We have shown that pre-clinical atherosclerosis as quantified by ultrasound measurements of carotid IMT is increased in HIV-infected participants compared with controls, even after adjusting for demographics and traditional CVD risk factors. Thus while HIV infection and its therapies are associated with increases in several traditional CVD risk factors (e.g., decreased HDL cholesterol, increased non-HDL cholesterol and diabetes)[15
], there is an additional effect of HIV infection beyond that on traditional CVD risk factors. The association of HIV infection with carotid IMT is similar in magnitude to that of traditional risk factors such as diabetes and smoking. The HIV association is of the magnitude of a 5-9 year increase in age. The association of HIV infection with carotid IMT was stronger in women than in men. These results have several implications for both research and clinical practice.
Previous findings from analyses of registries and administrative databases have suggested that the rates of CVD or MI are higher in HIV-infected patients than in uninfected patients. [9
] Such studies, however, are unable to fully adjust for differences in the distribution of traditional CVD risk factors between HIV-infected and control participants. Given the many effects of HIV infection and antiretroviral drugs on metabolic parameters[15
], the finding that there is an association of HIV infection with atherosclerosis beyond that explained by metabolic disturbances has important implications for risk assessment in patients. The residual increase in atherosclerosis as measured by IMT implies increased independent risk of coronary artery disease and stroke associated with HIV infection and/or its therapies. Now that patients with HIV infection are living longer, these data suggest that clinicians should consider HIV infection as a candidate CVD risk factor. This may be especially important for HIV-infected patients who have an intermediate level of risk as determined by predictive equations such as that from the Framingham Study.[35
The finding that a stronger association of HIV infection with carotid IMT is seen in women compared to men is consistent with one registry study.[9
] In that study, HIV-infected women had significantly more cardiovascular events than women controls, but the association in men was much smaller and did not reach statistical significance. Our data suggest that HIV infection may confer increased CVD risk in both sexes, but to a greater extent in women. In women, the association of HIV infection with IMT was greater than that of smoking; in men, the association of HIV infection with IMT was similar to that of smoking.
In the non-HIV-infected population, the effect of some risk factors, such as diabetes, on CVD are also more marked in women than men.[37
] For example, after adjustment for other risk factors, diabetes was associated with a 70% higher risk of death from CVD in diabetic men compared to men without diabetes, and 230% higher risk in diabetic women compared to women without diabetes. Gender differences have also been observed for associations of risk factors with carotid IMT; for example, metabolic syndrome is more of an independent risk factor for greater carotid IMT in women than in men.[38
Furthermore, we have previously shown that Caucasian women have the most atherogenic lipid profile among HIV-infected demographic groups, as LDL levels are not decreased by HIV infection[31
] Those findings raise the possibility of additional increased risk in HIV-infected women relative to HIV-infected men mediated by traditional CVD risk factors.
We found that the HIV association was stronger with internal carotid IMT (including the bulb region) than with common carotid IMT. It is therefore of interest that the studies which found little association of HIV infection with IMT made those measurements only in the common carotid.[21
] For example, one study of triads of 45 subjects, 89% male, found the common carotid to be 0.002 mm greater (95%CI -0.013,0.017; p = 0.80) in HIV-infected subjects not on protease inhibitors and 0.010 greater (95%CI -0.011,0.031; p = 0.34) in HIV-infected subjects continuously on protease inhibitors compared to controls.[23
] A larger study of both men and women that included 1510 controls found evidence that HIV infection was not associated with greater common carotid IMT after adjustment for demographic, traditional CVD risk factors and lifestyle factors, as the adjusted association was -0.007 mm for both HIV-infected men (95%CI -0.027,0.012, p=0.47) and women (95%CI -0.018,0.003, p=0.12) compared to controls.[25
] However, the other large study that included 1168 controls did find an independent association of HIV infection with carotid IMT, with a much larger association seen at the bifurcation (HIV = +0.250mm, 95%CI, 0.198,1.303, p<0.0001) than in the common carotid (HIV = +0.044mm, 95%CI 0.021,0.066, p=0.0001).[20
] The later results are comparable to our finding of an adjusted HIV association of 0.148mm (95%CI 0.072,0.224, p=0.0001) in the internal carotid including the bulb and 0.033mm (95%CI 0.010,0.056, p=0.005) in the common carotid. Furthermore, the earlier, smaller study finding an independent association of HIV infection with IMT also measured IMT in the bulb.[19
] The reasons for the discrepancies among these reports deserve further study, but our results suggest that future studies in HIV infection should include the internal carotid and the bulb, which may be the locations where increased atherosclerosis due to HIV infection begins.
Limitations of our study include the use of cross-sectional data for both risk factors and carotid IMT. Given that the effects of HIV and anti-retroviral therapy on CVD risk factors are dynamic and cumulative, it might have been ideal to have longitudinal data for risk factors such as cholesterol, HDL and blood pressure. However, examination of the data from the first and second FRAM examinations shows surprisingly little change in metabolic parameters despite switches in antiretroviral therapy (data not shown). Controls ideally would have been identical except for the presence of HIV infection, but such a cohort would be impractical and perhaps impossible to develop. However, a major strength of this study was a large control group with extensive data on CVD risk factors that enabled us to adjust for relevant traditional CVD risk factors, including age, which was our major aim. Furthermore, we measured both the common carotid and the internal/bulb regions, which enabled us to explain the discrepancies in earlier reports.
Although we cannot rule out an association of HIV-related factors with IMT, we did not identify any HIV-related factor that could explain much of the HIV effect. The effects of HIV infection reported here include any effects of anti-retroviral drugs that are independent of their metabolic effects. Unlike in Maggi et al
, who found a higher prevalence of lesions in those with PI therapy[39
], we did not find a substantial association of PI exposure (or other antiretroviral drugs or classes) with increased IMT.
In summary, even after adjusting for traditional CVD risk factors, HIV infection is associated with increased pre-clinical atherosclerosis as measured by carotid IMT. The association of HIV infection with IMT is stronger in the internal and bulb region than in the common carotid. The association of HIV infection is more pronounced in women than in men. These results should be considered when clinicians assess CVD risk in HIV infected patients.