The Microbicides Trial Network released promising results from its “MTN-007” Phase I safety and acceptability study, funded by the National Institutes of Health, looking at a new formulation of one percent tenofovir gel for rectal use Tuesday. The results were presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. Earlier formulations of the gel contained higher levels of glycerin – which was found not to be acceptable for anal use by many participants in earlier trials.
“Researchers conducting an earlier Phase I study of vaginal tenofovir gel for rectal use, RMP-02/MTN-006, noted that participants tended to have more diarrhea-related side effects than noted in studies in which the gel was used vaginally,” according to the MTN. Attempting to avoid these side effects associated with rectal use, investigators decided to test a gel formulation with lower levels of glycerin – a common additive to gel products – to draw less fluid from cells. The original formulation had an osmolality (or concentration of a solution in terms of osmoles of solute per kilogram of solvent) of 3,111 mOsmol/kg, whereas the new product’s osmolality is 836 mOsmol/kg.
Investigators enrolled 65 healthy HIV-negative men and women at three trial sites in the U.S. at The University of Pittsburgh, the University of Alabama, and Fenway Health in Boston to test out the new formulation. Study inclusion criteria included participation in receptive anal sex at least once in the previous year, and a willingness to be anal intercourse abstinent. The majority of participants were white males with a mean age of 36, but 31 percent of the study population were female.
For a one week period, participants were randomized to one of four groups assigned to receive either: daily use of the reduced glycerin rectal gel formulation containing one percent tenofovir; daily use of a rectal gel containing two percent nonoxynol-9 (or N-9); daily use of a rectal placebo gel; no rectal gel but all other prevention counseling and testing procedures. Study participants were evaluated for adherence and side effects.
“This product was much better tolerated than the previous product,” said the study’s lead investigator, Ian McGowan, MD, PhD, at a press conference. Minor side effects were reported by 80 percent of study participants, and 18 percent reported moderate side effects. Adherence to study products was high – with 94 percent using the assigned product daily as directed. Eighty-seven percent of the tenofovir gel group indicated a willingness to use the gel in the future, compared with 93 percent of those in the placebo group, and 63 percent in the N-9 group. McGowan noted that 56 percent of those in the reduced glycerin formulation tenofovir gel arm experienced some gastrointestinal (GI) adverse events – whereas 100 percent of the higher glycerin formulation users reported GI events in the earlier study.
Investigators collected mucosal sampling throughout the study – to assess whether the tenofovir gel induced mucosal changes that might facilitate HIV infection. “We saw very little change in these parameters with tenofovir gel in most cases,” McGowan said. However, he called the mucosal findings “intriguing” because investigators saw changes in 600 genes in the tenofovir arm of the study, which they are doing pathway analysis on now. They hope to present data on those findings at the International Microbicides Meeting in Sydney this April.
Although N-9 has been ruled out as a potential microbicide, investigators chose to include it in the study in order to construct “a detailed profile of its effect on rectal tissue.” Investigators are conducting gene expression tests to see which immune system cell types are present, the particular genes that are being turned “off” or “on,” and which of several chemical proteins are in force. They also hope comparing N-9’s profile to the tenofovir and placebo gels might reveal “reliable measures for evaluating the safety of potential products and help to determine the specific effects of each product.”
As a follow up to the 007 study, investigators are enrolling 186 men-who-have-sex-with-men and transgender women at clinical trial sites in Peru, South Africa, Thailand and the U.S. in a Phase II trial called MTN-017. This study will compare daily use of the new formulation of tenofovir one percent gel; use of the new gel formulation pre- and post-anal sex; and Truvada (emtricitabine plus tenofovir) antiretroviral taken orally daily.