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Can Combination Prevention Strategies Reduce HIV Transmission in Generalized Epidemic Settings in Africa? The HPTN 071 (PopART) Study Plan in South Africa and Zambia

Vermund, Sten H. MD, PhD*; Fidler, Sarah J. MBBS, PhD; Ayles, Helen MBBS, PhD‡,§; Beyers, Nulda MBChB, PhD; Hayes, Richard J. PhD, DSc

JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1st, 2013 - Volume 63 - Issue - p S221–S227
doi: 10.1097/QAI.0b013e318299c3f4
Supplement Article

Abstract: The HIV Prevention Trials Network (HPTN) is conducting the HPTN 071 (PopART) study in 21 communities in Zambia and South Africa with support from a consortium of funders. HPTN 071 (PopART) is a community-randomized trial of a combination prevention strategy to reduce HIV incidence in the context of the generalized epidemic of southern Africa. The full PopART intervention strategy is anchored in home-based HIV testing and facilitated linkage of HIV-infected persons to care through community health workers and universal antiretroviral therapy for seropositive persons regardless of CD4+ cell count or HIV viral load. To further reduce the risk of HIV acquisition among uninfected individuals, the study aims to expand voluntary medical male circumcision, diagnosis and treatment of sexually transmitted infections, behavioral counseling, and condom distribution. The full PopART intervention strategy also incorporates promotion of other interventions designed to reduce HIV and tuberculosis transmission, including optimization of the prevention of mother-to-child HIV transmission and enhanced individual and public health tuberculosis services. Success for the PopART strategy depends on the ability to increase coverage for the study interventions whose uptake is a necessary antecedent to a prevention effect. Processes will be measured to assess the degree of penetration of the interventions into the communities. A randomly sampled population cohort from each community will be used to measure the impact of the PopART strategy on HIV incidence over 3 years. We describe the strategy being tested and progress to date in the HPTN 071 (PopART) study.

*Department of Pediatrics, Vanderbilt Institute for Global Health, Vanderbilt University School of Medicine, Nashville, TN;

Department of Medicine, Imperial College London, London, United Kingdom;

Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom;

§Zambia AIDS Related Tuberculosis (ZAMBART) Project, Lusaka, Zambia;

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa; and

MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Correspondence to: Sten H. Vermund, Vanderbilt Institute for Global Health, Vanderbilt University, 2525 West End Avenue, Suite 750, Nashville, TN 37203 (e-mail:

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID, NIMH, NIDA, PEPFAR, 3ie, Inc., or the Bill & Melinda Gates Foundation.

HPTN 071 Study Team members are listed in the acknowledgments section.

HPTN 071 (PopART) is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) under Cooperative Agreements UM1-AI068619, UM1-AI068617, and UM1-AI068613, with funding from the U.S. President's Emergency Plan for AIDS Relief (PEPFAR). Additional funding is provided through NIAID, the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), and the International Initiative for Impact Evaluation (3ie, Inc.) with support from the Bill & Melinda Gates Foundation. NIH, PEPFAR, and/or 3ie, Inc. support the participating institutions with grants and money for travel (S.H.V., S.J.F., H.A., N.B., and R.J.H.). Money is paid to the authors' institutions through grants (S.H.V., S.J.F., H.A., N.B., and R.J.H.). One institution also receives money from UK MRC for travel and an author receives payment as member of board of UK MRC (R.J.H.). One author receives textbook royalties from Chapman and Hall (R.J.H.).

Received May 01, 2013

Accepted May 01, 2013

Combining prevention interventions is a familiar approach for public health interventions in low- and middle-income countries (LMIC). Control of tuberculosis (TB), for example, is recommended through the combination of case finding, contact tracing, isoniazid preventive therapy, optimized therapy, often directly observed, and environmental risk reduction to improve fresh air exchange in airplanes, housing, prisons, or health care settings.1–6 The public health challenge is how to implement what we know works to reduce TB transmission. Another example is malaria control that relies on the use of insecticide-treated bednets, environmental control of mosquito breeding sites, indoor residual spraying, seasonal malaria chemoprophylaxis, improved diagnosis and therapy (eg, artemisinin combination therapy) in the context of expanded primary care access, community education and engagement, and use of mosquito repellents.7,8 A malaria vaccine may join this list of intervention tools within a decade.9 Similar to TB and malaria, HIV now has a sound public health evidence base from both clinical trials10 and from observational studies to suggest appropriate elements of a strong combination prevention package suitable to target the generalized epidemic of sub-Saharan Africa (Table 1).



There is mixed evidence supporting the benefits of other biomedical interventions (ie, those not listed in Table 1). A tenofovir-containing vaginal microbicide worked to reduce short-term risk in the CAPRISA 004 trial, as did tenofovir–emtricitabine oral pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM in the iPrEx trial) and discordant couples in Africa (Partners PrEP and TDF-2 trials), whereas other clinical trials have been disappointing.49–54 Adherence levels have not yet been high enough to take full advantage of the biological potential of the topical or oral PrEP concept. Similarly, tools like the control of sexually transmitted infections (STI)15,55–58 and diagnosis/treatment of coinfections59–66 have demonstrated inconsistent evidence for their utility in HIV control, although they are valuable contributions to the health of individuals and the well-being of the community and may be justified as components of combination prevention in certain epidemic settings. Hence, both STI and TB programmatic improvements are being included in the PopART intervention but oral/topical PrEP are not.

As evidence accumulates in the future, other prevention approaches may be considered in combination prevention. HIV vaccines are an obvious choice if products prove efficacious, safe, and are licensed and produced for use.67,68 Future trials may prove both topical and oral PrEP to be more consistently efficacious if adherence can be improved. For example, 2 dapivirine vaginal ring microbicide efficacy trials are underway, one called The Ring Study, sponsored by the International Partnership for Microbicides,69 and a sister trial sponsored by the Microbicides Trials Network, called ASPIRE (MTN-020).70,71 The dapivirine microbicide ring delivers drug with only a monthly ring change needed, to potentially mitigate the adherence barrier of event-driven or daily use of oral or topical products.72–74

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In the context of growing evidence of the efficacy of multiple modalities for HIV prevention, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) leadership determined the need to conduct research to determine the effectiveness of a combination of prevention interventions on HIV incidence at a population level. With support from PEPFAR, the National Institute of Allergy and Infectious Disease, the National Institute of Mental Health, the National Institute on Drug Abuse, and the Bill and Melinda Gates Foundation, the HPTN 071 (PopART) study [Population Effects of Antiretroviral Therapy (ART) to Reduce HIV Transmission] was designed to answer this important question. The implementation of the study interventions in South Africa and Zambia is supported through PEPFAR supplements to implementing partners through the United States Centers for Disease Control and Prevention and the U.S. Agency for International Development.

Covering greater numbers of persons with such interventions as testing and enhanced linkage to expanded care and voluntary medical male circumcision (VMMC) would both help reduce morbidity and mortality among HIV-infected persons receiving combination antiretroviral therapy (cART) and also reduce transmission risk to others. Although there are encouraging data from ecological and observational studies supporting the potential for HIV treatment to help with HIV prevention,29–31 none to date have tested the acceptability and operational challenges of delivering a combination universal test and treat and prevention intervention package in sub-Saharan Africa (SSA).

Testing expansion as an intervention in and of itself was assessed in the National Institute of Mental Health Project ACCEPT (HPTN 043) study which found that although expanded HIV testing was well accepted,20 it did not confer a significant reduction in population-level HIV incidence.19 One might speculate that the lack of a substantial impact on HIV transmission from expanded testing alone was the consequence of limited posttesting behavioral change and suboptimal linkage to ART-based care for those found to be HIV infected. In addition, the balance of benefits versus risks associated with very early and longer-term therapy (currently under study in the START trial),75 and particularly in LMIC settings, is unknown. LMIC with limited health care resources and minimal access to viral load testing might experience a high risk of the emergence of viral resistance from suboptimal adherence in asymptomatic persons, for example.76–79 At a population level, the need for controlled clinical trials in real-world field settings is underscored by the challenges of behavioral disinhibition (also termed risk compensation) for persons on cART who may sometimes perceive themselves healthier and/or less infectious to others.80–85 Finally, we do not know the logistical feasibility and cost-effectiveness of implementing expanded HIV detection and cART coverage within health care systems struggling to manage high overall disease burdens.86,87

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HPTN 071 (PopART) Study Design Synopsis

Of the 21 communities participating in the HPTN 071 (PopART) study, 14 previously participated in the Zambia-South Africa TB and AIDS Reduction (ZAMSTAR) study, conducted by some of the investigators involved in this study.88–93 Thus, the HPTN 071 (PopART) study builds on strong relationships established between the investigators and the communities including the presence of active community advisory groups. Continuous consultative feedback from both communities and from government health officials has been essential in forging the details of the trial. The Ministries of Health of South Africa and Zambia and the relevant state, provincial, and district health authorities have been engaged fully in ethical vetting, implementation, and planning for the dissemination of study results.

The 21 communities of HPTN 071 (PopART) include 9 in the Western Cape Province of South Africa and 12 communities in Zambia and arranged in 7 matched triplets, with 4 triplets in Zambia and 3 in South Africa. Within each country, communities were matched based on the best available estimates of HIV prevalence and on geographical location and implementing partner for HIV services, with the aim of minimizing the between-community variance in baseline HIV incidence within matched triplets. Restricted randomization was used to ensure overall balance in cluster size, ART uptake and mean HIV prevalence across the study arms.94 In a public randomization ceremony in February 2013, 1 community from each triplet was randomly assigned to each of the 3 study arms (Fig. 1).



Arm A will receive the full PopART combination prevention program consisting of the following:

  • Offering voluntary HIV counseling and testing annually to every household (ie, home-based testing18 and couples counseling) with expanded HIV testing in health facilities.
  • Linking those with HIV infection to care at the local health facility.
  • Offering immediate cART to all HIV-infected persons regardless of CD4+ cell count or viral load.
  • Initiating cART for those HIV-infected persons already in care.
  • Promoting VMMC for men who test HIV seronegative.
  • Promoting prevention of mother-to-child HIV transmission services to HIV-infected pregnant women.
  • Improving the diagnosis and treatment of STI.
  • Providing risk reduction education and condoms in the community and in the health facilities.

Arm B will receive all the HIV prevention strategies in the PopART combination prevention program, except that cART will not be universal but will be offered to those who are eligible according to prevailing national guidelines, typically at a threshold of ≤350 CD4+ cells per microliter.95

Arm C will receive the current standard of care. However, special attention will be paid to ensure that there are no drug and laboratory reagent shortages or stock-outs in any of the 21 communities, ie, in all 3 study arms.

The full population in all 21 communities is estimated to be about 1.2 million persons. To measure the impact of the strategy, a population cohort will be selected from the general population consisting of a random sample of 2500 adults (one per household) aged 18–44 years from each community. Thus, the population cohort will have 52,500 persons recruited from the 21 communities (all 3 study arms; Fig. 1). A baseline survey of the cohort will be carried out at the time the intervention is initiated to assess the comparability of the 3 study arms. Follow-up surveys of the cohort will be carried out at 12, 24, and 36 months to measure HIV incidence, success in coverage of the interventions in the communities, and other outcomes.

The primary study outcome will be HIV incidence over 3 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. HPTN 071 (PopART) is very well powered to detect an effect of more than 35% in Arm A or Arm B compared with Arm C and is moderately well powered to detect an effect of 30%. To compare Arms A and B, the study is well powered to detect a difference between effects of 60% and 30%, 55% and 25%, and 50% and 20%. Assumptions are that there is a baseline HIV prevalence of 15% and that there will be losses to follow-up of 25% over 3 years in the population cohort.

The secondary outcomes will be measured in the population cohort to assess the effect of the intervention on a number of additional factors, including HIV incidence during each year of follow-up, reported sexual risk behavior, ART adherence and toxicity, HIV-related stigma, HIV disease progression, community viral load, ART drug resistance, herpes simplex virus-2 incidence, and TB case notification rates.

Process variables to be measured in the intervention clusters will include the following: acceptance of HIV testing and retesting; uptake of male circumcision among men testing HIV negative; proportion started on cART within 3 months of HIV diagnosis; and uptake of prevention of mother-to-child HIV transmission services. In addition, case–control studies will be conducted to examine factors related to the following: uptake of HIV testing during the first round of home-based testing in Arms A and B; uptake of immediate treatment in Arm A; and uptake of HIV testing in the second round of home-based testing in Arms A and B.

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Formative Research

To inform the intervention before it is deployed in the communities, social science research has been undertaken to better understand the communities, their previous and current HIV landscape, and attitudes toward different prevention approaches. In addition, further social science research will be carried out throughout the study period to examine the acceptability of the PopART intervention and to document the effects of the interventions on a number of factors, including risk behaviors, social networks, HIV identity, 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 reason for their decision. In addition, interviews will be carried out with randomly selected patients with good or poor adherence to ART.

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Economic Evaluations and Modeling

Economic studies are planned to measure the incremental cost of the intervention packages, to estimate their cost-effectiveness, and to measure the burden on local health facilities of implementing the intervention. Hence, we are recording costs of all implementation efforts for such activities as testing, linkage, care, VMMC, expanded laboratory and ART costs, and community-level educational efforts. Mathematical modeling will use these data to assess the magnitude of the expected impact, given the process inputs, as the trial progresses.

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A large population-based combination prevention study is also planned in Botswana with funding from PEPFAR and sponsorship of the CDC.96–99 The study builds on work from an ongoing study of the Botswana-Harvard AIDS Institute Partnership in Mochudi, a community of 40,000 persons in Botswana.100–105 PEPFAR and the Bill and Melinda Gates Foundation have subsequently sponsored a harmonization effort between the HPTN 071 (PopART) study and the Botswana Combination Prevention Project that shares similar goals as those of HPTN 071 (PopART) but has a different study design. Laboratory, questionnaire, cost/economic assessments, and design/analytic issues have all been addressed to facilitate future meta-analysis opportunities. Another large combination prevention study is planned by the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS in France) with the Africa Centre for Health and Population Studies in KwaZulu Natal Province, South Africa.30,106–108 Initial work of the Africa Centre is promising in suggesting the potential impact of increases in cART coverage in patients with advanced HIV disease on HIV incidence.30,109 The findings from the latter study in rural South Africa are encouraging as it provides more rigorous ecological data than hitherto available.31,32,110,111 Other studies addressing treatment as prevention and/or combination prevention for HIV have been reviewed elsewhere.106

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The opportunity to combine known efficacious interventions for HIV prevention into combination packages allows the examination of potential synergies that may be achieved in control of HIV transmission.10,15,16,112–115 Challenges are daunting given the need to have a high degree of coverage and efficiency in testing coverage, linkage to care, and high adherence in the context of expanded cART coverage.86,87,116,117 The extent to which efforts are successful in deploying needed interventions to the field at the levels needed to interrupt transmission cycles is the critical unknown at present. The engagement of national health authorities and local communities is essential for conduct of the study, dissemination of results, and future scale-up of successful approaches that are discovered. Combining known efficacious prevention approaches is complex to design and test, but their use in a synergistic strategy may open the door to substantial reductions in HIV incidence in some of the world's most afflicted nations.

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The authors thank Dr. Wafaa El-Sadr, Ms. Megan Valentine, and Ms. Megan Pask for their help with the manuscript. The study is made possible with the support of the regional and national Ministries of Health of Zambia and South Africa. HPTN 071 Protocol Team members: Helen Ayles, Megan Baldwin, Nulda Beyers, Peter Bock, Virginia Bond, David Burns, Nathaniel Chishinga, Deborah Donnell, Lynda Emel, Susan Eshleman, Sarah Fidler, Sian Floyd, Christophe Fraser, Peter Godfrey-Faussett, Sam Griffith, James Hargreaves, Katharina Hauck, Richard Hayes, Tanette Headen, Lyn Horn, Corey Kelly, Peter Kim, Estelle Piwowar-Manning, Ayana Moore, Kalpana Sabapathy, Ab Schaap, Kwame Shanaube, Peter C. Smith, Sten H. Vermund, Deborah Watson-Jones, Rhonda White.

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                                                          HIV; prevention; combination prevention; cluster randomized trial; treatment for prevention; antiretroviral therapy; HIV testing; circumcision; South Africa; Zambia

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