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.
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-γ [IFNγ], and interleukin-10), and immunoglobulin secretion were assessed. Intraclass correlation (ICC) was calculated to assess endpoint stability.
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 (IFNγ) and T-cell phenotype (CD3, CD4, CD8, CD19, CD4/CCR5, and CD4/CD38) between the tissue samples collected at 10 and 30 cm.
These data help to provide a rationale for the selection of endpoints for future phase 1 rectal safety studies.
From the *Center for Prevention Research in the Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA; †Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA; ‡Departments of Biostatistics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA; and the §National Institute of Allergy and Infectious Diseases, Bethesda, MD.
Received for publication January 30, 2007; accepted July 30, 2007.
Funded by a grant from the HIV Prevention Trials Network of the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health (AI46749/645-12).
Study data presented as an oral presentation at Microbicides 2006; 2006; Cape Town, South Africa.
Correspondence to: Ian McGowan, MD, PhD, FRCP, Magee Womens Research Institute, University of Pittsburgh, 204 Croft Ave., Room B505, Pittsburgh, PA 15213 (e-mail: firstname.lastname@example.org).