Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women: a phase 1, single-blind, randomised, controlled trial

Keller, Marla J.; Wood, Lianna; Billingsley, James M.; Ray, Laurie; Goymer, Jessica; Sinclair, Shada; McGinn, Aileen P.; Marzinke, Mark A.; Frank, Bruce; Srinivasan, Sujatha; Liu, Congzhou; Atrio, Jessica; Espinoza, Lilia; Mugo, Nelly; Spiegel, Hans; Anderson, Peter L.; Fredricks, David N.; Hendrix, Craig W.; Marrazzo, Jeanne; Bosinger, Steven E.; Herold, Betsy C.

doi:10.1016/s2352-3018(19)30145-6

Cited by 38 publications

(30 citation statements)

References 30 publications

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“… 2 Moreover, two trials of tenofovir application directly to the female genital tract or the rectum as topical PrEP demonstrated a pro-inflammatory effect on the mucosa. 6 , 7 Analogous to these studies of topical PrEP, oral PrEP offers a unique opportunity to define the immunological effects of tenofovir-emtricitabine without interference by HIV infection, HIV-associated comorbidities, or the additional drugs that PLWH must take. Because the oral use of tenofovir and emtricitabine is more common than the topical use of tenofovir by orders of magnitude, lacking information on its mucosal impact in fact constitutes a startling knowledge gap.…”

Section: Introductionmentioning

confidence: 99%

Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection

Hughes

Levy

Calienes

et al. 2020

Cell Reports Medicine

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Summary Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here, we assess the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induces type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r = 0.91) and between the rectum and duodenum (r = 0.81). Gene set testing also indicates stimulation of the type I/III pathways in the ectocervix and of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence confirm IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.

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Section: Introductionmentioning

confidence: 99%

Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection

Hughes

Levy

Calienes

et al. 2020

Cell Reports Medicine

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“…IVRs have high acceptability amongst users and can be designed to deliver different active ingredients using the same ring [16,17]. Furthermore, in a recent clinical trial, it was reported that placebo IVRs did not significantly induce an inflammatory response within the FGT of women suggesting that IVRs are safe for long-term use, e.g., 28 days [18]. In this study, we developed a dual-combination IVR system designed to prevent HIV infection by incorporating two distinct approaches.…”

Section: Introductionmentioning

confidence: 99%

Segmented intravaginal ring for the combination delivery of hydroxychloroquine and anti-CCR5 siRNA nanoparticles as a potential strategy for preventing HIV infection

Traoré

Chen

Padilla

et al. 2021

Drug Deliv. and Transl. Res.

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Vaginal drug delivery has been shown to be a promising strategy for the prevention of sexually transmitted infections. Therapy delivered at the site of infection has many advantages including improved therapeutic efficacy, reduction in systemic toxicity, and reduced potential for development of drug resistance. We developed a “smart” combination intravaginal ring (IVR) that will (1) provide continuous release of hydroxychloroquine (HCQ) to induce T cell immune quiescence as the first-line of defense and (2) release nanoparticles containing anti-CCR5 siRNA only during sexual intercourse when triggered by the presence of seminal fluid as the second-line of defense. The IVR was capable of releasing HCQ over 25 days with a mean daily release of 31.17 ± 3.06 µg/mL. In the presence of vaginal fluid simulant plus seminal fluid simulant, over 12 × more nanoparticles (5.12 ± 0.9 mg) were released over a 4-h period in comparison to IVR segments that were incubated in the presence of vaginal fluid simulant alone (0.42 ± 0.19 mg). Anti-CCR5 siRNA nanoparticles were able to knockdown 83 ± 5.1% of CCR5 gene expression in vitro in the CD4+ T cell line Sup-T1. The IVR system also demonstrated to be non-cytotoxic to VK2/E6E7 vaginal epithelial cells. Graphical abstract

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“…Since then, seven steroid-releasing contraceptive rings (Estring®, Femring®, NuvaRing®, Progering®, Fertiring®, Ornibel® and Annovera™) and various generic products have reached market ( Algorta et al, 2017 ; Archer et al, 2019 ), and a raft of new experimental drugs and devices are currently at various stages of preclinical and clinical development ( Vincent et al, 2018 ; Keller et al, 2019 ; Boyd et al, 2014 ; Verstraete et al, 2017 ; Fetherston et al, 2014 ; McBride et al, 2019 ; Zhao et al, 2017 ; Clark et al, 2014 ; Baum et al, 2015 ; Welsh et al, 2019 ; Brache et al, 2012 ; Weiss et al, 2019 ). Many of the advances in ring design and technology during the last twenty years have been driven by concerted global efforts to develop new antiretroviral-releasing ring products for preventing sexual transmission of HIV infection in women ( Vincent et al, 2018 ; Keller et al, 2019 ; Baum et al, 2015 ; Kiser et al, 2012 ; Woolfson et al, 2006 ; Malcolm et al, 2005 ; Baeten et al, 2020 ; Malcolm et al, 2016 ; Malcolm et al, 2014 ; van der Straten et al, 2016 ; Malcolm et al, 2010 ; Spence et al, 2015 ; Malcolm et al, 2012 ; Thurman et al, 2013 ). A matrix-type silicone elastomer vaginal ring providing sustained release of the antiretroviral drug dapivirine (DPV) – a potent non-nucleoside reverse transcriptase inhibitor – was developed by the International Partnership for Microbicides (IPM) to offer women a self-initiated, long-acting HIV prevention option ( Devlin et al, 2013 ; Nel et al, 2009 ; Nel et al, 2016a ; Baeten et al, 2016 ; McCoy et al, 2017 ; Nel et al, 2014 ; Chen et al, 2019 ; Bunge et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Use of simulated vaginal and menstrual fluids to model in vivo discolouration of silicone elastomer vaginal rings

McCoy

Spence

Bashi

et al. 2021

International Journal of Pharmaceutics: X

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Vaginal rings releasing antiretrovirals – either alone or in combination with contraceptive progestins – are being developed for prevention of human immunodeficiency virus (HIV) transmission via vaginal sex. Following Phase I trials, significant discolouration was observed on the surface of investigational silicone elastomer antiretroviral-contraceptive matrix-type vaginal rings containing either 25 mg dapivirine or 200 mg dapivirine plus levonorgestrel. In this study, potential causes of the discolouration have been assessed in vitro using simulated vaginal and menstrual fluids (SVF and SMF, respectively) to model in vivo exposure. The fluid compositions also included hydrogen peroxide (H 2 O 2 ), hydrogen peroxide plus a copper intrauterine device (IUD), or synthetic dyes (representing personal care and household cleaning products). No discolouration was observed for rings exposed to SVF + hydrogen peroxide (with or without an IUD). However, the SVF + dye compositions showed significant ring discolouration, with staining patterns similar to those observed with rings that had been exposed to highly-coloured personal care and household cleaning products during clinical trial use. Exposure of rings to SMF compositions invariably caused yellow surface discolouration, dark spotting and markings, similar to the staining patterns observed following clinical use. The darker marks on the ring surface were identified as blood debris derived from the SMF. The study indicates that surface discolouration of rings in vivo can be attributed to exposure to menstrual fluid or highly coloured personal care or household cleaning products. Discolouration of the rings was not associated with any specific safety risks for the user, though severe discolouration could potentially impact acceptability and adherence.

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Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women: a phase 1, single-blind, randomised, controlled trial

Cited by 38 publications

References 30 publications

Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection

Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection

Segmented intravaginal ring for the combination delivery of hydroxychloroquine and anti-CCR5 siRNA nanoparticles as a potential strategy for preventing HIV infection

Use of simulated vaginal and menstrual fluids to model in vivo discolouration of silicone elastomer vaginal rings

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