and control clusters to
measure the incremental cost of the intervention. Cost data together with data from the trial
will provide estimates of the cost-effectiveness of the intervention. Cost data for the different
components of the intervention will also be used in combination with mathematical
modelling results to estimate the cost-effectiveness of the intervention and alternative
intervention packages over different time horizons in the study populations as well as in other
geographical settings.
Timeline
The project will be carried out over a 5-year period from January 2012 to December 2016.
Project team
The trial will be carried out by a multi-national research consortium involving the following
institutions:
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London School of Hygiene and Tropical Medicine: Overall coordination;
epidemiological, statistical and data management support.
Imperial College London: Clinical support; mathematical modelling; costing studies.
ZAMBART programme, Lusaka, Zambia in partnership with Zambian Ministry of Health
FHI, CIDRZ and SFH: Implementation of intervention and evaluation in Zambia clusters
Desmond Tutu TB Centre, South Africa in partnership with the South African
Department of Health, Provincial Department of Health: Implementation of intervention
and evaluation in South African clusters
Within the two study countries, the design and delivery of the intervention will be carried out
in close partnership with the Ministries of Health, PEPFAR and local implementing agencies.
5 September 2011