Thesis (M.S.) -- Worcester Polytechnic Institute. / Keywords: gene function and regulation; splicing; apobec3; genetics. Includes bibliographical references (p. 55-58).

During the course of HIV pathogenesis, the virus induces multiple defects in immune cells, altering their functional ability to efficiently control HIV itself and other infections. Whilst the widespread implementation of antiretroviral therapy (ART) has led to reduced morbidity and mortality in most HIV-infected individuals having access to treatment, we still do not know whether full restoration of immune function occurs. The aim of this study was to assess the extent to which ART restores both phenotypic and functional T and B cell immunity. HIV-infected women were studied before and 1 year after ART initiation. In Chapter 2, the effect of ART on T cell activation and differentiation profiles was evaluated in HIV-infected individuals (n=28; pre- and post-ART), and compared to HIVuninfected age- and sex-matched controls (n=23). In Chapter 3, the restoration of copathogen specific CD4+ T cells was determined by comparing their cytokine secretion ability and memory differentiation profiles in response to Mycobacterium tuberculosis and cytomegalovirus in HIV-infected (n=15; pre- and post-ART), compared to uninfected (n=9) individuals. Finally, Chapter 4 examined changes in B cell activation and memory profiles in HIV-infected persons (n=19; pre- and post- ART), and compared profiles to HIV-uninfected individuals (n=19). Multiparameter flow cytometry was performed to address the study objectives. T cell activation, as measured by CD38 and HLA-DR expression, was significantly reduced one year after ART for both CD4+ and CD8+ T cells, but normalisation to levels in HIV-uninfected individuals did not occur, despite suppression of viral load. In addition, skewed CD4+ and CD8+ T cell memory profiles were not completely restored. Furthermore, no change in the cytokine production capacity and memory profile of pathogen-specific CD4+ T cells was found before and after ART, but pathogen-specific CD4+ T cells exhibiting a late differentiated profile (CD27- CD45RO+) had a lower ability to replenish (p=0.02; r = -0.5) compared to cells with an early differentiated profile (CD27+CD45RO+; p=0.04; r = 0.45) prior to ART. Similar to T cells, activated B cells (CD40+CD86+) were only partially normalised post-ART, and remained significantly higher than B cells of HIV-uninfected individuals. The frequency of all B cell memory subsets were comparable between HIV-treated and uninfected individuals, with the exception of plasmablasts, whose frequency was still significantly higher than in HIV-uninfected subjects. In summary, these results demonstrate that HIV-infected women on suppressive ART show a substantial but only partial normalisation of T cell and B cell memory subsets, and lower levels of T cell and B cell activation. In addition, restoration of co-pathogen specific memory CD4+ T cells upon treatment was dependent on their memory profile before ART. Understanding the impact of HIV on T and B cell dysfunction and restoration upon ART may provide important insights into the mechanisms of HIV pathogenesis in the era of ART.

There are currently more than 30 0 000 children under the age of 15 living with HIV in South Africa (SA). Due to a combination of recent success in preventing new vertical infections and success of paediatric antiretroviral treatment (ART) programmes in improving life-expectancy in perinatally HIV-infected (PHIV) children, the burden of paediatric HIV in SA has changed to older children. An increasing population of PHIV children on ART is reaching adolescence, yet information on long-term treatment outcomes in this group is lacking. There is very limited published data on treatment outcomes in PHIV children after ≥10 years on ART in high income countries (HIC), and none in low- and middle-income countries (LMIC). We conducted a retrospective cohort study of PHIV adolescents on ART for ≥ 10 years at a single ART facility. The main objective of the study was to describe long-term clinical, growth, immunologic and virologic outcomes in the cohort. Part A, the protocol, as submitted for departmental and ethical approval, details the purpose and methodology of the study. Part B, the literature review, discusses what is known about long-term treatment outcomes in PHIV children on ART to date. It compares findings between HIC and LMIC. Long-term growth, immunologic and virologic outcomes, as well as factors associated with viral failure are described. The paucity of long-term data is demonstrated, indicating the need for further research on the topic. Part C, the journal-ready manuscript, details the methodology, results and interpretation of the longitudinal analysis of long-term treatment outcomes among 127 PHIV-infected adolescents and young adults on ART for ≥10 years. After median follow-up of 12 years since ART initiation, 80% of the cohort were virally suppressed and 79% had optimal immunologic status (CD4 >500 cells/μl). These results are favourable overall, but >40% of adolescents were on 2nd-line ART with poorer immunologic outcomes than those on 1st-line ART, and approximately one in three children experienced viral failure during adolescence. This highlights the vulnerability of this group, which requires careful further management. Appendices include all supporting documentation necessary for the above parts of the mini-dissertation.

Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. People living with HIV are particularly susceptible to TB infection, and treatment of HIV-TB co-infection is challenging for multiple reasons, including potential drug-interactions. Drug-resistant TB is difficult to treat and is associated with high treatment failure rates, mainly because the antimycobacterial drugs currently available are ineffective against drug-resistant TB. Bedaquiline is a new antimycobacterial drug which has shown great promise through its excellent efficacy for treating drug-resistant TB. Being a new drug, however, potential drug interactions with antiretrovirals are a major concern. Bedaquiline is metabolized in the liver by an enzyme called cytochrome P450 3A (CYP3A). The antiretrovirals nevirapine, efavirenz, and lopinavir/ritonavir (LPV/r) can affect the activity of this enzyme, and consequently affect the concentration of bedaquiline in the patient's blood. Nevirapine and efavirenz increase the activity of CYP3A, which may result in increased metabolism of bedaquiline, thus decreasing the concentration of bedaquiline, with consequent risk of treatment failure or the further development of drug-resistance. LPV/r inhibits the CYP3A enzyme, which may result in decreased bedaquiline metabolism, thus causing high concentration of bedaquiline in the blood, with consequent risk of toxicity. We conducted a pharmacokinetic study in 43 adult patients with drug-resistant TB to evaluate the drug-interactions between bedaquiline and the antiretrovirals nevirapine and LPV/r. We did serial measurements of the bedaquiline concentration in their plasma over 48 hours, and compared these concentrations in patients who were on antiretroviral and those who were not on antiretrovirals. Our results showed that nevirapine had no significant effect on bedaquiline concentrations, while patients on LPV/r had bedaquiline concentrations 2 fold higher than patients not on antiretrovirals. We could not determine the clinical significance of this, but recommend that patients receiving LPV/r and bedaquiline in combination must be closely monitored for side-effects.

A dissertation submitted to the Faculty of Education in partial fulfillment of the requirements for the Degree of Masters in Educational Psychology in the Department of Educational Psychology & Special Needs Education at the University Of Zululand, 2017 / The aim of this study was to assess the mental health status of school going adolescents on ART. The objectives of the study being to establish the status of mental health before and after these adolescents are placed on ART. A literature study was done in order to determine the feasibility of the study and in order to strengthen the need for such information to be known. A qualitative approach was used so as to gain insight into the topic. Data was collected using face to face interviews and an interview guide was prepared to guide the discussions between the researcher and the participants. The data collected was thematically analysed and the results were presented using the research questions and the themes that emerged in answering those questions. Themes and sub-themes that emerged included compliance; fear of disclosing; normalisation of life with HIV; acceptance and support from family; fear of rejection, stigma and discrimination; institutional support; morally judged. Since participants were young when they tested mental health changes occurred once their status was disclosed to them. The adolescents have unresolved mental health issues and which become unknown to the healthcare workers due to ineffective communication. Participants were still preoccupied with the thought that they will be on ARVs for the rest of their lives. Key problems faced by the adolescents included preoccupation about the future, fear of stigma and discrimination and reject from society. There were no feelings of anger towards their caregivers once their status was disclosed to them. Only feelings of fear and confusion were raised which were quickly addressed by caregivers. Recommendations were included to address the concerns highlighted in the study and these included a need to address factors such as disclosure, stigma and discrimination as these directly and indirectly have an impact on the mental health of HIV positive adolescents and follow-up research needs to be done to document the lives of adolescents post admission in the ART programme.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree Master of Family Medicine, October 2013 / Botswana has one of the highest HIV prevalence rates in the world, with 32% of pregnant women and 24% of adults in the general population living with HIV. Although antiretroviral therapy (ART) or HIV/AIDS treatment is widely available in the public sector in Botswana, not all treatment-eligible patients utilise the services in a timely manner. The study aims to identify the factors associated with the intention of already screened HIV positive/AIDS patients, who met the government criteria, to enrol into the HIV treatment programme in Lobatse, Botswana. Methods: A Cross-sectional descriptive study was used, conducted at the Infectious Disease Control Clinic, Athlone Hospital, Lobatse over a 6-month period. A questionnaire was administered on systematically sampled participants, who met Botswana National antiretroviral treatment or HIV/AIDS treatment guidelines. Results: A total of 342 participants were enrolled, mostly female (67.3%) and single (50%). Majority of the participants were age 35-44 years (17%), attained up to primary level education (44%) and were mostly unemployed (54%). A majority (59%) intended to enroll into ART or HIV/AIDS treatment programme due to sickness, while others were motivated by voluntary testing and counseling (24%). The majority of the respondents received post-test counseling (97.3%) and most was motivated to seek ART or HIV/AIDS treatment (88.3%). Only (60%) disclosed their status to their relative. Although most participants (59.6%) were willing to be linked to care and support, most (65.1%) were ignorant of support groups and services available for them. Discussion: Although there is increasing access to ART or HIV/AIDS treatment, most participants still wait until they are sick or have symptoms before they enroll into ART. Supportive post-test counseling and conducive family environment were some of the enabling factors. Distance to health facilities and long queues are barriers to accessing care as well as stigma and discrimination. The most significant reasons for not continuing with the treatment were health facilities being far from place of residence and queuing for a long time to see a doctor and or collect medications. Conclusion: Sickness, public education, supportive family environment and effective post-test counseling were found to be significant motivators for intention to enroll into ART. Perceived barriers to accessing treatment include distance and time spent in the health facilities. Interventions are required to reduce stigma, bring health facilities nearer to the people, and increase efficiency in health facilities and increase access and utilization of the care and support groups.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Science in Epidemiology in the field of Epidemiology & Biostatistics June, 2017 / Background: The burden of HIV infection is still high in South Africa. However, the use of ART has greatly improved treatment outcomes and survival. People infected with HIV and receiving ART are therefore living longer but with a likely increase in their cardiometabolic risk. Both HIV infection and anti-retroviral drugs have been shown to affect serum lipid levels and this may be among the reasons for the increased cardiometabolic risk in these subjects. The aim of this study was therefore to characterize the principal determinants of lipid levels in a large rural South African population with a high prevalence of HIV infection in which an array of factors that possibly modulate serum lipid levels had also been measured. Materials and methods: Data for this secondary analysis are drawn from a population-based cross-sectional study: the HAALSI/AWI-Gen collaborative study conducted in the Agincourt sub-district of the Mpumalanga province. 2110 adults 40+ years being monitored by the Agincourt health and socio-demographic surveillance system were randomly selected and recruited, after giving informed consent, between 2013-2016. Pretested questionnaires were used to collect personal, household, socio-demographic, behavioral, dietary, physical activity and self-reported health status. Anthropometric measurements were also conducted. Multivariable linear and logistic regression analyses were used to determine factors associated with serum lipid levels and dyslipidemia, respectively. Results: Results are presented for 2110 participants in this secondary analysis of which 60.3% were women with a mean population age of 58.54 ± 10.91 years. The HIV prevalence was 16.16% and did not differ substantially between men and women. Factors associated with total cholesterol level included age (unstandardized beta [95% CIs] was: 0.02 [0.01, 0.03]; p=0.014), male gender (-0.31 [-0.57, -0.05]; p=0.019), diabetes (0.31 [0.01, 0.61]; p=0.039), alcohol consumption (0.25 [0.02, 0.48]; p=0.038) and BMI (0.02 [0.01, 0.04]; p=0.030). Factors associated with triglycerides included age (0.01 [0.01, 0.03]; p=0.003), male gender (-0.09 [-0.19, 0.01]; p=0.053), diabetes (0.27 [0.13, 0.40]; p<0.0001), BMI (0.01 [0.01, 0.03]; p=0.044), hip circumference (-0.01 [-0.02, -0.01]; p=0.001) and waist circumference (0.01 [0.01, 0.02]; p<0.0001). Factors associated with HDL-C level included age (-0.01 [-0.01, 0.01]; p=0.055), male gender (-0.14 [-0.26, -0.02]; p=0.018), receiving ART (0.17 (0.04, 0.31); p=0.038), alcohol consumption (0.19 [0.07, 0.30]; p=0.002), waist circumference (-0.01 [-0.01, -0.001]; p=0.001) and visceral adipose tissue (-0.03 [-0.04, -0.01]; p=0.002). Age (0.02 (0.01, 0.03); p=0.005), male gender (-0.22 (-0.43, -0.01); p=0.044) and waist circumference (0.01 (0.01, 0.02); p<0.0001) were all associated with LDL-C levels. Being HIV+ and ART naive was associated with a higher risk of dyslipidemia (odds ratio [95% CIs] was 3.79 [1.27, 11.30]; p=0.032) compared to HIV negative participants. Other factors associated with dyslipidemia included being overweight (1.66 [1.20, 2.30] p=0.002) and obese (OR 1.85 [1.02, 3.35]; p=0.0004) and increased waist circumference (OR 1.02 [1.01, 1.03]; p<0.0001). Discussion and conclusion: We have demonstrated a high prevalence of HIV in an older population of rural South Africa, which mirrors the typical epidemiology of the epidemic in southern and eastern African regions. Our data suggest that HIV/ART status mainly influences HDL-C levels with ART use associated with higher HDL; and that untreated HIV infection can be linked to a greater risk of dyslipidemia. Dyslipidemia in the study population is driven by prevailing traditional cardiovascular risk factors such as obesity and diabetes. This data suggests that high ART coverage may reduce atherogenic risk and that lifestyle interventions to reduce the risk of obesity and diabetes are essential. / MT2017

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Pharmaceutical Affairs Johannesburg, 2012 / Objective: To determine the proportion of HIV+ patients who fail treatment on a yearly basis in a 5-year treatment cohort in Tshwane District Hospital and to determine the correlation of treatment failure with variables routinely measured at the clinic namely WHO stage, CD4 count, HIV viral load, age, gender, presence of concomitant diseases, concomitant medication and distance travelled to clinic. Design: A retrospective study with an analytical component was conducted using the hospital records of adult patients receiving antiretroviral therapy in 2004 and followed for 5 years (until 2009) at the Tshwane District Hospital. Methods: All adult patients receiving antiretroviral therapy in 2004 were identified and followed for the next 5 years till 2009 at Tshwane District Hospital. The proportion of patients that failed treatment yearly was calculated. Univariate analysis was used to compare all patients who failed at any time point with the patients who did not fail at all for all variables. A repeated measures logistic regression model was developed to determine the variables that impacted on the binary outcome, namely treatment failure or not. Results: Of the 1104 adult patients who were attending the TDH Immunology clinic in 2004, 870 adults were receiving ARVs. 333 patients (38.28 %) experienced treatment failure throughout the study period. 6.9 % (60/870) of the study population failed virologically. 307 of the 870 patients (35.29 %) failed treatment immunologically. 102 patients (11.72 %) experience treatment failure at the 12 month time point, 37 patients(4.49 %) at the 24 month time point, 57 patients(6.93 %) at 36 month time point, 101 patients(12.27 %) at the 48 month time point and 140 patients (7.01 %) failed treatment at 60 month time point. Univariate analysis showed significant correlation between treatment failure and non-adherer, interrupting treatment, defaulted treatment, viral load at baseline, 12, 24, 36, 48, 60 months, and CD4 count at baseline, 12, 24, 36, 48, 60 months. In the multivariate analysis, there was a significant association between short term stoppage of treatment (STSTOP) (coefficient ratio = 1.41; p<0.001), long term stoppage of treatment (LTSTOP) (coefficient ratio = 3.24; p<0.001), transfers from other health institutions (coefficient ratio = 1.96; p<0.001), regimen (coefficient ratio = -0.1734) and treatment failure. The change in log viral load at 12 months from baseline (LOGVLBL12) (coefficient ratio =-1.7145; p<0.001) was highly significant for reaching the end point - treatment v failure. Older patients were less likely to fail treatment (coefficient ratio = -0.0517, p<0.001) and patients with an advance stage of the disease (WHO stage 3 or 4) were at a lower risk of failing treatment (coefficient ratio = -0.4175; P=0.008). The CD4 count was significant in the univariate analysis P<0.01) and XTGEE (coefficient ratio =- 0.0001; p<0.001). There was no significant correlation between gender, place of residence, employment status and treatment failure. Conclusion: More than one–third of the patients receiving treatment in TDH failed treatment within the 5 year study period. The determinants of treatment failure are age, WHO stage, transfer from other institutions, short term stoppage of treatment, long term stoppage of treatment, CD4 cell count and the level of viral suppression within the first year of treatment (LOGVLBL-12). This study reinforces the need for identifying high risk patients earlier in treatment in order to implement strategies that might strengthen adherence to treatment.

Thesis (Ph.D.)--Kent State University, 2007. / Title from PDF t.p. (viewed Mar. 11, 2009). Advisor: Miguel Quiñones-Mateu. Keywords: HIV/AIDS, drug discovery, small molecule library screening, characterization of new antiretroviral drugs, highly active antiretroviral therapy. Includes bibliographical references (p. 180-200).

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.