L’importante diversité génétique des VIH-1 a conduit à la classification actuelle en 4 groupes - M, N, O et P - dont seul le premier est pandémique. Les VIH-1 non-M sont endémiques au Cameroun, mais circulent aussi en France, du fait de liens étroits entre les deux pays. Il a été largement démontré que la diversité génétique, en particulier des VIH-1/O, avait un impact sur les tests de dépistage sérologique et de quantification virale. En revanche, peu de données sont disponibles quant aux conséquences de cette diversité génétique sur la prise en charge thérapeutique des patients infectés. Il a été décrit in vitro que la présence naturelle de la mutation Y181C conduisait à une résistance naturelle aux inhibiteurs non nucléosidiques de la transcriptase inverse, et que le polymorphisme important de la protéase avait un impact au moins génotypique, sur l’utilisation de certaines molécules, limitant ainsi les options thérapeutiques ; d’autre part, la réponse immuno-virologique des patients aux antirétroviraux (ARV) est méconnue, du fait d’études anciennes et/ou réalisées sur un nombre limité de patients. Les objectifs de ce travail était donc i) d’étudier la sensibilité naturelle des VIH-1/non-M aux classes d’ARV les plus récentes ; ii) d’analyser la réponse immuno-virologique aux ARV d’un grand nombre de patients infectés par un VIH-1/O et chez l’unique patiente infectée par un VIH1/P actuellement suivie. En lien avec l’usage actuellement répandu des inhibiteurs d’intégrase (INI), nous avons montré sur un large panel de 39 isolats cliniques VIH-1 non-M, l’absence d’impact majeur du polymorphisme naturel de l’intégrase sur la sensibilité phénotypique au raltegravir et au dolutegravir mais une importante disparité des réponses phénotypiques avec l’elvitegravir, possiblement corrélée à l’association de 4 mutations sur l’intégrase (V72I, I200L, N222K et R224Q). Nous avons également établi que le polymorphisme génétique des variants non-M, avec la présence naturelle des mutations M426L, M434I et S375H/M de la gp120, variables selon les groupes, serait préjudiciable à l’efficacité du fostemsavir, représentant de la nouvelle classe des inhibiteurs d’attachement. Aussi, l’analyse de la réponse immuno-virologique aux ARV de 101 patients infectés par un VIH-1/O et vivant en France a permis de montrer que la réponse était globalement satisfaisante. En nous intéressant plus particulièrement aux patients recevant une trithérapie incluant un INI lors d’un échec ou d’un switch, nous avons observé un taux de succès virologique de 80 à 90%, résultats en cohérence avec nos données phénotypiques et en faveur des recommandations à utiliser largement de cette classe ; lors des échecs virologiques, l’émergence des mutations de résistance suivait, a minima, des voies de sélection similaires à celles décrites pour les VIH-1/M. Enfin, le suivi de la patiente RBF168 infectée par un VIH-1/P a été l’occasion de décrire pour la première fois, l’évolution naturelle de cette infection rare, l’excellente réponse immuno-virologique, mais aussi le polymorphisme génétique de cette souche singulière. Nous avons enfin étudié certaines des propriétés virologiques de la souche RBF168 en lien avec ses capacités d’adaptation à l’Homme.L’ensemble de nos travaux a contribué à obtenir des données sur l’impact du polymorphisme génétique des VIH-1 non-M aux nouvelles classes thérapeutiques et sur la réponse immuno-virologique des patients. Ces nouvelles connaissances permettront d’adapter en conséquence et d’améliorer, la prise en charge thérapeutique des patients infectés par ces variants divergents, aussi bien en France qu’en zone d’endémie. / The high genetic diversity of the HIV-1 leads to a classification in 4 distinct groups: M, N, O and lastly P, but only the first being pandemic. The non-group M HIV-1 (non-M HIV-1) are endemic in Cameroon, but are also found in France due to the close link between the two countries. The high genetic diversity, particularly for HIV-1/O, has an impact on the serological screening assay and the viral quantification. But, little is known about the consequences on the therapeutic management. In vitro, it has been shown that the Y181C mutation lead to the natural resistance of non-nucleoside reverse transcriptase inhibitors and the high level of polymorphism in the protease region had a genotypic impact on several drugs, restricting the therapeutic options. The immune-virological response to antiretroviral drugs (ARV) is also unknown, because of old studies and/or in a limited number of patients. Our aims were the study of the natural susceptibility of the non-M HIV-1 to the most recent class of ARV and the analysis of the immuno-virological response, in a large cohort of HIV-1/O-infected patients and the unique patient infected with an HIV-1/P still followed up. From the current usage of the new class of integrase strand transfer inhibitors (INSTI), we have demonstrated for the first time on a panel of 39 non-M HIV-1 clinical isolates, that i) the natural genetic integrase polymorphism has no major impact on the phenotypic susceptibility to raltegravir, dolutegravir ii) a wide disparity of phenotypic response to elvitegravir exists and could be correlated to the association of 4 mutations in the integrase (V72I, I200L, N222K and R224Q). We also showed that the non-M HIV-1 natural polymorphism, with the presence of the M426L, M434I and S375H/M on the gp120, according to the group, would be detrimental to the efficacy of fostemsavir, the representative of the emerging class of attachment inhibitors. Then, we analysed the immunological and virological response to ARV, of 101 patients HIV-1/O infected and living in France, in the ORIVAO ANRS EP50 study. This unique data on the largest cohort of patients, allowed us to demonstrate a good. Focusing on the patients receiving a combination including an INSTI (at a failure or in a switch), a high virological success rate was observed (around 80 to 90%), confirming our phenotypic results and arguing for a wide usage of this class. At a failure, the emergence of resistance mutations was, at least, not different from the one observed in HIV-1/M.Lastly, the unique monitoring of the RBF168 patient infected by an HIV-1/P strain, provided the opportunity to describe, for the first time, the natural evolution, the excellent immuno-virological response, the natural genetic polymorphism and this unique strain and to study some of its virological properties, linked with its adaptation to the Human host.All together, these data contribute to describe the impact of the natural genetic polymorphism of non-M HIV-1 on the new class of drugs, better characterize the immune-virological response and finally allow to adapt the therapeutic management of the infected patients in France as well as in the endemic area.

Orientador: Lenice do Rosário Souza / Banca: André Pentean Trindade / Banca: Cilmery Suemi Kurokawa / Banca: Érika Ferrari Rafael da Silva / Banca: Mariangela Ribeiro Resende / Resumo: O uso da terapia antirretroviral (TARV) tem aumentado a sobrevida com melhora da qualidade de vida das pessoas vivendo com HIV/Aids (PVHA), o que também tem resultado em maior expectativa de vida. A infecção crônica pelo HIV e seu tratamento prolongado têm sido associados a diversas complicações ou eventos tardios, tais como, doenças metabólicas, cardiovasculares e renais, anormalidades na densidade mineral óssea (DMO) e osteoporose. Assim, o uso crônico da TARV tem demonstrado alta prevalência de deficiência de vitamina D, maior declínio da DMO e aumento do risco de fraturas de quadril, coluna vertebral e punhos, que têm sido relacionados principalmente ao uso de efavirenz, tenofovir e/ou inibidores de protease. Objetivos: estimar a prevalência e os fatores de risco das alterações ósseas e de fraturas, pela ferramenta FRAX, verificando a interferência da TARV sobre o nível sérico da vitamina D e na DMO em portadores do HIV. Casuística e métodos: foram estudadas 160 PVHA, com idades acima de 20 anos, de ambos os sexos, que atenderam aos critérios de inclusão para o estudo. Tratouse de estudo observacional realizado no Serviço de Ambulatórios Especializados de Infectologia "Domingos Alves Meira", Botucatu/SP. Foram incluídos pacientes adultos, com idade de 20 anos ou mais, em uso ou não de TARV e excluídos gestantes e mulheres menopausadas, além de indivíduos com diagnóstico de hipogonadismo. Prontuários médicos além de questionário específico foram utilizados para... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The use of antiretroviral therapy (ART) has increased survival and improved quality of life for people living with HIV/Aids (PLWH), this therapy has also resulted in longer life expectancy. Chronic HIV infection and its prolonged treatment have been associated with various complications or late events, such as metabolic, cardiovascular and renal diseases, abnormalities in bone mineral density (BMD), and osteoporosis. Thus, chronic usage of ART, has caused high prevalence of vitamin D deficiency, greater decline in BMD, and increased risk of hip, spine and fist fractures, that has been mainly related to use of efavirenz, tenofovir and/or protease inhibitors. Objectives: To estimate the prevalence and risk factors of bone alterations and fractures using the fracture risk assessment tool (FRAX), to verify the interference of ART on the serum level of vitamin D and in BMD among HIV patients. Casuistry and methods: 160 PLWH were studied, of both sexes, with ages over 20 years, who meet inclusion criteria for the study. This observational study was performed at the Domingos Alves Meira Department of Specialized Ambulatory Infectology (SAEI-DAM) - Botucatu/SP/Brazil. The study included adult patients, aged 20 years or older, in regular use of ART or not; pregnant, menopausal women and individuals who had been diagnosed with hypogonadism were excluded. Medical records and a specific questionnaire were used to obtain demographic data, information on life habits, family and individual histories of bone fractures and antiretroviral uses. Serum dosages were measured, with chemiluminescence for vitamin D and parathyroid hormone and dry chemistry for calcium, phosphorus and alkaline phosphatase, CD4+ T lymphocyte counts were made using flow cytometry, HIV viral load determinations were taken using real-time PCR and sandwich enzyme linked immunosorbent assay (ELISA Kit Elabscience) was used for a ... (Complete abstract click electronic access below) / Doutor

Fléau mondial depuis des millénaires, la tuberculose (TB) a régressé dans la deuxième moitié du 20ème siècle avant de connaitre une résurgence à partir des années 1980 à la faveur de la pandémie du VIH. Les deux maladies se potentialisent mutuellement et forment un « couple infernal ». En Afrique, la TB est la première cause de mortalité des adultes infectés par le VIH, quel que soit leur niveau d’immunité. Une des mesures pour lutter contre la TB associée au VIH est la chimioprophylaxie, consistant à traiter une infection tuberculeuse latente pour prévenir l’évolution vers une TB maladie. La mieux évaluée, consiste à prescrire 6 à 12 mois de monothérapie d’isoniazide (Isoniazid Preventive Therapy, IPT). Depuis 1993, l’OMS recommande la prescription de 6 mois d’IPT chez toutes les personnes infectées par le VIH sans signe de TB active. Malgré des preuves scientifiques solides à l’appui de cette recommandation, l’utilisation de l’IPT est toujours restée faible. Avant notre travail, trois raisons expliquaient cette faiblesse : (i) la crainte qu’une chimioprophylaxie mal appliquée ne favorise l’émergence de résistances ; (ii) le fait que les essais avaient démontré l’efficacité de l’IPT pour réduire l’incidence de TB, pas pour réduire la mortalité ; (iii) le fait que les essais d’IPT avaient eu lieu en majorité avant l’ère des antirétroviraux (ARV), chez des personnes très immunodéprimées. Les ARV permettant également de réduire le risque de TB en faisant régresser l’immunodépression, certains considéraient que l’IPT était devenue inutile. Dans cette thèse nous faisons d’abord un rappel des connaissances essentielles sur l’infection par le VIH, la TB, l’association TB/VIH, et le concept de chimioprophylaxie antituberculeuse. Puis nous exposons les résultats de l’analyse du suivi prolongé de l’essai randomisé Temprano ANRS 12136, qui s’est déroulé entre 2008 et 2015. Cet essai a suivi 2056 adultes infectés par le VIH dans 9 centres de soins à Abidjan. Les participants qui avaient des CD4 élevés (moyenne 477/mm3) étaient randomisés en 4 bras pour étudier deux interventions : 6 mois d’IPT (reçu vs. non reçu) et ARV (début immédiat vs. début différé). Les participants ont été suivis pendant 4,9 ans en moyenne. 89% d’entre eux ont débuté des ARV. Pendant le suivi, il y a eu 86 décès, 34 dans le groupe avec IPT (probabilité à 6 ans : 4,1% ; IC95% 2,9–5,7) et 52 dans le groupe sans IPT (probabilité à 6 ans: 6,9% ; 5,1–9,2). Le Hazard ratio de décès dans le groupe avec IPT par rapport à l’autre groupe était 0,63 (95% CI 0,41-0,97). Il n’y avait pas d’interaction entre IPT et ARV précoce, ni entre IPT et le temps. Ces résultats ont été publiés dans The Lancet Global Health. Enfin nous discutons ces résultats avec ceux des essais d’IPT précédents, dans une revue critique de la littérature analysant les données d’efficacité et de tolérance, les déterminants de l’efficacité, et les risques de résistance. Nous montrons que l’essai Temprano complète et élargit le spectre des connaissances, et que les preuves scientifiques accumulées depuis 1993 jusqu’à l’essai Temprano inclus suggèrent que les ARV modifient certains paramètres de l’IPT qu’on pensait solidement établis. Avant l’ère des ARV on considérait que l’efficacité de l’IPT était forte chez les personnes avec IDR positive mais très faible voire inexistante chez les personnes avec IDR négative, qu’il y avait une perte d’efficacité de l’IPT au cours du temps et que l’IPT n’avait pas d’effet sur la mortalité. Avec les ARV, on voit que l’IPT est efficace quel que soit le résultat des tests tuberculiniques, que cette efficacité est prolongée, et qu’elle se traduit non seulement par une réduction de la TB mais aussi de la mortalité. L’IPT reste donc une intervention d’une grande actualité à l’ère des ARV. Ces résultats devraient convaincre les pays jusque-là réticents à appliquer les recommandations de l’OMS. / Tuberculosis (TB) has been a worldwide scourge for millennia. It has regressed in the second half of the 20th century before resurging in the 1980s because of the HIV pandemic. Both diseases potentiate each other and form a "cursed duet". In Africa, TB is the leading cause of mortality among HIV-infected adults, regardless of their level of immunity. One of the measures to fight HIV-associated TB is chemoprophylaxis, which consists in treating latent TB infection to prevent the progression to TB disease. The most evaluated chemoprophylaxis, referred to as "Isoniazid Preventive Therapy" (IPT), consists in prescribing 6 to 12 months of isoniazid monotherapy. Since 1993, WHO recommends the prescription of 6 months of IPT in all HIV-infected persons who do not have evidence of active TB. Despite strong scientific evidence to support this recommendation, the use of IPT has remained low. Before our work, there were three reasons for this:(i) people feared that chemoprophylaxis might favor the emergence of resistance to TB drug; (ii) the IPT trials demonstrated the effectiveness of IPT in reducing TB incidence, not in reducing mortality; (iii) most IPT trials took place before the antiretroviral treatment (ART) era, in highly immunocompromised individuals. As ART also reduces the risk of TB by decreasing immunosuppression, some people considered that IPT had become useless. In this work, we first go over the basic knowledge about HIV infection, TB, the combination of the two diseases, and the concept of antituberculous chemoprophylaxis. Then we present the results of the long-term follow-up of the Temprano ANRS 12136 randomized trial, which took place between 2008 and 2015. This trial followed 2056 HIV infected adults in 9 care centers in Abidjan. Participants with high CD4 counts (mean: 477 cells/mm3) were randomized into 4 arms to study two interventions: 6 months of IPT (received vs. not received) and early ART (immediate initiation vs. delayed initiation). Participants were followed for an average of 4.9 years. Eighty nine percent of participants received ART. During follow-up, there were 86 deaths, 34 in patients randomized to IPT (6-year probability: 4.1%, 95% CI 2.9-5.7) and 52 in those randomized to no-IPT (6-year probability: 6.9%, 5.1-9.2). The Hazard ratio of deaths among those randomized to IPT compared to others was 0.63 (95% CI 0.41-0.97). There was no interaction between IPT and early ART, nor between IPT and time. These results were published in The Lancet Global Health. Finally, we discuss these results with those of previous IPT trials, after reviewing all available randomized-controlled evidence on efficacy, safety, efficacy determinants and risks of resistance. We show that the Temprano trial complements and widens the spectrum of evidence accumulated since 1993 and that ART modifies some key parameters of IPT previously thought to be strongly established. Prior to the ART era, evidence suggested that the efficacy of IPT was high in people with positive Tuberculin Skin Test (TST) but very low in those with negative TST; that there was a loss of IPT efficacy over time; and that IPT had no effect on mortality. With ART, IPT appears to be effective regardless of TST results, have prolonged efficacy, and reduce not only TB but also mortality. IPT remains a very topical intervention in the ART era. These results should convince IPT-reluctant countries to implement WHO recommendations.

Nous avons évalué l’accessibilité, l’acceptabilité et l’efficacité à 12 mois du traitement antirétroviral précoce (TAP) initié avant 2 ans chez l’enfant infecté par le VIH en Côte d’Ivoire et au Burkina Faso. Nous avons mené deux enquêtes de base, puis analysé le recrutement et la réponse dans la cohorte thérapeutique recrutée en amont de l’essai MONOD ANRS 12206. En dépit d’une couverture prénatale du dépistage VIH élevée de 88%, seulement 29% [IC à 95% : 27-32] des enfants exposés avaient eu accès au diagnostic virologique précoce en 2011 à Ouagadougou. En termes de connaissances, 97% des parents/tuteurs d’enfants connaissaient la principale voie de transmission du VIH chez les nourrissons. Tous les parents pensaient que le TAP de l’enfant était nécessaire, sans savoir en quoi il consistait. Parmi les 217 enfants référés pour inclusion, 161 (74%) ont initié un TAP à un âge médian de 13,5 mois ; 70% avaient atteint le stade 3/4 de l'OMS, et 57% un déficit immunitaire sévère. Les raisons de non-inclusion étaient : peur ou refus du père (48%), mortalité (24%), faux-positifs (16%), autres (12%). Avoir déjà partagé le statut VIH de l'enfant ou de la mère avec le père et avoir un âge ≥12 mois étaient les deux facteurs associés à l’initiation du TAP. Parmi les 156 enfants ayant reçu un TAP à base de LPV/r, 11 enfants sont décédés (7%), 5 perdus de vue (3%), 140 ont été suivis à 12 mois (90%), avec 70% de succès virologique (charge virale<500 cp/mL). En 2011-2013, les défis pour améliorer l’accès au TAP chez les enfants infectés par le VIH en Afrique de l'Ouest demeurent. L’accès tardif est associé à une forte mortalité précoce. Néanmoins, le taux de succès au TAP est élevé. / We assessed the accessibility, acceptability and efficacy at 12 months of early antiretroviraltherapy (EAT) initiated before two years of age in children HIV-infected in Côte d'Ivoire andBurkina Faso.We conducted two baseline surveys and analyzed the enrolment and therapeutic response inthe cohort recruited ahead of the MONOD ANRS 12206 trial.Despite a high prenatal HIV screening coverage of 88%, only 29% [95% CI: 27-32] exposedchildren had access to early HIV diagnosis in 2011 in Ouagadougou.In terms of knowledge, 97% of parents/caregivers of children were aware of the main route ofHIV transmission in infants. All the parents thought the child EAT was necessary, withoutreally know in what it consists.Among the 217 children referred for inclusion, 161 (74%) have initiated EAT with a medianage of 13.5 months; 70% had reached the 3/4 WHO stage, and 57% had a severe immunedeficiency. The reasons for non-inclusion were: fear or the father's refusal (48%), mortality(24%), false positives (16%), others (12%). Having already shared the child or the motherHIV status with the father and having an age ≥ 12 months were the factors associated with theinitiation of EAT.Among the 156 children who received an EAT-based lopinavir/ritonavir, 11 children died(7%), 5 were lost to follow-up (3%), 140 were followed for 12 months (90%), with 70%virological success (viral load <500 cp / mL).In 2011-2013, the challenges for improving access to EAT in HIV-infected children in WestAfrica remain. Late access is associated with a high early mortality. Nevertheless, the successrate of EAT is high.

HIV and AIDS pandemic have been declining in South Africa. HIV and AIDS affect individuals, families, organizations and the communities at large. While the roll out of the antiretroviral treatment (ART) has brought much excitement and hope to both patients and the health practitioners, it has also brought challenges (Maskew, Macphail, Menez & Rubel, 2007:853). In order for ART to be effective patients need to adhere to antiretroviral treatment, thus adherence is a critical component of ART. Patients who discontinue treatment are at high risk of illness and death because of AIDS related diseases or developing drug resistant virus. With a better understanding of the reasons for defaulting antiretroviral treatment interventions can be designed to improve adherence to antiretroviral treatment. Thus the purpose of this study was to explore the reasons why HIV and AIDS infected patients default antiretroviral treatment because adherence to ART is of utmost important. Within the context of qualitative and applied research the researcher utilized the collective case study design. Semi structured interviewing was used as data collection method to elicit qualitative information on the reasons why patients default ART. The main research question that was put forward to all participants was: What are your reasons for defaulting ART? The participants in this study were patients who have default their ART during 2012. By using systematic sampling fourteen participants from Thekganang ARV Clinic in Seshego District Hospital, Limpopo province, were selected to form a sample for this study. Some conclusions based on the findings were that: The participants were knowledgeable about the basic facts of HIV and AIDS and they had a good understanding about the importance of adherence even though they defaulted their antiretroviral treatment. The use of ART may also be challenging to individuals. The findings of this study were that not all participants in the study experienced challenges with taking ART. Those who experienced challenges included fear of disclosing HIV status, fear of stigmatization and physical challenges due to ill health. Regarding the reasons for defaulting ART, participants’ reasons for defaulting antiretroviral treatment were similar although some of the reasons applied to only one participant. Participants’ reasons for treatment default were classified into socio-economic factors, patient related, psychological related and medication related factors. Socio- economic factors included shortage of food in the household and lack of money for transport to attend clinic appointments. Patient related factors included substance abuse, lost appointment cards, participants were too busy with personal issues and relocation to another area of residence. Psychological factors that contributed to non-adherence to treatment were depression and denial. Medical related factor voiced was that participant was too confused about the drug regimen. Most participants were satisfied with the services in Thekganang ARV clinic although some participants raised concerns about staff attitudes and long queue. The findings will assist the hospital management and the clinic staff to make informed decisions about the management of defaulters in the clinic. The study was concluded with the relevant recommendations to the ART facilities. The recommendations included implementation of the multi-disciplinary centred approach, establishing patient education programmes and on-going support services to patients who fail to adhere to treatment. Future research studies should determine the prevalence of drug resistant HIV patients in the ART facilities and the development of a systematic method of capturing ‘‘lost to follow up’’ patients who pass away within hospitals. / Dissertation (MA)--University of Pretoria, 2014. / lk2014 / Social Work and Criminology / MA / Unrestricted

Objective: The objective of this retrospective cohort study is to assess whether demographic and anthropometric parameters, laboratory tests, co-morbidity, co-infection, treatment regimen, IRIS and adherence predict response to HAART as measured by CD4 count, weight gain and functional status in a cohort of patients in Roma, the Kingdom of Lesotho. Method: Data were collected from a computerised database of the Antiretroviral Centre of the hospital. A cohort of 300 subjects was identified from hospital records from January 2007. Each of these subjects was followed up over a period of 12 months with data obtained for at least two visits within the 12-month span. Data were obtained on weight and CD4 at baseline, three months and also at six and 12 months, and data for haemoglobin were obtained only at 12 months. Variables that may be potential confounders were identified and univariate and multivariate logistic regression analyses were carried out to establish differences independent of confounding factors for the combined endpoints, as well as for each endpoint separately. Results: Three-hundred patient records were analysed. Approximately 70% of the patients had a CD4 increase of at least 150 cells over baseline values at the end of the review period and in 52.3% of the patients an increase in weight of 10% over baseline measurements was seen. Seventy-nine patients (26.3%) had a haemoglobin level of at least 14g/dL at 12 months, regardless of baseline values or gender. The inclusion of Zidovudine (AZT) in treatment regimens was found in 73% of the patients and in multivariate analysis AZT was associated with not having anaemia at the end of the review period. However there was a slight reduction in haemoglobin level in the first two to three months of therapy in comparison with both Stavudine (d4T) and Tenofovir (TDF) but not significant enough to result in clinical anaemia. Baseline CD4 values were similar for all treatments options but dissimilar in other outcome variables and continued to vary significantly throughout the review period. The outcomes of multivariate analyses suggest that the male gender appears to have better response to HAART as seen in each of the multivariate models. The most important determinant of haemoglobin response was baseline haemoglobin values. In the haemoglobin-associated multivariate model, HAART is associated with an increase in haemoglobin over baseline values. A history of TB prior to HAART was a major factor in weight response and it is thought to be as a result of IRIS, which is the unmasking of latent infections as the immune system reconstitutes. CD4 values have no direct influence on weight however, but an increase in weight was observed in all therapy groups. Conclusion: Clinical and immunological parameters can be used to monitor response to HAART and predict treatment outcomes. These parameters can be organised into monitoring tools that will be useful in resource-limited areas. This study suggests that AZT-containing regimens appear not to result in anaemia and that symptomatic anaemia might need additional investigation. Treatment with TDF appeared to have shown the best possible response pattern more but patients on TDF therapy will have to be included in the study to justify this observation. / Dissertation (MSc)--University of Pretoria, 2012. / Clinical Epidemiology / unrestricted

The aim of the study was to evaluate the effect of human immunodeficiency virus infection (HIV) and antiretroviral treatment on the retinal nerve fibre layer (RNFL). The RNFL hickness defined by standard parameters(TSNIT average, Superior average and Inferior average) was assessed in 48 HIV positive patients using scanning laser polarimeter, GDx VCC device. Results were compared to normal values and tested against factors suspected to affect the RNFL thickness. The mean values of the RNFL standard parameters were for TSNIT average, Superior average and Inferior average, 57,65 ± 6,18  m, 69,38 ± 8,34  m, 68,89 ± 9,50  m respectively, in our cohort. The RNFL thinning was not confirmed in our HIV positive group compared to values on healthy population. No significant correlation between the RNFL thickness and the immune profile or antiretroviral therapy was detected. However, a significant negative correlation between the RNFL thickness with increasing duration of HIV infection was foundin our study that is hypothesized to be possibly on an immune pathological basis. Powered by TCPDF (www.tcpdf.org)

>Magister Scientiae - MSc / Background and Aims Human Immunodeficiency Virus (HIV) type 1 group M subtype C (HIV-1C) accounts for nearly half of global HIV-1 infections, with South Africa (SA) being one of the countries with the highest infection burden. In recent years, SA has made great strides in tackling its HIV epidemic, resulting in the country being recognized globally as the one sub-Saharan country with the largest combination antiretroviral therapy (cART) programme. Regardless of the potency of cART, the efficacy of the treatment is limited and hampered by the emergence of drug resistance. The majority of research on HIV-1 infections, effect of antiretroviral (ARV) drugs and understanding resistance to ARV drugs has been extensively conducted, but mainly on HIV-1 subtype B (HIV-1B), with less information known about HIV-1C. HIV-1’s viral Integrase (IN) enzyme has become a viable target for highly specific cART, due to its importance in the infection and replication cycle of the virus. The lack of a complete HIV-1C IN protein structure has negatively impacted the progress on structural studies of nucleoprotein reaction intermediates. The mechanism of HIV-1 viral DNA’s integration has been studied extensively at biochemical and cellular levels, but not at a molecular level. This study aims to use in silico methods that involve molecular modeling and molecular dynamic (MD) simulations to prioritize mutations that could affect HIV-1C IN binding to DNA and the IN strand-transfer inhibitor (INSTI) dolutegravir (DTG). The purpose is to help tailor more effective personalized treatment options for patients living with HIV in SA. This study will in part use patient derived sequence data to identify mutations and model them into the protein structure to understand their impact on the HIV-1C IN protein structure folding and dynamics. Methods Our sample cohort consisted of 11 sample sequences derived from SA HIV-1 treatmentexperienced patients who were being treated with the INSTI raltegravir (RAL). The sequences were submitted to the Stanford HIV resistance database (HIVdb) to screen for any new/novel variants resulting from possible RAL failure. Some of these new variants were analyzed to analyse their effect, if any, on the binding of DTG to the HIV-1C IN protein. Additionally, an HIV-1C IN consensus sequence constructed from SA’s HIV-1 infected population was used to model a complete three-dimensional wild type (WT) HIV-1C IN homology model. All samples were sequenced by our collaborators at the Division of Medical Virology, Stellenbosch University together with the National Health Laboratory Services (NHLS), SA. The HIV-1CZA WT-IN protein enzyme was predicted using SWISS-MODEL, and the quality of the resulting model validated. Various analyses were conducted in order to study and assess the effect of the selected new variants on the protein structure and binding of DTG to the IN protein. The mutation Cutoff Scanning Matrix (mCSM) program was used to predict protein stability after mutation, while PyMol helped to study any changes in polar contact activity before and after mutation. PyMol was also used to generate four mutant HIV-1C IN complex structures and these structures together with the WT IN were subjected to production MD simulations for 150 nanoseconds (ns). Trajectory analyses of the MD simulations were also conducted and reported. Results A total of 21 new variants were detected in our sample cohort, from which only six were chosen for further analyses within the study. A homology model of HIV-1C IN was successfully constructed and validated. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90.0% confidence in modelled regions. Of the six selected variants, only one (S119P) was calculated to be slightly stabilizing to the protein structure, with the other five found to be destabilizing to the IN protein structure. Variant S119P showed a loss in polar contacts that could destabilize the protein structure, while variant Y143R, resulted in the gain of polar contacts which could reduce flexibility of the 140’s region affecting drug binding. Similarly, mutant systems P3 (S119P, Y143R) and P4 (V150A, M154I) showed reduced hydrogen bond formation and the weakest non-bonded pairwise interaction energy. These two systems, P3 and P4, also showed significantly reduced to none polar contacts between DTG, magnesium (MG) ions and the IN protein, compared to the WT IN and P2 mutant IN systems. Interestingly, the WT structure and systems P1 (I113V) and P2 (L63I, V75M, Y143R) showed the highest non-bonded interaction energy, compared to systems P3 and P4. This was further supported by the polar interaction analyses of simulation clusters from the WT IN and mutant IN system P2 (L63I, V75M, Y143R), which were the only protein structures that formed polar contacts with DTG, MG ions and DDE motif residues, while P1 only made contacts with DNA and IN residues. Conclusion Findings from this study leads to a conclusion that double mutants (S119P, Y143R) and (V150A, M154I) may result in a reduction in the efficacy of DTG, especially when in combination. Furthermore, variants identified in systems P1 and P2 may still allow for effective DTG binding to IN and outcompete viral DNA for host DNA to prevent strand transfer. To the best of our knowledge, this is the first study that uses the consensus WT HIV1C IN sequence to build an accurate 3D homology model to understand the effect of less frequently detected/reported variants on DTG binding in a South African context. https://etd.

Magister Curationis / The National Programme of Prevention of Mother to Child transmission (PMTCT) in relation to HIV/AIDS was introduced by the Department of Health in different sites per province in South Africa in 2001. The number of women has a chance to access antenatal clinic services during pregnancy but they start to attend usually in late gestation.

Magister Public Health - MPH / Background: With the improvements in the effectiveness and availability of antiretroviral therapy (ART), perinatally infected children are surviving to adolescence and emerging as a significant sub-population living with HIV/AIDS in Zimbabwe. Adolescents, aged 10-19 years, face unique challenges related to adherence to chronic medication due to this period of vulnerability that is characterised by decreased parental support and supervision, decreased inhibition, increased risk-taking, and immature judgement. It is widely reported that poor adherence to ART leads to viral rebound, disease progression and drug resistance, in addition to increasing the risk of transmitting resistant strains of HIV to others. It is imperative to determine the factors that influence ART adherence among HIV positive adolescents so that effective interventions can be put in place. The current study described the factors that are associated with adherence to ART among HIV positive adolescents in Zimbabwe. Methodology: A cross-sectional survey of 136 randomly selected adolescents (10-19 years) who were receiving ART at two referral hospitals in Masvingo District in 2019 was undertaken. A questionnaire was administered to collect data on socio-demographic characteristics, adherence and factors related to adherence such as person/patient, health system, medication, disease characteristics and social factors. Clinical data were extracted from the Electronic Monitoring Patient System. SPSS v24 was used for descriptive and inferential analysis. Results: More than half of the participants (61%) had combined optimal adherence (dose adherence, schedule adherence and adhered to dietary instructions) in the previous three days. The most frequent reasons reported for missing HIV medications in the previous month was being away from home (50%); forgetfulness (25%); and having too many pills to take (25%). In bivariate analysis, only duration of time since HIV diagnosis was significantly associated with combined adherence to ART in the previous three days. Conclusion: Tailored interventions are recommended to address low adherence amongst adolescents. These interventions should include convenient clinic appointment schedules for adolescents to pick up medication, reminders to take medication, regimen change to a single dose, and peer education and adherence clubs to improve knowledge about HIV and treatment, and curb treatment fatigue.