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

Maaike Krikke, Kiki Tesselaar, Joop E Arends, Julia Drylewicz, Sigrid A Otto, Steven F L van Lelyveld, Frank J L Visseren, Andy I M Hoepelman, Maaike Krikke, Kiki Tesselaar, Joop E Arends, Julia Drylewicz, Sigrid A Otto, Steven F L van Lelyveld, Frank J L Visseren, Andy I M Hoepelman

Abstract

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.

Keywords: Abacavir; Cardiovascular disease; Immune activation; Inflammation; Maraviroc.

Figures

Fig. 1
Fig. 1
Flow diagram (CONSORT). The patients enrolled, randomized and analyzed in the MASTER study. The diagram shows the cross-over design, pooling all interventions (left) and all controls (right) to be compared
Fig. 2
Fig. 2
Study design and changes in FMD. a Arm A: INT1 intervention period 1, C2 control period 2. Arm B: C1 control period 1, INT2 intervention period 2. FMD flow-mediated dilatation measurement; BS blood sampling. b Changes in the brachial artery FMD after maraviroc treatment (intervention) and after control. Horizontal bars represent the median with interquartile ranges
Fig. 3
Fig. 3
Change in CCR5 expression in CD4+ and CD8+ T cells. Change in CCR5 expression in a CD4+ and b CD8+ T cells comparing intervention to the control periods. The change in CCR5 expression in c CD4+ and d CD8+ T cells at week 0, 8 and 16. The relation between the change (Δ) in CCR5 expression in e CD4+ and f CD8+ T cells and change (Δ) in FMD (in the intervention period)
Fig. 4
Fig. 4
Relation between change in (Δ) FMD and change in inflammatory and coagulation markers and immune activation. The relation between ΔFMD and a ΔD-dimer, b Δannexin expression in CD4+ T cells, c ΔCD38+ HLA-DR+ expression in CD4+ T cells, d ΔCD95 expression in CD4+ T cells, e ΔCD40+ CD14+ expression in monocytes and ΔCD169+ CD14 expression in monocytes (all in the intervention period)

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