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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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Related in: MedlinePlus

Changes in pro-inflammatory markers associated with aprepitant treatment.
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Figure 4: Changes in pro-inflammatory markers associated with aprepitant treatment.

Mentions: Aprepitant treatment resulted in significant decreases in several pro-inflammatory markers at day 14 that were not seen in the placebo group (Fig. 4). Although we did not see changes in CD4+ T-cell counts, we did observe a median reduction in PD-1 expression by 4.8% (P = 0.04) (Fig. 4a). This effect was transient and limited to the treatment phase. PD-1 expression returned to baseline by day 42. No significant changes in PD-1 expression were detected in the placebo group. Plasma substance P levels at day 14 decreased in the aprepitant group (median change = −34 pg/ml, P = 0.05), but not in the placebo group (median change = +30 pg/ml, P = 0.55) (Fig. 4b). By day 42, however, the values in both the groups were similar to the baseline levels. sCD163 levels decreased in the aprepitant group at day 14 (median change = −563 ng/ml, P = 0.02), and remained below baseline at day 42, although no longer statistically significant (median change = −594 ng/ml, P = 0.09) (Fig. 4c). No changes were observed in the sCD163 level within 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 pro-inflammatory markers associated with aprepitant treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Changes in pro-inflammatory markers associated with aprepitant treatment.
Mentions: Aprepitant treatment resulted in significant decreases in several pro-inflammatory markers at day 14 that were not seen in the placebo group (Fig. 4). Although we did not see changes in CD4+ T-cell counts, we did observe a median reduction in PD-1 expression by 4.8% (P = 0.04) (Fig. 4a). This effect was transient and limited to the treatment phase. PD-1 expression returned to baseline by day 42. No significant changes in PD-1 expression were detected in the placebo group. Plasma substance P levels at day 14 decreased in the aprepitant group (median change = −34 pg/ml, P = 0.05), but not in the placebo group (median change = +30 pg/ml, P = 0.55) (Fig. 4b). By day 42, however, the values in both the groups were similar to the baseline levels. sCD163 levels decreased in the aprepitant group at day 14 (median change = −563 ng/ml, P = 0.02), and remained below baseline at day 42, although no longer statistically significant (median change = −594 ng/ml, P = 0.09) (Fig. 4c). No changes were observed in the sCD163 level within 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