ETD Collection

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Subject: search.filters.subject.HIV infections--Treatment

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    Prevalence of dyslipidaemia in HIV-infected children and adolescents treated with protease inhibitors
    (2018) Sipambo, Nosisa
    Background – HIV infection and antiretroviral therapy (ART) are associated with dyslipidaemia in children. Protease inhibitor (PI) based regimens, in particular, have shown the highest association. Methods – We conducted a retrospective study of children treated with either a first- or second-line lopinavir/ritonavir (LPV/r) regimen who had any lipid tests done from 2004 to 2015. Dyslipidaemia was defined as hypercholesterolaemia [total cholesterol ≥5.13mmol/l (≥200mg/dl)] and /or hypertriglyceridaemia [total triglycerides ≥1.69 mmol/l (≥150mg/dl)]. There were 4 cross sectional points of analysis in this study: ART start, LPV/r-start, 12 and 24 months after starting LPV/r. Demographic and clinical characteristics were compared using univariate and multivariate analyses to determine risk factors for dyslipidaemia at each time point using logistic regression to obtain odds ratios and 95% confidence intervals (95% CI). Results - Few children had lipids measured over the follow-up period, increasing from 7% (146/2145) at ART initiation to 24% (365/1522) after 24 months on LPV/r. The median age at ART-start was 1.6 (0.4; 4.4) increasing to 3.6 (2.6; 6.2) years by 24 months. The majority (51%) of the children had severe immune suppression at ART-start. The prevalence of dyslipidaemia at ART-start was 47%, decreasing to 36% at 24 months. Multivariate analysis at 12 months found that children less than 10 years of age with near suppressed viral loads (viral load < 4 logs) were more likely to have dyslipidaemia. At 24 months on LPV/r, ART duration greater than 60 months and high viral loads were protective factors. Conclusion – The high prevalence of dyslipidaemia in young children is concerning as lopinavir/ritonavir is the mainstay of ART in young children for the foreseeable future.
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    Genetic variants of d4T drug transporters and dNTP pool regulators, and their association with response to d4T-ART
    (2017) Moketla, Blessings Marvin
    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.