A Randomized, Placebo-Controlled, Pilot Clinical Trial of Dipyridamole to Decrease Human Immunodeficiency Virus-Associated Chronic Inflammation

Bernard J C Macatangay, Edwin K Jackson, Kaleab Z Abebe, Diane Comer, Joshua Cyktor, Cynthia Klamar-Blain, Luann Borowski, Delbert G Gillespie, John W Mellors, Charles R Rinaldo, Sharon A Riddler, Bernard J C Macatangay, Edwin K Jackson, Kaleab Z Abebe, Diane Comer, Joshua Cyktor, Cynthia Klamar-Blain, Luann Borowski, Delbert G Gillespie, John W Mellors, Charles R Rinaldo, Sharon A Riddler

Abstract

Background: Adenosine is a potent immunoregulatory nucleoside produced during inflammatory states to limit tissue damage. We hypothesized that dipyridamole, which inhibits cellular adenosine uptake, could raise the extracellular adenosine concentration and dampen chronic inflammation associated with human immunodeficiency virus (HIV) type 1.

Methods: Virally suppressed participants receiving antiretroviral therapy were randomized 1:1 for 12 weeks of dipyridamole (100 mg 4 times a day) versus placebo capsules. All participants took open-label dipyridamole during weeks 12-24. Study end points included changes in markers of systemic inflammation (soluble CD163 and CD14, and interleukin 6) and levels of T-cell immune activation (HLA-DR+CD38+).

Results: Of 40 participants who were randomized, 17 dipyridamole and 18 placebo recipients had baseline and week 12 data available for analyses. There were no significant changes in soluble markers, apart from a trend toward decreased levels of soluble CD163 levels (P = .09). There was a modest decrease in CD8+ T-cell activation (-17.53% change for dipyridamole vs +13.31% for placebo; P = .03), but the significance was lost in the pooled analyses (P = .058). Dipyridamole also reduced CD4+ T-cell activation (-11.11% change; P = .006) in the pooled analyses. In post hoc analysis, detectable plasma dipyridamole levels were associated with higher levels of inosine, an adenosine surrogate, and of cyclic adenosine monophosphate.

Conclusion: Dipyridamole increased extracellular adenosine levels and decreased T-cell activation significantly among persons with HIV-1 infection receiving virally suppressive therapy.

Keywords: HIV; adenosine; dipyridamole; inflammation.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Percentage change from baseline (BL) to week 12 in plasma levels of sCD14, sCD163, and interleukin 6 (IL-6). Bars show median and interquartile range; whiskers, minimum and maximum values (linear regression model). (For IL-6, note that 2 outlier values from the placebo group—1593.2% and 1079.6%—were excluded from the graph but included in the statistical analyses.)
Figure 2.
Figure 2.
Percentage change from baseline (BL) to week12 in T-cell immune activation (coexpression of CD38 and HLA-DR) (A) and cell cycling (intracellular Ki-67 expression) (B). Bars show median and interquartile range; whiskers, minimum and maximum values (linear regression model).
Figure 3.
Figure 3.
Spaghetti plots show pooled 12-week changes before and after dipyridamole (DP) treatment among all study participants (DP arm, baseline to week 12; placebo arm, weeks 12–24). Median pre-DP and post-DP values, respectively, were as follows: macrophage activation (sCD163 level), 548.4 and 531.8 ng/mL (left panel); CD8+ T-cell immune activation (HLA-DR+CD38+), 5.60% and 5.30% (middle panel); and CD4+ T-cell immune activation, 2.60% and 2.20% (right panel) (linear regression model).
Figure 4.
Figure 4.
A, Dipyridamole levels (median with interquartile range) for both study arms at each study visit time point. B, Cumulative inosine level (mean with standard error of the mean; n = 33) at time points when dipyridamole was detected versus when none was detected in plasma (t test). Only 1 participant in each arm had no detectable level of dipyridamole while taking dipyridamole.
Figure 5.
Figure 5.
Urinary 3’5’-cyclic adenosine monophosphate (cAMP) (A) and 3’5’-cyclic guanosine monophosphate (cGMP) (B) levels (mean with standard error of the mean; n = 33) at time points with or without detectable dipyridamole levels in plasma (t test).

Source: PubMed

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