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Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults.

Tebas P, Spitsin S, Barrett JS, Tuluc F, Elci O, Korelitz JJ, Wagner W, Winters A, Kim D, Catalano R, Evans DL, Douglas SD - AIDS (2015)

Bottom Line: Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 (-4.8%; P = 0.04), plasma substance P (-34.0 pg/ml; P = 0.05) and soluble CD163 (-563 ng/ml; P = 0.02), with no significant changes in the placebo arm.Aprepitant was safe and well tolerated.At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity.

View Article: PubMed Central - PubMed

Affiliation: aDepartment of Medicine bDepartment of Pediatrics cDepartment of Psychiatry, Perelman School of Medicine, University of Pennsylvania dThe Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania eWestat, Rockville, Maryland, USA.

ABSTRACT

Objective: We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant - a neurokinin 1 receptor antagonist.

Design: Phase IB randomized, placebo-controlled, double-blinded study.

Methods: Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks.

Results: There were no significant changes in the plasma viremia or CD4(+) T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 (-4.8%; P = 0.04), plasma substance P (-34.0 pg/ml; P = 0.05) and soluble CD163 (-563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 ± 3.1 μg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low-density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively).

Conclusion: Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4(+) programmed death 1-positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit.

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Changes in cholesterol levels associated with aprepitant treatment.
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Figure 3: Changes in cholesterol levels associated with aprepitant treatment.

Mentions: The use of aprepitant was associated with increases in lipid measurements (Fig. 3). The median within-participant change in total cholesterol in the aprepitant group at the end of treatment (day 14) was +31 mg/dl (P = 0.01) (Fig. 3a). Median change in low-density lipoprotein (LDL) cholesterol was +26 mg/dl (P = 0.02) and the median change in high-density lipoprotein (HDL) cholesterol was +3 mg/dl (P = 0.02) (Fig. 3b and c). These lipid levels generally returned to close to their baseline values by day 42, after treatment was discontinued. No significant changes were observed in the placebo group.


Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults.

Tebas P, Spitsin S, Barrett JS, Tuluc F, Elci O, Korelitz JJ, Wagner W, Winters A, Kim D, Catalano R, Evans DL, Douglas SD - AIDS (2015)

Changes in cholesterol levels associated with aprepitant treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4472318&req=5

Figure 3: Changes in cholesterol levels associated with aprepitant treatment.
Mentions: The use of aprepitant was associated with increases in lipid measurements (Fig. 3). The median within-participant change in total cholesterol in the aprepitant group at the end of treatment (day 14) was +31 mg/dl (P = 0.01) (Fig. 3a). Median change in low-density lipoprotein (LDL) cholesterol was +26 mg/dl (P = 0.02) and the median change in high-density lipoprotein (HDL) cholesterol was +3 mg/dl (P = 0.02) (Fig. 3b and c). These lipid levels generally returned to close to their baseline values by day 42, after treatment was discontinued. No significant changes were observed in the placebo group.

Bottom Line: Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 (-4.8%; P = 0.04), plasma substance P (-34.0 pg/ml; P = 0.05) and soluble CD163 (-563 ng/ml; P = 0.02), with no significant changes in the placebo arm.Aprepitant was safe and well tolerated.At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity.

View Article: PubMed Central - PubMed

Affiliation: aDepartment of Medicine bDepartment of Pediatrics cDepartment of Psychiatry, Perelman School of Medicine, University of Pennsylvania dThe Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania eWestat, Rockville, Maryland, USA.

ABSTRACT

Objective: We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant - a neurokinin 1 receptor antagonist.

Design: Phase IB randomized, placebo-controlled, double-blinded study.

Methods: Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks.

Results: There were no significant changes in the plasma viremia or CD4(+) T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 (-4.8%; P = 0.04), plasma substance P (-34.0 pg/ml; P = 0.05) and soluble CD163 (-563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 ± 3.1 μg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low-density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively).

Conclusion: Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4(+) programmed death 1-positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit.

Show MeSH
Related in: MedlinePlus