BACKGROUND: Since the introduction of the first nucleotide reverse transcriptase inhibitors thymidine analogues such as AZT and d4T (NRTIs), the major problem has been to try to avoid the development of side effects such as those associated with mitochondrial toxicity , lipodystrophy peripheral neuropathy or pancreatitis. HYPOTHESIS: Polymorphisms of the pyrimidine pathway enzymes, as Thymidylate Synthase (TS) which are associated with decreased enzymatic activity, are related to higher drug intracellular concentrations and therefore more risk of mitochondrial toxicity and side effects. METHODS: A prospective non-randomized study of patients with HIV-1 infection receiving d4T- based regimens. A case-control study of HIV-1 patients receiving d4T-based regimens who had developed pancreatitis, peripheral neuropathy or lipodystrophy. Multivariate analysis was performed in both cases. RESULTS: In the first study, the average concentration in patients with and without lipodystrophy was 20.60 fmol / l x106 cels and 13.85 fmol / l x106cels (p = 0.013) respectively. The two independent variables associated with the development of lipodystrophy were the presence of an AIDS-defining condition and the intracellular levels of d4T-TP. Polymorphisms associated with reduced activity of TS concentrations were associated with d4T-TP intracellular older (11.50 vs. 21.40 fmol/106 fmol/106 Cels, p <0.0001). In the second study, in multivariate analysis, the factors associated with lower probability of occurrence of pancreatitis and peripheral neuropathy were the nadir CD4 count> 200 cells/mm3 and the presence of lipodystrophy syndrome. The only factor associated with increased likelihood of developing pancreatitis and / or neuropathy was TS low expression genotype.
|Date of Award||31 Oct 2013|
|Supervisor||Pedro Domingo Pedrol (Director) & Mª Mercedes Gurgui Ferrer (Tutor)|