How 'place' matters for addressing the HIV epidemic: evidence from the HPTN 071 (PopART) cluster-randomised controlled trial in Zambia and South Africa

Virginia Bond, Graeme Hoddinott, Lario Viljoen, Fredrick Ngwenya, Melvin Simuyaba, Bwalya Chiti, Rhoda Ndubani, Nozizwe Makola, Deborah Donnell, Ab Schaap, Sian Floyd, James Hargreaves, Kwame Shanaube, Sarah Fidler, Peter Bock, Helen Ayles, Richard Hayes, Musonda Simwinga, Janet Seeley, HPTN071 (PopART) study team, Virginia Bond, Graeme Hoddinott, Lario Viljoen, Fredrick Ngwenya, Melvin Simuyaba, Bwalya Chiti, Rhoda Ndubani, Nozizwe Makola, Deborah Donnell, Ab Schaap, Sian Floyd, James Hargreaves, Kwame Shanaube, Sarah Fidler, Peter Bock, Helen Ayles, Richard Hayes, Musonda Simwinga, Janet Seeley, HPTN071 (PopART) study team

Abstract

Background: In a cluster-randomised trial (CRT) of combination HIV prevention (HPTN 071 (PopART)) in 12 Zambian communities and nine South African communities, carried out from 2012 to 2018, the intervention arm A that offered HIV treatment irrespective of CD4 count did not have a significant impact on population level HIV incidence. Intervention arm B, where HIV incidence was reduced by 30%, followed national guidelines that mid trial (2016) changed from starting HIV treatment according to a CD4 threshold of 500 to universal treatment. Using social science data on the 21 communities, we consider how place (community context) might have influenced the primary outcome result.

Methods: A social science component documented longitudinally the context of trial communities. Data were collected through rapid qualitative assessment, interviews, group discussions and observations. There were a total of 1547 participants and 1127 observations. Using these data, literature and a series of qualitative analysis steps, we identified key community characteristics of relevance to HIV and triangulated these with HIV community level incidence.

Results: Two interdependent social factors were relevant to communities' capability to manage HIV: stability/instability and responsiveness/resistance. Key components of stability were social cohesion; limited social change; a vibrant local economy; better health, education and recreational services; strong institutional presence; established middle-class residents; predictable mobility; and less poverty and crime. Key components of responsiveness were community leadership being open to change, stronger history of HIV initiatives, willingness to take up HIV services, less HIV-related stigma and a supported and enterprising youth population. There was a clear pattern of social factors across arms. Intervention arm A communities were notably more resistant and unstable. Intervention arm B communities were overall more responsive and stable.

Conclusions: In the specific case of the dissonant primary outcome results from the HPTN 071 (PopART) trial, the chance allocation of less stable, less responsive communities to arm A compared to arm B may explain some of the apparently smaller impact of the intervention in arm A. Stability and responsiveness appear to be two key social factors that may be relevant to secular trends in HIV incidence. We advocate for a systematic approach, using these factors as a framework, to community context in CRTs and monitoring HIV prevention efforts.

Trial registration: ClinicalTrials.gov NCT01900977 . Registered on July 17, 2013.

Keywords: Communities; Community randomised trials (CRTs); Social context; Southern Africa; Stability.

Conflict of interest statement

The authors declare they have no competing interests.

Figures

Fig. 1
Fig. 1
Process of synthesising qualitative community level data to identify stability/instability
Fig. 2
Fig. 2
Responsive/resistant social factor
Fig. 3
Fig. 3
Community HIV incidence by arm and triplet. The three communities in each triplet (one randomised to each arm) are shown joined by a line and labelled. The symbol for each community illustrates the level of both stability (the inner shading) and responsiveness (the outer shading)

References

    1. UNAIDS. UNAIDS Data 2018 Geneva: UNAIDS; 2018 [Available from: .
    1. Hayes RJ, Donnell D, Floyd S, Mandla N, Bwalya J, Sabapathy K, Yang B, Phiri M, Schaap A, Eshleman SH, Piwowar-Manning E, Kosloff B, James A, Skalland T, Wilson E, Emel L, Macleod D, Dunbar R, Simwinga M, Makola N, Bond V, Hoddinott G, Moore A, Griffith S, Deshmane Sista N, Vermund SH, el-Sadr W, Burns DN, Hargreaves JR, Hauck K, Fraser C, Shanaube K, Bock P, Beyers N, Ayles H, Fidler S, HPTN 071 (PopART) Study Team Effect of universal testing and treatment on HIV incidence - HPTN 071 (PopART) N Engl J Med. 2019;381(3):207–218. doi: 10.1056/NEJMoa1814556.
    1. Havlir DV, Balzer LB, Charlebois ED, Clark TD, Kwarisiima D, Ayieko J, Kabami J, Sang N, Liegler T, Chamie G, Camlin CS, Jain V, Kadede K, Atukunda M, Ruel T, Shade SB, Ssemmondo E, Byonanebye DM, Mwangwa F, Owaraganise A, Olilo W, Black D, Snyman K, Burger R, Getahun M, Achando J, Awuonda B, Nakato H, Kironde J, Okiror S, Thirumurthy H, Koss C, Brown L, Marquez C, Schwab J, Lavoy G, Plenty A, Mugoma Wafula E, Omanya P, Chen YH, Rooney JF, Bacon M, van der Laan M, Cohen CR, Bukusi E, Kamya MR, Petersen M. HIV testing and treatment with the use of a community health approach in rural Africa. N Engl J Med. 2019;381(3):219–229. doi: 10.1056/NEJMoa1809866.
    1. Makhema J, Wirth KE, Pretorius Holme M, Gaolathe T, Mmalane M, Kadima E, Chakalisa U, Bennett K, Leidner J, Manyake K, Mbikiwa AM, Simon SV, Letlhogile R, Mukokomani K, van Widenfelt E, Moyo S, Lebelonyane R, Alwano MG, Powis KM, Dryden-Peterson SL, Kgathi C, Novitsky V, Moore J, Bachanas P, Abrams W, Block L, el-Halabi S, Marukutira T, Mills LA, Sexton C, Raizes E, Gaseitsiwe S, Bussmann H, Okui L, John O, Shapiro RL, Pals S, Michael H, Roland M, DeGruttola V, Lei Q, Wang R, Tchetgen Tchetgen E, Essex M, Lockman S. Universal testing, expanded treatment, and incidence of HIV infection in Botswana. N Engl J Med. 2019;381(3):230–242. doi: 10.1056/NEJMoa1812281.
    1. Iwuji CC, Orne-Gliemann J, Larmarange J, Balestre E, Thiebaut R, Tanser F, Okesola N, Makowa T, Dreyer J, Herbst K, McGrath N, Bärnighausen T, Boyer S, de Oliveira T, Rekacewicz C, Bazin B, Newell ML, Pillay D, Dabis F, Bärnighausen T, Herbst K, Iwuji C, Makowa T, Naidu K, Newell ML, Okesola N, de Oliveira T, Pillay D, Rochat T, Tanser F, Viljoen J, Zuma T, McGrath N, Balestre E, Dabis F, Karcher S, Orne-Gliemann J, Plazy M, Prague M, Thiébaut R, Tiendrebeogo T, Boyer S, Donfouet H, Gosset A, March L, Protopopescu C, Spire B, Calmy A, Larmarange J, Inghels M, Diallo H, Calvez V, Derache A, Marcelin AG, Dray-Spira R, Lert F, el Farouki K, Lessells R, Freedberg K, Imrie J, Chaix ML, Newell C, Hontelez J, Bazin B, Rekacewicz C. Universal test and treat and the HIV epidemic in rural South Africa: a phase 4, open-label, community cluster randomised trial. Lancet HIV. 2018;5(3):e116–ee25. doi: 10.1016/S2352-3018(17)30205-9.
    1. Boily M-C, Mâsse B, Alsallaq R, Padian NS, Eaton JW, Vesga JF, et al. HIV treatment as prevention: considerations in the design, conduct, and analysis of cluster randomized controlled trials of combination HIV prevention. PLoS Med. 2012;9(7):e1001250. doi: 10.1371/journal.pmed.1001250.
    1. Gregson S, Adamson S, Papaya S, Mundondo J, Nyamukapa CA, Mason PR, et al. Impact and process evaluation of integrated community and clinic-based HIV-1 control: a cluster-randomised trial in eastern Zimbabwe. PLoS Med. 2007;4(3):e102. doi: 10.1371/journal.pmed.0040102.
    1. Abdool Karim SS. HIV-1 epidemic control — insights from test-and-treat trials. N Engl J Med. 2019;381(3):286–288. doi: 10.1056/NEJMe1907279.
    1. Storeng KT, Abimbola S, Balabanova D, McCoy D, Ridde V, Filippi V, et al. Action to protect the independence and integrity of global health research. BMJ Global Health. 2019;4(3):e001746. doi: 10.1136/bmjgh-2019-001746.
    1. Wells M, Williams B, Treweek S, Coyle J, Taylor J. Intervention description is not enough: evidence from an in-depth multiple case study on the untold role and impact of context in randomised controlled trials of seven complex interventions. Trials. 2012;13(1):95. doi: 10.1186/1745-6215-13-95.
    1. Hawe P. Minimal, negligible and negligent interventions. Soc Sci Med. 2015;138:265–268. doi: 10.1016/j.socscimed.2015.05.025.
    1. Pfadenhauer LM, Gerhardus A, Mozygemba K, Lysdahl KB, Booth A, Hofmann B, Wahlster P, Polus S, Burns J, Brereton L, Rehfuess E. Making sense of complexity in context and implementation: the context and implementation of complex interventions (CICI) framework. Implement Sci. 2017;12(1):21. doi: 10.1186/s13012-017-0552-5.
    1. Craig P, Gibson M, Campbell M, Popham F, Katikireddi SV. Making the most of natural experiments: what can studies of the withdrawal of public health interventions offer? Prev Med. 2018;108:17–22. doi: 10.1016/j.ypmed.2017.12.025.
    1. Hanrahan CF, Schwartz SR, Mudavanhu M, West NS, Mutunga L, Keyser V, Bassett J, van Rie A. The impact of community- versus clinic-based adherence clubs on loss from care and viral suppression for antiretroviral therapy patients: findings from a pragmatic randomized controlled trial in South Africa. PLoS Med. 2019;16(5):e1002808. doi: 10.1371/journal.pmed.1002808.
    1. Sikazwe I, Eshun-Wilson I, Sikombe K, Czaicki N, Somwe P, Mody A, Simbeza S, Glidden DV, Chizema E, Mulenga LB, Padian N, Duncombe CJ, Bolton-Moore C, Beres LK, Holmes CB, Geng E. Retention and viral suppression in a cohort of HIV patients on antiretroviral therapy in Zambia: regionally representative estimates using a multistage-sampling-based approach. PLoS Med. 2019;16(5):e1002811. doi: 10.1371/journal.pmed.1002811.
    1. Wallman S, Bond V, Montouri MA, Vidali M, Conte RL. The capability of places: methods for modelling community response to intrusion and change. London: Pluto Press; 2011.
    1. Bates I, Fenton C, Gruber J, Lalloo D, Lara AM, Squire SB, Theobald S, Thomson R, Tolhurst R. Vulnerability to malaria, tuberculosis, and HIV/AIDS infection and disease. Part 1: determinants operating at individual and household level. Lancet Infect Dis. 2004;4(5):267–277. doi: 10.1016/S1473-3099(04)01002-3.
    1. Bates I, Fenton C, Gruber J, Lalloo D, Lara AM, Squire SB, Theobald S, Thomson R, Tolhurst R. Vulnerability to malaria, tuberculosis, and HIV/AIDS infection and disease. Part II: determinants operating at environmental and institutional level. Lancet Infect Dis. 2004;4(6):368–375. doi: 10.1016/S1473-3099(04)01047-3.
    1. Hayes R, Ayles H, Beyers N, Sabapathy K, Floyd S, Shanaube K, Bock P, Griffith S, Moore A, Watson-Jones D, Fraser C, Vermund SH, Fidler S, The HPTN 071 (PopART) Study Team 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. Trials. 2014;15(1):57. doi: 10.1186/1745-6215-15-57.
    1. Simwinga M, Bond V, Makola N, Hoddinott G, Belemu S, White R, et al. Implementing community engagement for combination prevention: lessons learnt from the first year of the HPTN 071 (PopART) community-randomized study. Curr HIV/AIDS Rep. 2016;13(4):194–201. doi: 10.1007/s11904-016-0322-z.
    1. Bond V, Chiti B, Hoddinott G, Reynolds L, Schaap A, Simuyaba M, et al. “The difference that makes a difference”: highlighting the role of variable contexts within an HIV Prevention Community Randomised Trial (HPTN 071/PopART) in 21 study communities in Zambia and South Africa. AIDS Care. 2016;28(sup3):99–107. doi: 10.1080/09540121.2016.1178958.
    1. Bond V, Ngwenya F, Thomas A, Simuyaba M, Hoddinott G, Fidler S, et al. Spinning Plates: Livelihood mobility, household responsibility and anti-retroviral treatment in an urban Zambian community during the HPTN 071 (PopART) study. J Int AIDS Soc. 2018; in press.
    1. Bond V, Ngwenya F, Murray E, Ngwenya N, Viljoen L, Gumede D, Bwalya C, Mantantana J, Hoddinott G, Dodd PJ, Ayles H, Simwinga M, Wallman S, Seeley J. Value and limitations of broad brush surveys used in community-randomized trials in Southern Africa. Qual Health Res. 2019;29(5):700–718. doi: 10.1177/1049732318809940.
    1. Wallman S. The diversity of diversity: implications of the form and process of localised urban systems. In: Second ENGIME (Economic Growth and Innovation in Multicultural Environments). London; 2003. Available at .
    1. Moore GF, Audrey S, Barker M, Bond L, Bonell C, Hardeman W, Moore L, O'Cathain A, Tinati T, Wight D, Baird J. Process evaluation of complex interventions: Medical Research Council guidance. Br Med J. 2015;350(mar19 6):h1258. doi: 10.1136/bmj.h1258.
    1. Hargreaves JR, Stangl A, Bond V, Hoddinott G, Krishnaratne S, Mathema H, Moyo M, Viljoen L, Brady L, Sievwright K, Horn L, Sabapathy K, Ayles H, Beyers N, Bock P, Fidler S, Griffith S, Seeley J, Hayes R, on Behalf of the HPTN 071 (PopART) study team HIV-related stigma and universal testing and treatment for HIV prevention and care: design of an implementation science evaluation nested in the HPTN 071 (PopART) cluster-randomized trial in Zambia and South Africa. Health Policy Plan. 2016;31(10):1342–1354. doi: 10.1093/heapol/czw071.
    1. Shanaube K, Schaap A, Chaila MJ, Floyd S, Mackworth-Young C, Hoddinott G, Hayes R, Fidler S, Ayles H, HPTN 071 (PopART) Study Team Community intervention improves knowledge of HIV status of adolescents in Zambia: findings from HPTN 071-PopART for youth study. AIDS. 2017;31(3):S221–SS32. doi: 10.1097/QAD.0000000000001530.
    1. Bond V, Hoddinott G, Viljoen L, Simuyaba M, Musheke M, Seeley J, on behalf of the HPTN071 (PopART) Study Team Good health and moral responsibility: key concepts underlying the interpretation of ‘treatment as prevention’ in 21 urban communities in South Africa and Zambia prior to rolling out universal HIV testing and treatment. AIDS Patient Care STDs. 2016;30(9):425–434. doi: 10.1089/apc.2016.0114.
    1. Milton S, Pliakas T, Hawkesworth S, Nanchahal K, Grundy C, Amuzu A, Casas JP, Lock K. A qualitative geographical information systems approach to explore how older people over 70 years interact with and define their neighbourhood environment. Health Place. 2015;36:127–133. doi: 10.1016/j.healthplace.2015.10.002.
    1. Hargreaves JR, Krishnaratne S, Mathema H, Lilleston PS, Sievwright K, Mandla N, et al. Individual and community-level risk factors for HIV stigma in 21 Zambian and South African communities: analysis of data from the HPTN071 (PopART) study. AIDS (London, England) 2018;32(6):783–793. doi: 10.1097/QAD.0000000000001757.
    1. Krishnaratne S, Bond V, Stangl A, Pliakas T, Mathema H, Lilleston P, Hoddinott G, Bock P, Ayles H, Fidler S, Hargreaves JR, on behalf of the HPTN 071 (PopART) Study Team Stigma and judgment toward people living with HIV and key population groups among three cadres of health workers in South Africa and Zambia: analysis of data from the HPTN 071 (PopART) trial. AIDS Patient Care STDs. 2020;34(1):38–50. doi: 10.1089/apc.2019.0131.
    1. Camlin CS, Seeley J. Qualitative research on community experiences in large HIV research trials: what have we learned? J Int AIDS Soc. 2018;21(S7):e25173. doi: 10.1002/jia2.25173.
    1. Geng EH, Holmes CB. Research to improve differentiated HIV service delivery interventions: learning to learn as we do. PLoS Med. 2019;16(5):e1002809. doi: 10.1371/journal.pmed.1002809.
    1. Patton GC, Sawyer SM, Santelli JS, Ross DA, Afifi R, Allen NB, Arora M, Azzopardi P, Baldwin W, Bonell C, Kakuma R, Kennedy E, Mahon J, McGovern T, Mokdad AH, Patel V, Petroni S, Reavley N, Taiwo K, Waldfogel J, Wickremarathne D, Barroso C, Bhutta Z, Fatusi AO, Mattoo A, Diers J, Fang J, Ferguson J, Ssewamala F, Viner RM. Our future: a Lancet commission on adolescent health and wellbeing. Lancet. 2016;387(10036):2423–2478. doi: 10.1016/S0140-6736(16)00579-1.
    1. Long D, Deane K. Wealthy and healthy? New evidence on the relationship between wealth and HIV vulnerability in Tanzania. Rev Afr Polit Econ. 2015;42(145):376–393. doi: 10.1080/03056244.2015.1064817.
    1. Camlin CS, Cassels S, Seeley J. Bringing population mobility into focus to achieve HIV prevention goals. J Int AIDS Soc. 2018;21:(S4):e25136, 1–5.
    1. Hargreaves JR, Glynn JR. Educational attainment and HIV-1 infection in developing countries: a systematic review. Trop Med Int Health. 2002;7(6):489–498. doi: 10.1046/j.1365-3156.2002.00889.x.
    1. Fonner VA, Kerrigan D, Mnisi Z, Ketende S, Kennedy CE, Baral S. Social cohesion, social participation, and HIV related risk among female sex workers in Swaziland. PLoS One. 2014;9(1):e87527. doi: 10.1371/journal.pone.0087527.
    1. German D, Latkin CA. Social stability and health: exploring multidimensional social disadvantage. J Urban Health. 2012;89(1):19–35. doi: 10.1007/s11524-011-9625-y.
    1. Bond V, Hoddinott G, Musheke M, Viljoen L, Abrahams K, Chiti B, et al. Broad brush surveys of HIV prevention, treatment and care in 21 Zambian and South African communities to prepare for HPTN 071 (PopART) 2013.
    1. Singer M, Clair S. Syndemics and public health: reconceptualizing disease in bio-social context. Med Anthropol Q. 2003;17(4):423–441. doi: 10.1525/maq.2003.17.4.423.
    1. O’Cathain A, Hoddinott P, Lewin S, Thomas KJ, Young B, Adamson J, Jansen YJFM, Mills N, Moore G, Donovan JL. Maximising the impact of qualitative research in feasibility studies for randomised controlled trials: guidance for researchers. Pilot Feasibility Stud. 2015;1(1):32. doi: 10.1186/s40814-015-0026-y.
    1. Oakley A, Strange V, Bonell C, Allen E, Stephenson J. Process evaluation in randomised controlled trials of complex interventions. Br Med J. 2006;332(7538):413–416. doi: 10.1136/bmj.332.7538.413.
    1. Davis K, Minckas N, Bond V, Clark C, Colbourn T, Drabble S, et al. Beyond interviews and focus groups: a framework for integrating innovative qualitative methods into randomised controlled trials of complex public health interventions. Trials. 2019;20(329):1–16.

Source: PubMed

3
Tilaa