ETD Collection

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Subject: search.filters.subject.Highly active antiretroviral therapy

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    Pattern of practice in carcinoma of the cervix: a retrospective analysis fo HIV positve patients treated with radiation at Charlotte Maxeke Johannesburg Academic Hospital 2008-2009
    (2017) Ndamase, Sibahle Nozuko Portia
    Carcinoma of the cervix is frequently diagnosed in the department of Radiation Oncology in Charlotte Maxeke Johannesburg Academic Hospital(CMJAH). It is therefore is a condition of priority and there is scarce literature in the management of HIV positive patients. OBJECTIVES: The primary objective of the research is to determine the overall survival of 2yrs and more, as well as to determine acute and late toxicity for patients completing prescribed radiation treatment. The secondary objective was to determine the impact of highly active antiretroviral therapy on survival and toxicity. The study is limited to HIV positive women presenting with cervical cancer. DESIGN & METHOD: The study is a retrospective study of patients treated at Charlotte Maxeke Johannesburg Academic Hospital between 2008-2009. Inclusion criteria: Females between the ages of 18 and 70, Stages IB2 – Stage IIIB carcinoma of the cervix who have completed planned radiation therapy with or without chemotherapy. The sample size was 151 patients. RESULTS: The mean age was 42.7yrs. The median CD4 count was 309 and 26.2% had CD4 counts below 200.The majority of patients had either Stage IIB (55.0%) or IIIB (31.8%). The total dose to Point A was a median dose of 74Gy. The majority of patients had either Grade II (38.4%) or III (31.1%) toxicity. Significant association between these adverse events and HAART status was rated as p=0.0008. The most common late complication was cystitis (15.9%). Overall survival at 2 years was 100% for Stage I, 92.8% for Stage II and 96% for Stage III. CONCLUSION: The median age was lower than in the HIV negative patients. The acute complications for those not on HAART, were higher in comparison to patients on HAART. The overall survival at 2 yrs. was above 90% for all stages in this study
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    Genetic variation influencing mitochondrial DNA copy number and the development of sensory neuropathy in HIV-positive patients exposed to stavudine
    (2017) Marutha, Tebogo Rector
    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.
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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.