Amélioration de la prise en charge des adolescents vivant avec le VIH en Afrique de l'Ouest, intégrant les problématiques de l'annonce du statut sérologique VIH et de santé sexuelle et reproductive

Les adolescents vivant avec le VIH (AVVIH) doivent faire face aux défis de la prise en charge (PEC) globale du VIH incluant l'annonce du statut, l'accès et l'observance au traitement antirétroviral, et leur santé sexuelle et reproductive (SSR). L'objectif global de cette thèse visait à améliorer les connaissances sur le rôle déterminant de l'annonce du statut d'infection par le VIH dans la prise en charge et le devenir des adolescents vivant avec le VIH en Afrique de l'Ouest pour améliorer leur prise en charge globale, incluant les questions de SSR. Nous avons étudié l'annonce du diagnoistic, ses facteurs associés et ses conséquences sur le devenir des AVVIH dans une cohorte pilote multicentrique en Côte d'Ivoire et au Togo. Nous rapportons également le vécu qualitatif de l'annonce du diagnostic VIH, chez les AVVIH. Nous avons analysé l'association entre annonce du diagnostic VIH, santé mentale et succès virologique. Ensuite nous avons analysé l'offre de services en SSR dédiée aux AVVIH dans les services pédiatriques de PEC du VIH. Enfin, nous avons synthétisé les données disponibles sur l'efficacité des interventions en SSR ciblant les AVVIH en Afrique Sub-Saharienne. Nos travaux montrent que malgré les progrès réalisés, l'annonce reste trop tardive, souvent réalisée à un stade avancé de la maladie. Nos travaux suggèrent l'importance d'associer aussi bien les professionnels de santé que les parents et les pairs dans ce processus d'annonce. Nos travaux soulignent le rôle déterminant de l'annonce dans de bonnes conditions pour améliorer la santé mentale des AVVIH, leur prise en charge et leur devenir. Enfin, les programmes pédiatriques de PEC du VIH à Abidjan intégraient peu de services de SSR et les interventions de soutien psychologique et des thérapies cognitives comportementales répétées, impliquant les professionnels et las pairs améliorent la SSR des AVVIH et pouraient être mises en Œuvre en Afrique de l'Ouest.Adolescents living with HIV (ALHIV) face the challenges of HIV care, including the HIV-status disclosure, access to and adherence to antiretroviral treatment, and their sexual and reproductive health (SRH). The overall objective of this thesis was to improve knowledge on the critical role of HIV-status disclosure in the care and outcomes of adolescents living with HIV in West Africa, to improve their care, including SRH issues. We analyzed ALHIV HIV-status disclosure, its associated factors, and its consequences on ALHIV's outcomes in a multicentre cohort in Côte d'Ivoire and Togo. We also report on the qualitative experience of the HIV-status disclosure among ALHIV. We analyzed the association between HIV-status disclosure, mental health, and virological success. We then analysed the availability of SRH services in paediatric HIV services. Finally, we have synthesized the available data on the effectiveness of SRH interventions targeting ALHIV in sub-Saharan Africa. Our work shows that despite the progress made, the HIV-status disclosure remains too late, often at an advanced stage of the disease. Our work suggests the importance of involving health professionals, parents, and peers in this advertising process. Our work highlights the crucial role of the HIV-status disclosure in good conditions to improve the mental health, care, and outcomes of ALHIV. Finally, paediatric HIV care programmes in Abidjan included few SRH services and, repeated psychological support interventions and cognitive behavioural therapies, involving professionals and peers, improve the SSR of AVHIV and could be implemented in West Africa

Targeting intracellular, multi-drug resistant Staphylococcus aureus with guanidinium polymers by elucidating the structure-activity relationship

Intracellular persistence of bacteria represents a clinical challenge as bacteria can thrive in an environment protected from antibiotics and immune responses. Novel targeting strategies are critical in tackling antibiotic resistant infections. Synthetic antimicrobial peptides (SAMPs) are interesting candidates as they exhibit a very high antimicrobial activity. We first compared the activity of a library of ammonium and guanidinium polymers with different sequences (statistical, tetrablock and diblock) synthesized by RAFT polymerization against methicillin-resistant S. aureus (MRSA) and methicillin-sensitive strains (MSSA). As the guanidinium SAMPs were the most potent, they were used to treat intracellular S. aureus in keratinocytes. The diblock structure was the most active, reducing the amount of intracellular MSSA and MRSA by two-fold. We present here a potential treatment for intracellular, multi-drug resistant bacteria, using a simple and scalable strategy

The type VII secretion system protects Staphylococcus aureus against antimicrobial host fatty acids

The Staphylococcus aureus type VII secretion system (T7SS) exports several proteins that are pivotal for bacterial virulence. The mechanisms underlying T7SS-mediated staphylococcal survival during infection nevertheless remain unclear. Here we report that S. aureus lacking T7SS components are more susceptible to host-derived antimicrobial fatty acids. Unsaturated fatty acids such as linoleic acid (LA) elicited an increased inhibition of S. aureus mutants lacking T7SS effectors EsxC, EsxA and EsxB, or the membrane-bound ATPase EssC, compared to the wild-type (WT). T7SS mutants generated in different S. aureus strain backgrounds also displayed an increased sensitivity to LA. Analysis of bacterial membrane lipid profiles revealed that the esxC mutant was less able to incorporate LA into its membrane phospholipids. Although the ability to bind labelled LA did not differ between the WT and mutant strains, LA induced more cell membrane damage in the T7SS mutants compared to the WT. Furthermore, proteomic analyses of WT and mutant cell fractions revealed that, in addition to compromising membranes, T7SS defects induce oxidative stress and hamper their response to LA challenge. Thus, our findings indicate that T7SS contribute to maintaining S. aureus membrane integrity and homeostasis when bacteria encounter antimicrobial fatty acids

24-Month Clinical, Immuno-Virological Outcomes, and HIV Status Disclosure in Adolescents Living With Perinatally-Acquired HIV in the IeDEA-COHADO Cohort in Togo and Côte d'Ivoire, 2015-2017

Background: Adolescents living with perinatally-acquired HIV (APHIV) face challenges including HIV serostatus disclosure. We assessed their 24-month outcomes in relation to the disclosure of their own HIV serostatus. Methods: Nested within the International epidemiologic Database to Evaluate AIDS pediatric West African prospective cohort (IeDEA pWADA), the COHADO cohort included antiretroviral (ART)-treated APHIV aged 10-19 years, enrolled in HIV care before the age of 10 years, in Abidjan (Côte d'Ivoire) and Lomé (Togo) in 2015. We measured the HIV serostatus disclosure at baseline and after 24 months and analyzed its association with a favorable combined 24-month outcome using logistic regression. The 24-month combined clinical immuno-virological outcome was defined as unfavorable when either death, loss to follow-up, progression to WHO-AIDS stage, a decrease of CD4 count >10% compared to baseline, or a detectable viral load (VL > 50 copies/mL) occurred at 24 months. Results: Overall, 209 APHIV were included (51.6% = Abidjan, 54.5% = females). At inclusion, the median CD4 cell count was 521/mm (3) [IQR (281-757)]; 29.6% had a VL measurement, of whom, 3.2% were virologically suppressed. APHIV were younger in Lomé {median age: 12 years [interquartile range (IQR): 11-15]} compared to Abidjan [14 years (IQR: 12-15, p = 0.01)]. Full HIV-disclosure increased from 41.6% at inclusion to 74.1% after 24 months. After 24 months of follow-up, six (2.9%) died, eight (3.8%) were lost to follow-up, and four (1.9%) were transferred out. Overall, 73.7% did not progress to the WHO-AIDS stage, and 62.7% had a CD4 count above (±10%) of the baseline value (48.6% in Abidjan vs. 69.0% in Lomé, p 2 years compared to those who had not been disclosed to [aOR = 0.21, 95% CI (0.05-0.84), p = 0.03]. Conclusions: The frequency of HIV-disclosure improved over time and differed across countries but remained low among West African APHIV. Overall, the 24-month outcomes were poor. Disclosure before the study was a marker of a poor 24-month outcome in Lomé. Context-specific responses are urgently needed to improve adolescent care and reach the UNAIDS 90% target of virological success

Identification and characterization of the novel CEACAM-binding adhesin of Haemophilus influenzae

Haemophilus influenzae (Hinf), a mostly commensal inhabitant of human respiratory airways, is the causative agent of local infections such as middle ear infections, sinusitis, bronchitis, conjunctivitis and pneumonia, but can also cause life-threatening disseminating diseases, including meningitis and septicemia. The success of Hinf as commensal or opportunistic pathogen relies on the ability of the bacterium to use a combination of adhesive surface proteins, the so-called adhesins, which intimately bind to structures on the human mucosal tissue in order to overcome mechanical clearance and escape immune recognition. In that respect, Hinf targets carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), which are glycoproteins of the immunoglobulin superfamily and which are present on the apical side of nasopharyngeal epithelial cells. The first chapter of this work presents in detail the numerous advantages for the bacteria inherent in their interaction with epithelial CEACAMs (e.g.: strong attachment to the mucosal surface, internalization within epithelial cells and therefore protection against immune response).The interaction between Hinf and CEACAMs was postulated to be mediated by the outer membrane protein (OMP) P5, one of the major OMPs of Hinf. Therefore, we set out to characterize the molecular requirements of CEACAM-binding by OMP P5. However, (i) the ability of P5-deficient Hinf to strongly interact with CEACAMs; (ii) the similarity of P5 sequences from non-CEACAM-binding and CEACAM-binding Hinf strains, and (iii) the failure of OMP P5 to bind CEACAMs when heterologously expressed in Escherichia coli questioned the role of OMP P5 as the Hinf CEACAM-binding adhesin. A screen of a panel of Hinf mutants with defined deletions in their outer membrane proteins revealed that the depletion of OMP P1 totally abrogated the interaction of Hinf with CEACAMs. Furthermore, non-CEACAM-binding E. coli gained CEACAM-binding properties upon ectopic expression of Hinf OMP P1. Thus, OMP P1 is necessary and sufficient for CEACAM-targeting.Following the identification of OMP P1 as the bona fide CEACAM-binding adhesin of Hinf, we sought to identify the domain(s) of OMP P1 involved in CEACAM-recognition. Therefore, we took advantage of the high similarity between OMP P1 and its non-CEACAM-binding homolog FadL in E. coli. The solved crystal structure of FadL helped to model OMP P1, which is predicted to build a 14-stranded β-barrel. Interestingly, chimeras resulting from the fusion of OMP P1 with FadL fragments combined with OMP P1 mutants deprived of specific extracellular loops clearly underlined the involvement of the most prominent surface-exposed OMP P1 loops (L1, L3, L4 and L7) in CEACAM recognition. The flexibility of these loops appears important for the proper binding to CEACAM. In contrast to Hinf OMP P1, P1 homologs of other members of the Pasteurellaceae family were unable to recognize CEACAMs. Moreover, Hinf OMP P1 bound exclusively to human CEACAMs, but not to other distantly related mammalian CEACAMs.FadL, the OMP P1 homolog in E. coli, mediates the transport of long-chain fatty acids (LCFAs) across the bacterial outer membrane. The high structural homology shared by FadL and OMP P1 raised the question whether OMP P1 is involved in fatty acid transport and/or is regulated by fatty acids. Though the addition of fatty acids to the Hinf medium was able to potently stimulate bacterial growth, the role of OMP P1 in LCFA transport requires further investigations. However, it was obvious that LCFAs supplementations upregulated OMP P1 expression in Hinf. Furthermore, Hinf strains treated with LCFAs were able to better interact with recombinant CEACAMs and were more invasive in CEACAM-expressing epithelial cells, compared to untreated bacteria.In sum, this study not only identifies a novel CEACAM-binding adhesin in a prominent human pathogen, but also provides insights into a new CEACAM-binding interface built by 4 flexible loops of a bacterial outer membrane protein.publishe

Amélioration de la prise en charge des adolescents vivant avec le VIH en Afrique de l'Ouest, intégrant les problématiques de l'annonce du statut sérologique VIH et de santé sexuelle et reproductive

Adolescents living with HIV (ALHIV) face the challenges of HIV care, including the HIV-status disclosure, access to and adherence to antiretroviral treatment, and their sexual and reproductive health (SRH). The overall objective of this thesis was to improve knowledge on the critical role of HIV-status disclosure in the care and outcomes of adolescents living with HIV in West Africa, to improve their care, including SRH issues. We analyzed ALHIV HIV-status disclosure, its associated factors, and its consequences on ALHIV's outcomes in a multicentre cohort in Côte d'Ivoire and Togo. We also report on the qualitative experience of the HIV-status disclosure among ALHIV. We analyzed the association between HIV-status disclosure, mental health, and virological success. We then analysed the availability of SRH services in paediatric HIV services. Finally, we have synthesized the available data on the effectiveness of SRH interventions targeting ALHIV in sub-Saharan Africa. Our work shows that despite the progress made, the HIV-status disclosure remains too late, often at an advanced stage of the disease. Our work suggests the importance of involving health professionals, parents, and peers in this advertising process. Our work highlights the crucial role of the HIV-status disclosure in good conditions to improve the mental health, care, and outcomes of ALHIV. Finally, paediatric HIV care programmes in Abidjan included few SRH services and, repeated psychological support interventions and cognitive behavioural therapies, involving professionals and peers, improve the SSR of AVHIV and could be implemented in West Africa.Les adolescents vivant avec le VIH (AVVIH) doivent faire face aux défis de la prise en charge (PEC) globale du VIH incluant l'annonce du statut, l'accès et l'observance au traitement antirétroviral, et leur santé sexuelle et reproductive (SSR). L'objectif global de cette thèse visait à améliorer les connaissances sur le rôle déterminant de l'annonce du statut d'infection par le VIH dans la prise en charge et le devenir des adolescents vivant avec le VIH en Afrique de l'Ouest pour améliorer leur prise en charge globale, incluant les questions de SSR. Nous avons étudié l'annonce du diagnoistic, ses facteurs associés et ses conséquences sur le devenir des AVVIH dans une cohorte pilote multicentrique en Côte d'Ivoire et au Togo. Nous rapportons également le vécu qualitatif de l'annonce du diagnostic VIH, chez les AVVIH. Nous avons analysé l'association entre annonce du diagnostic VIH, santé mentale et succès virologique. Ensuite nous avons analysé l'offre de services en SSR dédiée aux AVVIH dans les services pédiatriques de PEC du VIH. Enfin, nous avons synthétisé les données disponibles sur l'efficacité des interventions en SSR ciblant les AVVIH en Afrique Sub-Saharienne. Nos travaux montrent que malgré les progrès réalisés, l'annonce reste trop tardive, souvent réalisée à un stade avancé de la maladie. Nos travaux suggèrent l'importance d'associer aussi bien les professionnels de santé que les parents et les pairs dans ce processus d'annonce. Nos travaux soulignent le rôle déterminant de l'annonce dans de bonnes conditions pour améliorer la santé mentale des AVVIH, leur prise en charge et leur devenir. Enfin, les programmes pédiatriques de PEC du VIH à Abidjan intégraient peu de services de SSR et les interventions de soutien psychologique et des thérapies cognitives comportementales répétées, impliquant les professionnels et las pairs améliorent la SSR des AVVIH et pouraient être mises en Œuvre en Afrique de l'Ouest

Improving the care of adolescents living with HIV in West Africa, integrating the issues of HIV status disclosure and sexual and reproductive health

Les adolescents vivant avec le VIH (AVVIH) doivent faire face aux défis de la prise en charge (PEC) globale du VIH incluant l'annonce du statut, l'accès et l'observance au traitement antirétroviral, et leur santé sexuelle et reproductive (SSR). L'objectif global de cette thèse visait à améliorer les connaissances sur le rôle déterminant de l'annonce du statut d'infection par le VIH dans la prise en charge et le devenir des adolescents vivant avec le VIH en Afrique de l'Ouest pour améliorer leur prise en charge globale, incluant les questions de SSR. Nous avons étudié l'annonce du diagnoistic, ses facteurs associés et ses conséquences sur le devenir des AVVIH dans une cohorte pilote multicentrique en Côte d'Ivoire et au Togo. Nous rapportons également le vécu qualitatif de l'annonce du diagnostic VIH, chez les AVVIH. Nous avons analysé l'association entre annonce du diagnostic VIH, santé mentale et succès virologique. Ensuite nous avons analysé l'offre de services en SSR dédiée aux AVVIH dans les services pédiatriques de PEC du VIH. Enfin, nous avons synthétisé les données disponibles sur l'efficacité des interventions en SSR ciblant les AVVIH en Afrique Sub-Saharienne. Nos travaux montrent que malgré les progrès réalisés, l'annonce reste trop tardive, souvent réalisée à un stade avancé de la maladie. Nos travaux suggèrent l'importance d'associer aussi bien les professionnels de santé que les parents et les pairs dans ce processus d'annonce. Nos travaux soulignent le rôle déterminant de l'annonce dans de bonnes conditions pour améliorer la santé mentale des AVVIH, leur prise en charge et leur devenir. Enfin, les programmes pédiatriques de PEC du VIH à Abidjan intégraient peu de services de SSR et les interventions de soutien psychologique et des thérapies cognitives comportementales répétées, impliquant les professionnels et las pairs améliorent la SSR des AVVIH et pouraient être mises en Œuvre en Afrique de l'Ouest.Adolescents living with HIV (ALHIV) face the challenges of HIV care, including the HIV-status disclosure, access to and adherence to antiretroviral treatment, and their sexual and reproductive health (SRH). The overall objective of this thesis was to improve knowledge on the critical role of HIV-status disclosure in the care and outcomes of adolescents living with HIV in West Africa, to improve their care, including SRH issues. We analyzed ALHIV HIV-status disclosure, its associated factors, and its consequences on ALHIV's outcomes in a multicentre cohort in Côte d'Ivoire and Togo. We also report on the qualitative experience of the HIV-status disclosure among ALHIV. We analyzed the association between HIV-status disclosure, mental health, and virological success. We then analysed the availability of SRH services in paediatric HIV services. Finally, we have synthesized the available data on the effectiveness of SRH interventions targeting ALHIV in sub-Saharan Africa. Our work shows that despite the progress made, the HIV-status disclosure remains too late, often at an advanced stage of the disease. Our work suggests the importance of involving health professionals, parents, and peers in this advertising process. Our work highlights the crucial role of the HIV-status disclosure in good conditions to improve the mental health, care, and outcomes of ALHIV. Finally, paediatric HIV care programmes in Abidjan included few SRH services and, repeated psychological support interventions and cognitive behavioural therapies, involving professionals and peers, improve the SSR of AVHIV and could be implemented in West Africa