A phase 1 randomized, double blind, placebo controlled rectal safety and acceptability study of tenofovir 1% gel (MTN-007)

Abstract

Objective: Rectal microbicides are needed to reduce the risk of HIV acquisition associated with unprotected receptive anal intercourse. The MTN-007 study was designed to assess the safety (general and mucosal), adherence, and acceptability of a new reduced glycerin formulation of tenofovir 1% gel.

Methods: Participants were randomized 1:1:1:1 to receive the reduced glycerin formulation of tenofovir 1% gel, a hydroxyethyl cellulose placebo gel, a 2% nonoxynol-9 gel, or no treatment. Each gel was administered as a single dose followed by 7 daily doses. Mucosal safety evaluation included histology, fecal calprotectin, epithelial sloughing, cytokine expression (mRNA and protein), microarrays, flow cytometry of mucosal T cell phenotype, and rectal microflora. Acceptability and adherence were determined by computer-administered questionnaires and interactive telephone response, respectively.

Results: Sixty-five participants (45 men and 20 women) were recruited into the study. There were no significant differences between the numbers of ≥ Grade 2 adverse events across the arms of the study. Likelihood of future product use (acceptability) was 87% (reduced glycerin formulation of tenofovir 1% gel), 93% (hydroxyethyl cellulose placebo gel), and 63% (nonoxynol-9 gel). Fecal calprotectin, rectal microflora, and epithelial sloughing did not differ by treatment arms during the study. Suggestive evidence of differences was seen in histology, mucosal gene expression, protein expression, and T cell phenotype. These changes were mostly confined to comparisons between the nonoxynol-9 gel and other study arms.

Conclusions: The reduced glycerin formulation of tenofovir 1% gel was safe and well tolerated rectally and should be advanced to Phase 2 development.

Trial registration: ClinicalTrials.gov NCT01232803.

Figure 1. Flow diagram of participant progress through the MTN-007 study.

Figure 2. Number of genes in rectal biopsies (9 cm) with significant expression changes between baseline and after 7 days of treatment.

The four ellipses represent each of the four treatment arms, Nonoxynol 9 (N-9) gel, tenofovir (TFV) gel, hydroxyethylcellulose (HEC) gel or no gel (No Rx). The numbers of genes changing expression exclusively in one study arm are indicated in fields of the diagram that do not overlap with another field (N-9, 93 genes; TFV, 608 genes; HEC, 11 genes; No Rx 12 genes). When identical genes changed in more than one treatment arm, their number is placed into the respective overlapping fields of the diagram. Choice of colors is arbitrary to help visually distinguish each separate field of the diagram. cRNA preparation, gene chip hybridization, and data significance analysis was carried out as described in the Materials and Methods section of the paper.