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      HPTN 071 (PopART): Rationale and design of a cluster-randomised trial of the population impact of an HIV combination prevention intervention including universal testing and treatment – a study protocol for a cluster randomised trial

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          Abstract

          Background

          Effective interventions to reduce HIV incidence in sub-Saharan Africa are urgently needed. Mathematical modelling and the HIV Prevention Trials Network (HPTN) 052 trial results suggest that universal HIV testing combined with immediate antiretroviral treatment (ART) should substantially reduce incidence and may eliminate HIV as a public health problem. We describe the rationale and design of a trial to evaluate this hypothesis.

          Methods/Design

          A rigorously-designed trial of universal testing and treatment (UTT) interventions is needed because: i) it is unknown whether these interventions can be delivered to scale with adequate uptake; ii) there are many uncertainties in the models such that the population-level impact of these interventions is unknown; and ii) there are potential adverse effects including sexual risk disinhibition, HIV-related stigma, over-burdening of health systems, poor adherence, toxicity, and drug resistance.

          In the HPTN 071 (PopART) trial, 21 communities in Zambia and South Africa (total population 1.2 m) will be randomly allocated to three arms. Arm A will receive the full PopART combination HIV prevention package including annual home-based HIV testing, promotion of medical male circumcision for HIV-negative men, and offer of immediate ART for those testing HIV-positive; Arm B will receive the full package except that ART initiation will follow current national guidelines; Arm C will receive standard of care. A Population Cohort of 2,500 adults will be randomly selected in each community and followed for 3 years to measure the primary outcome of HIV incidence. Based on model projections, the trial will be well-powered to detect predicted effects on HIV incidence and secondary outcomes.

          Discussion

          Trial results, combined with modelling and cost data, will provide short-term and long-term estimates of cost-effectiveness of UTT interventions. Importantly, the three-arm design will enable assessment of how much could be achieved by optimal delivery of current policies and the costs and benefits of extending this to UTT.

          Trial registration

          ClinicalTrials.gov NCT01900977.

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          Most cited references35

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          Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial.

          , Isabelle de Waziers (2011)
          Breastfeeding is essential for child health and development in low-resource settings but carries a significant risk of transmission of HIV-1, especially in late stages of maternal disease. We aimed to assess the efficacy and safety of triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis in pregnant women infected with HIV. Pregnant women with WHO stage 1, 2, or 3 HIV-1 infection who had CD4 cell counts of 200-500 cells per μL were enrolled at five study sites in Burkina Faso, Kenya, and South Africa to start study treatment at 28-36 weeks' gestation. Women were randomly assigned (1:1) by a computer generated random sequence to either triple antiretroviral prophylaxis (a combination of 300 mg zidovudine, 150 mg lamivudine, and 400 mg lopinavir plus 100 mg ritonavir twice daily until cessation of breastfeeding to a maximum of 6·5 months post partum) or zidovudine and single-dose nevirapine (300 mg zidovudine twice daily until delivery and a dose of 600 mg zidovudine plus 200 mg nevirapine at the onset of labour and, after a protocol amendment in December, 2006, 1 week post-partum zidovudine 300 mg twice daily and lamivudine 150 mg twice daily). All infants received a 0·6 mL dose of nevirapine at birth and, from December, 2006, 4 mg/kg twice daily of zidovudine for 1 week after birth. Patients and investigators were not masked to treatment. The primary endpoints were HIV-free infant survival at 6 weeks and 12 months; HIV-free survival at 12 months in infants who were ever breastfed; AIDS-free survival in mothers at 18 months; and serious adverse events in mothers and babies. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, ISRCTN71468401. From June, 2005, to August, 2008, 882 women were enrolled, 824 of whom were randomised and gave birth to 805 singleton or first, liveborn infants. The cumulative rate of HIV transmission at 6 weeks was 3·3% (95% CI 1·9-5·6%) in the triple antiretroviral group compared with 5·0% (3·3-7·7%) in the zidovudine and single-dose nevirapine group, and at 12 months was 5·4% (3·6-8·1%) in the triple antiretroviral group compared with 9·5% (7·0-12·9%) in the zidovudine and single-dose nevirapine group (p=0·029). The cumulative rate of HIV transmission or death at 12 months was 10·2% (95% CI 7·6-13·6%) in the triple antiretroviral group compared with 16·0% (12·7-20·0%) in the zidovudine and single-dose nevirapine group (p=0·017). In infants whose mothers declared they intended to breastfeed, the cumulative rate of HIV transmission at 12 months was 5·6% (95% CI 3·4-8·9%) in the triple antiretroviral group compared with 10·7% (7·6-14·8%) in the zidovudine and single-dose nevirapine group (p=0·02). AIDS-free survival in mothers at 18 months will be reported in a different publication. The incidence of laboratory and clinical serious adverse events in both mothers and their babies was similar between groups. Triple antiretroviral prophylaxis during pregnancy and breastfeeding is safe and reduces the risk of HIV transmission to infants. Revised WHO guidelines now recommend antiretroviral prophylaxis (either to the mother or to the baby) during breastfeeding if the mother is not already receiving antiretroviral treatment for her own health. Agence nationale de recherches sur le sida et les hépatites virales, Department for International Development, European and Developing Countries Clinical Trials Partnership, Thrasher Research Fund, Belgian Directorate General for International Cooperation, Centers for Disease Control and Prevention, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.

            Mina Hosseinipour, M Hudgens, J Wiener … (2010)
            We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi. We randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test. Among mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction. The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.) 2010 Massachusetts Medical Society
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              Contribution of sexually transmitted infections to the sexual transmission of HIV.

              Helen Ward, Minttu Rönn (2010)
              We review recent evidence about the link between sexually transmitted infections (STI) and HIV transmission and consider implications for control programmes. New studies and meta-analyses confirm the association of HIV acquisition and transmission with recent STIs, although there is considerable heterogeneity between organisms and populations. Much of the recent evidence relates to herpes simplex virus type 2 (HSV-2), for which the population-attributable risk percentage (PAR%) for HSV-2 is between 25 and 35 in Africa. Mathematical models show how transmission attributable to STI varies with HIV epidemic phase, and HSV-2 becomes increasingly important as the epidemic matures. HSV-2 suppressive therapy reduces HIV concentrations in plasma and the genital tract in people coinfected with HSV-2, in part due to direct inhibition of HIV reverse transcriptase. Recent trials of HSV-2 suppressive therapy have not shown an impact on the risk of HIV acquisition, nor in controlling transmission from dually infected people to their serodiscordant heterosexual partners. Although there is a plausible link between STI and HIV risk, intervention studies continue to be disappointing. This fact does not disprove a causal link, but mechanisms of action and the design and implementation of interventions need to be better understood.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Trials
                Journal ID (iso-abbrev): Trials
                Title: Trials
                Publisher: BioMed Central
                ISSN (Electronic): 1745-6215
                Publication date Collection: 2014
                Publication date (Electronic): 13 February 2014
                Volume: 15
                Page: 57
                Affiliations
                [1 ]Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
                [2 ]Department of Clinical Research, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
                [3 ]Zambia AIDS Related TB Project, University of Zambia, Rideway Campus, Nationalist Road, Lusaka, Zambia
                [4 ]Desmond Tutu TB Centre, Stellenbosch University, Francie van Zijl Avenue, Clinical Building, K Floor, Romm 0065, Tygerberg Campus, Western Cape 7505, South Africa
                [5 ]FHI360, Science Facilitation Department, 2224 E NC Hwy 54, Durham, NC 27713, USA
                [6 ]St Mary’s Campus, HIV Clinical Trials Unit, Winston Churchill Wing, London W2 1NY, UK
                [7 ]Institute for Global Health and Department of Pediatrics, Vanderbilt University, Institute for Global Health, 2525 West End Avenue, Suite 750, Nashville, TN 32703, USA
                [8 ]Department of Infectious Disease Epidemiology, Imperial College London, St Mary’s Campus, Norfolk Place, London W2 1PG, UK
                Author notes
                The HPTN 071 (PopART) Study Team
                Article
                Publisher ID: 1745-6215-15-57
                DOI: 10.1186/1745-6215-15-57
                PMC ID: 3929317
                PubMed ID: 24524229
                SO-VID: 186e4af2-699e-4ab6-a65c-4e4bd0632cc5
                Copyright © Copyright © 2014 Hayes et al.; licensee BioMed Central Ltd.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 18 July 2013
                Date accepted : 3 February 2014
                Categories
                Subject: Study Protocol

                ScienceOpen disciplines: Medicine
                Data availability:
                ScienceOpen disciplines: Medicine

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