HIV infection [1
] and its therapies [5
] are known to be associated with dyslipidemia. We now report that HIV infection remains associated with higher triglycerides, lower HDL-C and lower LDL-C than controls in this large study of HIV-infected and control men even after adjustment for adipose tissue volumes directly measured by MRI, as well as after adjustment for demographics and lifestyle factors. In HIV positive men, inclusion of HIV-related factors such as CD4+ count, viral load and antiretroviral drugs had little effect on the association of adipose tissue with lipids.
Most associations of adipose tissue volume with lipids were similar for HIV-infected and control men. For example, more VAT was associated with higher triglycerides and lower HDL-C in both HIV-infected and control men. Less leg SAT was associated with higher triglycerides in HIV-infected men, and also likely in control men.
The leg depot is of particular interest due to the prevalence of HIV-associated lipoatrophy. While clinical HIV-lipodystrophy has been associated with hypertriglyceridemia, past studies have usually pooled lipoatrophy and lipohypertrophy [10
]. Here we show that lower amounts of leg SAT (the fat depot most affected with lipoatrophy in HIV-infected men [20
] are independently and negatively associated with hypertriglyceridemia. Studies of familial and acquired lipodystrophy syndromes in HIV-uninfected patients have also shown a link between lipoatrophy and hypertriglyceridemia [32
]. To facilitate comparison of similar quantities of adipose tissue in HIV-infected and control men, we used tertiles based on cutoffs for control men. A similar quantitative relationship was found for HIV-infected and control men; being in the highest tertile for leg SAT was associated with 29% lower triglyceride levels. Given the prevalence of lipoatrophy in HIV-infected men, more HIV-infected men fall into the ranges of low leg fat, contributing to hypertriglyceridemia.
VAT is positively associated with triglyceride levels in both HIV-infected and Control men. We have shown previously that VAT and leg SAT are not inversely linked in HIV infection [20
], but that there are men with lipoatrophy who have high amounts of VAT [20
]. Thus HIV-infected men with both low leg SAT and increased VAT have two independent risk factors for high triglycerides.
HIV-related factors also contribute to hypertriglyceridemia. The association between a diagnosis of AIDS and higher triglycerides has previously been observed in men in the pre-HAART era [2
] and was found again here.
While more VAT is associated with lower HDL-C levels, the associations of leg SAT with HDL-C were very small and did not approach statistical significance. After controlling for HIV-related factors in the multivariable model, including ARV, little change was seen in the association with adipose tissue depots. Higher HIV viral load was also associated with lower HDL-C levels, consistent with the lower levels of HDL-C seen before the introduction of effective combination antiretroviral therapy[2
LDL-C levels do not strongly correlate with obesity or visceral adiposity in the general population. Therefore, it is not surprising that we found only a weak relationship of VAT with LDL-C. The associations with upper trunk and arm SAT found here are novel, but these depots are not traditionally measured. We have also found that upper trunk SAT is independently associated with insulin resistance in both HIV-infected and control subjects[36
]. The significance of these associations needs further exploration. The associations of CD4+ counts and HIV viral load are consistent with the previously described effect of HIV on lowering LDL [2
It is important to note that the median triglyceride and LDL-C levels in our cohort of men between 33 and 45 years of age remained in the normal ranges. More HIV-infected than control men were on lipid lowering agents. Sensitivity analyses excluding those on lipid-lowering therapy or controlling for those on lipid-lowering therapy showed little change in the relationships of adipose tissue depots and HIV infection status to lipids. However, 12% of HIV-infected men and 22% of Control men still had LDL-C levels above standard cutoffs where behavioral or lipid-lowering therapy should be considered (LDL-C ≥160). Despite this, only 27% of HIV-infected men and 3% of control men with LDL-C ≥160 were on lipid lowering therapy. The higher prevalence of smoking in HIV-participants offers another area in which cardiovascular risk reduction could be done.
A strength of our study is its size and direct measurements of regional adipose tissue volume, which allowed for multivariable analysis of associations of depots and HIV related factors with lipid levels. A limitation of our study is the cross-sectional design. Hence the study risks confounding of ARV effects by other factors, such as prior outcomes (participants may have been removed form a drug because of a metabolic effect, thus decreasing or even reversing the association). Nevertheless, similar to other studies, we found that being on ritonavir was associated with higher triglycerides[5
] and being on nevirapine or efavirenz was associated with higher HDL-C[37
]. While use of older antiretroviral drug regimens has declined greatly in industrialized nations, lipoatrophy persists after discontinuation of the responsible ARV drugs. Furthermore, similar drug regimens associated with lipoatrophy are still frequently used in the developing world. The associations of adipose tissue with lipids and lipoproteins in this analysis were independent of and not influenced by current ARV, hence can be extrapolated to current patients with HIV-associated lipoatrophy or visceral obesity. Finally, the cross-sectional design also limits the ability to make causal inferences regarding changes in HIV disease status. However, the ability to adjust for regional adipose tissue depot volumes provides important information on the link between those depots and HIV effects. The associations of regional fat distributions with lipid levels in HIV infection, while similar to findings in the general population, will require further validation in other cohorts.
In summary, HIV-infected men have higher triglycerides, lower HDL-C, and lower LDL-C than control men that are independent of amounts of adipose tissue. Less leg SAT and more VAT are important risk factors for adverse lipid profiles in men. Because leg fat is the fat depot most affected in HIV associated lipoatrophy, HIV-infected men may be at particular risk for hypertriglyceridemia as low leg fat adds to the effects of more VAT, ritonavir and HIV infection itself. Increased VAT also is associated with lower HDL. These data define the effects of body fat, HIV infection, and antiretroviral therapy that should help health care providers and patients understand the metabolic complications of HIV infection and its therapies.