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Thesis advisor: Welkin Johnson / HIV-associated comorbidities including neurological disorders (HAND) and cardiovascular diseases (CVD) persist in people living with HIV (PLWH) regardless of adherence to antiretroviral therapies (ART). The development of these comorbidities correlates with increased monocyte/macrophages activation and accumulation. Studies report that the development of CVD and HAND are connected in PLWH, but few studies have examined the roles that monocyte/macrophages activation have in their co-development. We first asked how frequently CD8+ T lymphocyte depleted, SIV-infected rhesus macaques with AIDS co-developed cardiac pathology and SIV encephalitis (SIVE) compared to animals that developed CVD or SIVE alone, and animals with no significant cardiac pathology (NSF) and SIV with no encephalitis (SIVnoE) (Chapter 2). We sought to determine whether animals with concomitant CVD and SIVE had more monocyte activation, cardiac macrophages accumulation, and productively infected SIV-RNA+ and SIV- gp41+ cells in the heart and brain compared to animals with CVD or SIVE alone, and animals with NSF and SIVnoE. We found that animals with AIDS co-developed CVD and SIVE more frequently than animals developed CVD or SIVE alone, and NSF and SIVnoE. Animals with CVD and SIVE had increased biomarkers of monocyte activation, cardiac macrophages inflammation, and productively infected macrophages in the brain. We found that the quantity of SIV-RNA+ cells in the heart was sparse compared to the brain. When detected, cardiac SIV-RNA+ cells are CD68+ and CD206+ cardiac macrophages. Levels of plasma soluble CD163 (sCD163) correlated with plasma galectin-3 (Gal-3), galectin-9, and interleukin-18 (IL-18), more so than plasma viral load. We then assessed cardiac tissues from PWLH with HIV encephalitis (HIVE) and HIV no encephalitis (HIVnoE). We found that PLWH with HIVE had more cardiac inflammation and fibrosis than PLWH with HIVnoE. These findings indicate that CVD and HAND pathogenesis are connected, and that the level of myeloid cell activation correlates with the development and severity of concomitant CVD and HAND. The findings from this study emphasize the importance that macrophages accumulation has in developing AIDS-related comorbidities. Our findings highlight the importance of targeting monocyte/macrophages activation and accumulation in future HIV therapies. The persistence of CVD in the post-ART era suggests that ART successfully inhibits AIDS pathogenesis and HIV replication, but fails to block monocyte activation and macrophages accumulation correlated with CVD pathogenesis. We hypothesize that the optimal therapeutic approach for HIV-infection includes blocking AIDS pathogenesis and viral replication, and inhibiting monocyte/macrophages activation. Methylglyoxal-bis-guanylhydrazone (MGBG) is a polyamine biosynthesis inhibitor selectively taken up by monocytes and macrophages. MGBG treatment blocks monocyte/ macrophages activation in vitro, AIDS pathogenesis, and decreases inflammation in cardiac and brain tissues of SIV- infected rhesus macaques. We asked whether animals treated with ART and adjunct MGBG (ART+MGBG) had an additive decrease in monocyte activation and turnover, cardiac macrophages inflammation and collagen deposition compared to animals on ART, and untreated animals (Chapter 3). We found that animals on ART+MGBG had lower percentages of cardiac collagen deposition than animals on ART. Animals on ART, and ART+MGBG did not develop AIDS, and had decreased cardiac inflammation and collagen, and monocyte activation and turnover compared to untreated animals. Finally, we identified two populations of Gal-3 expressing (Gal-3+) cells in the heart, CD163+ Gal-3+ cardiac macrophages and CD163- Gal-3+ cells. Animals on ART, and ART+MGBG had decreased numbers of CD163+ Gal-3+ cardiac macrophages compared to untreated animals. All animals had similar numbers of CD163- Gal-3+ cells, and low frequencies of SIV-RNA+ cardiac macrophages regardless of treatment. These data suggests that blocking AIDS pathogenesis with ART, and ART+MGBG correlates with decreased monocyte activation and cardiac inflammation and collagen deposition. Overall, we did not find an additive effect in animals on ART+MGBG compared to animals on ART. Our findings show how targeting monocyte/macrophages activation with ART+MGBG blocks AIDS pathogenesis and decreases cardiac macrophages inflammation. This study demonstrates the advantages of therapeutic strategies blocking myeloid cell activation in conjunction with ART. / Thesis (MS) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

This descriptive research used the Health Belief Model (HBM) to assess HIV/AIDS knowledge, perceived severity, perceived susceptibility, and behavioral practices within the population throughout the State of Sonsonate, El Salvador. Geographic Information Systems (GIS) was also utilized to display the results of this population study. The study population was composed of 15-39 year olds consisting of a total sample size of 1,500 (250 participants from each of the six cities). The basis of this study was to evaluate where this population fit within the Health Belief Model (HBM) and also to practically represent the results pictorially. Also, this information was collected so that the government of El Salvador could see and understand where their educational deficits existed so that future programs could be established to alleviate these discrepancies. An instrument consisting of 65 items including demographics, knowledge, perceived severity, perceived susceptibility, and behavioral practices was used for the general population. The analysis of the data was two-fold using Geographic Information Systems (GIS) mapping and statistical analysis. GIS mapping was used to graphically pinpoint areas of knowledge deficit and misinformation about HIV/AIDS. Results were based on a general population of 1,454. Various indices were created to show the level of knowledge or frequency of safe behavioral practices. The Perceived Severity and Perceived Susceptibility sections were not aggregated into an index but rather treated as individual variables. An item analysis of the questionnaire found that on average the general population responded correctly to 78% of the knowledge questions. However, a total of 11 questions in the knowledge section had less 75% (n=385) of the general population answering correctly. Another 3 questions in the behavior section were also found to have less than 75% (n=385) indicating safe behavioral practices. Linear regression analyses were performed to explore correlations between the areas of demographics, knowledge level, perceived severity, and perceived susceptibility to safe behavior. GIS maps were created to pictorially show where this population's deficiencies were in regard to the HBM. This research helped to pinpoint where this population fits within the construct of the Health Belief Model so that future educational efforts can be targeted in geographic areas with the greatest need. This will help to move this sample toward behavioral change. / Ph. D.

Ever since the seminal Marienthal studies during the Great Depression of the 1930s, studies have linked employment to health and well-being of individuals. However, employment participation for people living with HIV (PLHIV) may not necessarily provide positive health outcomes given negative social responses to HIV infection, particularly stigma and discrimination. Using causal steps approach, the study examines the extent to which the linkage between formal employment status and health-related quality of life is affected by both social capital and HIV-related stigma among PLHIV. Quantitative data were obtained from 554 male and female adults on HIV treatment for at least two years in South Africa. Health-related quality of life (HRQoL) was measured using the validated Medical Outcomes Short Form (SF-36) (Quality Metric, USA) and is represented by physical and mental component summary scores. Formally employed study participants experienced superior HRQoL in comparison to those not formally employed. Both employment status and physical and mental component summary scores were unrelated to objective measures of HIV disease status – CD4 count and viral load. Levels of social capital did not vary significantly by formal employment status. Perceived HIV-related stigma was significantly lower among formally employed study participants than those who were not formally employed, but only in the dimension of personalised stigma, after controlling for potential confounders. Social capital indicators were significantly positively associated with mental but were unrelated to physical component summary scores. All HIV-related stigma scale scores were inversely associated with social capital indicators and with physical and mental component summary scores, after controlling for potential confounders. These results provide little support for mediation of the relationship between formal employment status and HRQoL among PLHIV by social capital and HIV-related stigma. Both social capital and HIV-related stigma have independent relevance to, but formal employment accounts for the largest effect on the health and well-being of PLHIV.

Women face a number of physical, emotional and psychological challenges following an HIV positive diagnosis during pregnancy. Psychological challenges, such as maternal anxiety and low mood, have been associated with disruptions to mother-infant bonding in the general population. Despite significant numbers of women receiving an antenatal HIV diagnosis in the UK each year, there remains a limited understanding about the experiences of this group in bonding with their babies. This Grounded Theory study aimed to explore the experience of mothers in bonding with their baby following an HIV diagnosis during pregnancy. The study explored the perceived challenges to mother-infant bonding, and the factors mothers felt helped them to manage this process following diagnosis. Ten mothers diagnosed antenatally at a London sexual health service were interviewed about their experiences. Data analysis led to a theoretical model of mother-infant bonding following a maternal HIV positive maternal diagnosis. The model comprised four theoretical codes: facing barriers to bonding; feeling disconnected from the baby; developing a special bond; and strengthening and moving on. These codes were comprised of challenges to mother-infant bonding, as well as factors relating to maternal strength and resilience. The model used a chronological structure, with processes plotted from the point of antenatal diagnosis through to following the infant HIV testing process after birth. Challenges with bonding were experienced primarily during the early stages after birth, with maternal resilience and positivity about the future developing towards the end of infant testing. Circular relationships, in which positive and negative processes fed into and influenced each other, were highlighted throughout. The findings highlight important areas for development in clinical practice, including more targeted psychological support for women following an antenatal diagnosis, and the provision of timely information regarding mother-to-child transmission. Clinical implications from this study are discussed alongside suggestions for future research.

Student Number : 8403267 - PhD thesis - School of Pathology - Faculty of Health Sciences / Sub-Saharan Africa is the eye of the HIV epidemic. This study was conducted when treatment for the majority of HIV-infected patients in low resource settings was considered unattainable and the risks of diagnosing HIV often outweighed the benefits. Coupled with the complexities of HIV diagnosis in infancy, children typically were only diagnosed once already ill or not at all. Key strategies to address the paediatric epidemic focused on preventing mother to child transmission and reducing mortality and morbidity of infected children predominantly with co-trimoxazole prophylaxis. Both strategies required early diagnosis of HIV infection in infancy for monitoring prevention programs and identifying infected children respectively. The diagnostic algorithm for resource limited settings recommended the use of inexpensive, technically simpler HIV antibody detection assays that are unsuitable for use in HIV-exposed children under 12-months of age. Paradoxically this algorithm provided a barrier to HIV diagnosis in children because of high loss to follow-up rates and death in the first year of life. The objective of this study was to establish an accurate, affordable diagnostic algorithm for early diagnosis of HIV infection that could be rapidly implemented in South Africa and benefit other resource limited settings. The HIV infection status of 300 vertically exposed infants was determined according to first world criteria in a prospective, cohort study at Coronation Hospital, Johannesburg over 21 months. This status was used to assess the accuracy of clinical examinations and HIV assays in diagnosing HIV at 6-weeks, 3-, 7- and 12-months of age. The average cost of determining an infant’s HIV infection status was measured. A single HIV DNA PCR test at 6-weeks of age proved highly accurate in determining HIV status at a marginally increased cost to government and was incorporated by the South African Department of Health into national policy. The ultrasensitive p24 antigen assay and HIV antibody detection assays on serum and oral fluid were identified as valuable candidates where PCR testing is unavailable. Dried blood spot samples from heelpricks are critical for policy to be translated into practice since skills to perform venesection in 6-week old babies are limited. The next challenge lies in operationalising these findings at a clinical and laboratory level to the benefit of the 300 000 South African children annually exposed to HIV at birth. The urgency of early diagnosis has been increased by the availability of highly effective antiretroviral therapy.

Student Number : 9813645X - PhD thesis - Faculty of Health Sciences / Epidemiological information on sexually transmitted infections (STIs) is necessary to assess the magnitude of the burden of infections, to identify vulnerable population groups, to mobilise resources for intervention activities and to monitor the impact of these activities. In addition, specific STI surveillance systems, such as studies on the relative prevalence of aetiological agents of STI syndromes and their antimicrobial susceptibility patterns, are aimed at improving patient care. The studies included in this thesis were designed and implemented to improve our understanding of the epidemiology of STIs and HIV infection in southern Africa. In all the study populations, we observed that high level STI epidemics preceded the explosive spread of HIV infection among high-risk individuals. The studies reported here also demonstrate the importance of triangulating data collected from different recommended STI surveillance components, using a tiered surveillance approach. The studies reported here also explored the bidirectional interactions of HIV and STIs. We observed that different STIs have shown different magnitudes of interaction with HIV infection. We found particularly strong interactions between genital herpes and HIV. At the individual level, HIV-seropositive patients with genital herpes were more frequently found to have atypical clinical presentations, delays in spontaneous healing, longer duration of HSV shedding and increased association with HIV shedding from ulcer and genital exudates. Mixed infections involving chancroid and genital herpes were found to be common, particularly in HIV-seropositive patients. The effectiveness of syndromic treatment targeting only bacterial causes of genital ulceration was significantly reduced due to persistent ulcerations as a result of co-infection with genital herpes. The successful treatment of herpes in men and women was found to be associated with a decline or cessation in HIV shedding into ulcer exudates or genital fluid. The studies have also shown that HIV plasma viral load is the main determinant for HIV shedding in both men and women presenting with STIs. As was the case with HSV infection, there was a strong association between HIV and HPV infection in both men and women. A higher prevalence of HPV infection was found among HIV-seropositive patients in our study population and this may reflect the higher frequency of recurrences and/or longer duration of infection (i.e. persistency). The studies also found that the biological false positive reactions in syphilis serology (i.e. RPR) are not a common occurrence in our HIV-seropositive study population. On the other hand, syphilis serology could be falsely negative in patients with PCR-confirmed primary syphilis who are co-infected with HIV and other aetiological agents causing GUD. In conclusion, the findings of our studies have supported the bidirectional nature of interactions between conventional STIs and HIV infection in southern Africa.

A research report submitted to the School of Public Health, University of the Witwatersrand (Johannesburg, South Africa) in partial fulfilment of the requirements for the degree of Master of Public Health for the year 2014 / Introduction: After 12 years of implementing the national Prevention of Mother-to-Child Transmission of HIV (PMTCT) programme in South Africa, interventions to prevent MTCT of HIV are now offered in more than 95% of public antenatal and maternity facilities country-wide free of charge (MRC, 2010), even though HIV/AIDS-related diseases are said to be a major cause of death in young children (UNICEF, 2011). The context within which women make decisions about PMTCT participation depends on, amongst other things, the level of their knowledge about HIV/AIDS (Leonard et al, 2001; Sematimba et al, 2004). The concept of behavior-based programming is central to a behavior change approach to reducing Mother-to-Child Transmission of HIV. This places behaviours at the centre of the program design process (Moore, 2003). Understanding the providers and users of the PMTCT interventions’ knowledge and experience on HIV and PMTCT is therefore important to ensure appropriate interventions to address beliefs, attitudes, myths and misunderstandings. Methodology: Semi-structured interviews were conducted with users of the PMTCT programme, while structured survey questionnaires were collected with the providers of the PMTCT programme in early 2012. Users of the PMTCT programme were asked questions regarding HIV knowledge, experience of HIV testing in pregnancy, PMTCT knowledge and experience of the PMTCT programme. We also asked questions on infant feeding choices and practices. Forty six interviews were carried out with participants at three ANC Clinics with PMTCT services in Soweto - Gauteng. Thirty were users of PMTCT programme and sixteen were providers of PMTCT service. Results: All participants understood that HIV was a virus that affected the immune system. Results show that there is generally a good understanding of HIV and how it is transmitted. In addition there was a good understanding on methods to prevent acquiring HIV. There was a general feeling that a lot of people were afraid of being tested. Interestingly, most participants believed that people who were pregnant or sick had no choice but to get tested. Most of the participants believed that education should be a tool used to motivate more people to get tested for HIV. Most users in this study disclosed their HIV status and PMTCT programme use. Overwhelmingly the decision to participate was based on the desire not to infect their infants. Women had been informed that mixed feeding increased the risk of transmission by breast feeding. There were a few participants who believed that HIV infected women should not breastfed. It was found that almost two-thirds of the women in this study were formula feeding their infants. Reason cited for formula feeding was that they did not want to infect their infants. As far as PMTCT knowledge was concerned, it was found that almost all health care providers knew that the most common route of HIV acquisition was through heterosexual sexual practices. All the HCWs knew that prolonged breastfeeding increased the risk of transmission. Reassuringly all HCWs knew not to use invasive delivery procedures and that risk of transmission was decreased with low maternal viral load. Only 50% of the HCWs indicated that the first choice of WHO- recommended mother-to-child regimen for antiretroviral prophylaxis in PMTCT was Zidovudine (ZDV) and Nevirapine (NVP) (WHO, 2012). The HCWs understood that infant formula did not provide superior nutritional support or antibody protection. They also knew that formula feeding carried increased risk of diahorrea or bacterial infections. There was confusion regarding the duration of exclusive breast feeding. Only half of the HCWs stated that post-natal infant-feeding counselling and follow-up are required whenever a mother decides to change her feeding practice. HCW participants felt that most patients fail to adhere to their medication requirements. This was cited to be mainly due to the fact that patients may not have disclosed their HIV status to the household members. Baby feeding choices are cited as the strongest barriers to the success of the PMTCT programmes. Mothers who have not disclosed their HIV status to their household members find it difficult to comply with the chosen feeding choices especially bottle feeding; they therefore opt for exclusive breastfeeding –which family members attempt to interrupt with mixed feeding practices for a number of reasons. Conclusion: Contrary to studies cited in the literature review, health systems failure was not a major problem in Soweto and therefore was not a factor that could impact on either the knowledge or the experience of users and providers. Even though disclosure rates were high amongst the users interviewed in this study, participants believed that the biggest barrier to people participating in the PMTCT programme was because of stigma, ignorance, and fear that they may be recognised while accessing services by people they may know. Although women had been provided with information on exclusively breastfeed, most users of the PMTCT programme interviewed were bottlefeeding – not due to stigma, but due to fear of transmission. In terms of barriers – adherence was noted as a major problem by providers. This linked to issues of feeding practices - if mothers bottle-feed they are stigmatised and opt for exclusive feeding, but are then forced by family to supplement with the bottle for various reasons. Mothers do not reveal their status, which jeopardises their success on the programme

This research investigated the ethical and legal issues that impact on the urgent implementation of Nurse Initiated and Managed Anti-Retroviral Treatment (NIMART) in South Africa, which is part of the task-shifting strategy recommended by the World Health Organization (WHO) to deal with the human resource shortage that has negatively impacted access to Anti-Retroviral Treatment (ART) in developing countries (WHO;2006). The objectives were to review and analyse the existing legal framework and provisions for NIMART in South Africa; and to identify ethical issues and implications of NIMART within the current legal framework. It analysed the legal issues that impact on the implementation of NIMART within the public health service in South Africa, as well as the ethical basis and implications of NIMART on the practice of nurses in the scale-up of Anti-Retroviral Treatment in Primary Health Care (PHC). A comparative analysis was done with case studies of task-shifting in other developing countries and evidence-based recommendations for an enabling and long-term sustainable ethico-legal approach to task-shifting were established. The research concluded that despite the existing legal framework for NIMART in South Africa being firmly founded in the Constitution and further enabled by health policy, challenges exist in implementation of certain critical aspects of the enabling legislation relating to nurse training and accreditation required for full authorization to practice NIMART and that these technical challenges if not attended to could threaten the long-term sustainability of NIMART.

This researched aimed to explore the effects of the Human Immunodeficiency Virus (HIV) upon the visuospatial abilities of HIV-positive adolescents on antiretroviral treatment in South Africa. The literature suggests that the neurology responsible for visuospatial abilities (specifically various white-matter tracts in the brain) is very susceptible to the damaging effect that HIV has on the brain. The research sample consisted of vertically transmitted HIV-positive adolescents, on first line antiretroviral treatment, with a HIV-negative control group comparable on age and SES. The results indicated that there is a significant difference in the visuospatial abilities between adolescents with and without HIV. The expressions of these deficits were displayed differently between males and females, highlighting a differing developmental neurology, and the effect of HIV upon it. The viral strength and health of the immune system were also examined as variables and illuminated interesting results. Overall, the research illustrates the negative effect that HIV has upon developing neurology and the subsequent effects on visuospatial abilities.