Prior exposure to thymidine analogs and didanosine is associated with long-lasting alterations in adipose tissue distribution and cardiovascular risk factors

Abstract

Background: Thymidine analogues (TA) and didanosine (ddI) have been associated with redistribution of body fat from subcutaneous (SAT) to visceral (VAT) adipose tissue, which, in turn, is a risk factor for cardiovascular disease (CVD). We explored differences in adipose tissue distribution between people living with HIV (PLWH) with prior exposure to TA and/or ddI, without exposure, and uninfected controls and the association with CVD risk factors. Methods: 761 PLWH from the COCOMO study and 2,283 age-and sex-matched uninfected controls from the CGPS study were included. PLWH were stratified according to prior exposure to TA and/or ddI. VAT and SAT were determined by abdominal CT-scan. Hypotheses were tested using regression analyses. Results: Exposure to TA and/or ddI was associated with 21.6 cm 2 larger VAT (13.8-29.3) compared to HIV infection without exposure. HIV-negative status was associated with similar VAT compared to HIV infection without exposure. Cumulative exposure to TA and/or ddI (3.7 cm 2 per year [2.3-5.1]), but not time since discontinuation (-1.1 cm 2 per year [-3.4-1.1]), was associated with VAT. Prior exposure to TA and/or ddI was associated with excess risk of hypertension (aOR 1.62 [1.13-2.31]), hypercholesterolemia (aOR 1.49 [1.06-2.11]), and low HDL (aOR 1.40 [0.99-1.99]). Conclusions: This study suggests a potentially irreversible and harmful association of TA and ddI with VAT accumulation, which appears be involved in the increased risk of hypertension, hypercholesterolemia, and low HDL found in PLWH with prior exposure to TA and/or ddI, even years after treatment discontinuation.

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

“…The long-lasting lipodystrophic phenotype associated with previous use of thymidine NRTIs results in a higher risk of hypertension, high TC and reduced HDL [1,5]. Truncal adiposity is clearly related to a dysmetabolic phenotype with increased risk of CVD and diabetes and also of liver steatosis.…”

“…PLWH from the AGEhIV cohort have higher waist circumference and lower hip circumference than wellpaired non-infected individuals [4] and fat redistribution was associated with higher rates of hypertension [5]. In addition, in the COCOMO study, previous cumulative exposure to stavudine, zidovudine or didanosine is associated with long-lasting increased visceral adipose tissue (VAT) and decreased subcutaneous adipose tissue (SAT), as evaluated by abdominal CT scan, and related with excess risk of hypertension, high total cholesterol (TC) and low HDL [1].…”

“…All these dysmetabolic situations increase the atherogenic cardiovascular risk.Before 2000, PLWH received first-generation ART, as nucleoside analogue reverse transcriptase inhibitors (thymidine NRTIs, stavudine, zidovudine, didanosine) and protease inhibitors (PI, indinavir, ritonavir, nelfinavir) responsible for marked adverse events on lipid and glucose metabolism and on adipose tissue. These ART were replaced by newer molecules presenting a markedly lower metabolic toxicity.However, some PLWH, previously treated with first-generation NRTIs, present long-lasting fat alterations with metabolic consequences [1]. Some contemporary ART as integrase inhibitors (INSTI), considered as metabolic-friendly, were recently associated with weight/fat gain.…”

“…However, some PLWH, previously treated with first-generation NRTIs, present long-lasting fat alterations with metabolic consequences [1]. Some contemporary ART as integrase inhibitors (INSTI), considered as metabolic-friendly, were recently associated with weight/fat gain.…”

Long-lasting alterations in adipose tissue density and adiponectin production in people living with HIV after thymidine analogues exposure

“…Thymidine analogues (TA) and didanosine (ddI) have known deleterious effect on adipose tissue metabolism [1]. Previous results from our group suggested that prior use of TA and ddI in people living with HIV (PLWH) is associated with alterations in body fat distribution, particularly loss of subcutaneous (SAT) and accumulation of visceral adipose tissue (VAT) [1], even years after treatment discontinuation. This phenotype is known to be associated with increased of cardiometabolic risk.…”