Magister Public Health - MPH / Background: First line regimens give patients the best chance of long-term treatment success. It is imperative that patients stay on their original first line regimens to ensure program viability. As the ART programme matures in Namibia the proportion of patients who have had their first line regimens modified continues to increase. It is estimated that 3.1% of adults in Namibia are on second line regimens. Second line or other modified regimens are generally reserved for clinical, immunological or virological failure and toxicity related complications. These modified regimens often involve a higher pill burden, more toxicities and are often more expensive. A more detailed understanding of the factors associated with first line regimen modification could allow healthcare providers in Namibia to target these factors for intervention to reduce regimen modification and improve treatment outcomes. Methodology: This quantitative descriptive retrospective cohort study sought to describe factors associated with first line HAART regimen modification in treatment naïve adult patients who started HAART at Gobabis State Hospital between 1st January 2007 and 31st December 2010. Utilizing data from an existing electronic patient management system, quantitative methods were used to assess the prevalence, reasons and factors associated with first line HAART regimen modification. Results: The prevalence of HAART regimen modification was 14.1%. Treatment toxicity was the major reason (35%) for HAART regimen modification and this was largely due to D4T containing regimens. This was followed by treatment modification due to concurrent TB disease (27.3%), new drug availability (19%), pregnancy (6.6%) and virological failure (2%). A death rate of 9% was recorded by the end of the study period in each of the two groups, of those who had their first line HAART regimen modified and those who remained on original regimens respectively. There were statistically significant associations between regimen modification and type of regimen, care entry point, duration from HIV diagnosis to entry into HIV care, sex and functional status. Regimen modifications resulted in more AZT and TDF based regimes while 88.7% of patients had D4T taken off their HAART regimens. Conclusions: HAART regimen modification at Gobabis State hospital is lower than in other settings was largely due to treatment toxicity. The death rate is high and warrants further exploration. Regimen modifications resulted in more AZT and TDF based regimes and more patients had D4T taken off their HAART regimens. Recommendations: Patients still on D4T need close monitoring for side effects associated with this drug and should be promptly changed if this is the case. This study raises the important programmatic issue of the need for good data collection practices. HIV positive patients who are pregnant and those with concurrent TB disease need close monitoring to ensure that HAART regimens are modified appropriately.

Magister Public Health - MPH / The introduction of antiretroviral therapy (ART) brought new hope to HIV patients as it has transformed a fatal disease to a chronic manageable condition. In 2009 there were over 920,000 Malawians infected with HIV and 110,000 new infections. Malawi like other countries in the sub-Saharan Africa has made great strides in ensuring access to ART. The government of Malawi introduced free antiretroviral therapy (ART) in June 2004. By 2010, a total of 250,987 patients in the country were receiving ART. The success of ART requires, amongst others, a sustained adherence rate to medication of more than 95% to prevent viral replication and the development of drug resistant HIV strains. Identifying the factors that influence adherence is essential for the long-term success of public ART programmes. This study explored patient, socio-economic, cultural, and religious and health systems factors that influence adherence to ART in Zomba district in Malawi. An explorative qualitative study was conducted amongst ART patients and health workers in four health facilities in Zomba district of the Southern Region of Malawi. Data collection was through individual in-depth interviews with 25 ART patients and semi-structured key informant interviews with 13 health workers that were actively involved in the ART programme. Data was audio-recorded and transcribed verbatim. Thematic and content analysis of transcribed data was done. The study found high individual commitment, having social support from family and friends and continuous good counselling to be facilitators to adherence to ART. HIV-related stigma and discrimination, none disclosure of HIV status, lack of partner support, travelling to attend funerals and religious beliefs were noted barriers to adherence. Health system factors such as congestion in the clinic, negative staff attitudes and a lack of privacy at the pharmacy were also identified as barriers to clinic attendance and keeping appointments. Although pill burden was not mentioned, patients reported drug reactions as a barrier to adherence. Although there is good road network in the district, transport cost was still mentioned as a hindrance to treatment adherence. Treatment success was reported to be both a facilitator and a barrier to adherence. HIV-related stigma and discrimination among people need to be addressed to increase support to PLWHIV and encourage disclosure of HIV status. The improvement of the socio-economic status of ART patients needs to be addressed to reduce dependence on support from other people and provide money to make follow-up appointments. The health systems need to reduce clinic congestion and waiting times so that patients are not deterred from accessing ART.

In this thesis, some issues about the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) have been addressed by concentrating on the stochastic modelling of the dynamics of the viruses. The aim of this thesis is to determine parameters such as the mean number of free HIV, infectious free HIV and non-infectious free HIV which are essential in determining incubation period of the virus, the disease progression of an infected individual and the efficacy of the treatment used. This thesis comprises of six chapters. The first two chapters are introductory to the viruses and reasons why HIV-1 is given priority over HIV-2 are given. The pathogenesis of the virus is addressed. This is because knowledge of the pathogenesis and strains of the virus has become essential in the study of HIV in vivo dynamics which is still paving ways into extensive research of the ways to contain the disease better. In chapter three the distribution functions of the HIV incubation period and seroconversion time are determined via stochastic models by building on previous work of Lui et al. (1988) and Medley et al. (1988). Also AIDS incidence projection was done using the Backcalculation method. Chapter four deals with the formulation of stochastic model of the dynamics of HIV in an infected individual. Two stochastic models are proposed and analysed for the dynamics of the viral load in a HIV infected person and the multiplication process of the virions inside an infected T4 cell. Also a numerical illustration of the stochastic models derived is given. In chapter five, the T4 cell count which is considered one of the markers of disease progression in HIV infected individual is examined. WHO has recently advocated that countries encourage HIV infected individuals to commence antiretroviral treatments once their T4 cell count is 350 cells per ml of blood. This is because when the T4 cell count is low, the T4 cells are unable to mount an effective immune response against antigens (and any such foreign matters in the body) and consequently, the individual becomes susceptible to opportunistic infections and lymphomas. We developed a stochastic catastrophe model to obtain the mean, variance and covariance of the uninfected, infected and lysed T4 cells; also the amount of toxin produced in a HIV infected person from the time of infection to the present time is derived. A numerical illustration of the correlation structure between uninfected and infected T4 cells, and infected and lysed T4 cells is portrayed. Antiretrioviral treatments were introduced while we await a cure. Treatment with single drug failed due to the fact that HIV evolved rapidly because of its high replication rate. Thus drug resistance to single therapeutic treatment in HIV infected individuals has promoted research into combined treatments. In chapter six a stochastic model under combined therapeutic treatment is derived. Mean numbers of free HIV, infectious free HIV and non-infectious free HIV are obtained. Variance and co-variance structures of our parameters were obtained unlike in previous work of Perelson et al. (1996), Tan and Xiang (1999). / Thesis (PhD)--University of Pretoria, 2009. / Statistics / unrestricted

Background: Clinical management of dyslipidemia is challenging, particularly hypertriglyceridemia in patients with HIV-infection. Changing combined anti-retroviral therapy (CART) and the use of lipid-lowering drugs have proven useful in treating dyslipidemia in HIV infected patients Objective: To assess the efficacy of lipid lowering drugs (LLDs) and/or CART switching, in the management of HIV-associated dyslipidemia Design: A retrospective, longitudinal cohort study Setting: Phidisa HIV research project, 6 sites in South Africa, period April 2008 and April 2011 Patients: HIV positive South African National Defence Force (SANDF) members and their dependents; who are on CART and are 18 years or older. Four hundred and forty eight participants with dyslipidemia had non-fasted, total serum cholesterol ≥ 8.0mmol/l, serum triglyceride levels ≥4.52 mmol/l and naïve to lipid lowering drugs at baseline. Measurements: Mean change over time of total serum cholesterol and serum triglyceride in the following treatment strategies were used: exercise and dietary advice, lipid-lowering drugs (statins or fibrates or both), CART switches separately and combined lipid lowering drug with ART switch was measured using panel data with first–order autoregressive-response and xtabond. Results: The mean age for a total of 448 participants was 39.9 years; males were 87%, females were only 13%. The participants contributed to 1861 follow-up visits. CD4 count was normally distributed with the baseline mean value of 402 cells/mm3 (18.5%). Mean change over time for total serum cholesterol and triglycerides increased by 0.099 mmol/l (p=0.007) and 0.248 mmol/l (p=0.018) respectively, with an increase in body mass index while an increase in CD4 cell percent decreased mean over time for total serum cholesterol by 0.045 mmol/l (p=0.002). Our hypothesis was confirmed when lipid lowering drugs and ART switch combined treatment strategy even more decrease in the mean total serum cholesterol and triglycerides levels over time by 0.754 mmol/l (p<0.001) and 2.073 mmol/l (p<0.001) respectively compared to the exercise and dietary advice treatment strategy. Our findings showed that combined treatment strategy maintained a decrease in both the mean total serum cholesterol and triglycerides levels over time of 0.283 mmol/l (p=0.038) and 0.941 mmol/l (p=0.016) respectively, when compared to lipid lowering drugs; the mean serum triglycerides over time were also reduced by 0.486 mmol/l (p=0.048) when the combined treatment strategy was compared to CART switch only. Furthermore combined treatment strategy of lipid lowering drugs with ART switch showed significant virological suppression by decreasing log of viral load, 0.486 (p<0.001) when compared to the exercise and dietary advice group. Conclusions: Combining lipid lowering drugs and ART switching as a treatment strategy in the management of HIV-associated dyslipidemia is effective in lowering the mean over time of both total serum cholesterol and triglycerides when compared to exercise and dietary advice strategy, while maintaining virological suppression. / Dissertation (MSc)--University of Pretoria, 2015. / tm2015 / School of Health Systems and Public Health (SHSPH) / MSc / Unrestricted

Given the pathophysiology associated with the Human Immunodeficiency Virus (HIV) and the reported predilection for frontal circuitries and deep white matter, one might expect that executive dysfunction forms part of the neurocognitive profile of people living with HIV. However, such deficits have mainly been reported for adults living with HIV. Adolescence is a period where significant growth and refinement of executive functioning occurs and therefore specific research focused on HIV-positive adolescents is needed. Adolescence is also a developmental period where poor adherence to Antiretroviral Therapy (ART) persists despite marked increases in the national roll out of ART in South Africa, which has significantly decreased HIV-related morbidity and mortality rates. Poor adherence is not only a threat to the efficacy of ART but is also linked to the emergence of drug-resistant HIV strains and identified as a key contributor in the persistence of some cognitive impairments among people living with HIV. Studies show that executive dysfunction can undermine adherence to ART particularly in adolescents, whose frontal lobes are still developing. The first aim of this study was to compare the executive function profile of a group of HIV positive adolescents with that of a matched HIV negative control group. Using P. Anderson's (2002) model, executive functions were considered along the four subdomains: attentional control, processing speed, cognitive flexibility and goal setting. A second aim of the study was to investigate the relationship between executive function and levels of adherence to ART amongst the HIV positive adolescents in the sample. This cross sectional, between-groups study used a comprehensive neuropsychology test battery which was sorted into composite domains to investigate differences in executive functioning between the two study groups of adolescents aged between 14 to 16 (n = 22 in each group) using t-tests. Correlation coefficients were further computed to establish association between adherence and executive functioning. Apart from processing speed (p = 0.42, after the removal of outliers), there were no significant between-group differences in executive functioning outcomes that emerged between the HIV-positive and HIV-negative groups. The neuropsychological test scores for both groups were largely in the borderline range. Correlations between adherence and executive functioning outcomes did not yield any significant associations for each of the executive function domains. The lack of significant between-group differences may be explained by the mitigating effects of ART in the CNS in the HIV-positive group. However, consideration should be given to social factors as these may be important mediators of cognition and may therefore confound neuropsychological performance outcomes for both groups. Although the findings in the current study did not conclusively provide evidence for the role of executive functions in adherence, given the noted limitations, further studies with larger samples should confirm such outcomes.

The human immunodeficiency virus (HIV)-hepatitis C virus (HCV) coinfection is one of the most common coinfections across the globe. There are over 2 million people living with both HIV and HCV worldwide. In the United States, HIV-HCV coinfections present a huge public health issue. There are several risk factors associated with developing this coinfection. One of the greatest risk factors is injection drug use and the practice of sharing needles. With the advent of the opioid epidemic, the number of people contracting both infections have skyrocketed. Despite the large prevalence rate, people with HIV-HCV coinfections can be treated for both infections. Medical professionals have begun successfully controlling HIV infections through antiretroviral therapies and treatments. These HIV regimens have worked well to increase the cluster of differentiation 4 (CD4) cell counts to manageable levels in many patients. Clinicians have used several different HIV medications that are easily categorized into five separate categories: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, protease inhibitors, and C-C chemokine receptor type 5 (CCR5) antagonists. Of these medications, nucleoside reverse transcriptase inhibitors and protease inhibitors have been commonly used with direct-acting antivirals. Like antiretroviral treatments, these direct-acting antivirals (or HCV regimens) have been largely successful in reducing HCV ribonucleic acid (RNA) levels and effectively “curing” the HCV infection. However, some serious complications occurred in several cases because of drug-drug interactions between antiretroviral and direct-acting antiviral medications. This study was dedicated (1) to exploring the many benefits that these medications have for coinfected patients and (2) to analyzing the significant consequences of these drug-drug interactions. To achieve both goals, a review of various research studies, websites, and textbooks was instigated through PubMed, Google Scholar, and the Boston University library system. The resulting research studies spanned a period from the 1980s to the 2010s. The implications from these sources suggest that more extensive testing of medications, regimens, and drug combinations is needed to allow for a more individualized and simplified HIV-HCV treatment plan for each patient. Additional testing may also lead to more generalizable findings that could be applied to a large swath of the population in the United States.

Magister Public Health - MPH / 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.

Master of Public Health - MPH / Adequate levels of adherence to treatment for tuberculosis (TB) and HIV at the same time poses a problem for public health in South Africa. TB/HIV co-infected patients face many potential barriers to adherence to treatment for both conditions. There is a need for more knowledge about factors influencing treatment adherence in co-infected patients on concomitant treatment. The aim of this study was to explore the barriers and facilitators to treatment adherence among people co-infected with TB/HIV living in the Alfred Nzo District, Eastern Cape, in order to identify the barriers and facilitators to adherence.

Background: Antiretroviral therapy (ART), notably lopinavir and nevirapine substantially reduces Human immune-deficiency virus (HIV) associated morbidity and mortality in HIVinfected children. Low concentrations of nevirapine and lopinavir have been linked to inferior virological outcomes; it is recommended that lopinavir and nevirapine concentrations are maintained above 1 mg/L and 3 mg/L, respectively, in order to maintain viral suppression. Adherence to both lopinavir and nevirapine ART, respectively has long known to be a crucial contributor to HIV treatment success. Lopinavir and nevirapine pharmacokinetics demonstrate considerable inter-individual variability, which may affect treatment outcomes. At least part of this variability may be explained by host genetic factors. Associations between human genetic variants and exposure to lopinavir and nevirapine are incompletely understood, and have not been studied in a South African paediatric population. Data in this thesis were from a clinical trial conducted at Rahima Moosa Mother and Child Hospital in Johannesburg to assess whether NVP can be re-used (Post-randomization Phase) among 323 children exposed to NVP for PMTCT if they are first suppressed on ritonavir-boosted lopinavir based regimen (Pre-randomization Phase). This thesis assessed the relationship between serial clinic visits lopinavir (Pre-and-Post-randomization) and nevirapine (Postrandomization) concentrations and/or percentage adherence(Pre-and-Post-randomization) and virological outcomes in children. Moreover, population pharmacokinetics models were used to characterise lopinavir and nevirapine parameters. From the final models parameters were derived and were used to assess the relationship between lopinavir and nevirapine pharmacokinetics and genetic polymorphism relevant to both drugs Methods: Cox proportional hazard regression modelling for multiple failure events was used to estimate the crude and adjusted hazard effect of lopinavir (Pre-and Post-randomization) and nevirapine(Post-randomization) concentrations and/or percent adherence(Pre-and Post-randomization) of viral load>400 copies/mL (Pre-randomization) and >50 copies/mL (Post-randomization), respectively. The population means and variances of lopinavir and nevirapine pharmacokinetic parameters at steady state were estimated using non-linear mixed-effects regression. The final models of lopinavir and nevirapine were used to derive individual clearances (CL/F), minimum concentrations (Cmin) and area under the concentration time curves (AUC). The associations between model-derived pharmacokinetic parameters and genotypes in selected genes relevant to lopinavir or nevirapine were explored. Results: In 237 children pre-randomization with viral loads and lopinavir concentrations, the crude and adjusted Cox models revealed significant associations between virologic failure (viral load>400 copies/mL) and both lopinavir plasma concentrations (<1/mg/L) and pretreatment height-for-age z-scores but not percent adherence. In 99 children postrandomization, lopinavir concentrations >1 mg/L reduced the risk of viremia (viral load >50 copies/mL) with about 40%, compared to children with LPV <1 mg/L. No association was found with percent adherence in this group. In 95 children on nevirapine post-randomization, nevirapine concentrations were not significantly associated with increased hazard of viremia (viral load >50 copies/mL). Similarly, there was no significant association with percent adherence in this group. Lopinavir and nevirapine pharmacokinetics were both separately best described with a one compartment models with absorption lag time and transit compartment absorption models, respectively. There was an age driven effect on lopinavir and nevirapine relative bioavailability, respectively. After adjusting for multiple testing, there was no significant association between lopinavir CL/F, Cmin and AUC and genetic polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1. CYP2B6 516G→T and CYP2B6 983T→C were associated with NVP CL/F. CYP2B6 983T→C was associated with NVP Cmin and AUC. Additionally, polymorphisms in the ABCB1 and CYP3A5 were independently associated with NVP CL/F, Cmin and AUC. Conclusions: Lopinavir concentrations <1mg/L were associated with the increased hazard of viremia (viral load >400 copies/mL or >50 copies/mL). The results suggest that lopinavir plasma concentration monitoring at a routine clinic visit may be a useful tool in identifying sub-therapeutic antiretroviral concentrations in children, and this could be used as a guide to therapeutic drug monitoring in children. There was no statistically significant association between polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1 and lopinavir pharmacokinetics. Polymorphisms in the ABCB1, CYP2B6 CYP3A4 and CYP3A5 predicted nevirapine pharmacokinetics.

Magister Public Health - MPH / Approximately 1.75 million adolescents (10-19 years old) globally were living with human immunodeficiency virus (HIV) in 2020, with the Eastern and Southern African regions the most affected by HIV. Progress has been made to increase access to antiretroviral therapy (ART) for adolescents living with HIV (ALHIV) to improve their survival. However, ALHIV still have worse treatment adherence and viral suppression compared to adults and children. This is in part because routine monitoring of HIV treatment programmes does not report for ALHIV; thus making their lack of progress in ART not visible. It is imperative to determine viral suppression and the factors that are associated with viral suppression among adolescents to assess treatment outcomes at local service levels.