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Maraviroc Intensification Improves Endothelial Function in Abacavir-Treated Patients, an Open-Label Randomized Cross-Over Pilot Study

Background The increased risk of abacavir in cardiovascular disease (CVD) in HIV-infected patients is still being debated. Maraviroc, a CCR5 blocker, has been shown to decrease immune activation and monocyte infiltration in atherosclerotic plaques in murine experiments. Therefore, we examined the effect of maraviroc intensification on flow-mediated dilatation (FMD) in abacavir-treated HIV-infected patients and its effect on immunological and inflammatory parameters. Methods A open-label prospective crossover study with a duration of 16 weeks: 8 weeks of intervention (maraviroc intensification) and 8 weeks of control (unchanged cART regimen). FMD, HIV-specific variables, expression of HIV co-receptors, markers of inflammation and coagulation and cellular markers of immune activation were measured at weeks 0, 8 and 16. The changes (Δ) in these variables were compared between intervention and control periods using non-parametric tests. To evaluate the relation with the change in FMD, linear regression modeling was used. Results Twenty-one male patients with suppressed plasma HIV-RNA, on cART, had a known HIV infection for 9.2 years (IQR 6.9–13.5) with abacavir use for 6.5 years (2.8–9.3). A significantly increased FMD of 0.73% (IQR −0.25 to 1.70) was seen after maraviroc intensification compared to a decrease of −0.42% (IQR −1.89 to 0.25; p = 0.049) in the control period. There was a negative relation between ΔFMD with ΔD-dimer (β −22.70, 95% CI −39.27; −6.13, p = 0.011) and ΔCD95+ CD4+ T cells (β −0.16, 95% CI −0.28; −0.04, p = 0.013), adjusted for age and duration of HIV. Conclusion Maraviroc intensification modestly improves endothelial function in HIV-infected patients on an abacavir-containing regimen. Trial registration NCT01389063. Electronic supplementary material The online version of this article (doi:10.1007/s40121-016-0115-0) contains supplementary material, which is available to authorized users.

The changes (D) in these variables were compared between intervention and control periods using non-parametric tests. To evaluate the relation with the change in FMD, linear regression modeling was used.
Results: Twenty-one male patients with suppressed plasma HIV-RNA, on cART, had a Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/ 58D4F0605862A836.

Electronic supplementary material
The online version of this article (doi:10.1007/s40121-016-0115-0) contains supplementary material, which is available to authorized users.

INTRODUCTION
Cardiovascular disease (CVD) is more prevalent among HIV-infected patients than in the general population [1][2][3]. Some combination antiretroviral therapy (cART) is independently associated with CVD [4]. An analysis of the HIV-positive D:A:D cohort showed a higher risk for myocardial infarction in patients on protease inhibitors and those currently using abacavir [5,6]. However, this effect of abacavir on CVD remains controversial, as two recently published meta-analyses refuted this increased risk [7,8]. However, in HIV-infected patients on abacavir, endothelial function, as assessed by flow mediated dilatation (FMD), was significantly lower compared to those not on abacavir (2.8% versus 4.9%; p = 0.01) [9]. FMD of the brachial artery is inversely related to the risk of cardiovascular events and is recognized as a surrogate cardiovascular endpoint for evaluating pharmacological interventions [10,11].
CCR5 and its ligands CCL3, CCL4 and CCL5 have been linked to the pathogenesis of atherosclerosis [12]. In patients with homozygous CCR5delta32 deletion a reduced risk of severe CVD was observed [12,13].
Moreover, experimentally blocking the CCR5 receptor in mice led to a decrease in circulating monocytes, infiltration of monocytes in plaques and a reduction of atherosclerotic lesions [14,15]. This effect was independent of hypercholesterolemia [14][15][16][17]  If there was an inter-observer difference of more than 2% in the FMD result, the FMD analysis was repeated. After completion of all the FMD analyses, the scans were unblinded.

Data Analyses
The primary outcome of the study was the change in FMD between the intervention and control periods. To detect a difference (two tailed) in change in FMD between the intervention and control of 1.5% [21]

Baseline Characteristics
A total of 23 patients were included from January 2012 till August 2014. However, 2 patients declined participation for personal reasons after consent had been obtained; therefore, finally 21 patients participated in the study (Fig. 1). Three patients missed the last study visit; one patient was admitted to a psychiatric clinic because of preexisting manic depression, one patient was a no-show because of personal reasons, and one patient had acute abdominal surgery because of preexisting diverticulitis (no increase in inflammatory parameters was seen in this patient prior to the surgery). This resulted in the loss of data for two control and one intervention period. All 21 patients (see characteristics in Table 1)   When discarding C2 because of the carry-over effect of maraviroc, a net increase of 1.15% is seen in FMD comparing intervention to control (Fig. 2b). A significant increase in FMD of ?0.73% (IQR -0.25 to 1.70) in the intervention was found in contrast to a decrease of -0.42% (IQR -1.89 to 0.25) in the control period (p = 0.049). This is comparable to the effect seen for statins (?1.2%) in HIV-infected patients receiving statins versus placebo (?0.5%) [22], but moderate compared to  T cells (b -0.02, 95% CI -0.13; 0.10) (Fig. 4b).
When analyzing hsCRP, D-dimer and vWF, only DD-dimer showed an inverse relation with DFMD (Fig. 4a)  In this study, we hypothesized that a decrease in inflammation, coagulation and immune activation, due to maraviroc intensification, would lead to an improvement of endothelial function. We did not find an effect of maraviroc on immune activation in our pilot study, even though a decrease in activated CD8? CD38? [19,20]. Yet another (placebo-controlled trial)

HLA-DR? T cells was found in other studies
reported an increase in immune activation [28].
The authors postulated that the maraviroc-mediated increases in CCR5 ligands activated T cells via CCR3 and/or CCR4 [28]. However, even though we did observe an overall increase of CCR5 in T cells in our study, no increase or decrease of T cell activation between arms was seen. Furthermore, no significant relation between inflammatory markers with DFMD was observed. However, a significant inverse relation was found for the coagulation marker D-dimer, adjusted for the age and duration of HIV. This in in line with other studies where D-dimer has been linked to increased CVD risk in the general population and in HIV-infected patients in particular [29,30]. Therefore, lower D-dimer levels in those patients with a high FMD could be a result of maraviroc intensification.
Alternatively, another indirect pathway could be through the effect of blocking CCR5 in T cells and monocytes. These immune cells play an important role in inflammation and formation of atherosclerotic plaques [31,32]. In

HIV-infected individuals, levels of activation in T cells and monocytes are increased compared
to HIV-negative patients [33,34]. In our study, a significant relation was seen for the expression of CD40 and CD169 in monocytes with DFMD.
Increased expression of CD40 and CD169 in monocytes was related to an increase in DFMD.
Monocytes can migrate to the intima of the vessel wall to form foam cells [31] and have been shown to be abundantly present in atherosclerotic plaques [18]. Moreover, in murine models, maraviroc decreased the infiltration of monocytes in atherosclerotic plaques [18]. In our study, the increase in FMD may partially be explained by the possible mobilization of monocytes from plaques to peripheral blood [35,36]