Gravité potentielle, traitement et recherche clinique sur la Covid-19 pauci-symptomatique et modérée chez des Adultes en Afrique de l'Ouest

Early predictors of short and long term adverse health outcomes among at-risk individuals with mild to moderate COVID-19 in Sub-Saharan Africa

• Auteur / Autrice : Mwinmalo Da
• Direction : Denis Malvy, Armel Poda
• Type : Projet de thèse
• Discipline(s) : Santé publique Option Epidémiologie
• Date : Inscription en doctorat le 16/12/2022
• Etablissement(s) : Bordeaux
• Ecole(s) doctorale(s) : Sociétés, Politique, Santé Publique
• Partenaire(s) de recherche : Laboratoire : Bordeaux Research Center for Population Health
• Partenaire(s) de recherche : Equipe de recherche : E2 - Global Health in the global South_GHiGS

Mots clés

Mots clés libres

Covid 19

Afrique Sub-Saharienne

Populations vulnérables

Covid 19

Sub-Saharan Africa;

Vulnerable population

Résumé

Titre : Gravité potentielle, traitement et recherche clinique sur la Covid-19 pauci-symptomatique et modérée chez des Adultes en Afrique de l'Ouest Problème, objet de la recherche, originalité du travail : L'épidémie de SARS-CoV-2 a causé, depuis janvier 2020, plus de 6 564 677 décès dans le monde. La situation en Afrique est paradoxale avec 11.979.753 de cas notifiés et une séroprévalence estimée au Burkina Faso de 56% suggérant une sous-notification des cas. Si la grande majorité des personnes infectées par le SARS-CoV-2 retrouvent leur état de santé initial, certaines manifestations cliniques peuvent persister au long terme voire apparaître à distance de l'infection. De plus, les cas graves ont du mal à être pris en charge en Afrique, par manque de plateaux techniques adéquats dans les centres de réanimation. Plusieurs études, telles que l'essai ANRS COV33 Coverage Africa et ANRS 0140 EVOL-COV-AFRICA ont été mises en œuvre en Afrique de l'Ouest. Coverage Africa est un essai ouvert, randomisé et contrôlé mis en place en Guinée et au Burkina Faso depuis avril 2021. EVOL-COV-AFRICA est une étude observationnelle qui propose un suivi prolongé comprenant des évaluations cliniques, immunologiques et de santé mentale jusqu'à 2 ans après l'infection initiale chez les patients inclus dans la cohorte de Coverage Africa. Ces deux études serviront de cadre d'étude pour cette analyse. Objectif principal : Evaluer le risque d'aggravation aiguë ou chronique de la Covid-19 pauci/modérément symptomatique, des stratégies potentielles de prévention médicamenteuse de l'aggravation et les conditions de prise en charge dans des essais cliniques, en Afrique de l'Ouest Méthodes : Quatre axes seront explorés dans le cadre de cette thèse : i.l'évaluation de l'efficacité et la sécurité d'une prise en charge précoce par bithérapie Ciclésonide/Nitazoxanide sur l'infection au SARS-CoV-2 ; ii.l'identification de facteurs de risque cliniques et biologiques associés à l'aggravation de l'état de santé des patients, iii.la description de la survenue du COVID long au sein de la cohorte de patients EVOL-COV-Africa ; iv.la description du contexte et la mise en œuvre d'un essai thérapeutique sur la COVID-19 au Burkina Faso. Enjeux, questions posées, résultats attendus : cette thèse déterminera l'efficacité d'un schéma thérapeutique proposé ainsi que les facteurs associés à une aggravation clinique et biologique chez les personnes vulnérables inclus dans un essai thérapeutique en Afrique subsaharienne. Etapes opérationnelles et calendrier de la recherche : La durée prévue de cette thèse de doctorat en épidémiologie est de trois années, d'octobre 2022 à octobre 2025. L'analyse des données sera effectuée au cours du premier semestre de l'année 2023, ce qui permettra de publier un premier manuscrit au cours du 2e trimestre. Les second et troisième manuscrits seront élaborés au troisième trimestre et publiés au 4e trimestre de l'année. Enfin le manuscrit de la thèse sera finalisé entre juin 2023 et février 2024. Insertion dans l'équipe de recherche et rôle de la doctorante : Actuellement cheffe de projet Coverage Africa et EVOL-COV-Africa au Burkina Faso, mon rôle est de coordonner les activités de collecte des données et d'interagir avec l'équipe du Centre de Méthodologie et de Gestion (CMG) international (équipe GHiGS) de Bordeaux. La réalisation de cette thèse est complémentaire au travail et à mes missions actuelles. Je serai basée au Burkina Faso afin d'assurer la continuité de la coordination du projet et j'effectuerais un séjour d'un mois minimum chaque année à Bordeaux, afin de participer à des formations, séminaires, animations scientifiques et journées de l'école doctorale. Mot clés : COVID 19, Afrique subsaharienne, population vulnérable

Over the past three years, the global scientific community has mobilized to address the health crisis caused by COVID-19. By June 2023, 768,237,788 people [1] had been affected, 14% of whom had developed severe disease [2,3] , and 6,951,677 had died worldwide. Beyond the acute phase of the disease, the vast majority of symptomatic patients regain their initial status of health, but 40 to 60% develop post-acute and chronic manifestations known as "long COVID19" [4–7]. These chronic forms of COVID-19 are known as "long COVID" [8,9] and can affect all categories of people with COVID-19, but especially those who developed a severe form of the disease at the acute phase [10,11]. To date, there are limited data on this emerging public health problem, which has been particularly under investigated in Sub-Saharan Africa. Although the epidemiological situation of COVID-19 has evolved and the disease is no longer considered an international public health emergency [4], vulnerable populations continue to face increased risks of unfavorable health outcomes, whether it be in terms of severe and sometimes fatal disease at the acute phase, or in terms of persisting clinical manifestations in the mid and long-term. The factors associated with these outcomes in vulnerable patients in sub-Saharan Africa remain underexplored. Many clinical trials of therapeutic interventions for COVID-19 have been conducted worldwide. Among them, few have focused on early outpatient treatment of individuals at increased risk of progression to severe disease, and even less have been conducted in Sub-Saharan Africa. The COVERAGE Africa platform trial, part of the ANTICOV consortium initiative, is one of these. ANTICOV is a multinational (13 country), adaptive platform clinical trial that evaluated the safety and efficacy of repurposed drugs for the early treatment of COVID-19 among ambulatory at-risk patients. Coverage Africa is a daughter trial part of the ANTICOV initiative. It is an open label, randomized, controlled trial conducted in Guinea and Burkina Faso since April 2021. Prof. Denis Malvy and Prof. Armel Poda served as the joint coordinating investigators for this trial, and I was appointed as the National Project Officer for Burkina Faso. In terms of treatment strategies, Coverage Africa evaluated i) telmisartan, ii) the inhaled ciclesonide + oral nitazoxanide combination, iii) fluotexine + budesonide versus the standard of care. Additionally, ivermectine + artesunate/amodiaquine was evaluated within the ANTICOV platform trial: Overall, 1753 participants have been enrolled in the ANTICOV trial, including 482 in Coverage Africa (Burkina Faso n = 427; Guinea n = 55 ). EvolCov Africa is an observational study that offers extended follow-up, including clinical, immunological, and mental health assessments for up to 2 years after the initial infection for 187 patients of Coverage Africa and 141 from Intense Cov trials. In a post-pandemic context, it seems important to draw lessons from the implementation of such large pioneering trials in the Sub-Saharan context. For this reason acceptability studies were carried out in each country. In my thesis project I will make a synthesis to draw lessons from it. My PhD project stands out for its unique approach of analyzing data collected during the above-mentioned trials and ancillary studies to address these research questions. Objectives of the project: - Estimate the incidence and identify early predictors for progression to severe disease - Estimate the prevalence, describe the evolution profile, and identify risk factors for the occurrence of COVID-19-related mid and long-term post-acute and chronic clinical and mental manifestations. - Describe the implementation as well as the acceptability of a trial evaluating the efficacy of repurposed drugs for the early treatment of COVID-19 in ambulatory patients at increased risk of progressing to severe disease. Methodology: The COVERAGE Africa/ANTICOV platform trials enrolled a population of at-risk patients with mild to moderate COVID-19 who have received early experimental drug interventions aiming at reducing the risk of progression to severe disease. A subset of 328 participants were followed up to 2 years after the acute phase of the disease as part of the EVOL-CoV study. Taken together, these datasets gives us the opportunity to evaluate the prevalence and to identify risk factors for short, mid, and long-term health outcomes of interest, taking into account contextual characteristics that are specific to Sub-Saharan Africa. In parallel, we will describe the implementation and acceptability of the COVERAGE Africa / ANTICOV trials in pandemic context through a complex partnership in Sub-Saharan Africa. Our population of interest are participants in the COVERAGE Africa, ANTICOV trials and in the EvolCov study. After the presentation of the PhD project to the ANTICOV consortium scientific committee, access to the study database was granted by the consortium. Data will be available soon. The data collected in ANTICOV will be extracted into a specific database which will be hosted at the University of Bordeaux and analyzed to meet the above-mentioned objectives. The database will be stored for the duration of this analysis and will be destroyed after publication of the final manuscript. This PhD will be organized into 04 research areas Axis 1: short-term outcomes Outcome of interest: reaching criteria for severe disease (desaturation, hospitalization or death) between inclusion (Day 0 [D0]) in the COVERAGE Africa / ANTICOV trials and D21. Axis 2: mid to long-term outcomes Outcomes of interest: post-acute and chronic clinical and mental manifestations (defined as occurring and/or persisting after the acute phase of the disease, i.e. after the end of follow-up in the clinical trial (D28) and during the subsequent EvolCov study follow-up, up to 2 years after inclusion). Axis 3: description of the implementation's context including acceptability of the COVERAGE Africa trial in Burkina Faso Data collected from key actors involved in the Coverage Africa trial, as well as activity reports, will be used to describe the opportunities and difficulties of implementing a complex trial in an emergency situation in sub-Saharan Africa. Moreover, the data collected as part of the acceptability sub-studies will be exploited to draw lessons learned on community involvement in implementing a trial in a health emergency context Axis 4: interactions between identified risk factors for health outcomes of interest and experimental treatments' effect. This axis will be exploratory as the COVERAGE Africa trial did not reach the target sample size. Outcomes of interest: same than for Axis 1 and Axis 2. Expected results Overall, the expected results of this thesis will contribute to our understanding of COVID-19's impact on vulnerable populations in Sub-Saharan Africa. The evidence produced will inform public health policies, as well as the design and implementation of future trials addressing treatment of epidemic prone emerging infectious diseases in Sub-Saharan Africa. More specifically, it will provide reference data regarding the incidence/prevalence, the evolution pattern and risk factors for short, mid, and long term clinical/mental outcomes among vulnerable individuals in Sub-Saharan Africa. It will also provide an insight into the implementation and acceptability of a pioneering and complex platform trial on a threatening epidemic disease in Sub-Saharan Africa. Overall, the resulting evidence will inform public health policies and offer valuable lessons for future clinical trials on threatening emerging infectious disease in a Sub-Saharan context. Key words: COVID 19, sub-Saharan Africa, vulnerable population