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Associations of Hepatosteatosis With Cardiovascular Disease in HIV-Positive and HIV-Negative Patients: The Liverpool HIV-Heart Project
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JAIDS Aug 15 2021
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In contrast to the general population, HS is a strong and independent predictor of CVD in HIV-positive individuals. This suggests that metabolic dysfunction may be attributable to the excess CVD risk seen with these patient groups. Assessment of HS may help accurate quantification of CVD risk in HIV-positive patients.
In conclusion, in these well-characterized cohorts, we have demonstrated a significant difference in the impact of HS as an independent CVD predictor between the HIV-positive and HIV-negative groups. This may represent a unique metabolic process that drives the excess CVD risk seen in PLWHIV. Our finding, showing that HS is an independent predictor of CVD in HIV-positive but not in HIV-negative group, suggests potential differences in the drivers of CVD between these 2 cohorts. HS that manifests in HIV-positive populations may represent a more severe adverse metabolic phenotype compared with that in non-HIV populations.
The principal finding from this study is that HS is independently associated with CVD in HIV-positive patients, whereas there was no significant association in HIV-negative patients. To our knowledge, our study is the first to directly compare the effect of HS on CVD in both HIV-positive and HIV-negative patients. The finding that HS was independently associated with CVD in HIV-positive patients but not in HIV-negative patients was confirmed in our sensitivity analysis.
HS drives cardiovascular risk through increased atherogenic lipid profiles, inflammation, and insulin resistance. HIV-positive patients have been shown to have increased rates of lean adiposity compared with HIV-negative groups.7 Ectopic fat deposition has also been shown to be associated with previous CVD events.25 An individual's susceptibility to this process may also be derived from genetic factors.26 The findings from this study further demonstrate the unique pathophysiological process underpinning the increased CVD risk seen in PLWHIV.
Abstract
Background:
Hepatosteatosis (HS) has been associated with cardiovascular disorders in the general population. We sought to investigate whether HS is a marker of cardiovascular disease (CVD) risk in HIV-positive individuals, given that metabolic syndrome is implicated in the increasing CVD burden in this population.
Aims:
To investigate the association of HS with CVD in HIV-positive and HIV-negative individuals.
Methods and results:
We analyzed computed tomography (CT) images of 1306 subjects of whom 209 (16%) were HIV-positive and 1097 (84%) HIV-negative. CVD was quantified by the presence of coronary calcification from both dedicated cardiac CT and nondedicated thorax CT. HS was diagnosed from CT data sets in those with noncontrast dedicated cardiac CT and those with venous phase liver CT using previously validated techniques. Previous liver ultrasound was also assessed for the presence of HS. The HIV-positive group had lower mean age (P < 0.005), higher proportions of male sex (P < 0.005), and more current smokers (P < 0.005). The HIV-negative group had higher proportions of hypertension (P < 0.005), type II diabetes (P = 0.032), dyslipidemia (P < 0.005), statin use (P = 0.008), and HS (P = 0.018). The prevalence of coronary calcification was not significantly different between the groups. Logistic regression (LR) demonstrated that in the HIV-positive group, increasing age [odds ratio (OR): 1.15, P < 0.005], male sex (OR 3.37, P = 0.022), and HS (OR 3.13, P = 0.005) were independently associated with CVD. In the HIV-negative group, increasing age (OR: 1.11, P < 0.005), male sex (OR 2.97, P < 0.005), current smoking (OR 1.96, P < 0.005), and dyslipidemia (OR 1.66, P = 0.03) were independently associated with CVD. Using a machine learning random forest algorithm to assess the variables of importance, the top 3 variables of importance in the HIV-positive group were age, HS, and male sex. In the HIV-negative group, the top 3 variables were age, hypertension and male sex. The LR models predicted CVD well, with the mean area under the receiver operator curve (AUC) for the HIV-positive and HIV-negative cohorts being 0.831 [95% confidence interval (CI): 0.713 to 0.928] and 0.786 (95% CI: 0.735 to 0.836), respectively. The random forest models outperformed LR models, with a mean AUC in HIV-positive and HIV-negative populations of 0.877 (95% CI: 0.775 to 0.959) and 0.828 (95% CI: 0.780 to 0.873) respectively, with differences between both methods being statistically significant.
Conclusion:
In contrast to the general population, HS is a strong and independent predictor of CVD in HIV-positive individuals. This suggests that metabolic dysfunction may be attributable to the excess CVD risk seen with these patient groups. Assessment of HS may help accurate quantification of CVD risk in HIV-positive patients.
INTRODUCTION
Hepatosteatosis (HS) is the most common cause of liver disease in patients living with HIV (PLWHIV), affecting between 13% and 65%1-3of individuals. HS describes hepatic ectopic fat accumulation and is present when it affects >5% of the liver by weight. HS encompasses a spectrum of clinical entities, including nonalcoholic fatty liver disease (NAFLD). The prevalence of HS is underreported.
Histologically, progressive hepatic fat accumulation is associated with lipotoxicity and chronic inflammation, progressing in many cases to cirrhotic liver disease, and with a 3-fold increase in mortality.4 The relationship of obesity, insulin resistance, type II diabetes, and HS is well defined in non-HIV populations.5 The estimated prevalence of NAFLD in the United States is predicted to reach 33% of the adult population by 2030.6
PLWHIV have unique risk factors for the development of HS compared with non-HIV populations. They have been shown to develop lean NAFLD, defined as NAFLD in BMI <25 kg/m2, at increased rates compared with that in non-HIV populations.7 The complex interplay of viral-related factors, antiretroviral medications, and chronic inflammation may cause PLWHIV to be more susceptible to the development of HS. Liver disease represents a huge source of morbidity and mortality in PLWHIV, with up to 13% of deaths in the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort study attributable to liver disease.8 In both HIV-positive and HIV-negative populations, dyslipidemia, insulin resistance, and overt type II diabetes are strongly associated with the presence of HS.
HS has been shown to be associated with cardiovascular disease (CVD) in HIV-negative populations;9-11 however, this is not universal.12-14 Given the increasing burden of HS in HIV-positive populations, we sought to examine whether HS was independently associated with CVD in HIV-positive compared with that in HIV-negative populations.
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