Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults.
OBJECTIVE
We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant - a neurokinin 1 receptor antagonist.


METHODS
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).


CONCLUSIONS
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.
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.
Pablo
P
Tebas
Sergei
S
Spitsin
Jeffrey S
JS
Barrett
Florin
F
Tuluc
Okan
O
Elci
James J
JJ
Korelitz
Wayne
W
Wagner
Angela
A
Winters
Deborah
D
Kim
Renae
R
Catalano
Dwight L
DL
Evans
Steven D
SD
Douglas
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D015703:Antigens, CD / Q000097:blood*; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood*; D000077608:Aprepitant; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage*; D064729:Neurokinin-1 Receptor Antagonists / Q000008:administration & dosage; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000097:blood*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000097:blood*; D055815:Young Adult; D000098902:CD163 Antigen
D019380:Anti-HIV Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D000098902:CD163 Antigen; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D061026:Programmed Cell Death 1 Receptor; D011956:Receptors, Cell Surface; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D013373:Substance P