Rectal Microbicide Safety and Acceptability Trial of Topically Applied Tenofovir Compared With Oral Tablet

Summary

To date, the majority of microbicide research has focused on the assessment of the safety and effectiveness of vaginal microbicides used for the prevention of HIV transmission via the vaginal compartment. Receptive anal intercourse (RAI) is common among men who have sex with men (MSM), and there is increasing evidence that heterosexual women in the developed and developing world also practice anal sex. It can, therefore, be anticipated that once vaginal microbicides are licensed, they will be used in both the vaginal and rectal compartments. As a consequence, there is a need to evaluate both the rectal and vaginal safety profile of candidate microbicides. Therefore, the primary objective of this study is to evaluate the systemic safety of 1% vaginally formulated tenofovir gel applied rectally. In addition, this study will evaluate the immunotoxicity of the gel and evaluate its acceptability; it will also use the oral tenofovir disoproxil fumarate tablets (TDF), rectally-applied tenofovir gel,and a placebo gel to compare their systemic and compartmental pharmacokinetic (pK) profiles. This study was designed to address the following hypotheses: * Vaginally-formulated tenofovir 1% topical gel when applied rectally will be safe using a combination of clinical and laboratory markers including assays specifically designed to measure mucosal toxicity * Tenofovir will be detectable at different concentrations in the various anatomic compartments sampled for pharmacokinetics following single and 7-day topical exposures * Exposure to tenofovir 1% gel will demonstrate prevention of ex vivo HIV-1 challenge using in vivo drug-exposed tissue as compared to baseline tissue samples * Orally delivered, single dose, 300 mg tenofovir disoproxil fumarate tablets will have similar safety profiles using routine blood safety indices as have been established in other trials and will show no mucosal safety concerns * The oral dose will have different multi-compartment concentration kinetics than the topical tenofovir and will also demonstrate preliminary (ex vivo) prevention using the explant infectivity assay * Vaginally formulated tenofovir 1% topical gel applied rectally will be acceptable to participants, as indicated by a score in the upper one third of the 10-point Likert scale on intentionality to use in the product in the future

Timeline

Start

2009-09

Primary completion

2010-06

Completion

2010-07

Publications

• Richardson-Harman N, Hendrix CW, Bumpus NN, Mauck C, Cranston RD, Yang K, Elliott J, Tanner K, McGowan I, Kashuba A, Anton PA. Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study. PLoS One. 2014 Oct 28;9(10):e111507. doi: 10.1371/journal.pone.0111507. eCollection 2014.
• Yang KH, Hendrix C, Bumpus N, Elliott J, Tanner K, Mauck C, Cranston R, McGowan I, Richardson-Harman N, Anton PA, Kashuba AD. A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate. PLoS One. 2014 Oct 28;9(10):e106196. doi: 10.1371/journal.pone.0106196. eCollection 2014.
• Anton PA, Cranston RD, Kashuba A, Hendrix CW, Bumpus NN, Richardson-Harman N, Elliott J, Janocko L, Khanukhova E, Dennis R, Cumberland WG, Ju C, Carballo-Dieguez A, Mauck C, McGowan I. RMP-02/MTN-006: A phase 1 rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 1% gel compared with oral tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses. 2012 Nov;28(11):1412-21. doi: 10.1089/aid.2012.0262. Epub 2012 Oct 9.
• Richardson-Harman N, Mauck C, McGowan I, Anton P. Dose-response relationship between tissue concentrations of UC781 and explant infectibility with HIV type 1 in the RMP-01 rectal safety study. AIDS Res Hum Retroviruses. 2012 Nov;28(11):1422-33. doi: 10.1089/AID.2012.0073. Epub 2012 Sep 20.

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Indications