Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients

Abstract

PurposeTo assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS).MethodsThree-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method.ResultsHALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53–3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/106 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): ‘A+A’; OR for ‘A+B’ vs. ref.: 1.39 [0.69–2.80]; OR for ‘B+A’ vs. ref.: 2.16 [1.22–3.83]; OR for ‘B+B’ vs. ref.: 3.13, 95%CI: 1.54–6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56–4.14, P = 0.001), (c) use of EFV (1.10 [1.00–1.21], P = 0.008, per year of use).ConclusionHALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine.

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“…Long-term protease inhibitor use has been associated with lipodystrophy syndrome. 17,[19][20][21][22] The choice of the protease inhibitor can affect lipid elevations. The finding that DRV/r has a favorable lipid profile is supported by a meta-analysis of 12 clinical trials examining the effect of different ritonavirboosted protease inhibitors on lipid changes at 48 weeks in over 4000 treatment-naïve patients.…”

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“…Insulin Receptor Substrate 1 (IRS1) SNPs (rs 1801278) has been associated with increased risk of limbs lipoatrophy in the same Spanish Caucasian cohort [23] . Low-expression thymidylate synthase SNPs have also been associated with lipodystrophy in HIV-infected patients exposed to estavudine [24] .…”

“…Low-expression thymidylate synthase SNPs have been related to increased stavudine triphosphate intracellular levels [24] . Methylenetetrahydrofolate reductase (MTHFR) 1298 A > C SNP has been associated with decreased activity of this enzyme and abnormalities of folate metabolism.…”

“…Methylenetetrahydrofolate reductase (MTHFR) 1298 A > C SNP has been associated with decreased activity of this enzyme and abnormalities of folate metabolism. The conjunction of a low-expression thymidylate synthase plus a MTHFR genotype in HIV-infected patients exposed to stavudine has been associated with the development of peripheral neuropathy and lipodystrophy in HIV-infected individuals [24,25] . Mitochondrial haplogroup T MTND1*LHON4216C and MTND2-*LHON4917G genotypes and mitochondrial haplogroup T and 7028C > T, 10398G > A, and 13368G > A, SNPs were independently linked to increased susceptibility to A recent meta-analysis has quantified the utility of HLAB*5701 testing [13] .…”

HLA Alleles Association with Changes in Bone Mineral Density in HIV-1-Infected Adults Changing Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine

“…Genetic screening in HIV-infected patients for HLA-B*5701 is used to predict abacavir hypersensitivity [13], and HLA-B*3505 has been associated with nevirapine-induced rash [14]. Recently, HLA-B*4001 was suggested as a genetic risk factor for stavudine-associated lipodystrophy in Thai patients [15], though this association was not found in Caucasians patients [16]. Cordery et al showed that HIV-infected adults carrying HLA-A01, B08 or DQ2 supertypes may be resistant to peripheral fat-loss induced by thymidine analogue nucleotide reverse transcriptase inhibitors (NRTIs) [17].…”