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.

Thesis (Ph. D. (Sociology)) -- University of Limpopo, 2014. / This study investigated the challenges to antiretroviral therapy adherence. Qualitative and quantitative research methodologies were applied in the study. Purposive sampling was used to select clients on antiretroviral therapy, convenience sampling was applied to select clients who participated in the focus group discussions and health care workers and lay counsellors were selected through the simple random sampling method. In-depth interviews were conducted with 31 clients on antiretroviral therapy at 8 health facilities, 2 focus group discussions comprising of 7 members each were conducted at two health facilities, medical records of all respondents on antiretroviral therapy were reviewed and a stigma scale was administered. A questionnaire was distributed amongst 17 health care workers and lay counsellors. Most of the respondents who participated in this study were females. Data gathered in this study confirmed that women are more vulnerable to HIV than men. The majority of the respondents were poor African people. The predominant language amongst the respondents was the Xitsonga language; hence the world-view of the Va-Tsonga people was assessed. HIV and AIDS cause many social problems in communities. Some of the major findings are that: Literacy levels were found to be very low as most of the respondents pointed out that they had only obtained grade 7 or below. However, this did not have an impact on treatment adherence. Some respondents indicated that they were unemployed; the majority said they were employed. Even though the stigma and discrimination experienced by the respondents was very low, the few who experienced it had very traumatic and cruel experiences perpetrated by their own family members and people in the community. In terms of disclosure, data indicates that most people prefer disclosing to their mothers as they feel that they will get support. The majority of the respondents disclosed to female family members and they were supported by the people they disclosed to. viii Social support is very crucial for people who are on antiretroviral therapy (ART), most of the respondents indicated that they had treatment supporters. Institutional support was very minimal in that most pointed out that they did not belong to any support groups. There were some who did not even know about the existence of any support groups at the health facilities where they were receiving their treatment. Most of the respondents indicated that they disclosed to their colleagues and others had not as they feared that they would lose their jobs. Those who had disclosed indicated that they needed support from their colleagues and employers with regard to compliance with their clinic appointments. Most of the respondents had sexual partners, and had also disclosed to their sexual partners, and disclosure was almost immediately after being diagnosed HIVpositive. There are those who had not disclosed to their sexual partners as they feared rejection or violent reaction. There were sero-discordant couples amongst the respondents who supported each other regarding adherence. Most of the respondents indicated that they had taken care of a family member living with HIV. HIV prevalence also varies amongst health facilities. Strategies employed by health facilities to monitor and evaluate HIV and AIDS programmes differ. Health Care Workers and lay counsellors provided contrasting information. Primary Health Care facilities have been accredited to provide ART, however the down-referral system seems to be failing as some clinics now have more clients on ART than hospitals. Health Care Workers and counsellors also need to be familiarized with the World Health Organization (WHO) standards. The level of adherence acceptable for an individual on ART is 95%; there is however health facilities that indicated the adherence level far below the required level.

The earlier optimism generated by the efficacy of antiretroviral drugs in human immuno-deficiency virus (HIV) patients has been dissipated in the face of the enormous chal-lenge of maintaining a nearly perfect adherence indefinitely. This study set to determine the influence of HIV adherence self-efficacy and beliefs about medicines on antiretrovi-ral therapy adherence, with the aim of developing a framework for enhancing antiretrovi-ral therapy (ART) adherence through focused intervention on modifiable factors from study variables that are strongly associated with ART adherence. A descriptive correlational design was used to assess the predictive relationships of HIV adherence Self-Efficacy, Beliefs about Medicines and ART adherence among 232 HIV-infected patients in a large public health facility in Pretoria. Participants' medication be-liefs were assessed using the Beliefs about Medicines Questionnaire, HIV adherence self-efficacy was assessed with HIV adherence self-efficacy scale (HIV-ASES) and ART adherence was assessed using the AIDS Clinical Trial Group questionnaire. Pearson correlation analysis was used to assess bivariate associations among the variables, and multiple regression analysis was used to examine the relationships among the inde-pendent variables and ART adherence. Mean adherence for the 232 participants was 95% (SD=13.2). Correlation analysis re-vealed positive bivariate associations between perceived general harm and overuse of medications, and ART adherence (p<0.05); between specific necessity and concerns about ARVs, and perceived general harm and overuse of medications (p<0.05); be-tween HIV adherence self efficacy and ART non-adherence (p<0.05). Multiple regres-sion analysis showed significance for perceived general harm and overuse of medica-tions on ART adherence (F(1;231)=11,583;p<0,001) with perceived general harmful ef-fects and overuse of medications explaining 4.8% of the variance. There was signifi-cance for HIV adherence self-efficacy on ART non-adherence (F(1;41)=4.440; p<0.041), with HIV-ASES explaining 9,8% of the variance. Based on the results, a framework for enhancing ART adherence was developed. Activities in the framework consist of baseline screening for adherence facilitators and barriers using the beliefs about medicine questionnaire and HIV ASES, this is followed by focused interventions on identified barriers of ART adherence / Health Studies / D.Litt. et Phil. (Health Studies)

The earlier optimism generated by the efficacy of antiretroviral drugs in human immuno-deficiency virus (HIV) patients has been dissipated in the face of the enormous chal-lenge of maintaining a nearly perfect adherence indefinitely. This study set to determine the influence of HIV adherence self-efficacy and beliefs about medicines on antiretrovi-ral therapy adherence, with the aim of developing a framework for enhancing antiretrovi-ral therapy (ART) adherence through focused intervention on modifiable factors from study variables that are strongly associated with ART adherence. A descriptive correlational design was used to assess the predictive relationships of HIV adherence Self-Efficacy, Beliefs about Medicines and ART adherence among 232 HIV-infected patients in a large public health facility in Pretoria. Participants' medication be-liefs were assessed using the Beliefs about Medicines Questionnaire, HIV adherence self-efficacy was assessed with HIV adherence self-efficacy scale (HIV-ASES) and ART adherence was assessed using the AIDS Clinical Trial Group questionnaire. Pearson correlation analysis was used to assess bivariate associations among the variables, and multiple regression analysis was used to examine the relationships among the inde-pendent variables and ART adherence. Mean adherence for the 232 participants was 95% (SD=13.2). Correlation analysis re-vealed positive bivariate associations between perceived general harm and overuse of medications, and ART adherence (p<0.05); between specific necessity and concerns about ARVs, and perceived general harm and overuse of medications (p<0.05); be-tween HIV adherence self efficacy and ART non-adherence (p<0.05). Multiple regres-sion analysis showed significance for perceived general harm and overuse of medica-tions on ART adherence (F(1;231)=11,583;p<0,001) with perceived general harmful ef-fects and overuse of medications explaining 4.8% of the variance. There was signifi-cance for HIV adherence self-efficacy on ART non-adherence (F(1;41)=4.440; p<0.041), with HIV-ASES explaining 9,8% of the variance. Based on the results, a framework for enhancing ART adherence was developed. Activities in the framework consist of baseline screening for adherence facilitators and barriers using the beliefs about medicine questionnaire and HIV ASES, this is followed by focused interventions on identified barriers of ART adherence / Health Studies / D.Litt. et Phil. (Health Studies)