Class of 2005 Abstract / Objectives: To determine compliance rate of patients enrolled in the AIDS Drug Assistance Program (ADAP) at El Rio Health Center. Methods: This study was a retrospective observational study design that utilized medication refill data obtained from computerized pharmacy records. Lists were created for each anti-retroviral drug that included the following data: medical record number, medication, quantity dispensed, days supply and refill date. Patient age, gender and ethnicity were also obtained. The data was compiled into a database using Microsoft Excel©. The medication possession ratio (MPR) was calculated for each drug as well as for each drug group. The subjects in this study were patients enrolled in the ADAP at El Rio Health Center who obtained prescription refills between December 1, 2003 and November 30, 2004. The mean age was 44.56 (range 25-78); 94.8% were male and 5.2% were female. Ethnic distribution included 52.6% Caucasian, 39.6% Hispanic, 3.2%African American, 1.3% Asian, and 3.2% other. Results: The MPR was calculated for each drug as well as for each drug group. MPRs for individual drugs ranged from 0.586-0.906; MPRs for drug groups ranged from 0.717-0.756. Implications: The results of the study indicated that ADAP patients did not have adequate (>95%) compliance rates. The implications of the results are that patients are not fully benefiting from their medication, while at the same time promoting the development of resistant strains of HIV.

BACKGROUND: Highly active antiretroviral therapy(HAART) is used in pregnancy to suppress viral load(pVL) before delivery, reducing risk of vertical HIV-transmission. Nelfinavir(NFV) containing HAART has been highly used in pregnancy, but dosages may be inadequate due to the physiologic changes that occur. Given concerns regarding optimal viral suppression in pregnancy, drug toxicity and resistance development, NFV levels need to be evaluated in this population to guide dosing recommendations. METHODS: As part of a prospective cohort study maternal blood was collected at 18-28wks, 32-37wks and at delivery. Times of last medication dose and blood sampling were recorded and drug levels were measured using HPLC MS-MS. NFV concentration-ratios(NFV-CRs) were calculated by dividing individual levels by a time-adjusted population value. Plasma NFV concentrations and NFV-CRs were compared across gestational age and correlated to variables of interest. Rate and maintenance of viral suppression were analyzed in relation to NFV concentrations and CRs. Statistical tests included ANOVA, χ2, linear regression, and Kaplan Meier estimates. RESULTS: 113 samples were collected from 32 subjects. Samples were eliminated if not in steady state (n=20); 93 samples from 32 subjects were analyzed. Mean NFV-CR at 18-28wks (1.1±0.73) and 32-37wks (0.86±0.73) were not significantly different but were both significantly higher by ANOVA (p=0.049) than the mean NFV-CR at delivery (0.44±0.50). CRs were highly variable. Of 49 antepartum samples, 49%(24) had a CR<0.90 (clinically relevant threshold). Four women reached a pVL <50 copies/mL by 34wks but had a detectable pVL at delivery. One woman never reached an undetectable pVL in pregnancy. Minimum and mean NFV-CRs in these 5 women were not significantly different than those who achieved and maintained virologic suppression. Vertical HIV transmission rate was 0%. CONCLUSIONS: There were no HIV transmissions but 16% (5/32) of women were inadequately suppressed at delivery, which is of concern. Factors associated with inadequate suppression and NFV-CRs need to be explored in conjunction with patient/physician reported adherence and viral resistance profiles. Extreme variability in CRs may limit the potential usefulness of random timed drug levels in all pregnant women. / Medicine, Faculty of / Obstetrics and Gynaecology, Department of / Graduate

A dissertation 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 Epidemiology and Biostatistics. Johannesburg, November 2017. / Introduction Viral load is the most reliable indicator of poor adherence to anti-retroviral therapy (ART). However, this assay is difficult to implement in resource-limited settings due to financial and technical constraints. Laboratory markers, combined with the patient’s demographic and clinical details, have been described as better proxies of adherence than the current self-reported adherence measures. However, the real diagnostic value of these biomarkers remains unknown. Therefore, the aim of this study was to assess the usefulness of a composite marker to identify poor adherence to ART defined as a detectable plasma viral load in HIV-positive patients on first-line regimen at Themba Lethu Clinic (TLC) in Johannesburg, South Africa Materials and Methods: This study was retrospective cohort analysis of data collected on HIV-positive ART naïve adults initiating first line antiretroviral regimen at TLC following the 2010 South African antiretroviral treatment guidelines. The data collection was carried out as part of the low-cost monitoring (LCM) study at Themba Lethu Clinic in Johannesburg from February 2012 to 2014. The LCM cohort which aims to look at low cost monitoring of HIV treatment in resource limited settings was initiated in 2009 in Johannesburg, South Africa. The study or treatment outcome was failure to suppress viral load (VL ≥ 400 copies/ml) at 6 and at 12 months. Adherence to antiretroviral treatment was assessed using four (4) self-reported adherence (SRA) measures namely: a self-reporting questionnaire, a Visual Analogue Scale (VAS), a pill identification test (PIT) and the Simplified Medication Adherence Questionnaire (SMAQ). The result of each self-reported measure was classified as either positive or negative given a conventional threshold. In our study three (3) self-reported adherence (SRA) measures were combined into a multi-method approach tool which included self-reports combined with VAS and the pill identification test (PIT). Continuous variables were summarized by median with interquartile range. Categorical variables were summarized by giving their frequencies. To compare continuous variables, we used an unpaired t-test if the variable was normally distributed. When continuous variables were compared from baseline to the previous 6 months, a paired t-test was done. In the case of skewed distribution, we used a non-parametric variant of the t-test such as the Mann-Whitney U-test. To compare categorical variables, we used cross-tables with corresponding chi-square test or Fisher exact test. A Modified Poisson Generalized Linear Model (GLM) with robust variance was used to estimate adjusted relative risks (aRR) of failing to suppress viral load at 6 and at 12 months adjusting for age age, gender, self-reported adherence measures, changes in laboratory markers and missed appointments at 6 and 12 months after ART initiation. As there was missing values in the covariatess and the outcome, we performed a multiple imputation technique under missing at random (MAR) assumption in order to compare the robustness of the estimations between the complete case analysis and the imputation model under MAR after imputing missing values. with the imputed dataset. Additionally, we calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each self-reported adherence measure using viral load as the reference standard. Thus, we derived two diagnostic risk scores from rounding and adding together the adjusted regression coefficients used to estimate adjusted relative risk and following the Spiegelhalter and Knill-Jones approach, at 6 and at 12 months. The Receiver Operating characteristic (ROC) curves were computed to see the overall discriminative value of each continuous risk score. To assess the clinical usefulness of the continuous riskscores we dichotomized them from 2 ≥ vs < 1 to 5 ≥ vs < 5 and calculated the sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) at each cut-off, taking detectable viral load as a gold standard. Results: There were 353 HIV-positive patients initiated on first line ART at TLC for the LCM cohort study. Of these, 80.7% did not suppress viral load after 6 months while 30.1% did not suppress viral load at 12 months. The proportion of patients classified as being highly adherent was 86.7% but this proportion decreased to 60% at 12 months. By 6 months, after adjusting for gender and age, the variables that were significantly associated with detectable viral load included: having missed at least two ARV visits by ≥ 7 days (aRR: 2.35 95% CI: 1.08 -5.11); platelet count < 150 cells/mm3 (aRR: 2.73 95% CI: 1.04 -7.18) and VAS ≤ 95% (aRR: 1.65. 95% CI: 1.01-2.71). At 12 months, the estimates showed a positive relationship only with age group and unemployment. There were no similarities in the results found using complete case analysis and analysis with imputed datasets. However, the largest standard errors were obtained from the complete case analysis. At 6 months, the AUC ROC curve was calculated as 0.63 (95% CI, 0.53 - 0.72) while, for the visual analogue scale, the AUC decreased to 0.55 (95% CI, 0.49 - 0.62); for the Simplified Medication Adherence Questionnaire (SMAQ), the AUC decreased to 0.52 (95%CI, 0.45 - 0.60), while for the multi-method approach, it decreased to 0.53 (95% CI, 0.46 - 0.58). The optimal diagnostic accuracy was obtained with the score 5 (≥5 vs <5 Se: 64% and a Sp: 50.0%) followed by a risk score of 4 (Se of 76.0%, Sp of 34.7%). At 12 months, the AUC of the diagnostic risk score was calculated as 0.44 (95%CI, 0.40 - 0.60) while for the three self-reported adherence methods, it decreased to 0.48 (95% CI, 0.40 - 0.60), 0.51 (95%CI, 0.40 - 0.60) and 0.50 (95%CI, 0.41 - 0.59) respectively for the visual analogue scale, the SMAQ and the multi-method approach method respectively. Conclusion. This study shows that after ART initiation, the 6-month’s adherence can be better diagnosed using laboratory markers combined with patient’s information and traditional self-reported adherence measures at Themba Lethu Clinic. The advantage of this proposed method is that it is based on routine and accessible informations collected during HIV-positive patient visits, thus incurring no additional cost for its implementation. An external validation of this diagnostic risk score is needed for its translation into clinical practice in resource-limited settings. / LG2018

Objective: To investigate hearing loss among perinatally HIV-infected (PHIV+) adolescents on antiretroviral therapy (ART), and HIV-non-infected (HIV-) adolescents in Cape Town, South Africa. Methods: A cross-sectional analysis was carried out to describe the prevalence, nature and predictors (demographic, past medical history, clinical findings) of hearing loss in adolescents between 9 and 14 years of age. Screening pure-tone air-conduction (AC) thresholds above 30 decibels (dB) were considered to be indicative of debilitating hearing loss. Statistical analysis included univariate analysis and multivariate logistic regression. Results: The cross-sectional analysis included data from 540 participants; consisting 273 males (51%), 267 females, 432 PHIV+ and 108 HIV-, with a median age of 12 years. Hearing impairment was observed in 19% of all the adolescents in the study. Multivariate analysis showed the following predictors for any hearing loss: an unmarried primary caregiver (odds ratio (OR) 0.59; 95% confidence interval (CI), 0.39;0.91, p = 0.015), being female (OR 1.67; 95% CI, 1.12;2.51; p = 0.013) and reports of being troubled by ear pain or discharge in the last month (OR 2.54; 95% CI, 1.55;4.17; p = <0.001) after adjustment. Univariate analysis showed an association between hearing loss and a longer duration on ART among PHIV+ adolescents (OR 1.80, 95%CI 1.17;2.75, p = 0.007). Conclusion: The prevalence of hearing loss appears to be comparable between PHIV+ and HIVadolescents in Cape Town. In low resource settings, a history of ear pain or discharge within the last month may be used as a screening tool for a hearing assessment, and guide referral for formal hearing tests.

The cornerstone in the fight against HIV/AIDS is prevention followed by the access to and use of highly active antiretroviral treatment (HAART). Adherence is the greatest patient- enabled predictor of treatment outcome for the patients on HAART, as good adherence leads to a decrease in disease progression and death. There is no ‘gold standard’ in the measurement of adherence. Also, factors that influence adherence and hence the prevalence of adherence differ across different settings making it necessary to determine local adherence prevalence as well as factors that might impact on it. This was a cross sectional study which assessed the prevalence of one- week adherence to antiretroviral therapy at St Rita’s hospital through an abridged version of the questionnaire developed by the Adult Aids Clinical Trials Group in the United States. Results from the questionnaires were compared to the results from a decrease in plasma viral load to undetectable limits within six months. The study found out that the prevalence of one- week adherence by self-report was 96.8% (95% CI: 93.2 – 98.9%). Using a decrease in viral load to undetectable limits within six months of initiating treatment as a tool to assess adherence, the prevalence in this study was 96%. A combined prevalence of 94% was found for this study. These results were identical to a few results locally but it was much higher than most local studies. The explanation for this apparent higher adherence rate might be that the study site has not reached its maximum capacity for the delivery of service as it is still operating at just below the staff/patient ratio recommended by the Department of health. The study also found out that being a member of an AIDS support group was a facilitator to adherence while lack of adherence counselling and monitoring is a barrier. Based on these findings it is therefore recommended that measures should be put in place to ensure improving existing adherence counselling and monitoring, encouraging patients to belong to at least one AIDS support group, more decentralization of antiretroviral therapy roll out to the districts that are yet to roll out and providing financial assistance through improved access to disability grants for those who qualify and income generating activities for the unemployed that do not qualify for disability grant.

Research report submitted in fulfilment of the degree of Master of Public Health (MPH) at the University of Witwatersrand July 2015 / Introduction: Swaziland is facing a very high HIV prevalence and critical human resources for health (HRH) crisis. The Nurse Initiated and Managed Anti-Retroviral Treatment (NIMART), a task shifting program to capacitate nurses to offer ART services, was introduced in 2009 by the government of Swaziland to address the human resources for health (HRH) challenges in the country. Although the country has attained 80% coverage in ART provision amongst adults, the ART coverage in children below 15 years of age is 9% which falls way below the WHO stipulated proportion of 15% in that age group. In addition, ever since the NIMART was introduced there have been limited studies done in Swaziland to explore the perceptions of health workers with regards to its implementation. This study explored providers’ perceptions on the facilitators and barriers to the NIMART implementation in Manzini Region. Materials and Methods: An exploratory qualitative study was used to explore providers’ perceptions of the facilitators and barriers to the implementation of NIMART services in Manzini Region, Swaziland. A semi-structured interview guide was used to interviews with nurses, clinic managers and medical doctors who were purposively selected from five urban and three rural clinics offering NIMART services in Manzini Region, Swaziland. Thematic content analysis was used to analyse data guided by the Donabedian conceptual framework. Results: The findings showed that two weeks training was offered to the professional nurses before they were certified as NIMART nurses. The first week of training was mainly theory classes while the second week was on-site practical training. The NIMART program was perceived as vital by the providers interviewed as it improved access to ART, reduced patient waiting times, empowered nurses and was a cost effective program to address the shortages of doctors in the country. Structural factors like availability of health facilities, professional nurses, antiretroviral drugs and antiretroviral treatment guidelines at the facilities visited were reported by most respondents as facilitators of the implementation of the program. Process factors like the training of NIMART nurses in some facilities, the partnership between the Ministry of Health and various nongovernmental organisations, the health workers commitment and team work greatly facilitated NIMART implementation. Structural barriers like limited paediatric antiretroviral regimen choices and limitations in paediatric ART policy and legislation were mentioned to negatively affect ART uptake in children. Other barriers like children’s dependency on adult caregivers for their health issues and poor socioeconomic circumstances in communities were mentioned to be hampering ART uptake in children. Process factors like inadequate training of the NIMART nurses in some clinics, parents’ and caregivers’ myths and misconceptions around HIV, AIDS and ART, high HIV and AIDS stigma and poor access to health services were also raised. Conclusion and Recommendations: Even though there were facilitating factors of the NIMART program like availability of ART drugs and ART treatment guidelines which have been seen to have played a major role in ART uptake in adults, there are still many barriers to the implementation of NIMART as evidenced by the poor ART uptake in children. The inadequate training of NIMART nurses on paediatric ART, children’s total dependency on adults for their health needs and parents’ and caregivers’ misconceptions around HIV and AIDS negatively impacted the paediatric ART program. Other barriers included poor socioeconomic status and paediatric ART policy and legislation limitations. As a result, the recommendations are that the NIMART training program for nurses be improved with particular emphasis on paediatric ART. There is need to incorporate NIMART training into the nursing curriculum to ensure that more nurses are trained in ART provision. Community awareness needs be raised to address the issues around stigma, myths and misconceptions of HIV and AIDS through educational programs. There is also a need to increase the recruitment of nurses and improve motivation of nurses through provision of incentives.

Background: Whether the non-inferior efficacy and safety results of switching virologically suppressed HIV-1-infected patients from nevirapine immediate-release (NVP-IR) to NVP extended-release (NVP-XR) demonstrated in the TRANxITION study conducted in Europe and North America are also applicable to virologically suppressed HIV-infected Taiwanese patients remains unknown. We evaluated the comparative safety and efficacy of continuing NVP-IR versus switching to NVP-XR in virologically suppressed HIV-infected Taiwanese adults receiving combined antiretroviral therapy (cART) regimens. Methods: We conducted a retrospective cohort study at Kaohsiung Veterans General Hospital from April 1, 2013, to March 31, 2015. Eighty-four virologically suppressed HIV-infected adults receiving NVP-IRcART were split into two groups: those continuing with NVP-IR (n = 49) and those being switched to NVP-XR (n = 35). Demographic characteristics, clinical variables, and laboratory findings were compared. Therapeutic drug monitoring of steady-state plasma NVP concentrations and genotype analysis of CYP2B6 516 were also performed in 22 participants. The primary endpoint was continued virological suppression at the end of the study. Secondary endpoints were time to loss of virological response and adverse events. Results: During a mean follow-up of 18.4 months, the NVP-XR group demonstrated similar success at maintaining virological response compared with the NVP-IR group (82.9% vs. 85.7%; P = 0.72). Cox regression analysis indicated that there were no significant differences between NVP regimens for time to loss of virological response (hazard ratio: 0.940; P = 0.754). Furthermore, there were no significant differences in adverse events between these two groups. In the 22 participants, there was a non-significantly lower level of steady-state plasma NVP concentrations in the NVP-XR group than in NVP-IR recipients (5145.0 ng/mL vs. 6775.0 ng/mL; P = 0.267). The prevalence of CYP2B6 516 GT was 86.6%, and there was no significant difference in the distribution of CYP2B6 516 between these two groups. Conclusions: We found that switching from NVP-IR to NVP-XR appeared to have similar safety and efficacy compared with continuing NVP-IR among virologically suppressed, HIV-infected Taiwanese patients. Our finding of higher C-trough levels in both groups compared with other studies conducted in Caucasian populations and the high prevalence of CYP2B6 516 GT requires further investigation in a larger Taiwanese cohort.

MSc (Med), Epidemiology and Biostatistics, Faculty of Health Sciences, University of the Witwatersrand / Background. South Africa is currently experiencing one of the most severe AIDS epidemics in the world. The major challenge lies in prompt identification and early initiation of treatment in those eligible for HAART. Clinical staging has previously been recommended for use in settings where CD4 + count testing is not available. We conducted secondary data analysis to determine whether clinical symptoms and signs are useful in predicting the need for HAART initiation (CD4 + count < 200 cells/μL) in South Africa. Methods. Screening data from a randomized controlled trial in women who were HIV positive were analysed. All participants were interviewed using a structured questionnaire to elicit symptom history and then physical examination was done. Participants were staged using WHO criteria. Blood was drawn for CD4 + testing. The association between signs and symptoms and a CD4 + < 200 cells/μL was assessed using logistic regression. Results. Among 589 HIV infected women aged between 18 and 58 years, 90% were assessed as WHO clinical stages I/II. The median CD4 + count was 403 cells/μL (IQR: 273-586). Among women who were WHO stage I/II, 13% had CD4 + count < 200 cells/μL and required HAART. The WHO clinical staging had a low sensitivity (4%) but high specificity for detecting those that require treatment. Conclusion: In a setting where asymptomatic patients are diagnosed with HIV, clinical assessment can not replace CD4 + count testing as a method of identifying those that need treatment.

Cervical cancer is the third most commonly diagnosed cancer globally and it has also been identified as one of three AIDS defining malignancies. Highly active antiretroviral therapy (HAART) is a combination of three or more antiretroviral drugs which are classified as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). HAART has been shown to play a significant role in reducing the incidence of some AIDS defining malignancies, although its effect on cervical cancer is still unclear. It is hypothesized that HAART might reduce cancer risk by interacting with different signalling molecules and pathways that are involved in cancer in order to induce cell death and thus inhibit cell proliferation. The broader aim of this study was to understand the relationship between cervical cancer and HAART. This was achieved by studying the expression of key signalling molecules in cancer; MUC1 and NFkB (P65) and morphological features using scanning electron microscopy following 24 hour treatment of a cervical cancer cell line, HCS-2 with drugs which are commonly used as part of HAART; Emtricitabine (FTC), Tenofovir disoproxil fumarate (TDF), Efavirenz (EFV), Atripla combination (ATP) and Kaletra combination (LPV/r) at their clinical plasma concentrations. Quantitative real time polymerase chain reaction (qPCR) was used in order to study the gene expression of MUC1 and P65 and the data was analysed using the 2-ΔΔCT method to calculate fold change. The statistical analysis was conducted using JMP 11 software. MUC1 and P65 gene expression was reduced following drug treatment. Protein expression was studied by means of Immunofluorescence and MUC1 and P65 protein expression was reduced following drug treatment. Scanning electron microscopy revealed characteristic features of apoptotic cell death such as loss of cell contacts, reduced density and size of microvilli, increase in surface blebbing and budding and degradation of apoptotic bodies following treatment with all the drugs. In conclusion, the drugs used in this study

There have been great strides in increasing access to antiretroviral treatment for HIV-positive people in South Africa. However it has been observed that men are not accessing treatment to the same extent as women. In Soweto only 30% of the people accessing treatment are men, where the expected rate would be around 45%. Whilst there have been some studies observing treatment uptake, they do not explain the behavioural component.