In this randomized, double-blinded, placebo-controlled study, we found that the addition of raltegravir to a suppressive antiretroviral regimen did not have a significant impact on cardiovascular risk, as assessed by endothelial function (FMD) or microvascular function (hyperemic velocity). In addition, in this expanded cohort which included immunologic responders we confirmed our earlier results that raltegravir intensification did not have a significant effect on immune activation, ultrasensitive plasma HIV RNA, or proviral HIV DNA 11
While the precise mechanisms linking HIV disease and cardiovascular disease have not been clearly defined, several studies have suggested that viral replication and persistent immune activation may play a key role. HIV-infected individuals (even those receiving HAART) have dampened endothelial function as assessed by FMD compared to HIV uninfected individuals 32
, and the initiation of HAART has been associated with a significant improvement in FMD 33
. The importance of the relationship between plasma viremia and cardiovascular disease was further highlighted by the SMART study, in which continuous HAART was associated with reduced cardiovascular events as compared to intermittent or delayed HAART 34,35
. Moreover, the link between CD4+ T cell count and cardiovascular events has been reported in two large cohorts 36,37
. Finally, our own group has found a consistent relationship between nadir CD4+ T cell count and surrogate markers of cardiovascular risk, including carotid intima-media thickness 2
, arterial stiffness 38
, and endothelial function 39
Initial treatment studies with raltegravir demonstrated significantly higher rates of decline in plasma HIV RNA compared to antiretroviral drugs in other drug classes 40
, which led to widespread interest in the possibility of using raltegravir as an intensification agent. However, subsequent studies have for the most part shown no effect of raltegravir intensification on markers of viral replication or immune activation. For example, in the ACTG 5244 study, 12 weeks of raltegravir intensification did not reduce ultrasensitive plasma RNA levels 41
. A prior analysis from the immunologic non-responder subset of our current study showed that in individuals with a CD4+ T cell count < 350 cells/mm3
, raltegravir intensification did not result in a significant decrease in ultrasensitive plasma RNA, cell-associated RNA, proviral DNA, immune activation in PBMCs or GALT, or HIV-specific responses in PBMCs or GALT 11
. Our current study adds to these findings by the inclusion of individuals with all CD4+ T cell counts and by also studying a subset of individuals for 48–60 weeks; however, intensification did not affect measures of viral persistence or immune activation.
Our baseline values for FMD and hyperemic velocity were much lower than values reported in the literature for HIV-uninfected men of a similar age (age 49 years, FMD 8.6%, hyperemia 121.6 cm) 14
. Since treatment intensification in antiretroviral-treated individuals does not appear to provide much benefit in terms of vascular function, other novel adjunctive therapies will likely be needed. Of note, we observed that regardless of treatment group, individuals with a low baseline CD4+ T cell count (<350 cells/mm3
) displayed a slow improvement in hyperemic velocity over time (data not shown). These data suggest that endothelial function may improve with longer term HAART, although it is unlikely that these measurements will ever improve to the level of the general population 2,4,5
. In multivariable analysis, older age and longer duration of HIV infection were associated with more impaired FMD, and lower CD4+ T cell count was associated with more impaired hyperemic velocity. Collectively, our data add to the growing body of literature in support of earlier initiation of HAART 42–45
. Finally, although the association of abacavir with cardiovascular disease remains an area of debate 46–49
, we observed that current abacavir use was associated with lower FMD and hyperemic velocity, which is consistent with our previous report (involving a different cohort of subjects) on abacavir use being a risk factor for cardiovascular disease 46
Limitations of this study include a modest sample size, limited number of female subjects, and multiplicity of analyses. However, this study expands upon prior studies of cardiovascular disease in treated HIV infection because it includes the assessment of endothelial function as well as microvascular function (hyperemic velocity); the latter has not been previously reported in the setting of HIV disease. Given that lower CD4+ T cell count was associated with lower hyperemic velocity but not FMD, and having a lower CD4+ T cell count on treatment has been associated with an increased risk of cardiovascular disease 39,42
, one could speculate that the measurement of microvascular function is a more sensitive measure of future cardiovascular disease than FMD in the setting of treated HIV infection, or that it may identify a distinct type of vascular dysfunction that occurs in immunologic non-responders vs. responders; future studies will be needed to explore these hypotheses.
In this randomized, double-blinded, placebo-controlled study of 56 HAART-suppressed individuals, raltegravir intensification was not associated with any significant change in endothelial function, hyperemic velocity, immune activation, ultrasensitive plasma RNA, or proviral DNA. Older age, longer HIV duration, and current abacavir use were independently associated with lower FMD, while lower current CD4+ T cell count and current abacavir use were associated with lower microvascular function. Additional studies will be needed to identify mechanisms to decrease cardiovascular risk in the setting of treated HIV infection.