This study compare immunological and virological outcomes in antiretroviral therapy naïve patients exposed to Isoniazid prevention treatment.Medical records of antiretroviral naïve patients managed in the public sector from 1st January 2006 to 31st December 2006 were analysed.Multivariate analysis of variance showed that each treatment group achieved statistically significant increases in CD4+ cell count and viral load decay at each follow-up time point. Pairwise post hoc contrast tests showed patients in NVPipt-past group and EFVipt-past group to have superior immunological and virological outcomes respectively. / Health Studies / M.A. (Public health)

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree in Master of Science in the School of Molecular and Cell Biology August 2017 / Antiretroviral therapy (ART) drugs such as stavudine (d4T) are known to have off-target side-effects, including the inhibition of DNA polymerase gamma which replicates mitochondrial DNA (mtDNA). ART-induced depletion of mtDNA copy number may cause mitochondrial toxicities such as sensory neuropathy (SN). Genetic variation in DNA polymerase gamma or in other nuclear genes influencing mtDNA replication and mtDNA copy number may therefore contribute to susceptibility to d4T-induced SN. DNA samples from 263 HIV-positive South African adults exposed to d4T were classified as cases with SN (n = 143) and controls without SN (n = 120). A total of 28 single nucleotide polymorphism (SNPs) were chosen in nuclear genes from the mtDNA replication pathway and from a GWAS paper examining SNP association with ART-induced SN (Leger et al. 2014). Genotyping was performed using Sequenom Mass Spectrometry. MtDNA copy number was determined using a qPCR assay. Associations between SN and genetic variants, between genetic variants and mtDNA copy number, and between mtDNA copy number and SN were evaluated in univariate and multivariate models using Plink v1.07 and GraphPad v7. Age and height were significantly different in the cases with SN vs controls without SN. In univariate analyses, three SNPs and two haplotypes were significantly associated with SN, three SNPs were associated with pain intensity and three haplotypes were significantly associated with mtDNA copy number. However, there were no significant associations with SN, pain intensity or mtDNA copy number after correction for multiple SNP testing. No significant difference in mtDNA copy number in cases vs. controls was observed. In conclusion variation in nuclear-encoded mitochondrial genes examined in the current study do not play a role in ART-related mitochondrial complications such as changes in mtDNA copy number, or occurrence of SN. / MT2018

A research report submitted to the Faculty of Health Sciences, the University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Child Health Neurodevelopment Johannesburg, 2013 / Human Immunodeficiency Virus (HIV) infection in infancy may influence the developing brain and lead to adverse neurodevelopmental consequences. We aim to describe the neurodevelopmental characteristics of a cohort of young children infected with HIV prior to antiretroviral therapy (ART) initiation and after achieving viral suppression. A retrospective analysis of data collected as part of a randomised equivalence trial between April 2005 and May 2009, at a hospital in Johannesburg, South Africa. 195 HIV-infected children under 2 years of age were assessed. A simple, inexpensive screening questionnaire (Ages and Stages Questionnaire - ASQ) was used to identify neurodevelopmental delays. The ASQ was administered prior to ART initiation, and again after viral suppression on a protease inhibitor-based regimen had been achieved. Median age pre-ART was 8.8 months (range 2.2 - 24.9), 53.9% were male. Mean time to viral suppression was 9.4 months (range 5.9 - 14.5) and the ASQ was administered to 108 caregivers at this time. Compared to pre-ART, at viral suppression, there was significant reduction in the proportion of children failing the gross motor (31.5% vs. 13%, p<0.01), fine motor (21.3% vs. 10.2%, p=0.02), problem solving (26.9% vs. 9.3%, p<0.001) and personal social (17.6% vs. 7.4%, p=0.02) domains. The proportion of children failing the communication domain was similar at each time point (14.8% vs. 12%, p=0.61). At time of viral suppression 10.2% failed at least one of the five domains. Achieving viral suppression on ART resulted in significant improvements in the neurodevelopmental function of young HIV-infected children, however, neurodevelopmental problems still persisted in a large proportion. Appropriate screening for neurodevelopmental delay and timely referral could help improve outcomes.

HIV-associated peripheral neuropathy (PN), and related functional limitations that affect the quality of life (QoL), may now be one of the most formidable challenges in the health care of people living with HIV (PLHIV). The most common PN is distal sensory polyneuropathy (DSP). It is likely that there is a high prevalence of PN among PLHIV in Rwanda. The available data on the prevalence of PN are poor and there are none on how PN is associated with functional abilities and the QoL of PLHIV, which can guide management. In addition, current management of PN is mostly related to symptomatic management and is mainly pharmacological which may not rehabilitate the neuromuscular function that has been affected by PN. This thesis planned to re-validate and adapt the lower extremity functional scale (LEFS) and the brief peripheral neuropathy screen (BPNS), establish the prevalence of PN, and determine the effects of physiotherapeutic exercises on PN, lower extremity functional limitations and QoL, among Rwandan PLHIV receiving antiretroviral therapy (ART). Methods Study 1 translated LEFS from English to Kinyarwanda, modified it accordingly, and tested its reliability among 50 adult PLHIV on ART. The study also piloted

A research report submitted to the faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Science in Medicine (Pharmacotherapy) / Background: The decision of when to start treatment in an HIV-infected individual has always been problematic as far as CD4 count is concerned. Aims: To determine the clinical outcome of patients who commence HAART at different CD4 cell count levels. Method: Retrospective analysis of records of a cohort of patients who are received ART at workplace wellness clinics in three mines in Limpopo province from January 2003 to December 2009. Patients were divided into three groups based on their baseline, group A (CD4 <100), group B (CD4 101-200) and group C (CD4 201-250) Each patient’s data was analyzed one year after his/her commencement. Results: The percentage of patients who died in group A (16%) differs significantly from the percentage of patients who died in group B (4%) (Fisher exact test p= 0.038) and also differ significantly from the percentage of patients who died in group C (0%) (Fisher exact test p= 0.011). The percentages of patients who developed TB in the three groups are 8%, 8% and 2.9% respectively. When compared statistically, these percentages do not differ significantly (Fisher exact test p=0.059).The percentages of patients with severe bacterial pneumonia in the three groups (2%, 2% and 0% respectively) do not differ significantly (Fisher exact test p=0,276).The percentage of hospital admissions for patients in group A (18%) differ significantly from the percentage in group B (6%) and the percentage in group C (6%) (Fisher exact test p= 0.05). The percentage of patients with weight loss of more than 10% of baseline value in group A (24%) differ significantly from the percentage in group B (4%) (Fisher exact test p= 0.003) and also differ significantly to from the percentage in group C (0%) (Fisher exact test p= 0.001). The percentage of patients with undetectable viral load in group B (89%) is significantly different from the percentage in group A (69%) (Fisher exact test p= 0.03) and is also significantly different from the percentage in group C (61%) (Fisher exact test p= 0.008).The change in mean CD4 cell count was found to be statistically significant within each group (paired t test, p<0.0001), but the mean changes between the three groups (132,141 and 172) respectively, do not differ significantly (ANOVA test). Conclusion: Patients with baseline CD4 cell count of less than 100 have a poor clinical outcome when compared to patients with baseline CD4 cell count of more than 100. Efforts must be made to identify patients early before CD4 cell count fall to below 100 and preferably initiate HAART when CD4 cell count is above 200.

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Genetics. Johannesburg, South Africa 2017 / Background: Stavudine (d4T) use is associated with the development of sensory neuropathy (SN), several mechanisms may underlie d4T-induced toxicity, including: (1) Inter-patient genetic variability in the genes modulating the deoxynucleotide triphosphate (dNTP) pool sizes. (2) Variation in intracellular ARV drug concentrations due to genetic variation in drug transporters. In our study we examined the genetic variation in four stavudine transporter genes and seven genes regulating the deoxythymidine triphosphate (dTTP) synthesis and their associations with d4T-induced SN or CD4+ T cell count or mtDNA copy number. Methods: We examined a cohort of HIV-positive South African (SA) adults exposed to d4T, including 143 cases with SN and 120 controls without SN. 26 single nucleotide polymorphisms (SNPs) from the literature were chosen, prioritised on being tagSNPs with minor allele frequency >5% in Kenyan Luhya (a proxy population for the SA Black population); SNP functional effects and suitability for multiplex analysis on the genotyping platform. Genotyping was performed using Sequenom mass spectrometry. A qPCR assay was used to measure the mtDNA copy number. Association of sensory neuropathy, CD4+ T cell count and mtDNA copy number with genetic variants was evaluated using PLINK. Results: All 26 SNPs were in Hardy-Weinberg equilibrium (HWE) in both the cases and controls. SNP rs8187758 of the SLC28A1 transporter gene and a 3-SNP haplotype ABCG2 were significantly associated with CD4+ T cell count after correction for multiple testing (p = 0.043 and p=0.042 respectively), but were not significant in multivariate testing. No SNP remained significantly associated with SN or mtDNA copy number, after correction for multiple testing. Conclusion: Variation in genes encoding molecular transporters of d4T may influence CD4+ T cell counts after ART. This study presents a positive step towards achieving personalized medicine in SA. / MT 2018

A research report submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Diagnostic Radiology Johannesburg, 2013 / INTRODUCTION: There is limited information on the radiographic presentation of children eligible to start HAART in resource-limited settings. OBJECTIVES: Determine radiographic patterns on pre-HAART chest X-rays (CXRs) in children, compare findings in immune-suppressed vs. non immune-suppressed children, compare the percentage of children with radiographic features of pulmonary TB to the percentage of children on TB treatment and assess inter-observer agreement between 3 radiologists. METHODS: Children (0-8 years) participating in a cohort study of TB and BCG-IRIS who had an acceptable routine pre-HAART CXR were included. CXRs were independently assessed by 3 radiologists, blinded from clinical data, using a standardised assessment form. All 3 readings were used to create a majority consensus finding during the data analysis phase. RESULTS: Amongst 161 children, the median age at enrolment was 2.3 years (25% (41/161) were <1year), 54% (87/161) were on TB treatment and 65% (100/154) were immune-suppressed. The majority (71%) had an abnormal CXR finding, predominantly air space disease (42%) and parenchymal interstitial disease (21%). Of the sub-group of 112 (70%) CXRs that could be assessed for lymphadenopathy, 75(67%) had one or more features suggestive of TB (74 lymphadenopathy, 2 cavities, 18 miliary infiltration) and 65% (70/107) were immune-suppressed. Statistically significant differences between immune-suppressed and non-immune-suppressed children were noted for features of lymphadenopathy and radiographic pulmonary TB. Amongst the sub-group of 112 CXRs a high percentage 49/75 (65%) were on TB treatment, with 26/75 (35%) not on TB treatment. Inter-observer agreement between all 3 readers was fair for overall abnormal CXR findings (K=0.23), airspace disease (K=0.22), moderate for parenchymal interstitial disease (K=0.54) and slight for lymphadenopathy (K=0.05). CONCLUSION: Among children eligible to start HAART, most (71%) presented with abnormal CXR findings and the majority (67%) had one or more CXR signs suggestive of TB. Of concern was the high proportion of CXRs (30%) that were of insufficient quality to be assessed for lymphadenopathy and the poor inter-observer agreement for lymphadenopathy.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment of the requirements for the degree of Master of Science in Medicine in Pharmacotherapy, Johannesburg, 2011 / Long term antiretroviral therapy (ART) use is known to cause various toxic adverse effects in patients. Hepato-toxicity is one of the most significant adverse effects which have been associated with all antiretroviral therapy drugs in South Africa and worldwide.

Introduction: Stavudine is a commonly used drug in paediatric antiretroviral treatment (ART) regimens. Due to toxicity concerns, however, the drug abacavir has replaced stavudine in first-line paediatric regimens inmany countries.Wedescribe the frequency of stavudine toxicity in children receiving ART at a treatment clinic in Soweto, South Africa. Methods: Data on patient characteristics and outcomes of ART were collected from a cohort of 2222 HIV-infected children initiating ART between 2004 and 2008 when stavudine-containing regimenswere routinely recommended. At several time-points after treatment initiation, we estimate the proportion of children where an attending clinician discontinued stavudine due to lipodystrophy, pancreatitis, lactic acidosis or peripheral neuropathy. Factors associated with stavudine-related toxicities were identified. Results: At ART initiation, most children had advanced disease. The majority initiated an efavirenz/lamivudine/stavudine regimen (n¼1422), and 76% of children remained on their initial ART regimen after a median 19.9 months of ART. Replacement of stavudine due to drug toxicity occurred at a rate of 28.8 per 1000 child years on treatment (95% confidence interval¼23.6–35.2). Rates of toxicity increased with treatment duration (in their first year of ART stavudine was replaced in 0.5% of children, but after 3 years stavudine had been changed to abacavir in 12.6% of children). Toxicity was more common in older children and in girls. Lipodystrophy accounted for 87 of 96 toxic events. Conclusion: Stavudine-associated toxicity resulting in single-drug substitution was uncommon in this cohort, though its frequency increased steadily with ART duration, especially with lipodystrophy. Where drug options are limited, stavudine remains a relatively well tolerated and effective option for children.

Orientador: Ricardo Augusto Monteiro de Barros Almeida / Resumo: Introdução: Até há cerca de uma década, a infecção pelo HIV era considerada contraindicação absoluta para transplantes de órgãos. Estudos recentes sugerem que o transplante renal (TxR) é viável para pessoas vivendo com HIV/aids (PVHA) adequadamente selecionadas. Apesar de bastante efetivos, os TxRs em PVHA apresentam dificuldades importantes. A maioria dos estudos relatam incidências mais elevadas de rejeição aguda, chegando a mais de 50%. Fatores imunológicos e farmacológicos teriam grande influência. A literatura atual mostra que o melhor esquema antirretroviral (ARV) para os TxRs em PVHA ainda não foi identificado. Objetivo: Devido à relevância do tema e à ausência de ensaios clínicos randomizados (ECRs), o objetivo do estudo foi identificar, através de metanálise proporcional de série de casos, os esquemas de ARVs mais efetivos e seguros para PVHA submetidas ao TxR. Métodos: Foram incluídos estudos de relato e série de casos que tivessem avaliado qualquer esquema ARV utilizado em PVHA submetidas ao TxR e que fornecessem dados relacionados aos desfechos de interesse, que foram mortalidade, sobrevida do enxerto, episódios de rejeição aguda, função renal e curso clínico e laboratorial da infecção pelo HIV. A pesquisa em bases de dados foi realizada através das fontes: MEDLINE, EMBASE, Scopus e LILACS (até dezembro de 2014). Dois revisores independentemente selecionaram os estudos identificados pelas bases de dados. Foram realizadas metanálises proporcionais de série de casos comparando a ocorrência dos desfechos em diferentes esquemas ARVs por meio do software StatsDirect. A heterogeneidade estatística foi avaliada utilizando o teste estatístico I2 . Resultados e discussão: Dos 2841 estudos inicialmente identificados pela pesquisa bibliográfica, 24 respeitaram os critérios de inclusão e exclusão, totalizando 57 pacientes. Não houve diferença... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Until about a decade ago, HIV infection was considered absolute contraindication for organ transplants. Recent studies suggest that kidney transplantation (KTx) is feasible for people living with HIV/AIDS (PLWHA) in select cases. Although highly effective, the KTx in PLWHA presents major difficulties. Most studies report higher incidences of acute rejection, reaching more than 50%. Immunological and pharmacological factors have great influence. Current literature shows that the best antiretroviral (ARV) regimen for KTx in PLWHA has not been identified. Objectives: Due to the relevance of the subject and the absence of randomized controlled trials (RCTs), the objective of the study was to identify, the most effective and safest ARV regimens for PLWHA submitted to KTx. Methods: Case series studies that have evaluated any ARV regimen used in PLWHA submitted to KTx and that provided data related to the outcomes of interest - mortality, graft survival, acute rejection, renal function and clinical and laboratory course of HIV infection - were included. Research in databases was performed using the sources: MEDLINE, EMBASE, Scopus, and LILACS (until December 2014). Two reviewers independently selected studies through the databases. Meta-analyses of case series were conducted comparing the occurrence of different outcomes in ARV schemes through software StatsDirect. Statistical heterogeneity was assessed using the I2 statistic. Results and Discussion: From 2,841 studies initially identified by the literature search, 24 studies complied with the inclusion and exclusion criteria, totaling 57 patients. There was no statistically significant difference between groups of patients who used ARV regimens based on two nucleoside/nucleotide reverse transcriptase inhibitors plus one non-nucleoside/nucleotide reverse transcriptase inhibitors (2NRTI+NNRTI), a combination of abacavir, lamivudine... (Complete abstract click electronic access below) / Mestre