Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges

Smith J.M.; Rastogi R.; Teller R.S.Srinivasan P.Mesquita P.M.M.Nagaraja U.McNicholl J.M.Hendry R.M.Dinh C.T.Martin A.Herold B.C.Kiser P.F.

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Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges

机译：Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges

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Topical preexposure prophylaxis interrupts HIV transmission at the site of mucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitor tenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gel application. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs) may improve efficacy by providing long-term sustained drug delivery leading to constant mucosal antiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinical pipeline, 100 efficacy in a repeated macaque vaginal challenge model has not been achieved. Here we describe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate (TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRs generated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remained seronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue culture infectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of four exposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associated with tenofovir levels in vaginal fluid mean 1.8 × 105 ng/mL (range 1.1 × 104 to 6.6 × 105 ng/mL) and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support further advancement of TDF IVRs as well as the concept that extended duration drug delivery devices delivering topical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第40期|16145-16150|共6页
作者
Smith J.M.; Rastogi R.; Teller R.S.Srinivasan P.Mesquita P.M.M.Nagaraja U.McNicholl J.M.Hendry R.M.Dinh C.T.Martin A.Herold B.C.Kiser P.F.;
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作者单位

Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Centers for Disease Control and Prevention, Atlanta, GA 30333, United States;

Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, United States;

Department of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Controlled drug delivery; Nonhuman primate; Pharmacokinetics; PrEP;

Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges

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