Among long-term treated patients, there is a growing body of evidence that suggests the degree of prior or residual immunodeficiency while on therapy is associated with the short-term risk of cardiovascular disease. In our earlier study , we found that a nadir CD4+ T-cell count of 200 cells/μl or less was associated with carotid intima–media thickness (IMT), whereas other studies [28,29] have failed to detect an effect. The discrepancies between study results may be due to differences in methods of assessment of carotid artery IMT . Studies [31–33] have also suggested that the on-therapy CD4+ T-cell count is independently associated with an increased risk of cardiovascular disease. These observations suggest that for unclear reasons, persistent immunodeficiency during HAART has negative cardiovascular consequences. Given the manner in which treatment has been historically administered, the vast majority of individuals in these cohorts had chronic infection at the time they started HAART, and most had a CD4 nadir below 350 cells/μl. These studies were hence unable to determine whether earlier initiation of HAART is associated with better cardiovascular outcomes than delayed initiation of HAART. Defining with more precision, the role of prior or current immunodeficiency in driving heart disease could prove to be informative for the ongoing debate as to when to start combination ART . Our data show that advanced immunodeficiency as represented by a nadir CD4+ T-cell count below 350 cells/μl is independently associated with increased arterial stiffness. Although it is not possible to conclude from our cross-sectional study that earlier initiation of ART may help reduce cardiovascular risk, our study results provide important initial evidence that might support the further pursuit of prospective studies addressing this question.
The pathophysiologic mechanism by which immunodeficiency may mediate arterial stiffness and cardiovascular risk remains unclear. In the SMART study, elevations in interleukin-6 and D-dimer were strongly associated with all-cause mortality, suggesting that interruption of HAART may result in higher levels of HIV-associated inflammation . In our study, there was no correlation with hs-CRP and the degree of arterial stiffness; however, this may have been due to insufficient power to detect differences between participants.
Our study has many limitations common to cross-sectional studies. Although our study demonstrates a strong association between nadir CD4+ T-cell count and measures of arterial stiffness, it was a cross-sectional observational study, and is, therefore, subject to potential selection biases and limitations in establishing cause–effect relationships. Our data argue for early use of ART; however, we were unable to analyze whether treatment initiation during the acute versus chronic phases of HIV infection (and potential associated differences in lifestyle or behavioral factors) affected cardiovascular risk, independent of nadir CD4+ T-cell count, due to limited number of individuals who started HAART during acute infection.
Despite these limitations, the strengths of this study are that participants were recruited from two unique ongoing longitudinal cohorts, which included individuals who were treated with HAART both early and late in the course of their HIV infection, and were thus extremely well characterized with respect to their clinical and HIV-related parameters. Our study is the largest study examining arterial stiffness to date, and may provide important initial evidence to prompt longitudinal studies addressing whether early initiation of HAART may have any impact on cardiovascular risk.
This research was supported by grants from the National Institutes of Health (NIH)/University of California, San Francisco (UCSF)–Gladstone Institute of Virology and Immunology Center for AIDS Research, P30-AI027763 (J.E.H); from the NIH grants #5R01-HL095130 and 5K23-AI066885 (P.Y.H.); from the National Institute of Allergy and Infectious Diseases grant #K24-AI069994 (S.G.D.), the UCSF/Gladstone Center for AIDS Research grants #P30-AI27763 and P30-MH59037; and the UCSF Clinical and Translational Science Institute grant #UL1 RR024131–01. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
P.Y.H. has received honoraria from Gilead, and grant support from Pfizer. S.G.D. has received grant support from Pfizer, Merck, Bristol-Myers Squibb, Roche, and Gilead, and honoraria from GlaxoSmithKline.
J.E.H., S.G.D., F.M.H., and P.Y.H. were responsible for the study's conception and design. J.E.H., Y.X., and A.S. were involved in the study performance. J.E.H. did the statistical analyses and wrote the manuscript, and all authors participated in critical review and substantial input to the final manuscript.
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