The clinical development of rectal microbicides for HIV prevention

Introduction: Individuals practicing unprotected receptive anal intercourse are at particularly high risk of HIV infection. Men who have sex with men in the developed and developing world continue to have disproportionate and increasing levels of HIV infection. The last few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis, vaginal microbicides, and treatment as prevention but there has also been significant progress in the development of rectal microbicides. The purpose of this thesis is to summarise the status of rectal microbicide research, to identify opportunities, challenges, and future directions in this important field of HIV prevention, and to describe the results of a recently completed Phase 1 rectal microbicide study (MTN-007). Methods: MTN-007, a Phase 1, randomised, partially blinded, rectal safety study was undertaken to determine whether a reduced glycerin formulation of tenofovir 1% gel was safe and acceptable to men and women with a history of practicing receptive anal intercourse. The study was conducted at three clinical trial sites in the United States (Pittsburgh, Pennsylvania; Boston, Massachusetts; and Birmingham, Alabama). Study participants were randomized to one of three gel arms (tenofovir gel, a hydroxyethyl cellulose placebo gel, or a 2% Nonoxynol gel) or a no treatment arm and received a total of eight rectal daily doses of the study product. In addition to collecting conventional clinical safety and acceptability data, the study also included extensive mucosal safety assays to determine whether product administration was associated with changes in mucosal biology that might predispose to increased risk of HIV acquisition associated with unprotected receptive anal intercourse. 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. Microarray analysis of the mucosal transcriptome provided preliminary evidence that topical application of tenofovir 1% gel was associated with decreased mitochondrial function within the rectal mucosa. Conclusions: The MTN-007 study demonstrated that, using conventional criteria, tenofovir gel is safe and acceptable and should be advanced to Phase 2 development as a potential rectal microbicide. However, microarray analysis of mucosal tissue suggested that use of tenofovir gel may modulate mucosal mitochondrial function. This observation will require further evaluation in future studies