A research report submitted in submissible format to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of MSc in Child Health (Community Paediatrics) 20 June 2017 / Background: HIV antiretroviral therapy (ART) is associated with breast abnormalities in adults, especially efavirenz (EFV). Little is known about the prevalence of these adverse effects among adolescents receiving ART. Methods: A retrospective record review describing breast conditions in adolescents receiving ART at three facilities in Johannesburg, South Africa was conducted. Patients aged 10-19 years who presented from 1 January to 31 December 2014 were included. Analyses were conducted to determine whether EFV use was associated with an increase in breast conditions. Results: A total of 631 patient records were reviewed, 37 (6%) had an abnormal breast event documented of whom 24/37 (65%) were male. Patients with abnormal breast conditions developed them 1.5 years later than patients with normal breast development (p<0.0005). Forty-one abnormal breast events were observed in thirty-seven patients with twenty being described as gynaecomastia or lipomastia (49%). 44% had concurrent generalised lipodystrophy (n=19). Of those with an abnormal breast event, 71% of patients had CD4 counts >500 cells/μl and were virologically suppressed (n=29). Those on EFV had a significantly higher prevalence of breast abnormalities compared to other regimens (p=0.016) and all had been exposed to EFV before. No other ART drug was associated with breast abnormalities in this cohort. Sixteen patients had substitution of EFV and three breast events resolved once substituted from EFV. Breast abnormalities in adolescents on ART Conclusion: Six percent of patients had an abnormal breast condition in this study. Use of EFV and increasing age were associated with breast abnormalities in this population. Further research is needed to better understand this phenomenon. / MT2017

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

Sub-Saharan Africa is the region in the world most severely affected by HIV, and Tanzania is among the most severely affected countries in the region. The introduction of antiretroviral treatment has offered hope to people living with HIV/AIDS, improving their quality of life significantly. Still, there are individuals living with HIV who either lack access to ART, or choose not to make use of the available treatments. The purpose of this thesis is to identify underlying factors perceived as barriers for HIV- positive individuals to initiate and maintain Antiretroviral treatment in Babati District, Tanzania. Twenty semi-structured interviews were carried out between the 15th of February and 6th of March 2016. The interviews were conducted with ART-patients, health workers and members of the community. An analysis was made within a theoretical framework based upon Goffman's notion of stigma and the Initial Behavioral Model by Andersen. The following obstacles to access to ART were indicated by the findings: HIV/AIDS related stigma issues, discrimination, economic barriers, ignorance due to lack of education, counseling on HIV treatment, and beliefs that HIV can be cured by traditional healers.

<p>In 2018, the World Health Organization (WHO) reported approximately 37 million people are living with the Human Immunodeficiency Virus (HIV). Suppressing replication of the virus down to undetectable levels was achieved by combination antiretroviral therapy (cART) which effectively reduced the mortality and morbidity rates of HIV positive individuals. Despite the improvements towards combatting HIV/AIDS, no successful treatment exists to eradicate the virus from an infected individual. Treatment regimens are lifelong and prompt less than desirable side effects including but not limited to; drug-drug interactions, toxicity, systemic organ complications, central nervous system HIV triggered disorders and most importantly, drug resistance. Current therapies are becoming ineffective against highly resistant HIV strains making the ability to treat long-term viral suppression a growing issue. Therefore, potent and more effective HIV inhibitors provide the best chance for long-term successful cART. </p> <p>HIV-1 protease (PR) enzyme plays a critical role in the life cycle and replication of HIV. Significant advancements were achieved through structure-based design and X-ray crystallographic analysis of protease-bound to HIV-1 and brought about several FDA protease inhibitors (PI). Highly mutated HIV-1 variants create a challenge for current and future treatment regimens. This thesis work focuses on the design, synthesis, and evaluation of two new classes of potent HIV-1 PIs that exhibit a novel bicyclic oxazolidinone feature as the P2 ligand and a novel bis squaramide scaffold as the P2/P3 ligand. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Inhibitors 1.65g and 1.65h were further evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants and displayed antiviral activity similar to Darunavir. X-ray crystal structures of inhibitor 1.65a and inhibitor 1.65i were co-crystallized with wild type HIV-1 protease and solved at a 1.22 Å and 1.30 Å resolution and maintained strong hydrogen bond with the backbone of the PR enzyme. </p>

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Globally, ~17 million women and ~2.1 million children are living with HIV. Sub-Saharan Africa accounts for 70% of HIV-infected (HIV+) persons. Mother-To-Child Transmission of HIV (MTCT) during pregnancy, delivery and breastfeeding, is the main route of HIV infection in children. The World Health Organisation recommends lifelong antiretroviral therapy (ART) for all HIV+ pregnant and breastfeeding mothers to prevent MTCT, and breastfeeding for ≥24 months for optimal child health in resource limited settings (Option B+ strategy). Initiation of ART in HIV+ adults is associated with a 2-6% decrease in areal bone mineral density (aBMD) regardless of ART regimen, but data are limited in pregnant and lactating women. Tenofovir, a preferred first-line drug in Option B+ ART regimen, is associated with 1-2% greater decreases in aBMD. Pregnancy and lactation are associated with physiological changes in maternal bone mineral density, but most evidence shows that this is recovered after cessation of breastfeeding. The hypothesis of this thesis is that ART may accentuate the normal process of bone mobilisation during pregnancy and lactation, leading to bone loss that is not recovered in the mother and/or compromised infant growth and bone mineral accretion. The primary objective of this research was to investigate if HIV+ women experience greater reductions in bone mineral compared to HIV-uninfected (HIV-) counterparts. Two groups of pregnant women, 95 HIV+ on ART (Tenofovir-Lamivudine-Efavirenz, previously ART naïve) and 96 HIV- were followed prospectively in Kampala, Uganda. Data were collected at 36 wks gestation (PG36), 2 (PP2) and 14 wks postpartum (PP14). Dual-energy x-ray absorptiometry was used to measure bone phenotype (aBMD, bone mineral content (BMC), bone area (BA), and size-adjusted BMC (SA-BMC, adjusted for height or length, weight and BA) of the whole body (WB) and lumbar spine (LS) in mother-baby pairs, and total hip (TH) in mothers. The primary outcome was the difference between groups in % change (± SE) in maternal LS aBMD between PP2 and PP14. Secondary outcomes included changes in maternal markers of bone formation (P1NP and BAP) and resorption (CTX), serum 25-hydroxy vitamin D (25(OH)D), parathyroid hormone (PTH), plasma and urine concentrations of creatinine (Cr), calcium (Ca), phosphate (PO4) and magnesium (Mg), urine mineral:creatinine ratios, TmCa/GFR and TMP/GFR, respectively), breastmilk mineral composition (Ca, P, Na, K and Na/K ratio); and infant growth Z-scores and bone mineral. Statistical models were adjusted for potential confounders. Median maternal age was 24.5 (IQR 21.1, 26.9) yrs. Mean gestation was 40.9±1.8 wks and not significantly different between groups. All women were breastfeeding at PP2 and PP14. More HIV+ women reported exclusive breastfeeding (PP2: 82.9% v 58.7%, p=0.0008; PP14: 86.7% v 66.2%, p=0.002). Body weight was 4-5% lower in HIV+ women. By PP14, mean duration of ART was 29.3±5.1 wks, adherence was > 95%, and the median CD4 count was 403 (IQR 290-528) cells/mm3. Maternal aBMD decreased between PP2 and PP14 at all skeletal sites in both groups as expected in lactation. Reductions in LS aBMD were not significantly different between groups (-1.8±0.4% vs -2.5±0.4%, p=0.3). However, HIV+ women had a significantly greater reduction in TH aBMD which persisted after adjustment for body size (-3.7±0.3% vs -2.7±0.3%, p=0.04). Median serum 25(OH)D was 67.4 nmol/L (IQR 54.8, 83.7) at PG36 and 57.6 nmol/L (48.7, 70.1) at PP14 with no significant difference between groups. Changes in 25(OH)D and PTH from PG36 to PP14 were not significantly different between groups (25(OH)D: -13.9±4.1% vs -11.1±3.1%; PTH: +60.0±6.4% vs +57.6±6.4%; both p > 0.05). However, HIV+ women had 33-35% greater plasma PTH concentrations at both PG36 and PP14. Bone formation and resorption markers increased in both groups between PG36 and PP14. HIV+ women had greater increases (CTX: +74.6±5.9% vs +56.2±5.9%; P1NP: +100.3±5.0% vs +72.6±5.0%; BAP: +67.2±3.6% vs +57.1±3.6%, all p < 0.05). They also had a greater decrease in plasma Ca (-6.6±0.5% vs-3.8±0.5%, p≤0.0001) and greater increase in plasma phosphate (+14.4±2.0% vs +7.7±2.0%, p=0.02). Changes in plasma Cr and Mg, TmP/GFR and urine mineral:creatinine ratios were not significantly different between the groups. However, at both PG36 and PP14, HIV+ had significantly lower mean plasma Ca (PG36: -1.0±0.5%; PP14: -4.1±0.6%) and TmP/GFR (PG36: -11.4±3.1%; PP14: -7.2±3.0%) but higher PTH (PG36: +33.0±7.0%; PP14: +35.3±7.6%) compared to HIV- women (all p < 0.05). Mean breastmilk Ca decreased between PP2 and PP14, and the changes were not different between the groups (-19.9±3.0% vs -24.2±3.1%, p=0.3). There were no significant changes in breastmilk phosphorus (P) in both groups, but HIV+ women had significantly higher concentrations (PP2: +9.7±3.8%, p=0.01; PP14:+9.6±3.5 %, p=0.007). Breastmilk P was significantly correlated with maternal plasma [CTX] in a separate ANCOVA model (β = +0.13±0.04% per 1% increase in CTX, p=0.0003). Mean breastmilk Na, K concentrations and Na/K decreased between PP2 and PP14 in both groups. However, HIV+ women had a smaller decrease in breastmilk Na (-44.3±8.9% vs -72.6±9.0%, p=0.03). They also had a trend towards smaller reduction in Na/K ratio (-22.2±9.3% vs -46.6.6±9.5%, p=0.07). Babies born to HIV+ mothers (HIV-exposed infants, HEI) had significantly lower gains in weight +53.0±1.4% vs +57.5±1.4%, p=0.02) compared to HIV-unexposed infants (HUI), and also lower weight-for-age (-0.47±0.16, p=0.003) and length-for-age (-0.53±0.18, p=0.005) Z-scores at PP14. HEI had a slower gain in WB BMC (+51.2±1.9% vs +57.3±1.9%, p=0.02), but the difference was not significant after adjustment for body size (-6.0±3.5% vs -7.6±3.8%, p=0.2); showing that the bone mineral accretion was appropriate for achieved infant size. In contrast, HEI had a greater increase in LS BMC (+29.5±1.7% vs +24.4±1.7%, p=0.03), a difference which remained after size-adjustment (+9.4±5.8% vs +4.3±6.2%, p=0.02). This is the first study to compare changes in maternal aBMD and bone metabolism between HIV+ mothers on Option B+ ART and HIV- counterparts. The results show a greater reduction in TH aBMD in Ugandan HIV+ women on Option-B+ ART compared to HIV- in the first three months of lactation, consistent with their greater increases in bone turnover markers, lower TmP/GFR and plasma phosphate, and higher breastmilk phosphorus concentration. Also, HEI have slower growth and whole body bone mineral accretion compared to HUI. It is important to determine if these changes are temporary or have long-term consequences for the bone health of the mother and child.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.