Using direct measures of regional adipose tissue in our large cohort of HIV-infected and control women, we observed that more VAT and upper trunk SAT but less leg SAT were associated with higher triglycerides; more VAT was associated with lower HDL. After adjustment for adipose tissue volumes as well as demographic and other non–HIV-related factors, HIV infection was associated with 40% higher triglycerides, whereas the association between HIV infection and HDL-C was no longer statistically significant. A prior study in HIV-infected and uninfected women observed independent effects of HIV and waist-to-hip ratio on triglycerides and HDL-C but did not distinguish the separate effects of central versus peripheral fat.29
We found some important ethnic differences between HIV-infected African American and white women, which few studies have described. Both HIV-infected groups had higher triglycerides. In white women, HIV infection was associated with 21% lower HDL-C, and in African American women, HIV infection was associated with 8% higher HDL-C after adjustment. Furthermore, although HIV-infected African American women had lower LDL-C, the decrease in HIV-infected white women compared with controls was smaller. As a consequence, white women may be at more risk of cardiovascular disease. Another recent study of women with and at risk for HIV infection also found that white women had a more atherogenic lipid profile when compared with African American and Hispanic women.30
In our study, the differences observed in the HIV effect on HDL by ethnicity may be partly attributed to the unexpected finding that among control women, whites had higher HDL than African Americans. Interestingly, white controls also had lower VAT than African American controls. Among the HIV-infected women, African Americans had less VAT than whites; after controlling for VAT, being African American remained independently associated with higher HDL, suggesting that the higher HDL in African Americans compared with whites is not attributable to the difference in VAT. Being African American also remained independently associated with lower triglycerides and higher HDL, after controlling for CD4 cell count, HIV RNA level, and anti-retroviral drug use.
Few, if any, studies in HIV have demonstrated an association between less leg SAT (the fat depot most affected in HIV-infected men and women) and hypertriglyceridemia. In HIV-uninfected patients, studies of familial and acquired lipodystrophy syndromes have shown a link between lipoatrophy and hypertriglyceridemia.31
Another study in elderly HIV-uninfected participants found an association between lower thigh subcutaneous fat and higher triglycerides, independent of abdominal fat.32
Although more VAT has been shown to be associated with unfavorable lipid profiles in the general population, we found that higher amounts of VAT in HIV-infected women trended toward a stronger association with higher triglycerides than in control women. It is unclear whether VAT in HIV-infected women behaves differently metabolically. We previously observed that there may be some HIV-infected women who have more VAT than control women.
Among HIV-infected women, we demonstrated that higher plasma HIV RNA levels were associated with higher triglycerides, lower HDL-C, and lower LDL-C. The association between HIV infection and higher triglycerides, lower HDL-C, and lower LDL-C has previously been observed in men in the era before highly active antiretroviral therapy (HAART).1–4
Our findings suggest that uncontrolled viral replication in HIV-infected women in the HAART era is associated with these same outcomes, supporting a possible association between chronic inflammation and alterations in lipid metabolism in HIV infection.
It is important to note that the median lipid and lipoprotein levels in our cohort of women between 33 and 45 years of age remained in the normal ranges. More HIV-infected women (especially white women) were on lipid-lowering agents. Approximately one third to one half of HIV-infected women still had lipid and lipoprotein values higher than the standard cutoffs at which behavioral or lipid-lowering therapy should be considered, however. Yet, <10% of HIV-infected women were on lipid-lowering therapy.
In contrast to the association of HIV RNA levels with triglycerides, LDL-C, and HDL-C, we found differential associations of specific antiretroviral drugs and PIs on the individual lipoproteins. The association of antiretroviral drugs with lipid parameters may be confounded by other factors, however. For instance, participants may have been removed from an antiretroviral drug because of a metabolic effect or not prescribed an antiretroviral drug because of known metabolic abnormalities, thus decreasing or even reversing the association. Nevertheless, similar to other studies,33–36
we found that being on a PI or the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz was associated with increased triglycerides and that use of nevirapine was associated with increased HDL-C. In contrast to other studies,15,37
we observed that being on stavudine was associated with lower rather than higher triglycerides. Because we analyzed current use of an antiretroviral drug (because of the reported acute effect of antiretroviral drugs on lipid outcomes) and adjusted for adipose tissue volume, we may not have observed the cumulative drug effects that may occur. We also observed that tenofovir use was associated with higher triglycerides, lower HDL-C, and lower LDL-C. It is unclear if our findings represent a direct effect of tenofovir, prescriber bias (in which patients with known metabolic abnormalities were specifically started on tenofovir because of the minimal effect of tenofovir on lipids), or, rather, are suggestive of patients with advanced disease being on tenofovir. Subjects on tenofovir at the time of our study had lower CD4 cell counts and slightly higher HIV RNA levels, and the prevalence of tenofovir use was low, making adjustment difficult.
The limitations of our study include its cross-sectional design, which limited the ability to determine how changes in body fat and antiretroviral drugs affect lipid and lipoprotein levels. Likewise, it is difficult to make causal inferences regarding changes in HIV disease status; therefore, our findings that a higher plasma HIV viral load, and thus uncontrolled viral replication, was associated with higher triglycerides, lower HDL, and lower LDL should be interpreted with caution. The risks identified may also not extrapolate to cardiovascular risk in all settings. Other unmeasured factors such as inflammation, diet, and additional lipid parameters may alter cardiovascular risk. The ability to adjust for regional adipose tissue depot volumes provides important information on the link between those depots and HIV effects, however.
In summary, HIV-infected women have higher triglycerides, lower HDL-C, and lower LDL-C than control women. HIV-infected white women have a more proatherogenic lipid profile despite having a higher prevalence of taking lipid-lowering medication. Less leg SAT and more VAT are important risk factors for adverse lipid profiles in women. HIV-infected women may be at particular risk of developing a proatherogenic lipid profile, because leg SAT is the fat depot most affected in HIV infection and HIV-infected women often have high amounts of VAT. The effect of HIV infection on HDL-C is reduced after adjusting for total adipose tissue, however. Given the association of lipid abnormalities with HIV viral load, maintaining effective antiretroviral therapy (with minimal direct effects on lipid levels) to control HIV replication may be important in minimizing adverse lipid profiles, and thus cardiovascular disease risk.