A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel (MTN-007)

Abstract

ObjectiveRectal 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.MethodsParticipants 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.ResultsSixty-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.ConclusionsThe reduced glycerin formulation of tenofovir 1% gel was safe and well tolerated rectally and should be advanced to Phase 2 development.Trial RegistrationClinicalTrials.gov NCT01232803.

Vaginally Delivered Tenofovir Disoproxil Fumarate Provides Greater Protection than Tenofovir against Genital Herpes in a Murine Model of Efficacy and Safety

“…A small increase in ATP6 expression was observed in response to both the HEC and TDF gels. This observation contrasts with data obtained from a recent phase 1 clinical study of the rectal safety of a 1% TFV gel (31). Using a microarray approach, the investigators found that 505 genes were downregulated in response to seven doses of a 1% TFV gel, including ATP6 and other genes associated with mitochondrial function (F. Hladik, L. Flemming, J, McElrath, and I. McGowan, presented at the Microbicide Trials Network Annual Meeting, Bethesda, MD, 10 to 13 February 2013).…”

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

“…variety of chemokines and cytokines, including TNF-a and IL1b. 38 Combined with reports from MTN-007, 39 these findings merit ongoing attention in future trials. Although the participants demonstrated high adherence by the measures used, it was quite clear that only a minority of TFV gel recipients liked the product, providing an additional, user-based rationale to develop/test rectal specific formulations.…”

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

“…While these new products are directed at reducing the incidence of HIV among men who have sex with men (MSM), it has also been acknowledged that heterosexual anal intercourse may be underreported due to social taboos and other factors (27)(28)(29). This issue has shifted the paradigm of microbicide development toward a new generation of dual-compartment microbicides that are safe for both vaginal and rectal use (30,31). Hence, in this study, we used models of rectal and vaginal mucosal transmission to evaluate the potential of topically applied nAbs.…”