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Docteur De L'université De Bordeaux T ¡¢ £ ¤ ¥ ¦¢ £§T¦£ POUR OBTENIR LE GRADE DE DOCTEUR DE L’UNIVERSITÉ DE BORDEAUX ÉCOLE DOCTORALE : Sociétés, Politique et Santé publique SPÉCIALITÉ : Santé Publique OPTION: Epidémiologie Par Delphine PERRIAT Intégration et généralisation des stratégies du type “Dépistage et traitement universels du VIH” en Afrique sub-saharienne Exemple de l’essai ANRS 12249 TasP Integration and generalization of “Universal Test and Treat” strategies for HIV in sub-Saharan Africa The ANRS 12249 TasP Trial and beyond Sous la direction de : Joanna ORNE-GLIEMANN et François DABIS Soutenue le 12 décembre 2017 Membres du jury : M. ANGLARET, Xavier, DR, Inserm U1219, Université de Bordeaux, France Président Mme DESGRÉES DU LOÛ, Annabel, DR, Institut de Recherche pour le Développement, Paris, France Rapporteur Mme FIDLER, Sarah, Professeur, Imperial College, London, United Kingdom Rapporteur M. BÄRNIGHAUSEN, Till, Professeur, Heidelberg Institute of Public Health, Heidelberg, Allemagne Examinateur M. FONTANET, Arnaud, Professeur, Institut Pasteur, Paris, France Examinateur ADMINISTRATIVE INFORMATION The present PhD was realized within the “Infectious diseases in lower-income countries” (IDLIC) research team, in the Bordeaux Population Health research centre INSERM U1219, University of Bordeaux, located 146 rue Léo Saignat, 33076 BORDEAUX 2 FINANCING This PhD thesis was realized thanks to a PhD grant of the French Ministry of Higher Education and Research, via the EHESP School of Public Health (Ecole des Hautes Etudes en Santé Publique). 3 EPIGRAPH “Toutes les généralisations sont fausses, y compris celle-ci” “All generalizations are dangerous, even this one.” - Alexandre Dumas 4 ACKNOWLEDGEMENTS This PhD thesis is the result of three years of work during which I was lucky to benefit from the support of many people that I would like to sincerely thank. First of all, I would like to express my sincere gratitude to my PhD directors, Joanna Orne-Gliemann and François Dabis. Joanna, I couldn’t have dreamt of a better role model. Your faith in me over the past three years has enabled me to conduct this PhD work under the best possible conditions. You have influenced me greatly and I hope that one day, I can pass on the research values that you have given me. François, I feel privileged to have benefitted from your support and guidance throughout this work. Thank you for your mentorship and career advice. Your knowledge and experience have inspired me to strive to participate in the international efforts for global health. I would like to thank Xavier Anglaret for accepting to chair this jury, as well as Annabel Desgrées du Loû and Sarah Fidler who agreed to be rapporteurs of this work. I would also like to thank Arnaud Fontanet and Till Bärnighausen for being part of this jury. I feel very privileged to have this PhD work assessed by such inspiring scientists. I am indebted to the TasP trial researchers for their substantial involvement in this work. My deepest appreciation goes towards Mélanie Plazy, Joseph Larmarange, Collins Iwuji and Sylvie Boyer for their availability and critical advice. Working with them has taught me to be thorough, consistent and organised. I would also like to thank other advisors that have added considerably to my experience: Janet Seeley for her social sciences expertise; Rodolphe Thiebaut for his statistical advice, Evelyne Mouillet for her bibliographic skills, France Lert for her input to get the EHESP scholarship and Bruno Spire for his motivating commitment to the HIV fight. I am also grateful to Richard Hayes and Laura Balzer for their valuable inputs within the Universal Test-and-Treat Trials consortium (UT 3C). The success of this piece of work is also due to the TasP fieldwork team. The staff members with who I closely worked deserve a special mention: Sphephelo Dlamini for his organizational support, Dumile Gumede, Lindiwe Sibiya, Lobenguni Simelane, Mumsy Mthethwa and Ntokozo Zitha for their insights on the Zulu culture, and Jaco Dreyer for his nimble fingers with quantitative databases. My profound gratitude and respect go towards all the trial participants. They are the unsung heroes of our science. Without them, much of the work we did would not have been possible. I am immensely grateful to many people at the Africa Health Research Institute (AHRI). I would particularly like to thank Deenan Pillay, AHRI’s director, for his watchful eye on my work, as well as the international researchers for our numerous scientific and non-scientific exchanges. They fuelled my aspirations to continue working in intercultural environments. And, I would like to mention Dickman Gareta, whose trust has allowed me to blossom into a confident scientist. I am also very grateful to many people in the “Infectious diseases in Lower-income countries” research team in Bordeaux. Their advice and genuine concern meant a lot to me. Last but not least, I would like to thank my family and friends who have supported me in hundreds of ways throughout the development of this PhD. I am forever grateful to my parents and sisters who believed in every decision I made. 5 Figure 1: The ANRS 12249 TasP trial field staff 6 SYNTHESE DE LA THESE (FRANÇAIS) Introduction En 2016, il était estimé que 36,7 millions de personnes vivaient avec le VIH dans le monde, qu’il y avait eu 2,1 millions de nouvelles infections et 1,1 million de décès. L'Afrique subsaharienne restait de loin la région la plus touchée, regroupant près de 70% des personnes infectées, 66% des nouvelles infections et 74% des décès liés au sida cette année-là [1]. La récente vague d’optimisme pour le contrôle de l'épidémie de VIH repose en grande partie sur les traitements antirétroviraux (TARVs) [2]. Il a été démontré que l'instauration d'un TARV le plus tôt possible après le diagnostic du VIH (quel que soit le stade de la maladie) non seulement procurait de forts bénéfices cliniques individuels [3, 4], mais avait aussi le potentiel d’éliminer la transmission du VIH par voie sexuelle. Les bénéfices préventifs du TARV sur la transmission de l’infection ont été mis en évidence dans des études observationnelles et écologiques [5, 6] ainsi que dans l'essai randomisé contrôlé HIV Prevention Trial Network (HPTN) 052 [7]. Sur la base de ces résultats encourageants, l'Organisation mondiale de la santé (OMS) a recommandé en 2015 que les TARVs soient offerts à toute personne diagnostiquée séropositive, indépendamment de son nombre de cellules CD4 et de son stade clinique [8]. Le programme commun des Nations Unies sur le VIH / SIDA. (ONUSIDA) a proposé les objectifs 90-90-90 pour mettre fin à l’épidémie de sida d'ici 2020 (90% des personnes infectées par le VIH connaissent leur statut VIH, 90% de celles qui connaissent leur statut VIH positif prennent un TARV, et 90% de ceux sous TARV ont une charge virale indétectable) [9]. Les modèles mathématiques prédisent que l’initiation immédiate d’un TARV après un diagnostic VIH positif pourrait réduire l'incidence du VIH de façon spectaculaire dans le cadre d'une stratégie de dépistage et de traitement universel du VIH (Tester et Traiter Universellement (TTU)) qui inclut une offre régulière de dépistage et conseil du VIH à toute une population et une offre de TARV à tous ceux diagnostiqués VIH+ [10-12]. Dans un contexte où les financements alloués à la riposte au VIH sont stables, il est essentiel d'obtenir des preuves de l'impact à long terme des stratégies TTU et d’ainsi mesurer leur potentiel en tant que mesures de santé publique [13, 14]. Pour répondre à ce besoin, plusieurs projets de recherche, ont évalué ou évaluent actuellement l'efficacité des stratégies TTU contre l’épidémie de VIH. Ainsi, cinq essais randomisés contrôlés sont en cours en Afrique sub-saharienne : BCPP / YaTsie au Botswana [15], MaxART au Swaziland [16], HPTN 071 (PopART) en Afrique du Sud et en Zambie [17], SEARCH en Ouganda et Kenya[18] et ANRS 12249 TasP (TasP) en Afrique du Sud [19]. Justification et objectifs de thèse L’optimisation de l’impact d’une stratégie TTU requière l’atteinte de taux d'utilisation des services VIH qui sont sans précédent. Dans un tel contexte, des questions de recherche urgentes se posent sur la faisabilité, l'acceptabilité et le ratio coût-efficacité des stratégies du type TTU [2]. Ces éléments de preuve seront essentiels pour guider les politiques et les pratiques futures dans l’optimisation des systèmes de santé actuels vers le développement d’une offre de dépistage et traitement universels. Mon doctorat propose de répondre à certaines de ces 7 questions. J'ai concentré mon travail sur trois lacunes de la littérature scientifique, en prenant comme exemple l'essai TasP. Tout d’abord, comme il n'y a pas de recommandation claire, pas de «package d'interventions idéal» à mettre en place pour garantir le succès de la stratégie TTU, nous ne savons pas comment cette stratégie a été comprise, définie et mise en œuvre dans divers contextes. Nous ne savons pas non plus comment les travailleurs de santé exposés au TTU comprennent et s’approprient cette stratégie. Enfin, nous ne savons pas comment les personnes exposées au TTU se comportent lorsque ces interventions novatrices sont proposées dans leur routine de soins. L’objectif de ma thèse était d’explorer les conditions de mise en œuvre d’une stratégie TTU à large échelle en Afrique sub-saharienne, en prenant l'exemple de l'essai TasP. Cet objectif général fut divisé en trois objectifs spécifiques : 1. Caractériser et comparer les approches TTU des 5 essais randomisés populationnels en Afrique sub-saharienne, 2. Décrire les expériences et les perceptions des travailleurs de santé sur la faisabilité et l'acceptabilité de la stratégie TTU au sein de l'essai TasP, 3.
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