Metabolic events in HIV-infected patients using abacavir are associated with erythrocyte inosine triphosphatase activity

• Published in: Journal of antimicrobial chemotherapy Vol. 74; no. 1; pp. 157 - 164
• Main Authors: Peltenburg, N Chantal, Bierau, Jörgen, Schippers, Jolanda A, Lowe, Selwyn H, Paulussen, Aimée D C, van den Bosch, Bianca J C, Leers, Mathie P G, Andrinopoulou, Eleni-Rosalina, Bakker, Jaap A, Verbon, Annelies
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-01-2019
• Subjects: Adult; Aged; Diabetes Mellitus - epidemiology; Didanosine - adverse effects; Didanosine - therapeutic use; Dideoxynucleosides - adverse effects; Dideoxynucleosides - therapeutic use; Erythrocytes - enzymology; Female; Genotype; HIV Infections - drug therapy; Humans; Hypercholesterolemia - epidemiology; Hypertension - epidemiology; Male; Middle Aged; Pyrophosphatases - genetics; Pyrophosphatases - metabolism; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - therapeutic use; Tenofovir - adverse effects; Tenofovir - therapeutic use
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dky383

Abstract
Objectives
Abacavir use has been associated with an increased risk of cardiovascular disease (CVD) and metabolic events in HIV-infected patients, although this finding was not consistently found. It is unclear whether abacavir only increases this risk in subpopulations of HIV-infected patients. It may be hypothesized that inosine 5′-triphosphate pyrophosphohydrolase (ITPase), an enzyme involved in the metabolism of purine analogues used in HIV treatment, plays a role in the risk of CVD and metabolic events in HIV-infected patients.
Methods
ITPase activity and ITPA genotype were determined in 393 HIV-infected patients. ITPase activity <4 mmol IMP/mmol Hb/h was considered decreased. ITPA polymorphisms tested were: c.94C>A (rs1127354) and c.124 + 21A>C (rs7270101). ORs were determined using generalized estimating equation models for developing CVD in patients who had ever been exposed to abacavir, tenofovir or didanosine and for developing metabolic events in patients currently using these drugs.
Results
In patients using abacavir, metabolic events were associated with ITPase activity. No association was demonstrated for tenofovir or didanosine. The OR for metabolic events was 3.11 in patients using abacavir with normal ITPase activity (95% CI 1.34–7.21; P = 0.008) compared with patients with decreased ITPase activity [adjusted for age, BMI, cumulative duration of combination ART (cART) use and the use of PI and NNRTI]. CVD was not associated with ITPase activity or ITPA genotype.
Conclusions
This study shows, for the first time, that ITPase activity is associated with the occurrence of metabolic events in patients using abacavir. Further studies are needed to confirm this association and to elucidate the possible mechanism.