An intravaginal ring that releases three antiviral agents and a contraceptive blocks SHIV-RT infection, reduces HSV-2 shedding, and suppresses hormonal cycling in rhesus macaques

Abstract

Women globally need access to multipurpose prevention technologies (MPTs) that prevent human immunodeficiency virus (HIV), sexually transmitted infections that increase HIV acquisition/transmission risk, and unintended pregnancy. Seeking an MPT with activity against HIV, herpes simplex virus-2 (HSV-2), and human papillomavirus (HPV), we developed a prototype intravaginal ring (IVR), the MZCL IVR, which released the antiviral agents MIV-150, zinc acetate, and carrageenan (MZC for short) and the contraceptive levonorgestrel (LNG). Previously, we showed that an MZC gel has potent activity against immunodeficiency viruses, HSV-2, and HPV and that the MZCL (MZC with LNG) IVR releases all four components in macaques in vivo at levels associated with efficacy. Vaginal fluid from treated macaques has in vitro activity against HIV, HSV-2, and HPV. Herein, we assessed the ability of the MZCL IVR to protect macaques against repeated co-challenge with HSV-2 and SHIV-RT (simian immunodeficiency virus [SIV] containing the reverse transcriptase gene from HIV) and prevent hormonal cycling. We evaluated in vivo drug release in co-challenged macaques by measuring drug levels in blood and vaginal fluid and residual drug levels in used IVRs. The MZCL IVR significantly prevented SHIV-RT infection, reduced HSV-2 vaginal shedding, and prevented cycling. No non-nucleoside HIV reverse transcriptase inhibitor (NNRTI)-resistant SHIV was detected in macaques that became infected after continuous exposure to MZC from the IVR. Macaques wearing the MZCL IVR also had carrageenan levels in vaginal fluid expected to protect from HPV (extrapolated from mice) and LNG levels in blood associated with contraceptive efficacy. The MZCL IVR is a promising MPT candidate that warrants further development.

Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo

“…We evaluated activity in single virus models (SHIV, HSV, HPV alone) while exposure scenarios are likely to involve multiple viruses. Mixed inoculum studies in explant models and in vivo, such as those we have used to evaluate ARV-based microbicides 47 – 49 , will be essential to inform clinical progression of candidates that target multiple pathogens.…”

Drug delivery in female reproductive health

“…The former describes research on a MPT product that can potentially release three antiviral agents and a contraceptive [7]. The latter article reports on the anti-HIV activity of MIV-150, a non-nucleoside reverse transcriptase inhibitor and zinc acetate [8].…”

Intravaginal rings for continuous low-dose administration of cervical ripening agents

“…Since 2002, great progress has been made in the design and development of various antiretroviral-releasing VRs for reducing HIV acquisition (Kiser et al, 2012;Malcolm et al, 2015Malcolm et al, , 2010Thurman et al, 2013), with a dapivirine-releasing silicone elastomer ring having recently completed late-stage clinical testing and currently under regulatory review by the European Medicines Agency (Baeten et al, 2016;Devlin et al, 2013;Nel et al, 2016b). A major impetus for continued innovation in VR design has been the growing interest in combination HIV microbicide and multipurpose prevention technology products for which release needs to be individually tailored for each drug molecule (Baum et al, 2012;Derby et al, 2017;Fetherston et al, 2013;Friend et al, 2013;Malcolm et al, 2015Malcolm et al, , 2014Moss et al, 2016;Murphy et al, 2014;Smith et al, 2017;Shweta R. Ugaonkar et al, 2015;Shweta R Ugaonkar et al, 2015). However, other clinical indications within women's health are also likely to benefit from enhanced drug administration using existing or new VR technologies.…”