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

Abstract

Background: Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity, and adipose tissue density assessed by CTscan is associated with adipocyte size and function. We hypothesized that prior exposure to TA and ddI was associated with long-lasting adipose tissue dysfunction in people living with HIV (PLWH). Thus, we tested possible associations between markers of adipose tissue dysfunction (adipose tissue density and adiponectin) and prior exposure to TA and/or ddI, years after treatment discontinuation. Methods: Eight hundred forty-eight PLWH from the COCOMO study were included and stratified according to prior exposure to TA and/or ddI (with, n = 451; without n = 397). Visceral (VAT) and subcutaneous (SAT) adipose tissue area and density were determined by single slice abdominal CT-scan at lumbar 4th level. Venous blood was collected and analyzed for adiponectin. Multivariable linear and logistic regression analyses were used to test our hypotheses. Multivariable models were adjusted for age, sex, smoking, origin, physical activity, BMI, and adipose tissue area (VAT or SAT area, accordingly to the outcome). Results: prior exposure to TA and/or ddI was associated with excess risk of low VAT (adjusted OR (aOR) 1.74 [1.14; 2.67]) and SAT density (aOR 1.74 [1.18; 2.58]), for a given VAT and SAT area, respectively. No association between VAT and SAT density with time since TA and/or ddI discontinuation was found. 10 HU increase in VAT density was associated with higher adiponectin plasma level and this association was not modified by prior exposure to TA and/or ddI. Prior exposure to TA and/or ddI was associated with 9% lower [− 17;-2] plasma adiponectin levels and with excess risk of low adiponectin (aOR 1.74 [1.10; 2.76]). Conclusions: We described low adipose tissue density and impaired adiponectin production to be associated with prior exposure to TA and/or ddI even years after treatment discontinuation and independently of adipose tissue area. These findings suggest that prior TA and ddI exposure may have long-lasting detrimental effects on adipose tissue function and, consequently, on cardiometabolic health in PLWH.

Insulin resistance in people living with HIV is associated with exposure to thymidine analogues and/or didanosine and prior immunodeficiency

“…Accordingly, inhibition of GLUT4 may lead to insulin resistance which may explain the association between old generation ART and insulin resistance. Furthermore, old generation ART has been associated with changes in adipose tissue including lipodystrophy (11,12). Interestingly, the association between abdominal obesity and insulin resistance was stronger in PLWH with prior exposure to old generation ART.…”

“…Especially, abdominal obesity is thought to be associated with a high risk of developing insulin resistance (7,8). In PLWH, exposure to old generation antiretroviral therapy (ART) has been associated with both the development of diabetes and long-lasting alterations of body fat from subcutaneous adipose tissue to visceral adipose tissue (9)(10)(11)(12).…”

Hepatic Steatosis and Ectopic Fat Are Associated With Differences in Subcutaneous Adipose Tissue Gene Expression in People With HIV

“…Lower SAT attenuation was shown to be reflective of increased adipocyte size in PWH, ( 41 ) and lower attenuation was associated with prior exposure to ART regimens containing thymidine analogues. ( 42 ) The clinical significance of adipose tissue density in PWH has not been clearly defined, but may reflect fibrosis or local inflammation. Lake et al showed that greater SAT and VAT attenuation was associated with higher levels of circulating inflammatory cytokines, independent of tissue area.…”

Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients – a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown

“…Currently, the most documented organokines involved in body fat distribution are leptin and adiponectin, two adipokines mainly secreted by adipocytes. Available data on adiponectin indicate that ART and in particular the treatment with IPs (ritonavir), lowers the levels of adiponectin and leptin especially at the beginning of therapy and favors the progression of lipodystrophy, steatosis and IR (195,209,210). In turn, the development of lipodystrophy lowers the concentration of these two adipokines independent of the ARV agent (211)(212)(213)(214).…”