ETD Collection

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Subject: search.filters.subject.Antiretroviral agents

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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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    Antiretroviral drug susceptibility of a hinge region variant of HIV-1 subtype C protease
    (2018) Zondagh, Jake
    Since their discovery, protease inhibitors continue to be an essential component of antiretroviral treatment for human immunodeficiency virus type 1 (HIV-1). However, the development of resistance to protease inhibitors remains one of the most significant challenges in the fight for sustained viral suppression in those infected with HIV-1. Studies show that specific mutations arising within the HIV-1 gag and protease genes can lead to the development of resistance. In this research, a South African HIV-1 subtype C Gag-protease variant (W1201i) was investigated. This variant was considered due to the presence of a mutation and insertion (N37T↑V), located within the hinge region of the protease enzyme. Moreover, the variant displayed the following polymorphisms: Q7K, I13V, G16E, M36T, D60E, Q61E, I62V and M89L. Genotyping of W1201i Gag revealed a previously unreported MSQAG insertion between the CA/p2 and p2/NC cleavage sites. Additionally, a mutation and insertion (I372L↑M), and multiple polymorphisms (S369N, S371N, I373M and G377S) were discovered within the p2/NC cleavage site. Single-cycle phenotypic assays were performed to determine the drug susceptibility and replication capacity of the variant. The results show that the mutations present in the N37T↑V protease conferred a replicative advantage and reduced susceptibility to lopinavir, atazanavir and darunavir. Interestingly, the mutations in W1201i Gag were found to modulate both replication capacity and protease inhibitor susceptibility. In silico studies were performed to understand the physical basis for the observed variations. Molecular dynamics simulations showed that the N37T↑V protease displayed altered dynamics around the hinge and flap region and highlighted the amino acids responsible for the observed fluctuations. Furthermore, induced fit docking experiments showed that the variant bound the iv protease inhibitors with fewer favourable chemical interactions than the wild-type protease. Collectively, these data elucidate the biophysical basis for the selection of hinge region mutations and insertions by the HI virus and show that protease, as well as Gag, needs to be evaluated during resistance testing.