Characterization of baseline intestinal mucosal indices of injury and inflammation in men for use in rectal microbicide trials (HIV Prevention Trials Network-056).
OBJECTIVE
The purpose of this study was to evaluate the biologic stability of mucosal parameters that might be used as endpoints in phase 1 rectal safety studies.


METHODS
Sixteen male participants were enrolled into 4 groups defined by HIV status, viral load, and sexual activity. Each participant underwent 3 flexible sigmoidoscopies at 2-week intervals with collection of blood, intestinal biopsies, and rectal secretions. Intestinal histology, phenotypic characterization of mucosal mononuclear cells, cytokine messenger RNA (mRNA) profiles (RANTES, interferon-gamma [IFNgamma], and interleukin-10), and immunoglobulin secretion were assessed. Intraclass correlation (ICC) was calculated to assess endpoint stability.


RESULTS
Qualitative histology demonstrated minimal inflammation in >95% of biopsies and remained stable throughout the study period. ICC for the tissue cytokine mRNA measurements and several T-cell phenotypic markers was >0.7, indicating stability over time. Mucosal CD4 lymphopenia was seen in the HIV-positive participants and was more pronounced in those with higher viral loads. Modest differences were observed for cytokine expression (IFNgamma) and T-cell phenotype (CD3, CD4, CD8, CD19, CD4/CCR5, and CD4/CD38) between the tissue samples collected at 10 and 30 cm.


CONCLUSIONS
These data help to provide a rationale for the selection of endpoints for future phase 1 rectal safety studies.
McGowan
Ian
I
Center for Prevention Research in the Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of Clifornia, Los Angeles, Los Angeles, CA, USA. mcgowanim@mail.magee.edu
Elliott
Julie
J
Cortina
Galen
G
Tanner
Karen
K
Siboliban
Chomchay
C
Adler
Amy
A
Cho
Daniel
D
Boscardin
W John
WJ
Soto-Torres
Lydia
L
Anton
Peter A
PA
D000285:Administration, Rectal; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D015703:Antigens, CD / Q000032:analysis; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000235:genetics; D004724:Endoscopy; D018023:HIV Seronegativity; D006679:HIV Seropositivity / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007136:Immunoglobulins / Q000032:analysis; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics
D000890:Anti-Infective Agents; D015703:Antigens, CD; D016207:Cytokines; D007074:Immunoglobulin G; D007136:Immunoglobulins; D012333:RNA, Messenger