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Prior exposure to thymidine analogs and didanosine is associated with long-lasting alterations in adipose tissue distribution and cardiovascular risk factors
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This was presented at CROI, report from CROI below following the publication.
CROI: LONG-LASTING ALTERATIONS IN FAT DISTRIBUTION IN PLWH EXPOSED TO THYMIDINE ANALOGUES - (03/11/19)
Just published AIDS March 2019
Prior exposure to thymidine analogs and didanosine is associated with long-lasting alterations in adipose tissue distribution and cardiovascular risk factors.....
"Conclusions: This study suggests a potentially irreversible and harmful association of thymidine analogsand ddI with VAT accumulation, which appears be involved in the increased risk of hypertension, hypercholesterolemia, and low high-density lipoprotein found in PLWH with prior exposure to thymidine analogs and/or ddI, even years after treatment discontinuation."
ABSTRACT
Background: Thymidine analogs and didanosine (ddI) have been associated with redistribution of body fat from subcutaneous adipose tissue (SAT) to visceral adipose tissue (VAT), which, in turn, is a risk factor for cardiovascular disease. We explored differences in adipose tissue distribution between people living with HIV (PLWH) with prior exposure to thymidine analogs and/or ddI, without exposure, and uninfected controls and the association with cardiovascular disease risk factors.
Methods: In all, 761 PLWH from the Copenhagen Comorbidity in HIV Infection study, and 2283 age and sex-matched uninfected controls from the Copenhagen General Population Study were included. PLWH were stratified according to prior exposure to thymidine analogs and/or ddI. VAT and SAT were determined by abdominal computed tomography scan. Hypotheses were tested using regression analyses.
Results: Exposure to thymidine analogs and/or ddI was associated with 21.6 cm2 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 thymidine analogs and/or ddI [3.7 cm2 per year (2.3–5.1)], but not time since discontinuation [-1.1 cm2 per year (-3.4 to 1.1)], was associated with VAT. Prior exposure to thymidine analogs and/or ddI was associated with excess risk of hypertension [adjusted odds ratio (aOR) 1.62 (1.13–2.31)], hypercholesterolemia [aOR 1.49 (1.06–2.11)], and low high-density lipoprotein [aOR 1.40 (0.99–1.99)].
Conclusions: This study suggests a potentially irreversible and harmful association of thymidine analogsand ddI with VAT accumulation, which appears be involved in the increased risk of hypertension, hypercholesterolemia, and low high-density lipoprotein found in PLWH with prior exposure to thymidine analogs and/or ddI, even years after treatment discontinuation.
Subcutaneous adipose tissue in PLWH and uninfected controls
People living with HIV had smaller SAT area compared to uninfected individuals (140.7 vs. 184.8 cm2; P < 0.001). These results were reproduced when adjusting for confounders, with HIV infection being associated with 22.3 cm2 smaller SAT area compared to uninfected controls (-27.3 to -17.2). After stratification according to exposure to thymidine analogs and/or ddI, PLWH with exposure had smaller SAT area compared to both PLWH without exposure and uninfected controls (Supplementary Fig. 2b, http://links.lww.com/QAD/B418). In multivariable analysis, HIV infection with exposure to thymidine analogs and/or ddI was associated with 14.8 cm2 smaller SAT area compared to HIV infection without exposure (-23.3 to -6.3). Conversely, HIV-negative status was associated with 13.0 cm2 larger SAT area compared to HIV infection without exposure (5.8–20.3) (Table 2).
"This study suggests a potentially irreversible and harmful association of thymidine analogsand ddI with VAT accumulation, which appears be involved in the increased risk of hypertension, hypercholesterolemia, and low high-density lipoprotein found in PLWH with prior exposure to thymidine analogs and/or ddI, even years after treatment discontinuation.
.....The present study resulted in two key findings regarding abdominal adipose tissue distribution in PLWH. First, the redistribution of abdominal adipose tissue as VAT rather than SAT remains a concern in a subpopulation of PLWH, possibly due to harmful and irreversible side effects of prior thymidine analogs and/or ddI treatment. Second, our results suggested that PLWH who had been exposed to these agents were characterized by excess risk of hypertension, hypercholesterolemia, and low HDL, even years after treatment discontinuation, which may be mediated by increased VAT accumulation.
.....previous results from our group have shown that abdominal obesity remains a distinct characteristic of PLWH in the contemporary cART era
......Thymidine analogs have been proposed to affect adipose tissue distribution due to mitochondrial toxicity - read below
......The primary limitation of the present study is the cross-sectional design, where exposure and outcome are assessed at the same time. In conclusion, we present data suggesting prior exposure to thymidine analogs and/or ddI to be associated with long-lasting redistribution of abdominal adipose tissue from SAT to VAT and to negatively impact the risk of hypertension, hypercholesterolemia, and low HDL, even years after treatment discontinuation. If confirmed by prospective studies, our findings may help to identify a subgroup of PLWH who may benefit from more intensive cardiovascular prevention interventions."
Discussion
The present study resulted in two key findings regarding abdominal adipose tissue distribution in PLWH. First, the redistribution of abdominal adipose tissue as VAT rather than SAT remains a concern in a subpopulation of PLWH, possibly due to harmful and irreversible side effects of prior thymidine analogs and/or ddI treatment. Second, our results suggested that PLWH who had been exposed to these agents were characterized by excess risk of hypertension, hypercholesterolemia, and low HDL, even years after treatment discontinuation, which may be mediated by increased VAT accumulation.
The attention towards HIV-associated fat redistribution syndrome has decreased after the introduction of modern antiretroviral regimens with fewer metabolic side effects. However, previous results from our group have shown that abdominal obesity remains a distinct characteristic of PLWH in the contemporary cART era [8]. In the present study, we further characterized this phenotype, by assessing the relative distribution of VAT and SAT at abdominal level. The associations between HIV infection, accumulation of VAT and its determinants have been widely studied. However, whether this phenotype is a direct consequence of HIV infection, a side effect to cART or a back-to-health phenomenon in well treated PLWH is still unclear. In the present study, PLWH with a history of exposure to thymidine analogs and/or ddI had larger VAT area compared to PLWH without exposure, who, on the contrary, had comparable VAT area with uninfected controls. Interestingly, almost all of PLWH with exposure did not report a current use of thymidine analogs and/or ddI, and median since last exposure was more than 9 years, suggesting an irreversible effect of these agents on adipose tissue. This hypothesis was supported by the lack of association between VAT area and the time since discontinuation of thymidine analogs and/or ddI. On the contrary, we described a direct association between the cumulative exposure to these agents and VAT area. Taken together, these results suggest a cumulative and harmful effect of thymidine analogs and/or ddI affecting VAT accumulation, which appears to be irreversible in the time frame considered in the present study. Potential mechanisms leading to irreversibility of this phenotype are many. One may speculate that, once established, the accumulation of VAT, characterized by hypoxia and high content of activated macrophages [19], may lead to a pro-inflammatory environment, known to influence adipocyte proliferation and differentiation [20]. These events may cause a vicious and self-maintaining circle, resulting in the lack of improvement in VAT accumulation after the discontinuation of thymidine analogs and/or ddI. Interestingly, no association between duration of cART and VAT area was found in PLWH without exposure. This finding may suggest that cART regimens not including thymidine analogs or ddI have no deleterious effect on VAT accumulation.
The loss of subcutaneous adipose tissue related to HIV infection has been proposed to be a side effect of thymidine analogs [5]. While our findings support this hypothesis, they also suggest a concomitant role for HIV infection per se or modern cART regimens in determining this phenotype. Viral proteins, especially Vpr and Nef, have previously been described to have a harmful and inhibiting effect on adipogenesis [21,22], which may partly explain the loss of subcutaneous adipose tissue independently of thymidine analogs and/or ddI. Thus, in the present study HIV, infection was associated with smaller SAT area compared to uninfected controls also in PLWH without history of exposure to thymidine analogs or ddI, albeit to a lesser extent compared to those with exposure.
Recently, VAT-to-SAT ratio has been proposed as a better correlate of cardiometabolic risk compared to BMI and absolute abdominal adipose tissue volumes [9]. In the present study, PLWH with exposure to thymidine analogs and/or ddI were characterized by increased VAT-to-SAT compared to both uninfected individuals and PLWH without exposure. This finding may further support the hypothesis that the propensity to store fat viscerally versus subcutaneously in PLWH may be a side effect of the exposure to old generation cART. Fat redistribution syndrome is a well characterized risk factor of CVD [1,23] in PLWH, where a given BMI or waist-to-hip ratio may be associated with different CVD risk depending on the relative distribution of visceral and subcutaneous adipose tissue at abdominal level. Specifically, loss of SAT and VAT accumulation have been associated with increase in renin-angiotensin-aldosterone-system (RAAS) activation, free fatty acid (FFA), and insulin resistance, known risk factors of hypertension and abnormalities in lipid metabolism [24]. Accordingly, we found that increasing VAT area was associated with excess risk of hypertension, hypercholesterolemia, and low HDL, which, in turn, were associated with the use of thymidine analogs and/or ddI even after controlling for traditional risk factors. The latter association disappeared when further adjusting the model for VAT area. This finding may suggest that the harmful association between thymidine analogs and/or ddI, and excess risk of hypertension, hypercholesterolemia, and low HDL may be a result of VAT accumulation induced by these agents.
Thymidine analogs have been proposed to affect adipose tissue distribution due to mitochondrial toxicity [25]. The apparent contrast represented by lipohypertrophy in the visceral and the concomitant lipoatrophy in the subcutaneous compartment as a consequence of the same insult may reflect differences in resistance to mitochondrial toxicity in visceral and subcutaneous adipose tissues [26,27]. In the visceral compartment, the oxidative stress induced by thymidine analogs may result in mild mitochondria dysfunction in the adipocytes, and consequently to a pathological adipose tissue accumulation [28]. Due to lower mitochondrial content and different genes expression [27], SAT has been described to have lower resistance to mitochondrial toxicity compared to the visceral compartment. Thus, an equivalent oxidative insult on adipocytes may be amplified in SAT, causing more severe mitochondrial dysfunction, which may explain the tendency towards atrophy rather than hypertrophy in the subcutaneous compartment [28].
The primary limitation of the present study is the cross-sectional design, where exposure and outcome are assessed at the same time. Specifically, while possible associations between cumulative time of exposure to thymidine analogs and/or ddI, and the time since discontinuation of these agents and our outcomes were explored, causal relationships cannot be drawn because of the lack of longitudinal data. Minor differences in the ethnicity found between the two populations may explain part of the differences in abdominal adipose tissue distribution. However, a possible confounding effect of this variable was reduced by adjusting for, among the others, region of origin in multivariable analyses. The main strength of the present study is the large and well characterized study population who underwent CT scan, comprehensive of a sex and age-matched uninfected control group. Furthermore, all laboratory and CT-scan examinations were performed in identical locations between the two populations, thus eliminating potential bias due to differences in the equipment used.
In conclusion, we present data suggesting prior exposure to thymidine analogs and/or ddI to be associated with long-lasting redistribution of abdominal adipose tissue from SAT to VAT and to negatively impact the risk of hypertension, hypercholesterolemia, and low HDL, even years after treatment discontinuation. If confirmed by prospective studies, our findings may help to identify a subgroup of PLWH who may benefit from more intensive cardiovascular prevention interventions.
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