Adherence, safety, and choice of the monthly dapivirine vaginal ring or oral emtricitabine plus tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis among African adolescent girls and young women: a randomised, open-label, crossover trial

Article

作者: Jacobson, Cindy ; Nakabiito, Clemensia ; Garcia, Morgan ; Milan, Gakiema ; Siziba, Bekezela ; Tahuringana, Eunice ; Hendrix, Craig ; Macdonald, Pippa ; Nakalega, Rita ; Ngure, Kenneth ; Livant, Edward ; Bekker, Linda-Gail ; Szydlo, Daniel ; Anderson, Peter ; Brown, Elizabeth R ; Bunge, Katherine ; van der Straten, Ariane ; Reddy, Krishnaveni ; Hosek, Sybil ; Rooney, James F ; Muhlanga, Felix ; Akello, Carolyne A ; Celum, Connie ; Palanee-Phillips, Thesla ; Hillier, Sharon L ; Steytler, John ; McClure, Tara ; Baeten, Jared M ; Levy, Lisa ; Nair, Gonasagrie ; Johnson, Sherri ; Soto-Torres, Lydia ; Parikh, Urvi

BACKGROUNDHalf of new HIV acquisitions in Africa occur in adolescent girls and young women. Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine or the monthly dapivirine vaginal ring is efficacious but has lower adherence and effectiveness among adolescent girls and young women. We aimed to assess product adherence, safety, and choice of oral PrEP compared with the dapivirine ring among African adolescent girls and young women.METHODSMTN-034/REACH was a randomised, open-label, phase 2a crossover trial among HIV-seronegative, non-pregnant adolescent girls and young women aged 16-21 years at four clinical research sites in South Africa, Uganda, and Zimbabwe. Participants were randomly assigned (1:1) to either the dapivirine ring or daily oral PrEP (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) for 6 months, then switched to the other product option for 6 months, followed by a third 6-month period in which participants were given a choice of oral PrEP, the dapivirine ring, or neither. Fixed block randomisation was used, stratified by site. The primary adherence endpoint was use of each product during the randomised periods, with high use defined as tenofovir-diphosphate concentrations greater than or equal to 700 fmol/punch (associated with taking an average of four or more tablets per week in the previous month) and greater than or equal to 4 mg dapivirine released from the returned ring (continuous use for 28 days in the previous month) based on residual drug concentrations. The primary safety endpoint was grade 2 or higher adverse events during each randomised period of 24 weeks of ring and oral PrEP. This trial is registered at ClinicalTrials.gov, NCT03593655.FINDINGSFrom Feb 6, 2019 to Sept 9, 2021, 396 adolescent girls and young women were screened, 247 of whom were enrolled and randomly assigned (6 months of the ring followed by 6 months of oral PrEP n=124; 6 months of oral PrEP followed by 6 months of the ring n=123). Median age was 18 years (IQR 17-19). 54 grade 2 or higher product-related adverse events were reported during oral PrEP and five during dapivirine ring use, with no product-related serious adverse events. High adherence was observed in 753 (57%) of the 1316 oral PrEP visits and 806 (57%) of the 1407 dapivirine ring visits. Four women acquired HIV during follow-up.INTERPRETATIONAdherence was moderately high and similar between oral PrEP and the dapivirine ring with favourable safety and tolerability. Oral PrEP and the dapivirine ring are effective, safe, and well tolerated HIV prevention options for adolescent girls and young women who would benefit from a choice of PrEP formulations to meet their needs and preferences.FUNDINGNational Institutes of Health.

2023-08-01·Drug Delivery and Translational Research3区 · 医学

Refining the in vitro release test method for a dapivirine-releasing vaginal ring to match in vivo performance

3区 · 医学

Article

作者: Spence, Patrick ; Derrick, Tiffany ; Boyd, Peter ; McCoy, Clare F ; Armstrong, Ryan ; Malcolm, R Karl ; Lim, Deanna ; Devlin, Bríd ; Murphy, Diarmaid J ; Bashi, Yahya H Dallal

AbstractPreviously reported in vitro release test methods for drug-releasing vaginal rings containing poorly water-soluble drugs have described use of water-alcohol systems or surfactant solutions in efforts to maintain sink conditions. Here, as part of efforts to more closely match in vitro and in vivo release for the 25 mg dapivirine matrix-type silicone elastomer vaginal ring for HIV prevention, we have investigated alternatives to the 1:1 v/v water/isopropanol medium described previously. Specifically, we evaluated dapivirine release from rings into (i) monophasic water/isopropanol mixtures of varying compositions and (ii) biphasic buffer/octanol systems using pH 4.2 and pH 7.0 buffers. The rate and mechanism of dapivirine release were dependent upon the isopropanol concentration in the release medium, in accordance with the observed trend in drug solubility. At 0 and 10% v/v isopropanol concentrations, dapivirine release followed a partition-controlled mechansim. For media containing ≥ 20% v/v isopropanol, in vitro release of dapivirine was significantly increased and obeyed permeation-controlled kinetics. Cumulative release of ~3.5 mg dapivirine over 28 days was obtained using a water isopropanol mixture containing 20% v/v isopropanol, similar to the ~4 mg dapivirine released in vivo. Dapivirine release into the biphasic buffer/octanol system (intended to mimic the fluid/tissue environment in vivo) was constrained by the limited solubility of dapivirine in the buffer component in which the ring resided, such that cumulative dapivirine release was consistently lower than that observed with the 20% v/v isopropanol in water medium. Release into the biphasic system was also pH dependent, in line with dapivirine’s pKaand with potential implications for in vivo release and absorption in women with elevated vaginal pH.Graphical abstract

2022-12-01·International Journal of Pharmaceutics: X

In vitro drug release, mechanical performance and stability testing of a custom silicone elastomer vaginal ring releasing dapivirine and levonorgestrel

Article

作者: Hansraj, Bashir ; Malcolm, R Karl ; Martin, François ; Spence, Patrick ; Brown, Leeanne ; Dangi, Bindi ; Kleinbeck, Kyle ; Devlin, Bríd ; Boyd, Peter ; Dallal Bashi, Yahya H ; McCoy, Clare F ; Murphy, Diarmaid J ; McMullen, Nicole

We have previously reported a multipurpose silicone elastomer vaginal ring providing sustained release of dapivirine (an antiretroviral) and levonorgestrel (a progestin) for HIV prevention and hormonal contraception. During initial development, issues arose due to reaction between the ethynyl group in the levonorgestrel molecule and the hydride-functionalised polydimethylsiloxane components in the silicone elastomer formulation. This unwanted reaction occurred both during and to a lesser extent after ring manufacture, impacting the curing process, the mechanical properties of the ring, and the in vitro release of levonorgestrel. Recently, we reported custom silicone elastomer grades that minimise this reaction. In this follow-on study, we describe the manufacture, in vitro drug release, mechanical, and pharmaceutical stability testing of ring formulations prepared from a custom silicone elastomer and containing 200 mg dapivirine and 80, 160, 240 or 320 mg levonorgestrel. The rings showed mechanical properties similar to marketed ring products, sustained in vitro release of both drugs over 30 days in quantities deemed clinically relevant, offered acceptable assay values, and provided good product stability over 15 weeks at 40 °C and 75% relative humidity.

项与 International Partnership for Microbicides 相关的新闻（医药）

2021-02-17

·GlobeNewswire

Cavitation Technologies, Inc. Announces an Agreement with Partnership International, Inc.

Chatsworth, CA, Feb. 16, 2021 (GLOBE NEWSWIRE) -- via NewMediaWire -- Cavitation Technologies, Inc. (OTCQB: CVAT ) (BERLIN: WTC ) announces an Agreement with Partnership International, Inc. (“PI”) -- an international consulting firm specializing in infrastructure projects that promote sustainable development through renewable energy and clean water supply/treatment investments. Through this Agreement, Partnership International, Inc., will assist CVAT in securing strategic partnerships, financing, and grants for the Company’s patented water applications and technologies. Neil Voloshin, CFO/COO of Cavitation Technologies, Inc., stated, “Over the last several years we have made great progress in developing water treatment technologies and applications. Specifically, our joint venture with Enviro-Watertek, LLC. was immensely successful in the treatment of fracked and produced water. Now with the help of Partnership International, Inc. this agreement expands the utilization of our water treatment applications into sectors such as desalination, ballast water, reclamation water in agriculture, produced water and renewable fuels. We believe the addition of our technology in these sectors presents economic value to the company while also providing maximized returns for shareholders. We’re excited to be working with Partnership International and ready to execute our business goals in 2021 and moving forward.” Tracy Mathieu, Vice President of PI, commented, “Water purification is expensive, requires a lot of energy, leaves a terrible carbon footprint, and is a global problem. We feel that CVAT’s patented processes and technologies provide a viable solution to this global problem. Not only is CVAT’s innovative technology compact, modifiable, and sustainable in the global market-place, it requires no harsh chemicals, adds zero emissions, and uses minimal off-grid energy. We’re happy that through this agreement, we can help CVAT expand into new sectors with an initial focus on climate vulnerable areas. We have filed the first grant for CVAT’s water application technology with the Department of Interior, Bureau of Reclamation, for a desalination project of $500,000. We believe projects like these present extraordinary opportunities for CVAT to demonstrate the value of their technology in promoting sustainable development.” About Cavitation Technologies, Inc. Founded in 2007, the company designs and manufactures innovative flow-through devices and systems, as well as develops processing technologies for use in edible oil refining, renewable fuel production, water treatment, and alcoholic beverage enhancement. The company's patented Nano Reactor® systems and various technologies have over 40 patents issued and filed both domestically and abroad. Follow us on Twitter for real time updates: Like us on Facebook to receive live feed updates: About Partnership International, Inc. Partnership International Inc., established in 1990, comprises a team of experts that provide regulatory, institutional, technical, commercial and financial advisory services to clients on projects that promote sustainable development through infrastructure investments. PI is recognized for delivering pragmatic, market-driven solutions for public and private clients across multiple industries and sectors. Through offices in Washington, DC, and in the field, our staff targets meaningful sectoral reforms to stimulate sustainable economic growth in developing and emerging markets worldwide. Forward-Looking Statement This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, forward-looking statements can be identified by terminology such as ''may,'' ''should,'' ''potential,'' ''continue,'' ''expects,'' ''anticipates,'' ''intends,'' ''plans,'' ''believes,'' ''estimates,'' and similar expressions, and include statements such as, We believe the addition of our technology in these sectors presents economic value to the company while also providing maximized returns for shareholders. These forward-looking statements are based largely on the Company's expectations and are subject to a number of risks and uncertainties, certain of which are beyond the Company's control. Actual results could differ materially from these forward-looking statements as a result of a variety of factors including, among others, our ability to perform the installation as anticipated, the state of the economy, the competitive environment and other factors described in our most recent Form 10-K and our other filings with the SEC, including subsequent periodic reports on Forms 10-Q and 8-K. In light of these risks and uncertainties there can be no assurances that the forward-looking statements contained in this press release will in fact transpire or prove to be accurate. The information in this release is provided only as of the date of this release, and we undertake no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law. Jessica Steidinger 818-718-0905 jessica@ctinanotech.com

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药物(靶点)	适应症	全球最高研发状态

Dapivirine/Levonorgestrel ( PR x RT )	HIV感染更多	临床1期
Dapivirine ( RT )	HIV感染更多	终止
DS-003 ( HIV envelope protein gp120 )	HIV感染更多	无进展
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