3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Factors affecting virological outcome of paediatric patients on abacavir/stavudine-based first-line regimen(2019) Msiza, Duduzile PreciousBackground Viral load (VL) testing is recommended as the preferred monitoring approach for assessing the effectiveness of antiretroviral therapy (ART). Considering the factors which may predispose patients to treatment failure and the high rate of virological failure among paediatric patients, we investigate which characteristics have an effect on virological outcomes of young children. Objective To identify factors associated with an increased probability of first-line ART regimen failure and to report the rate of virological suppression in children below three years old initiated on stavudine (d4T) - or abacavir (ABC)-based first-line regimens. Methods This was a retrospective cohort study conducting a secondary analysis of an existing human immunodeficiency virus (HIV) treatment database of paediatric patients at the Empilweni Clinic based at the Rahima Moosa Mother and Child Hospital (RMMCH) in Johannesburg, South Africa, complemented by retrospective file review. Results From a population of 3,728 children attending the Empilweni clinic between 2008 and 2012, 296 were eligible for the study. The pre-treatment characteristics were gender, age, weight and height for age z-score, viral load, and cluster of differentiation 4 (CD4) count percentage at pre-ART. There was an upward trend in the VL suppression rate for all the variables during the study, with an average of 24% after 6-12 months of ART and 37% at 24-36 months of ART. The majority of patients were started on more than five different drugs in the first year of ART (99%), with an average adherence rate of 94%. Only a small percentage had treatment interruptions. Data on tuberculosis (TB) was available for 68% of the patients, of which 40% received HIV-TB co-treatment, mostly (90%) in the first year of ART. A total of 60% of patients had been exposed to prevention of mother-to-child transmission (PMTCT) therapy. Patients on a d4T-based first-line regimen had superior VL suppression compared to those on an ABC-based first-line regimen (p<0.0001). None of the other variables had a significant association on the VL suppression rate. Conclusion The study found that there was a delay in the VL suppression rate, with most patients still not being suppressed at 36 months of ART (40%). In this study ART regimen was found to be the only factor associated with viral load suppression.Item Gene variant screening for biomarkers significant for effective ARV therapy with a focus on tenofovir nephrotoxicity(2018) Tshabalala, Elizabeth SibongileRecent South African studies report an increase in hospital admissions due to adverse drug reactions (ADRs), including to tenofovir disoproxil fumarate (TDF). Pharmacogenetic studies conducted in African populations have reported notable differences compared to other populations in variants associated with ADRs, including TDF-induced nephrotoxicity (clinically manifesting as acute kidney injury (AKI)), warranting their further investigation in local populations. The aim of this study was to identify variants in eight TDF implicated ADME genes and to select a subset of SNPs for a genetic association study for TDF-associated nephrotoxicity. Using next generation sequencing (NGS) to screen a cohort of 40 HIV-infected patients of Bantuspeaking origin, 275 variants were identified, including three loss of function and 40 novel variants. Based on allele frequency information (MAF>0.1) and prior association with ADRs, nine polymorphisms within five genes were prioritised for genotyping. This was done in cases presenting with AKI following TDF treatment (n=53) and in controls of similar ethnic origin not presenting with AKI (n=84). The cohort was genotyped using TaqMan® assays. A case-control association study was performed with genotypes, alleles and haplotypes using tests. Suggestive associations were detected for the ABCC2 1249A allele (p=0.02) and ABCC2 haplotypes AAC and AAT (p=0.02 and 0.03 respectively) and TDF induced AKI. The ABCC2 GTT haplotype (p=0.02) appeared to be protective of TDF induced AKI. However, the observed associations were not deemed to be significant following corrections for multiple testing. A limitation of the study was its relatively low power because of the small sample size. Therefore, findings from this work will need to be replicated in more suitably powered cohorts. Despite this, we observed evidence that suggests the potential influence of a subset of ABCC2 variants on TDFinduced AKI.Item An exploration of clinic based influences that support or hinder the retention of HIV positive clients in pre-art care at a clinic in Johannesburg, South Africa from January 2010 to July 2014(2017) Mushipe, ShelterBackground: Retaining people living with HIV in the continuum of care (CoC) is a major challenge internationally and in South Africa. However, health care providers can play a role in strengthening retention at different points in the continuum. Understanding the perceptions of health care providers regarding barriers to retention of HIV positive pre-antiretroviral therapy (pre-ART) clients can productively inform pre-ART patient retention programmes. Objective To explore health care worker perceptions on factors associated with retention of pre-ART clients at a clinic in the city of Johannesburg, South Africa. Methods: A cross sectional qualitative study was conducted using semi structured interview guides with a total of 11 health care providers who were comprised of the facility manager, six professional nurses and four lay counsellors in the ART programme. The respondents were purposively sampled. One-on-one interviews were conducted and audio recorded. Field notes were collected during the interviews and the recordings were transcribed after the interviews. Thematic content analysis was conducted using MaxQDA software. Results: The major finding of the research was that there is a lack of understanding of the scope and extent of pre-ART care and not all health care providers seem to get adequate preparation for tracing potential LTFU clients or retaining them in care. Informants in the study indicated as particularly problematic the late return for care by pre-ART clients, which usually occurs when clients are already very sick. Other factors that were identified as challenges include fear of disclosure, shortage of designated health care professional for pre-ART clients, lack of work space in the clinic, inadequate record keeping of patient information, concerns of disclosure and negative attitudes from staff. Clients not returning for their CD4 results, in part due to nonavailability of the results or infrequent health care visits, also led to a loss of care even before eligibility for pre-ART or ART could be determined. Conclusions: This study highlights some of the causes of non-engagement or loss to follow up (LTFU) in the HIV CoC among pre-ART individuals based on the health providers’ perceptions. The research thus provides an impetus for future research involving both health care providers and the pre-ART individuals to explore best practices that will enhance retention of pre-ART individuals in the continuum of care to attain optimal public health services.Item The test-retest reliability of the lower extremity functional scale in HIV-related distal sensory peripheral neuropathy(2018) Munemo, Abraham CyrilBackground: The Human Immunodeficiency Virus (HIV) and the Acquired Immune Deficiency Syndrome (AIDS) have posed a serious disease burden on society. The side effects issuing from the anti`-retroviral drugs (ARVs) include Distal Sensory Peripheral Neuropathy (DSPN), a common neurological complication. The Lower Extremity Functional Scale (LLFS) is a reliable and valid tool that has been used for measuring the lower limb functional capacity of patients presenting with DSPN in countries other than Botswana. As such, it is necessary to test its test-retest reliability in Botswana. Aim: The aim of this study was to determine the test-retest reliability of the Lower Extremity Functional Scale (LEFS) among HIV-related DSPN patients in Botswana. Methodology: This study involved a test-retest reliability study based on a time interval of seven to 10 days. A total of 320 HIV patients from six hospitals in Gaborone, Botswana, were screened for DSPN according to the relevant inclusion and exclusion criteria .The percentage of the total patients who were diagnosed with DSPN was 26.3% (84). The lower extremity functional scale LEFS questionnaire was administered twice with a seven to 10-day period interval and the results of the assessment were recorded and analysed. Measurements of central tendencies were used to summarize the demographic data and the clinical information for the lower extremity functional scale information obtained. Because the data sets were categorical, Spearman’s correlation analysis was conducted to determine the efficacy of the test-retest reliability. Furthermore, the Intraclass correlation (ICC) was used for measuring the internal consistency of the LEFS questionnaire. Demographic data such as age, gender, education and marital status, and clinical information pertaining to the participants were used to describe them. Results: A total of 84 HIV patients from six hospitals who were on anti-retroviral therapy (ART) and presenting with DSPN participated in the study. The test-retest reliability was found to range from rs=0.74-0.99, ICC = 0.96. SEM=4.88 Conclusion: The study results showed strong test-retest reliability and good internal consistency. Hence, the LEFS questionnaire can be considered reliable as a standard from which to monitor lower limb functionality in HIV-related Distal Sensory Peripheral Neuropathy among patients in Botswana.Item Predictors of adherence among antiretroviral therapy naive patients on first-line regimen at Themba Lethu Clinic inJohannesburg: results from a prospective cohort study(2017) Mbengue, Mouhamed Abdou SalamIntroduction 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.Item The prevalence of helminth and malaria infections and the effects of de-worming on disease progression markers in HIV-1 infected pregnant women on antiretroviral therapy in Rwanda(2017) Emil, IvanBackground: Helminth and malaria co-infections have been hypothesized to be factors driving the HIV-1 epidemic in Africa, and the fact that both cause anaemia highlights the importance of addressing the interactions between HIV/AIDS, malaria and intestinal helminthic infections in pregnancy for individuals in resource limited settings. Aims: The aims of this thesis were to determine the prevalence and risk factors for malariahelminthic dual infections among HIV positive pregnant women on antiretroviral therapy in Rwanda. The second aim was to determine the effect of deworming on immune markers of HIV/AIDs disease progression among HIV-infected pregnant women on antiretroviral therapy (ART), and to elucidate the benefits of deworming, specifically in targeted versus untargeted deworming. Methods: A cross-sectional study was carried out in 328 HIV-positive pregnant women receiving ART. We determined the prevalence of helminth and malaria dual infections and the effects of ART on these infections were also examined. This cross sectional study acted as a pilot study for a deworming intervention, which took the form of a longitudinal study of targeted and untargeted deworming in which 980 HIV-infected pregnant women were randomized to ‘targeted’ and ‘untargeted’ arms with albendazole therapy. The effects of deworming on the prevalence of helminth infection and CD4 counts, viral load and haemoglobin levels were measured over time at 4 visits. Measurements were at baseline and every 3 months thereafter. The presence of Plasmodium falciparum was tested at each visit and anti-malarial therapy (Coartem: artemether-lumefantrine) was administered to all subjects who tested positive for P. falciparum. Baseline data was used to determine the risk factors for helminth infection. Helminthic infection was diagnosed using the Kato Katz method, whilst the presence of P. falciparum was identified from blood smears. The CD4 counts and viral load levels were also determined using standard laboratory methods. Results: Within the pilot study of 328 women residing in rural (n=166) and peri-urban (n=162) locations, 38% of those tested harboured helminths, 21% had malaria and 10% were infected with both. The most prevalent helminth species were Ascaris lumbricoides (20.7%), followed by Trichiuris trichiura (9.2%), Ancylostoma duodenale and Necator Americanus (1.2%). Helminth infections were characterized by low haemoglobin levels and low CD4 E. Ivan PhD thesis Page iii counts. Subjects treated with a d4T-3TC-NVP regimen had a reduced risk of Trichuris trichiura infection (OR, 0.27; 95% CIs, 0.10-0.76; p<0.05) and malaria-helminth dual infection (OR, 0.29; 95% CI, 0.11-0.75; p<0.05) compared to those receiving AZT-3TC-NVP therapy. Within the longitudinal study of deworming in 980 pregnant, HIV-infected females, analysis of the baseline data showed that education and employment reduced the risk of all types of infection whilst hand washing protected against helminth infection (0.29 [0.19-0.46]; p<0.0005). Logistic regression analysis, at baseline (odds ratio [95% CIs]), demonstrated that TDF-3TC-NVP (3.47 [2.21-5.45]; p<0.0005), D4T-3TC-NVP (2.47 [1.27-4.80]; p<0.05) and AZT-NVP (2.60 [1.33-5.08]; p<0.05) regimens each yielded higher helminth infection rates than the AZT-3TC-NVP regimen. Anti-retroviral therapy had no effect on the risk of malaria. The prevalence of P. falciparum infection was similar at all-time points for the targeted and non-targeted anti-helminth treatment arms, with a significant fall in helminth prevalence in both arms by visit 2. Albendazole therapy was associated with favourable changes in haemoglobin levels, CD4 counts and viral loads, in those subjects with helminth infections. Haemoglobin levels were similar in both arms at all study visits, rising significantly from visit 1 to visit 2 in both groups and peaking by visit 3. Thereafter, levels fell significantly (p<0.0005 for both comparisons) by visit 4. Conclusions: The prevalence of helminth infection in HIV infected pregnant women on antiretroviral therapy is common in rural and peri-urban settings in Rwanda. This study clearly shows that, albendazole treatment is associated with an increase in CD4 counts, a fall in viral loads and an increase in haemoglobin levels. The effects of albendazole are mediated by the eradication of helminth infection. The study also shows that treatment with albendazole using a targeted or non-targeted regimen is equally effective. The mechanism by which certain ART regimens reduce the risk of helminth infection warrants further study.Item The identification of cell-cycle related genes in response to antiretroviral drug treatment (ART) in lung cancer(2017) Marima, Rahaba MakgotsoSouth Africa has the largest ARV treatment programme in the world, wherein highly active antiretroviral treatment (HAART) has improved the health related quality of life (HRQoL) in HIV/AIDS patients. On the contrary, cancers not previously associated with HIV/AIDS (non-Aids defining cancers; NADCs) have been shown to be increasing, compared to the AIDS defining cancers (ADCs). Lung cancer, as a NADC has been documented in the HIV/AIDS population as a leading malignancy. The poor understanding of the association between ARV drugs and lung cancer places a burden on public health, both globally and in South Africa (SA). Furthermore, the deregulation of the cell-cycle is one of the hallmarks of cancer, including lung cancer. The main aim of this study was to elucidate the effects of HAART components Efavirenz (EFV) and Lopinavir/ritonavir (LPV/r) on cell-cycle related genes in an in vitro lung cancer model. To achieve this, cellular based, molecular and Bio-Informatics approaches were employed. First, the cytotoxic effects of EFV (at 4, 13, 26, 50 μM) and LPV/r (at 10, 32, 50, 80 μM), for 24h, 48h and 72h on normal lung fibroblasts (MRC-5) and lung adenocarcinoma (A549) cells, were evaluated using the Alamar Blue (AB) assay. This was then followed by cell-impedance “xCELLigence” real-time cell analysis (RTCA) assay. This was done to determine the effects of EFV (at 4, 13, 50 μM) and LPV/r (at 10, 32, 80 μM) on cell viability, cell death and proliferation. Cell-cycle analysis using propidium iodide (PI) by Fluorescence-activated cell sorting (FACS) was done to quantify DNA present at each of the cell-cycle stages of the cell-cycle in response to ARV treatment. Subsequently, an apoptosis assay using Annexin V FITC and Propidium iodide (PI) dual staining by FACS was carried out to confirm and quantify the ARVs potential apoptotic effects. Then, 4′,6-diamidino-2-phenylindole (DAPI) staining was used to assess changes in nuclear morphology exerted by the ARVs’ effects. A more in depth interrogation of the cell-cycle was performed using a focussed gene array panel of some 84 human cell-cycle related genes. First, total RNA was isolated from both treated and untreated MRC-5 and A549 cells and reverse transcribed to cDNA for use as template in the PCR array reactions. From the array gene expression results, by convention a ±2 fold up-or-down-regulation was used as the basis of target selection. Following this, a real-time quantitative PCR (RT-qPCR) validation of selected genes of interest was done to quantify and confirm the PCR array results. This was followed by in-silico Bio-informatics analysis to map the molecular pathways regulated by the identified targets. For this purpose, STRING, Database for Annotation, Visualization and Integrated Discovery (DAVID), Reactome and Ingenuity Pathway Analysis (IPA) databases were used. Interestingly, double-edged oncogenic properties of both EFV and LPV/r at different concentrations were identified. The proliferative effects of EFV at 4, 13μM and LPV/r at10 μM, were elucidated, while 26, 50μM of EFV, and 32μM of LPV/r had slight inhibitory effects on cell proliferation. LPV/r at concentrations of 50 and 80μM exerted cytotoxic effects on the cells, as demonstrated by the AB and xCELLigence RTCA assays. Cell-cycle analysis using PI staining, particularly showed cell-cycle arrest at 32μM LPV/r, and a shift to G2/M by 13μM EFV, plasma relevant doses, compared to the untreated cells. An increasing apoptosis percentage was observed with increasing LPV/r concentrations, that is, 80μM LPV/r raised the apoptosis percentage almost two-fold compared to 32μM. This was coupled by necrosis, observed in a time-dependant manner. DAPI staining confirmed loss of nuclear integrity post ARV exposure, suggesting that both EFV and LPV/r impose damage to the genomic DNA. To further assess the observed changes in nuclear morphology, the effects of EFV and LPV/r on the expression of an arrayed panel of human cell-cycle genes in cancer and normal lung cells was determined. Significantly differentially expressed targets were identified and further quantified and confirmed by RT-qPCR. Such targets included ATM, p53, cyclin-dependant kinase inhibitors (CDKIs), such as, p21, aurora kinase B (AURKB), Mitotic Arrest Deficient-Like 2 (MAD2L2) and the apoptosis related gene, caspase 3 (CASP3). Bio-Informatics analyses revealed close and direct protein-protein interactions (PPIs) between these targets, notably, with change in interaction between the gene products involved in DNA repair mechanisms, observed between ARV treated and untreated groups, as illustrated by STRING interactions. DAVID, Reactome and IPA analysis showed changes in expression of genes related to stress and toxicity and DNA damage response genes. In particular, ATM, p53 and its downstream targets such as GADD45A (growth arrest and DNA damage inducible alpha) gene were up-regulated by ARV treatment, while cyclin/CDK activity was down-regulated, resulting in reduced cell proliferation. Thus in summary, both EFV and LPV/r altered the expression levels of cell-cycle related genes, influencing overall cellular health, acting to either inhibit or stimulate cell proliferation. This suggests EFV’s and LPV/r’s proliferative and inhibitory roles in the proliferation of lung cells. Moreover, future directions can include the transfection of lung cells with HIV provirus followed by treatment of the cells with the same ARVs under study. This could be substantiated by including HIV positive patient samples on and off ARV drug treatment with lung cancer, including HIV negative patients with cancer as one of the controls.Item Validation of self reported measures of adherence to ART and factors associated with adherence in Jinja, Uganda(2016) Made, FelixBackground: Good adherence to ART prolongs survival and improves quality of life in people living with HIV/AIDS. Adherence is commonly assessed using self-reported measures, but these tend to over-estimate adherence. Viral load testing is the gold standard for measuring ART adherence but it is unaffordable in resource limited settings. Therefore, the aims of this small sub-study were to validate self-reported measures of adherence and to find factors associated with adherence to ART in Jinja, Uganda. Methods: This study was a secondary analysis of data collected from a cluster randomized equivalence trial which was carried out to compare facility based ART care versus home based care. In the main study, 1453 participants aged 18 and above were enrolled. A total of 1276 men and women qualified for this sub-study. Receiver operating characteristic (ROC) was computed to see how well two self-reported measures of adherence predicted virological failure. The two self-reported measures were firstly a visual analogue score (VAS) where participants rated the number of doses that they had taken in the past month on a scale from 0 (meaning no ART taken) to 100 (meaning that all required doses had been taken) and secondly an adherence score based on the number of pills missed in the three days before the visit. Logistic regression models were fitted with survey estimator to find factors associated with virological failure. Tobit models were fitted to find factors associated with self-reported adherence measures, since these were restricted to the range of 0-100% and censored. We then compared associated factors among the three different outcome measures. Results: There were 914 women and 362 men in this study. Home based care had larger number of patients (754) than facility based care (522). The median age of the patients was 38 years (IQR 32.0-44.0). Most of the participants were either married (518) or single (456). The majority of the trial participants had primary school education (n=713) and very few achieved tertiary education. A large number of participants had CD4 cell counts of less than 50 cells/mm3 (n=351), and very few of the patients in the trial had CD4 counts greater than 200 cells/mm3. The median CD4 count of the study participants was 116 cells / mm3 (IQR 43.0-167.0). A very large number of the patients were either in WHO clinical stage II or III (Stage II: n= 595; Stage III: n=577). A total of n=1079 (84.56%) and n=197 (13.44%) participants had no virological failure and failure respectively. The ROC methods showed that the iv self-reported adherence measures estimated virological failure with a sensitivity that ranged between 35-65%. Female patients had lower odds of experiencing virological failure (odds ratio: 0.7; 95% CI: 0.485, 0.968; p=0.033). The odds of virological failure decreased with each one year increase in age (OR: 0.95; 95% CI: 0.928, 0.979; p=0.001). Participants who found adherence reminders very useful were less likely to experience virological failure (P=0.001). Conclusion: This study show that self-reported measures are not good predictors of ART adherence since approximately only a half of the Jinja participants with virological failure were predicted by such measures. None of the factors associated with virological failure was also associated with both of the self-reported adherence measures. Viral load testing should be encouraged in place of self-reported adherence measures to ART. In addition, alternative methods of measuring adherence such as electronic medication monitoring, pharmacy refills and drug level detection should be investigated.Item Effects of human immunodeficiency virus infection and treatment with antiretroviral therapy on immunological responses to childhood vaccines(2017) Simani, Omphile ElizabethIntroduction: HIV-infected and HIV-exposed-uninfected children have a heightened susceptibility to some vaccine preventable disease. There is a paucity of data on immunogenicity of vaccines in these children, including HIV-infected children who are initiated on early antiretroviral therapy (ART). We evaluated the effect of maternal HIV-exposure and timing of ART in HIV-infected children on antibody responses to combined diphtheria-toxoid (DT) -tetanus-toxoid (TT)-whole cell pertussis (wP) and Haemophilus influenzae type b conjugate vaccine (HibCV); monovalent hepatitis B vaccine (HepB) and live-attenuated measles vaccine (MV). Methods: Samples obtained from children aged 6–12 weeks who had been enrolled into the CIPRA-SA study were analysed. Briefly, HIV-uninfected children born to HIV-uninfected (HIV-unexposed) and HIV-infected mothers (HEU). Additionally, we enrolled perinatally HIV-infected children with CD4+%≥25% randomized to deferred-ART (i.e. initiated when clinically or immunologically indicated per the then WHO recommended treatment criteria; ART-Def) or immediate-ART initiation (i.e. initiated on ART immediately upon confirmation of HIV-infection status at 4-10 weeks of age; ART-Immed). Children enrolled in the ART-Immed arm were further randomized to interrupt ART at one-year (ART/12m) or two-years of age (ART/24m). Additionally, a convenience sample of HIV-infected children with CD4+<25% initiated on immediate-ART was enrolled (ART-CD4+<25%). Children received a primary series of DTwP-HibCV/HepB at 6, 10 and 14 weeks of age; and MV at 40 weeks of age. Booster dose of DTwP and MV was given at 15-18 months of age. Sampling time-points were: prior to the first dose of vaccine, four weeks after the third dose (18 weeks age), 24 weeks after the third dose (39.3 weeks of age), at the time of the booster dose (15- 18 months age), two to four weeks after the booster dose and at 24 months of age. Samples were analysed for antibodies for DT, TT, PT, FHA, HepB measured by Luminex microbead-immunoassay; and MV antibodies were quantified by an indirect enzyme immunoassay. Results: Antibody kinetics and response to primary series of DTwP-HibCV/HepB: Pre-vaccination GMCs were higher in HIV-unexposed than HEU children for TT, but lower for HepB, DT and FHA. Post-vaccination, sero-conversion, sero-protection and GMCs were similar in HEU and HIV-unexposed children for all vaccines. Furthermore, GMCs were higher in HIV-unexposed for TT, DT, HepB and FHA than in ART-Immed children; and for TT, HepB and PT than in ART-Def children. Nevertheless, there was no difference in proportion of HIV-unexposed and HIV-infected children who developed sero-protective vaccine-specific antibody levels post-vaccination. The timing of ART initiation generally did not affect immune responses to vaccines between HIV-infected groups. Antibody kinetics and booster responses to DTwP-HibCV/HepB vaccines: Pre-booster GMCs were generally higher in HIV-unexposed than HIV-infected children for all vaccine epitopes. Post-booster and at 24 months of age the ART-Def group had lower GMCs (except to FHA), and were less likely to have sero-protective antibody levels compared to HIV-unexposed group. Also, post-booster and at 24 months of age, GMC were generally higher in HIV-unexposed than ART-Immed children, and a higher percentage of HIV-unexposed than ART-Immed children maintained antibody levels ≥1IU/ml to TT and DT at 24 months of age. The GMCs and percentage of children with sero-protective thresholds were similar pre-booster and at 24 months of age between HIV-unexposed and HEU children. Antibody kinetics and response to measles virus vaccine: At 7.3 weeks of age, the proportion with sero-protective titers was higher in HIV-unexposed (65.2%) compared to any HIV-infected group (range: 16.7% to 41.8%); but dropped to <17% in all Groups at age 19.6 weeks. Twenty-eight weeks following the first measles-vaccine, ART/12m were less likely to have sero-protective titers (79.3%) compared to HIV-unexposed (94.8%; p<0.001), ART-Def (95.7%; p=0.003) or ART/24m (92.1%; p=0.02). Although the proportion with sero-protective levels were similar between groups immediately post-booster dose, this was lower in HEU (79.6%; p=0.002) and ART/12m (80.3%; p=0.01) compared to HIV-unexposed (94.3%) 41-weeks later. Conclusion: Primary vaccination with DTwP-HibCV/HBV of HIV-infected children initiated on early-ART confers similar immunity compared to HIV-unexposed children. HIV-infected children had poor anamnestic responses, if ART was not initiated prior to primary vaccination. In contrast, the memory response and persistence of antibody to most vaccine epitopes were similar between HIV-unexposed and HEU children. Increased waning of vaccine induced immunity over a 24 month period in ART-Def, ART/12m and HEU children following MV booster-dose; indicating the need for further booster doses after two-years of age in these children. I recommend close monitoring of HEU children, as this group makes up most children born to HIV-infected mothers and what facets of the immune system have been impacted by maternal exposure to HIV.Item Exploring provider's perceptions on the facilitators and barries to implementation of nurse intiated management antiretroviral therapy in Manzini region, Swaziland(2015) Ngwarati, InnocentIntroduction: 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.