Adipose tissue dysfunction is associated with exposure to thymidine analogues and didanosine, even years after the treatment is discontinued and independent of adipose tissue area, indicating that thymidine analogues/didanosine exposure may have lasting negative effects on the cardiometabolic health of people living with HIV (PLWHIV), according to a study published in BMC Infectious Diseases.

Thymidine analogues and didanosine are associated with long-lasting adipose tissue redistribution even years after discontinuation of treatment, particularly the loss of subcutaneous fat and the accumulation of visceral adipose tissue — a distribution associated with cardiometabolic risk. To test the possible associations between adipose tissue dysfunction and prior thymidine analogues and/or didanosine exposure years after treatment discontinuation, study investigators measured adiponectin plasma levels (a maker of adipocyte activity) and subcutaneous and visceral adipose tissue density.

The study included 848 PLWHIV from the Copenhagen comorbidity in HIV infection (COCOMO) study, stratified according to prior thymidine analogues/didanosine exposure (n=451 with, and n=397 without). Subcutaneous and visceral adipose tissue density were measured using single-slice abdominal computed tomography scans at the level of the fourth lumbar vertebra, and venous blood was analyzed for adiponectin. Possible associations were identified using multivariable linear and logistic regression analyses, and models were adjusted for sex, age, smoking, physical activity, origin, body mass index, and subcutaneous or visceral adipose tissue area, depending on the outcome.

Analyses showed that PLWHIV with prior thymidine analogues or didanosine exposure had lower density of visceral adipose tissue than those without (P <.0001) and the excess risk for low visceral adipose tissue density persisted after adjusting for confounders (adjusted OR (aOR), 1.74; 95% CI, 1.14-2.67). The results also showed that PLWHIV with exposure to thymidine analogues or didanosine had slightly lower subcutaneous adipose tissue density (P =.0002), and this difference became more evident in linear regression models, which adjusted for confounders (aOR 1.74; 95% CI, 1.18-2.58). Prior thymidine analogues or didanosine exposure was associated with excess risk for low subcutaneous adipose tissue density after confounders (aOR, 1.74; 95% CI, 1.18-2.58). No association between subcutaneous/visceral adipose tissue area density with time since treatment discontinuation was found.

Prior thymidine analogues and/or didanosine exposure was associated with 9% lower adiponectin levels and an excess risk of low adiponectin (aOR, 1.74; 95% CI, 1.10-2.76). For a given visceral adipose tissue area, a 10 HU increase in density was associated with a 12% higher plasma adiponectin level in PLWHIV with thymidine analogues/didanosine exposure. The association between visceral adipose tissue density and adiponectin levels was not altered by prior thymidine analogues and/or didanosine exposure (P =.778). No association between subcutaneous adipose tissue density and adiponectin levels was found.

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Study limitations included a cross-sectional design, differences between the two study groups, and a lack of histologic samples.

Study investigators concluded that, “These results may suggest that long-lasting adipose tissue dysfunction accompanies alterations in fat distribution, even years after [thymidine analogues] and/or [didanosine] discontinuation. Given the central role of adipose tissue in the regulation of metabolism, cell morphology and function analyses may be warranted in order to confirm possible long-lasting detrimental effects of prior [thymidine analogues]and [didanosine] exposure on adipose tissue function and, consequently, on cardiometabolic health in [PLWHIV].”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Gelpi M, Knudsen AD, Larsen KB, et al. Long-lasting alterations in adipose tissue density and adiponectin production in people living with HIV after thymidine analogues exposure. BMC Infect Dis. 2019;19(1):708.