Association of Thymidylate Synthase Polymorphisms with Acute Pancreatitis and/or Peripheral Neuropathy in HIV-Infected Patients on Stavudine-Based Therapy

Pere Domingo,Irene Fernandez,Francesc Villarroya,Francesc Vidal,Montserrat Baiget,Ferran Torres,Esteban Martínez,Maria Del Carmen Cabeza,Esteban Ribera,Joan Carles Domingo,Maria Gracia Mateo,Juliana Salazar,Maria Del Mar Gutierrez,Rui Medeiros

doi:10.1371/journal.pone.0057347

Abstract

BackgroundLow expression thymidylate synthase (TS) polymorphism has been associated with increased stavudine triphosphate intracellular (d4T-TP) levels and the lipodystrophy syndrome. The use of d4T has been associated with acute pancreatitis and peripheral neuropathy. However, no relationship has ever been proved between TS polymorphisms and pancreatitis and/or peripheral neuropathy.MethodsWe performed a case-control study to assess the relationship of TS and methylene-tetrahydrofolate reductase (MTHFR) gene polymorphisms with acute pancreatitis and/or peripheral neuropathy in patients exposed to d4T. Student’s t test, Pearson’s correlations, one-way ANOVA with Bonferroni correction and stepwise logistic regression analyses were done.ResultsForty-three cases and 129 controls were studied. Eight patients (18.6%) had acute pancreatitis, and 35 (81.4%) had peripheral neuropathy. Prior AIDS was more frequent in cases than in controls (OR = 2.36; 95%CI 1.10–5.07, P = 0.0247). L7ow expression TS and MTHFR genotype associated with increased activity were more frequent in patients with acute pancreatitis and/or peripheral neuropathy than in controls (72.1% vs. 46.5%, OR = 2.97; 95%CI: 1.33–6.90, P = 0.0062, and 79.1% vs. 56.6%, OR = 2.90, 95%CI: 1.23–7.41, P = 0.0142, respectively). Independent positive or negative predictors for the development of d4T-associated pancreatitis and/or peripheral neuropathy were: combined TS and MTHFR genotypes (reference: A+A; P = 0.002; ORA+B = 0.34 [95%CI: 0.08 to 1.44], ORB+A = 3.38 [95%CI: 1.33 to 8.57], ORB+B = 1.13 [95%CI: 0.34 to 3.71]), nadir CD4 cell count >200 cells/mm3 (OR = 0.38; 95%CI: 0.17–0.86, P = 0.021), and HALS (OR = 0.39 95%CI: 0.18–0.85, P = 0.018).ConclusionsLow expression TS plus a MTHFR genotype associated with increased activity is associated with the development of peripheral neuropathy in d4T-exposed patients.

Highlights

The doubtless efficacy of highly active antiretroviral therapy (HAART) is still shadowed by drug toxicity, specially that appearing in the long-term [1]
We recently described how thymidylate synthase (TS) polymorphisms may modify d4T triphosphate (d4T-TP) intracellular concentrations, and how higher intracellular levels of d4T-TP are associated with the HIV/HAART-associated lypodystrophy syndrome (HALS) [7,8]
The incidence of d4T-associated pancreatitis and/or neuropathy was 19.05 cases per 1000 patient-years (PY) in those exposed to d4T and 4.28 (3.13–5.86) in those not exposed (P,0.0001)

Summary

Introduction

The doubtless efficacy of highly active antiretroviral therapy (HAART) is still shadowed by drug toxicity, specially that appearing in the long-term [1]. Among NRTI-associated toxicity, that caused by thymidine analogues, namely zidovudine (AZT) and stavudine (d4T) stands out. The ability of the triphosphate active NRTI to inhibit mitochondrial gamma polymerase causes mitochondrial DNA depletion that may eventually lead to mitochondrial respiratory chain protein depletion which in turn leads to mitochondrial dysfunction [4]. This can cause cellular dysfunction or even cellular death [5]. The use of d4T has been associated with acute pancreatitis and peripheral neuropathy. No relationship has ever been proved between TS polymorphisms and pancreatitis and/or peripheral neuropathy

Methods

Results

Discussion

Conclusion