A randomized pilot trial to evaluate the benefit of the concomitant use of atorvastatin and Raltegravir on immunological markers in protease-inhibitor-treated subjects living with HIV

Abstract

Objective: Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies.

Design: Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks.

Methods: We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks.

Results: Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of CD28-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group.

Conclusions: The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers.

Clinical trials registration: NCT02577042.

Conflict of interest statement

Unrelated to this work, JB is CEo founder and shareholder of AlbaJuna Therapeutics, S.L. This study was funded by Merk Sharp & Dome (MSD) through the MSD Investigator Studies Program (IIS # 52754), grant to EN. This funder did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript "This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Trial design.

A. Consolidated Standards of Reporting Trials (CONSORT) flow diagram for the trial showing Participant flow in Control and Raltegravir groups. B. Schematic representation of intervention, patients were randomized to the Control and Raltegravir groups and, after 24 weeks, atorvastatin was added to all participants. Follow up visits are indicated for each group.

Fig 2. of maturation subsets in CD4 and CD8 T cells.

Analysis Figure shows median values for the frequency of the maturation subsets (Naïve, Central Memory, Effector Memory, Transitional Memory and Effector Memory RA+) in CD4 (panel A) or CD8 T cells (Panel B) in Control (greyscale) and Raltegravir (blue) groups at three different time points: week 0 (start of the study), week 24 (treatment follow-up), and week 72 (48 weeks after atorvastatin treatment). Maturation stages were defined based on the combination of CD45RA, CD197 (CCR7) and CD27 as described in Methods. Asterisks denote p<0.05 either intergroups or longitudinally intragroup as indicated.

Fig 3. Evaluation of the changes in activation, CD38+ expression, immunosenescence and exhaustion levels in CD4 and CD8 T cells.

Measure of changes in mean activation levels (defined by HLA-DR+CD38+ coexpression, panels A and E) CD38+ cells (panels B and F) senescence (CD57+CD28–, panels C and G) and exhaustion (PD-1+, panels D and H) levels in CD4+ T cells (panels A-D) and CD8 T cells (panels E-H) comparing both study groups. These differences were evaluated between w0–w24, w0–w72 and w24–w72. Control group is represented in grey and the Raltegravir group in blue. Asterisks denote p