京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第18465号 / 社医博第55号 / 新制||社医||8(附属図書館) / 31343 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 中山 健夫, 教授 中原 俊隆, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Yes / Despite being a preventable disease, pediatric HIV infection continues to be a public health concern due to the morbidity and mortality associated with the disease. Vertical transmission of HIV occurs when a mother living with HIV passes the virus to her baby during pregnancy, childbirth, or breastfeeding. Globally, the vertical transmission rate of HIV is 9% with sub-Saharan Africa accounting for 90% of these infections. In Kenya, the national vertical transmission rates of HIV stood at 11.5% by the end of 2018, with a target to reduce vertical transmission rates to below 5% and 2% in breastfeeding and non-breastfeeding infants respectively, by the end of 2021. To determine the prognostic factors influencing HIV-free survival among infants enrolled for HIV early infant diagnosis (EID) services in selected hospitals in Nairobi County, Kenya. A prospective cohort study design was adopted. HIV exposed infants were recruited at six weeks to determine HIV-free survival over 12 months follow up. Simple random sampling was used to select 166 infants and data were collected from the mothers using semi-structured interviewer-administered questionnaires. Log-rank tests were used to test for associations at the bi-variable level while Cox-proportional regression was used to analyze data at the multi-variable level, with the aid of STATA 14 software. Ethical approval was obtained from Kenya Medical Research Institute, Scientific Ethics Review Unit. The overall infant HIV incidence rate over one-year follow-up was 9 cases per 100 person-years (95% CI: 5.465-16.290). The failure event was defined as an infant with a positive PCR test during the study period with total failures being 13 (9.41%) over 12 months. Prognostic factors associated with poor infant HIV-free survival were young maternal age (18-24 years) and mothers with a recent HIV diagnosis of ≤ 2 years since a positive HIV diagnosis (HR 5.97 CI: 1.20, 29.58) and (HR 6.97 CI: 1.96, 24.76), respectively. Maternal prognostic factors associated with poor infant HIV-free survival were young maternal age (18-24 years) and recent maternal HIV diagnosis of ≤ 2 years since positive HIV diagnosis. The study recommended the development of an intervention package with more rigorous adherence counseling and close monitoring for young mothers, and mothers with recent HIV diagnoses.

Dans la première partie de ce travail, nous passons en revue les sujets qui ont fait l’objet d’essais thérapeutiques randomisés dans le domaine de la prévention et de la prise en charge de l’adulte infecté par le VIH en Afrique sub-saharienne. Nous en tirons deux conclusions : (i) que beaucoup de questions de recherche n’ont pas été explorées par des essais, soit parce qu’elles n’ont pas été jugées prioritaires, soit parce qu’un essai pour répondre à la question n’était pas jugé possible ; (ii) que les essais ayant des résultats positifs débouchent souvent eux même sur de nouvelles questions, notamment sur l’interprétation à donner à leurs résultats, les implications pratiques, les projections à long terme, et la réplicabilité dans différents contextes. Il arrive que ces questions paralysent les décisions. La question se pose donc d’utiliser au mieux les outils complémentaires aux essais thérapeutiques, incluant l’outil « modélisation ». Dans la deuxième partie, nous situons les modèles multi-états d’histoire naturelle de la maladie dans le spectre des différents modèles mathématiques utilisés en recherche médicale, et nous décrivons en détail un de ces modèles, le modèle « Cost Effectiveness of Preventing Aids Complication » (CEPAC) conçu aux USA, et développé puis appliqué ensuite dans la collaboration « CEPAC international » avec des équipes françaises, ivoirienne, Sud-Africaine et indienne pour des analyses cout-efficacité. Dans la troisième partie, nous utilisons le modèle CEPAC pour explorer deux questions : La première question porte sur le choix entre efavirenz, potentiellement tératogène, et la névirapine, pouvant être responsable d’une toxicité sévère, pour servir de base à la première ligne de traitement antirétroviral chez les femmes en âge de procréer en Afrique subsaharienne. En projetant à 10 ans la survie chez la mère et le nombre cumulé de malformations chez l’enfant, nous montrons que la tératogénicité de l’efavirenz devrait être 2,3 fois plus élevée que celle de la nevirapine pour que le nombre de malformations chez les enfants dont les mères ont pris de l’efavirenz soit supérieur au nombre de décès chez les femmes qui ont pris de la nevirapine. La deuxième question porte sur l’efficacité et le coût-efficacité de plusieurs stratégies thérapeutiques après l’échec de la deuxième ligne de traitement ARV chez des adultes en Côte d’Ivoire. Cette analyse montre que l’utilisation des médicaments ARV de troisième ligne serait dores et déjà non seulement efficace mais également coût-efficace en Côte d’Ivoire, si elle était utilisée dans une stratégie comportant une phase de renforcement intensif de l’adhérence avant décision de changement de ligne. En conclusion, nous proposons de définir en quatre groupes les situations dans lesquelles la modélisation peut aider la recherche clinique : (i) pour aider à la conception d’un essai clinique ; (ii) pour mettre en perspective les résultats d’essais cliniques, en les projetant à plus long termes ou dans différents contextes ; (iii) pour étudier une question pour laquelle un essai clinique n’est pas faisable ; (iv) pour stimuler la réflexion sur de nouvelles questions sur lesquelles il n’y a pas encore eu d’essai. En même temps qu’on expérimente l’utilisation pratique de ces modèles, il y a également une réflexion à avoir sur les aspects de validation, de transparence et de standardisation, notamment au moment de la publication des études, pour les rendre accessibles aux cliniciens et aux chercheurs qui ne sont pas familiers avec la modélisation. / In the first part of this work, we review the issues that have been the subject of randomized clinical trials in the field of prevention and care of HIV-infected adults in sub-Saharan Africa. From this research, we draw two conclusions: (i) many research questions have not been explored with clinical trials, either because they were not considered as a priority, or because conducting a trial was not a feasible way to answer the question; (ii) trials with positive results often lead to new issues, especially regarding interpretation of results, practical implications, long-term projections, and replication in different contexts. At times, these issues paralyze health decisions. The question therefore becomes how to best use tools that complement clinical trials, including "disease modelling" tools. In the second part of this work, we place multi-state models of natural history of disease within different mathematical models used in medical research. We describe, in detail, one of these models--the “Cost Effectiveness of Preventing Aids Complication” (CEPAC) model, designed in the USA and then developed and implemented by the “CEPAC-International” collaboration, which includes French, Ivorian, South African and Indian teams, to conduct cost-effectiveness analyses. In the third part, we use the CEPAC model to explore two questions: The first question is concerned with whether to use efavirenz, which is potentially teratogenic, or nevirapine, which can induce severe toxicity, in first-line antiretroviral regimen for women of child-bearing age in sub-Saharan Africa. Projecting at 10 years the survival of the mothers and the cumulative number of malformations in their children, we show that the teratogenicity of efavirenz would have to be 2.3 times higher than that of nevirapine for the additional number of defects in children whose mothers are taking efavirenz to be greater than the number of additional deaths among women who are taking nevirapine. The second question focuses on the effectiveness and cost-effectiveness of different treatment strategies after the failure on second-line antiretroviral therapy (ART) in HIV-infected adults in Côte d'Ivoire. This analysis shows that the use of third-line ART would be effective and cost-effective in Côte d'Ivoire, if used within a strategy that mandated an intensive adherence reinforcement intervention before deciding to switch patients to third-line. In conclusion, we define four situations within which modelling can help inform clinical research: (i) to assist the design of clinical trials, (ii) to put in perspective the results of clinical trials, by projecting the results in the long term or in different contexts, (iii) to study any questions for which a clinical trial is not suitable, (iv) to fuel the discussion on new issues for which testing has not yet be done. While we experiment with the practical use of these models, we also have to reflect on the validation, standardization, and transparency of the model, especially at the time of publication, to make sure studies are accessible to clinicians and researchers who are not familiar with modelling.

The objectives of the study are to explore the effectiveness of the ABC HIV prevention strategy in South Africa with the purpose of establishing problem areas of the ABC HIV prevention strategy in South Africa. A systematic review design was followed. Electronic databases; Google scholar, Medline and PubMed were searched using broad combination of keywords to obtain all relevant articles. Studies written in English, published between 2000 and 2010, were selected if they met the inclusion criteria. In order to be included the study had to discuss the ABC HIV prevention strategy with the focus on effectiveness of the strategy. The Critical appraisal instrument for qualitative research studies (CASP, 2006) and Quality Assessment Tool for Quantitative studies (Effective Public Health Practice Project, 2005) were used to critically appraise the 9 studies that met the inclusion criteria. Thematic analysis was used for the analysis process. The findings regarding each objective were combined in a summary of findings. The findings revealed that the South African population engages in sexual activities at an early age. Males and females have concurrent sexual partnerships, which mean they are not faithful to their primary sexual partners and lastly, women are unable to use or negotiate condom use. Identified problem areas of the ABC HIV prevention strategy in South Africa were that the age gap between sexual partners is a problem as women cannot negotiate condom use with their seniors. The notion of love and romance that influences the use of condoms, has a negative impact whereby condom use is unacceptable in a long term relationship, irrespective of the level of faithfulness. Low socio-economic status of women that makes women to be dependent on men and also prone to engage in transactional sex. Lastly, local norms about sexuality that men subscribe to, to prove masculinity. / Thesis (M.Cur) North-West University, Mafikeng Campus, 2011

L’infection à VIH-1 est associée à une forte déplétion des lymphocytes T CD4+ à polarisation Th17 au niveau des tissus lymphoïdes associés aux muqueuses intestinales (GALT, gut-associated lymphoid tissues). Ceci conduit à la translocation microbienne, qui est une cause d’activation immunitaire chronique et de progression de la maladie. Les cellules épithéliales (CE) jouent un rôle critique dans le maintien de l’intégrité et de l’homéostasie au niveau des muqueuses intestinales via le recrutement des cellules de l’immunité innée (e.g., neutrophiles) et adaptative (e.g., cellules Th17). Les neutrophiles produisent des molécules antivirales (e.g., défensines-) et ont la capacité de limiter la réplication virale au niveau des muqueuses. Les cellules Th17 jouent un double rôle lors de l’infection à VIH. Elles contribuent d’une part à la défense contre différents pathogènes opportunistes en augmentant, via la production d’IL-17, la capacité des CE à attirer les cellules Th17 et les neutrophiles. D’autre part, les cellules Th17 jouent un rôle délétère en tant que cibles de réplication virale et sources de cytokines pro-inflammatoires. La fréquence des cellules Th17 est diminuée dans les GALT mais pas dans les poumons des patients infectés par le VIH, suggérant qu’il existe des mécanismes différents par lesquels les cellules Th17 sont recrutées vers ces sites anatomiques. Nous avons testé l’hypothèse selon laquelle le VIH interfère avec la capacité des CE intestinales et non pas pulmonaires à produire des chimiokines (CK) responsables de l’attraction des cellules Th17 et des neutrophiles. Nous avons démontré que les CE intestinales et pulmonaires produisent des CK spécifiques pour les cellules Th17 (CCL20) et les neutrophiles (CXCL8) en réponse à des stimuli pro-inflammatoires tels que l’IL-1 et le TNF-. Le TNF- agit en synergie avec l’IL-17, un « signal de danger » récemment identifié, et augmente la capacité des CE intestinales mais pas pulmonaires à produire la chimiokine CCL20. Cette synergie s’explique par l’augmentation préférentielle de l’expression du récepteur à l’IL-17 à la surface des CE intestinales suite à la stimulation par le TNF-. L’exposition au VIH n’affecte pas la production de CCL20 et de CXCL8 par les CE intestinales, mais altère la capacité des CE alvéolaires à produire ces chimiokines en accord avec la permissivité sélective de ces dernières à l’infection par le VIH. En conclusion, nos résultats démontrent que (i) le VIH n’interfère pas directement avec la capacité des CE intestinales à recruter des cellules Th17 et des neutrophils et que (ii) la production de CCL20 par ces cellules est dépendantes de la synergie entre le TNF- et l’IL-17. Ainsi, la déplétion des cellules Th17 et la pénurie en IL-17 dans les GALT des sujets infectés pourrait causer de façon préférentielle des altérations fonctionnelles au niveau des CE intestinales, se traduisant par l’altération du recrutement des cellules Th17 en réponse au CCL20. / The HIV-1 infection is associated with a severe loss of CD4+ T-cells with Th17 polarization from the gut-associated lymphoid tissues (GALT). These alterations lead to microbial translocation, which is a cause of chronic immune activation and disease progression in HIV-infected subjects. Epithelial cells (EC) play a critical role in maintaining mucosal integrity and homeostasis in the GALT by mechanisms including recruitment of innate (e.g., neutrophils) and adaptive immunity cells (e.g., Th17 cells). Neutrophils produce antiviral molecules (e.g., -defensins) that may limit HIV replication at mucosal sites. Th17 cells play a dual role in HIV pathogenesis. Th17 cells contribute to the defence against different opportunistic pathogens by increasing the ability of epithelial cells to attract neutrophils in an IL-17-dependent manner. On the other hand, Th17 cells play a deleterious role in HIV pathogenesis as they are sites of productive viral replication and a source of pro-inflammatory cytokines. The frequency of Th17 cells is decreased in the GALT but not in the lungs of HIV-infected individuals, suggesting distinct mechanisms of Th17 recruitment in these anatomic sites in the context of HIV pathogenesis. In this manuscript we tested the hypothesis that HIV differentially interfere with the ability of intestinal but not pulmonary EC to produce chemokines that attract Th17 cells and neutrophils. We demonstrated that both intestinal and pulmonary EC produce chemokines that specifically attract Th17 cells (CCL20) and neutrophils (CXCL8) upon stimulation with the pro-inflammatory cytokines IL-1 and TNF- . TNF-α acted in synergy with IL-17, a recently identified « danger signal », and increases the capacity of intestinal but not pulmonary EC to produce CCL20. This synergistic effect can be explained by the preferential upregulation of IL-17 receptor expression on intestinal EC upon TNF- stimulation. The exposure of intestinal EC to HIV did not affect their ability to produce CCL20 and CXCL8; however, exposure to HIV altered the production of these chemokines by alveolar EC, consistent with their selective permissiveness to infection. In conclusion, our results demonstrate that (i) HIV does not interfere directly with the ability of intestinal EC to attract Th17 cells and neutrophils and that (ii) the ability of intestinal EC to recruit the Th17 cells via CCL20 production is selectively dependent on the synergy between TNF- and IL-17. Thus, the depletion of Th17 cells and the shortage in IL-17 in the GALT of HIV-infected subjects may preferentially lead to functional alterations of the intestinal barrier resulting by the alteration of Th17 recruitment in response to CCL20.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. Johannesburg, 2016 / According to UNAIDS, there are ~36.9 million people infected with HIV-1 in the world. Of those, 25.8 million live in sub-Saharan Africa and 6.8 million in South Africa. HIV-1 subtype C accounts for over 95% of HIV infections in South Africa. HIV-1 retrovirus acquires mutations rapidly because of the viral reverse transcriptase. Naturally occurring polymorphisms distinguishing wild type C-SA PR from other proteases make it less susceptible to inhibitors. E35D↑G↑S is a C-SA PR variant with a double insertion in the flap region of the protease. The insertions and background mutations may decrease susceptibility to inhibitors as well as alter kinetic parameters due to increased flap flexibility. This study intended to characterise the effect of the mutations and insertions in E35D↑G↑S on structural, kinetic activity and drug susceptibility. Chemically-synthesised E35D↑G↑S autocatalyses rapidly, impeding further characterisation. There was no detectable overexpression of the E35D↑G↑S protease in Escherichia coli BL21 (DE3)pLysS and Rosetta 2® cells. If the protease is catalytically enhanced, attributed cytotoxicity may prevent overexpression of the protein. Increased autocatalytic activity could also prevent crystallisation. Inactive E35D↑G↑S D25A did not overexpress either, indicating that codon harmonisation with the expression host ought to be performed. C-SA PR was shown to be a predominantly beta-sheeted protein using circular dichroism spectroscopy. The KM of the fluorogenic substrate resembling the capsid/ p2 cleavage site for C-SA PR was 22.02 ±4.09 μM. The specific activity, catalytic turnover and catalytic efficiency of the wild-type C-SA PR protease were found to be 35.68 ±1.06 μmole.min-1.mg-1, 12.79 ±0.38 s-1 and 1.17 ±0.055 s-1.μM-1, respectively. The thermodynamics of binding of atazanavir, ritonavir and darunavir to C-SA PR were determined using isothermal titration calorimetry. The binding of atazanavir and ritonavir to C-SA PR is entropically driven and enthalpically opposed. However, the binding of darunavir to C-SA PR was found to be both entropically and enthalpically favourable. The dissociation constants of the inhibitors in the absence of substrate (Kd) are in the pico-molar range and increased by approximately one order of magnitude when saturating concentrations of substrate were introduced. Atazanavir, ritonavir and darunavir have dissociation constants (Kd) of 160.56 ±54.59 pM, 113.34 ±46.47 pM and 10.24 ±6.02 pM, respectively. Darunavir binds significantly tighter. Keywords: C-SA PR, E35D↑G↑S, insertion mutations, protease, autocatalysis, ITC.

Introdução As deficiências de vitaminas, verificadas em indivíduos com HIV/Aids em terapia antirretroviral de alta potência (HAART) têm sido associadas à piora do curso clínico da doença e maior risco de mortalidade. Objetivo Mostrar a distribuição das concentrações séricas de vitaminas A e E, e beta-caroteno em adultos com infecção pelo HIV/Aids e estudar a associação de suas concentrações, segundo diferentes esquemas de HAART. Métodos Foram selecionados 182 adultos de 20 a 59 anos de idade, de ambos os sexos, com HIV/Aids em HAART estável por no mínimo 6 meses, e com níveis de linfócitos T-CD4+ 200 células/mm3. Os indivíduos foram divididos em três grupos por esquema de HAART utilizado: inibidores de transcriptase reversa análogos de nucleosídeo (ITRN) associados a inibidores de transcriptase reversa não análogos de nucleosídeo (ITRNN); ITRN associada a inibidores de protease (IP); ITRN associadas a outras classes (inibidores de fusão, inibidores de integrase, inibidores de entrada e IP associada a essas medicações). A determinação dos micronutrientes foi realizada por cromatografia líquida de alta eficiência. Foram verificadas variáveis sócio-demográficas e econômicas, estilo de vida, história da doença, uso de medicações e variáveis antropométricas e laboratoriais. Para medir os efeitos das variáveis explanatórias (esquemas de tratamento, tempo de uso e adesão ao último esquema) sobre cada variável resposta (retinol, alfa-tocoferol e beta-caroteno), foram realizadas análises de regressão linear múltipla. Sexo, idade, escolaridade, tabagismo, prática de atividade física, tempo de infecção por HIV, presença de comorbidades, relação cintura-quadril e níveis de linfócitos T-CD4+ e colesterol foram usadas como variáveis de controle. Resultados Foram encontradas concentrações deficientes e baixas de vitaminas A (<0,70Nmol/L) e E (16,2Nmol/L), e beta-caroteno (<0,13Nmol/L) em 3,83 por cento, 18,68 por cento e 23,62 por cento dos indivíduos, respectivamente. Menores concentrações médias de vitamina E foram observadas em indivíduos em uso de ITRN associado a classes mais recentes de antirretrovirais (p= 0,037). Indivíduos com maiores índices de relação cintura-quadril apresentaram maiores concentrações de retinol (p=0,012) e menores concentrações de beta-caroteno (p=0,036). Foram também observadas associações positivas, pequenas e estatisticamente significantes entre as concentrações médias de retinol, alfatocoferol e beta-caroteno com os níveis de colesterol. Conclusão Os resultados sugerem que as alterações nas concentrações de vitamina A e E, e beta-caroteno podem estar relacionadas a múltiplos fatores, incluindo os esquemas de terapia antirretroviral / Introduction Deficiency of vitamins found in individuals with HIV/AIDS on highly active antiretroviral therapy (HAART) has been associated with an increased risk of disease progression and mortality. Objective To show the distribution of serum concentrations of vitamins A and E and beta-carotene in adults with HIV/AIDS, and to study the association of their concentrations, according to different regimens of HAART. Methods We selected 182 men and women aged 20-59 years with HIV/AIDS on stable HAART for at least six months and with levels of CD4+ T-lymphocytes 200 cells/mm3. Individuals were divided into three groups according to the HAART regimen used: nucleoside reverse transcriptase inhibitors (NRTI) combined with nonnucleoside reverse transcriptase inhibitors (NNRTI); NRTI combined with protease inhibitors (PI); NRTI combined with other classes (fusion inhibitors, integrase inhibitors, entry inhibitors, and PI associated with these medications). Determinations of vitamins A and E and beta-carotene were performed by high-performance liquid chromatography. Socio-demographic and economic variables, lifestyle, disease history, medication use, and anthropometric and laboratory variables were assessed. Multiple regression analyses were used to measure the effects of the explanatory variables (treatment regimens, duration and adherence to the last treatment regimen) on each response variable (retinol, alpha-tocopherol and beta-carotene). Sex, age, education, smoking, physical activity, duration of HIV infection, comorbidity, waist-to-hip ratio and levels of CD4+ T-lymphocytes and cholesterol were used as control variables. Results Deficient and low concentrations of vitamin A (<0,70Nmol/L) and E (16,2Nmol/L), and betacarotene (<0,13Nmol/L) were 3,83 per cent, 18,68 per cent and 23,62 per cent, respectively. Lower concentrations of vitamin E (p= 0,037) were observed in individuals using NRTI combined with the most recent classes of antiretrovirals. Individuals who had higher measurements of waist-to-hip ratio presented higher concentrations of retinol (p= 0,012) and lower concentrations of betacarotene (p=0,036). We also observed positive small statistically significant associations between mean concentrations of retinol, alpha-tocopherol and beta-carotene with cholesterol levels. Conclusion The results suggest that changes in the concentrations of vitamins A and E and beta-carotene may be related to multiple different factors, including antiretroviral therapy regimens

A l’ère de l’objectif cible « 90-90-90 » de l’ONUSIDA de réduction de la pandémie liée à HIV, il est important d’évaluer régulièrement la cascade de prise en charge des personnes vivant avec le virus HIV afin d’en vérifier l’avancement et d’identifier d’éventuels obstacles à sa réalisation. Pour cela nous avons étudié tout d’abord efficacité du traitement antirétroviral (TAR) dans le sang de personnes nouvellement dépistées séropositives à Bamako (Mali). Dans un deuxième travail nous avons évalué la faisabilité des tests de charge virale et de résistance génotypique aux antirétroviraux à partir de sang total séché sur un support de type buvard (DBS). La troisième partie de nos travaux était consacrée à des aspects plus physiopathologiques avec l’évaluation du traitement sur les réservoirs salivaires et génitaux (patients de Bamako) et sur le microbiote vaginal, ainsi que l’étude du profil de résistance des souches archivées dans l’ADN cellulaire de biopsies rectales. Nous avons tout d’abord observé un taux important de perdus de vue à un an dans la cohorte de Bamako (environ 45%). Nous avons également constaté un taux élevé de résistance primaire aux ARV à Bamako et au Tchad (>15%). De manière rassurante, le succès virologique au bout de 1 an chez les personnes traitées était d’environ 90% ce qui correspond à l’objectif de l’ONUSIDA (3ème 90) et un faible niveau de mutations acquises a été observé chez ces personnes adhérentes au traitement. Nous avons démontré l’efficacité du TAR sur le compartiment salivaire et constaté une compartimentation du virus au niveau cervico-vaginal chez certaines femmes traitées (27%) présentant une excrétion virale au niveau vaginal avec une charge virale plasmatique indétectable et/ou des séquences génétiques différentes sur le gène pol entre le virus isolé dans la muqueuse et celui provenant du sang. De plus, une dysbiose était observée avant la mise sous traitement, avec normalisation de la flore sous TAR efficace. En ce qui concerne le travail sur les biopsies rectales, des profils similaires ont été observés entre la souche plasmatique majoritaire au moment de la mise sous TAR et celle archivée dans le rectum 1 à 5 ans après traitement. En conclusion, nos travaux apportent des informations nouvelles sur le déroulement des différentes étapes de la prise en charge de l’infection par HIV dans les pays en développement : tout d’abord une faible adhésion au traitement ce qui peut constituer un obstacle majeur à la réalisation du plan 90/90/90 ; une forte prévalence de la résistance primaire qui plaident en faveur de l’accessibilité aux différentes classes d’antirétroviraux et de leur utilisation rationnelle, de l’utilisation généralisée en routine des tests de charge virale et du développement d’un réseau de surveillance de la résistance aux ARV dans les pays à ressources limitées ; des données d’efficacité de traitement sur les réservoirs muqueux mettant en évidence l’existence d’une dysbiose et d’une compartimentation du virus au niveau génital ce qui pose le problème du risque résiduel de transmission chez certaines personnes, même sous ARV. / Regularly assess to UNAIDS cascade 90-90-90 is important to check the progress and identify any obstacles to its implementation. For this we first studied efficacy of antiretroviral treatment (ART) in the blood of newly diagnosed HIV-positive in Bamako (Mali).In a second work we evaluated the feasibility of viral load and genotypic resistance tests from dried blood spot (DBS). The third part of our work is dedicated to pathophysiological aspects with evaluation of treatment on salivary and genital reservoirs (Bamako patients) and on the vaginal microbiota, as well as the study of the resistance profile of the strains archived in cellular DNA of rectal biopsies. We observed a high rate of lost to follow-up at one year in the Bamako cohort (45%). We also found a high rate of ART primary resistance in Bamako and Chad (> 15%). Reassuringly, the virological success after 1 year of treated follow was about 90% in these adherents. We also demonstrated the efficacy of ART in the salivary compartment and found a compartmentalization of the virus at the cervico-vaginal level in some women under ART. In addition, a dysbiosis was observed before ART, and a normal flora under effective ART. Similar profiles were observed on the main strain isolated in blood at the time of diagnosis and on the archived strain in the rectum after 1 to 5 years of ART.In conclusion, our work provides new information on the progress of the treatment stages of HIV infection in developing countries: low adherence to treatment which can constitute a major obstacle to achieve the plan 90/90/90; a high prevalence of primary resistance advocating accessibility and rational use of different classes of antiretrovirals drugs, widespread routine use of viral load tests and the development of ARVs resistance surveillance network in resource-limited countries; treatment efficacy data on mucosal reservoirs revealing the existence of genital dysbiosis and viral compartmentalization, which raises the problem of the residual risk of transmission in some people, even under ARVs.

Thesis (MPA.) -- University of Limpopo, 2018 / Background: Cancer of the cervix is the fourth most common cancer affecting women worldwide and is currently considered as a sexually transmitted cancer. This type of cancer is caused in most cases by a viral infection, Human Papilloma Virus (HPV) strains 16 and 18. Cervical screening aims to prevent invasive cervical carcinoma by detection and treatment of its precursors cervical intraepithelial neoplasia grade 2 (CIN2) and, particularly, grade 3 (CIN3). The current study aimed at determining the distribution of cervical cancer and the association of cervical cancer with HIV infection in Limpopo Province. Methods: The current study used quantitative retrospective method to systematically review the available data on Papanicolaou (Pap) smears from National Health Laboratory Services at Polokwane hospital from the year 2013 to 2015. The data was kept anonymously by not using the names of the patients and ethical clearance was received from the Turfloop Research Committee of University of Limpopo in consideration of section 14, 15, 16, and 17 of National Health Act 61 of 2004. The data was exported to excel spreadsheet and cleaned before exported into SPSS 23.0 software which was used for data analysis. Results: The findings from the current study show a decline of 33% in the number of Pap smears that were submitted for cytology between 2013 (82 041) and 2015 (23 527) in Limpopo province. However, the study revealed that there is an increase in prevalence of cervical cancer from 16.7% in 2013 to 19.2% in 2015 in Limpopo Province. In the same period this rural province already demonstrates a high burden of cervical cancer among the middle aged women. The positive cervical smears were classified as cervical intraepithelial neoplasia (CIN) I, II, or III and therefore, 78.5% were CIN I, 21% CIN II and 0,5% CIN III. HIV infections have been found to be associated with cervical cancer as the prevalence of cervical cancer among HIV positive women was found to be 25% and most of the affected women are the middle aged group. vi Conclusion: The screening coverage for cervical cancer has decreased in Limpopo Province but the prevalence of cervical cancer has increased by 2.5% therefore, this translates to the need for community awareness about prevention of cervical cancer. Majority of the cases were classified as CIN 1 at 78.5% which can be cured if treatment started early. The Limpopo Province should therefore strengthen strategies to integrate HIV and cervical cancer services as it was found that there is a strong association between the HIV and cervical cancer.

The ability to accelerate the accumulation of favorable combinations of mutations renders recombination a potent force underlying the emergence of forms of HIV that escape multi-drug therapy and specific host-immune responses. In this study, a mathematical model is developed that describes the dynamics of the emergence of recombinant forms of HIV following infection with diverse viral genomes. Mimicking recent in vitro experiments, target cells simultaneously exposed to two distinct, homozygous viral populations are considered and dynamical equations are constructed that predict the time-evolution of populations of uninfected, singly infected, and doubly infected cells, and homozygous, heterozygous, and recombinant viruses. Model predictions capture several recent experimental observations quantitatively and provide insights into the role of recombination in HIV dynamics. Comparisons of data from single round infection experiments with model predictions of the probability with which recombination accumulates distinct mutations present on the two genomic strands in a vision, indicates that »8 recombinational strand transfer events occur on average (95% confidence interval: 6-10) during reverse transcription of HIV in T cells. Model predictions of virus and cell dynamics describe the time-evolution and the relative prevalence of various infected cell subpopulations following the onset of infection observed experimentally. Remarkably, model predictions are in quantitative agreement with the experimental scaling relationship that the percentage of cells infected with recombinant genomes is proportional to the percentage of cells co-infected with the two genomes employed at the onset of infection. The model developed thus presents an accurate description of the influence of recombination on HIV dynamics in vitro. When distinctions between different viral genomes are ignored, the model reduces to the standard model of viral dynamics, which successfully predicts viral load changes in HIV patients undergoing therapy. The model developed may thus serve as a useful framework to predict the emergence of multi-drug resistant forms of HIV in infected individuals.