Prevention method preferences and factors influencing hypothetical choice among women in South Africa: a survey exploring opportunities for a multipurpose prevention technology implant.

Introduction: South African women bear an intersecting burden of HIV, sexually transmitted infections (STIs) and unintended pregnancy. Multipurpose prevention technologies (MPTs) are a class of products that address multiple needs and have the potential to improve uptake and use of prevention products. Methods: Analysing survey data from 703 HIV-negative women 18-40 years in three provinces in South Africa, collected between July and November 2022, this study explores their preferences for prevention methods and factors influencing choice of hypothetical prevention methods, including MPTs. Descriptive statistics and multinomial regression analyses were conducted to determine prevention method preferences and factors associated with choosing a pill, injectable or MPT-implant type prevention method. Results: Most women wanted to prevent HIV, STIs and pregnancy. The most important factors when choosing a prevention product were whether it provided dual and long-term protection and if side effects were manageable. If choosing only one method, half of women would choose any MPT-implant and a quarter each would choose a pill or an injectable method, with method choices differing by population group. Discussion: Prevention method choices were influenced by sexual-behavioural factors and current and prior contraceptive method use. Providing a choice of prevention methods and a population specific approach to new method development and introduction with access to accurate information could enhance their ability to fill a gap in prevention needs.

Perception of couples' on multipurpose prevention technology attribute choice: the case of MTN 045.

BACKGROUND: Multipurpose prevention technologies (MPTs) are products capable of simultaneously addressing multiple sexual and reproductive health needs such as unwanted pregnancy, STIs including HIV-1, and other reproductive tract infections. MPTs are urgently needed to address the double burden of unplanned pregnancy and HIV. While condoms are currently the only accessible MPTs, they are not solely under a woman's control, and female condoms face limitations due to poor acceptability and high cost. METHODS: We conducted a sub-analysis of qualitative data from 39 couples participating in the MTN 045 study to examine the perception of couples on choice and acceptability of a "2 in 1" MPT that combines HIV and pregnancy prevention. RESULTS: Couples recognized the benefits of MPTs for HIV and pregnancy prevention but perceptions tied to each indication and a novel prevention technology tool raised important concerns relevant to use of future MPTs. In the study, participants' perceptions of MPT use were influenced by pregnancy planning. When the timing was less critical, they prioritized HIV prevention. Misinformation about family planning methods, including MPTs, affected decision-making with potential to hinder uptake of future MPTs. Concerns about side effects, such as weight gain and hormonal imbalances, influenced willingness to use MPTs. CONCLUSION: Addressing the myths and misconceptions surrounding the use of contraceptives is crucial in promoting their acceptance and ultimate use. Strategies for addressing the drawbacks women might experience while using a particular product should be in place as new MPTs progress through the development pipeline and approach roll-out.

Two into one does go: Formulation development of a multipurpose combination vaginal ring releasing dapivirine and metronidazole for prevention of HIV infection and treatment of bacterial vaginosis.

Bacterial vaginosis (BV) is a common but often asymptomatic dysbiosis of the human vagina characterized by an imbalance in the normal vaginal microbiota due to loss of lactobacilli and an overgrowth of certain anaerobic bacteria. While BV itself is not a sexually transmitted infection, it is associated with an increased risk in women of various sexually acquired infections, including human immunodeficiency virus (HIV) infection. There is, therefore, a strong rationale for pursuing new multipurpose products that seek to treat or prevent BV alongside preventing HIV infection. With the dapivirine-releasing vaginal ring for HIV prevention now approved in several African countries, here we report formulation development of a next-generation ring product that releases both dapivirine (DPV) and the antibiotic drug metronidazole (MET). Following thermal analysis studies to characterize the phase behaviour of DPV-MET mixtures and rheological analysis to assess the cure characteristics of the active silicone elastomer mixes, matrix-type rings were manufactured containing 25 or 200 mg DPV in combination with 100, 250, 500, 1000 or 2000 mg MET. The results for drug content, in vitro release, mechanical testing, and Gardnerella vaginalis time-kill experiments demonstrate the feasibility of incorporating both DPV and MET in a matrix-type ring formulation and indicate that clinically effective release rates may be possible.

Preferences, educational messaging, and demand creation channels for multipurpose-prevention technologies (MPTs) among women in South Africa.

BACKGROUND: South African women, including female sex workers (FSWs), are disproportionately affected by HIV, experience a high unmet need for contraception and high rates of sexually transmitted infections (STIs). Products that address the interlinked risk between HIV, unplanned pregnancy, and other STIs are needed. There are several multipurpose-prevention technologies (MPTs) in development, aimed at preventing both HIV and pregnancy. This study aimed to explore educational messaging and demand creation channels to improve the potential uptake of a hypothetical MPT implant, using participatory action research. It also aimed to look at product and service provision attributes preferred by potential end users. METHODS: Between July and August 2022, 303 PrEP-eligible adolescent girls and young women (AGYW) (18-24 years), women > 24 years, and FSW's (≥ 18 years) participated in 4-hour workshops, where they were asked about their ideal messaging and demand creation channels and their preferences for different attributes of an MPT implant. Quantitative descriptive analysis was conducted to determine the frequency and ranking for each demand creation message, channel, and each product and service provision attribute, by population group. A chi-square test was used to assess MPT implant characteristics associated with age. Qualitative data were analysed using deductive and thematic analysis. RESULTS: A total of 104 AGYW, 157 women > 24 years, and 42 FSWs participated in the PAR workshops. Participants preferred demand creation messages that were empowering, motivational and encouraged body autonomy. The use of slang was popular. Community radio stations and newspapers, social media, and information at hospitals and clinics were participants' preferred MPT demand creation channels because they were easily accessible. Providing long-term and dual HIV and pregnancy protection, receiving implant services at the local clinic, manageable side effects, discreet and private implant, and numbing the area before insertion and removal, were the most preferred product and service provision attributes. CONCLUSION: Early considerations for women's product preferences are key to product development. Educational messaging around the MPT implant should be empowering and in local languages, this may motivate women to learn more about it and use it. Multiple demand creation channels should be used to engage both young and older populations, which may ensure better reach.

pH-triggered polymeric nanoparticles in gel for preventing vaginal transmission of HIV and unintended pregnancy.

Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/ AIDS) and unplanned pregnancy affect female reproductive health globally. A single product providing a dual purpose of HIV prophylaxis and contraception may improve adherence to the therapy. Thus, we formulated a female-centric multipurpose prevention technology (MPT) comprising of nanoparticle loaded vaginal gel formulation acting as a contraceptive and microbicide. Eudragit® S100 nanoparticles of Atazanavir sulphate (ATZ; antiviral) and Fluoxetine hydrochloride (FLX; repurposed spermicide) were prepared for pH dependent drug release and loaded in carrageenan and HPMC K200M gel. The particle size of ATZ and FLX nanoparticles was 396.7 ± 20.64 nm and 226.5 ± 2.08 nm respectively. The in vitro release of the gel formulation in simulated seminal fluid (pH 7.6) showed 96.16% and 95.98% release of ATZ and FLX respectively at the end of 8 h. The in vitro anti-HIV and spermicidal activity of the formulation was above 80% for low drug concentrations. In vivo studies on murine model showed no signs of inflammation or vaginal epithelial injury. Curcumin based imaging confirmed the retention of the formulation in the reproductive tract of mice with minimal leakage. Nanoparticles in gel enabled non-invasive and localised delivery with minimal side effects and can be an effective prophylactic therapy.

Biomedical, socio-behavioral, and implementation science gaps in multipurpose prevention technology research.

There is strong global need for the development of Multipurpose Prevention Technologies (MPTs) that prevent HIV, pregnancy, and/or other sexually transmitted infections (STIs). However, despite decades of research focused on the development of MPTs, numerous research gaps remain, contributing to reproductive health disparities. This commentary will highlight biomedical, socio-behavioral, and implementation science gaps in MPT research. Biomedical gaps and barriers include limited dosage forms, challenges around drug selection and stable coformulation of multiple drugs, and an unclear regulatory pathway. Behavioral, social, and structural gaps include lack of research around MPT preferences for some subgroups of potential end users, lack of knowledge around whether MPTs improve uptake, adherence, and persistence vs. separate products, and a need to further understand how social and cultural factors might impact MPT interest and use. Gaps in implementation science research will need to be addressed to better understand how to implement MPTs to maximize effectiveness and benefit. This commentary will also identify opportunities for integrating biomedical and behavioral science around MPTs.

A Brief History and Advancement of Contraceptive Multipurpose Prevention Technology (cMPT) Products.

The high incidence of HIV and other sexually transmitted infections (STIs), and an unmet need for modern contraception resulting in a high unintended pregnancy rate, are major problems in reproductive health. The concept of multipurpose prevention technology (MPT) was introduced following the failure of several leading microbicide candidates to prevent human immunodeficiency virus type 1 (HIV-1) transmission in large clinical trials in the early 2000s. MPTs are defined as products designed to simultaneously prevent at least two of the following conditions: unintended pregnancy, HIV-1, or other major STIs. The goal of contraceptive MPT products (cMPTs) is to provide contraception and protection against one or more major STI pathogen (eg, HIV-1, herpes simplex virus (HSV) type 2, Neisseria gonorrhoeae (gonorrhea), Treponema pallidum (syphilis), Trichomonas vaginalis, Chlamydia trachomatis (Chlamydia). This new field has great potential and will benefit from lessons learned from the early microbicide trials. The cMPT field includes candidates representing various categories with different mechanisms of action including pH modifiers, polyions, microbicidal peptides, monoclonal antibodies, and other peptides that target specific reproductive and infectious processes. More preclinical research is being conducted to ensure minimal side effects and maximum efficacy in vivo. Effective proven and novel candidates are being combined to maximize efficacy, minimize side effects, and avoid drug resistance. More attention is being paid to acceptability and new delivery systems. cMPTs have a very promising future if adequate resources can be mobilized to sustain the effort from preclinical research to clinical trials to bring effective, acceptable, and affordable products to market.

Safety of multiple administrations of spermicidal LL-37 antimicrobial peptide into the mouse female reproductive tract.

We have previously demonstrated spermicidal activity of LL-37 antimicrobial peptide on mouse/human sperm and its contraceptive effects in female mice. With its microbicidal action against Neisseria gonorrhoeae, LL-37 warrants development into a multipurpose prevention technology (MPT) agent for administering into the female reproductive tract (FRT). However, it is important to verify that multiple administrations of LL-37 do not lead to damage of FRT tissues and/or irreversible loss of fecundity. Herein, we transcervically injected LL-37 (36 µM-10× spermicidal dose) into female mice in estrus in three consecutive estrous cycles. A set of mice were sacrificed for histological assessment of the vagina/cervix/uterus 24 h after the last injection, while the second set were artificially inseminated with sperm from fertile males 1 week afterwards, and then monitored for pregnancy. Mice injected with PBS in parallel were regarded as negative controls, whereas those injected with vaginal contraceptive foam (VCF, available over the counter), containing 12.5% nonoxynol-9, served as positive controls for vaginal epithelium disruption. We demonstrated that the vagina/cervix/uterus remained normal in both LL-37-injected and PBS-injected mice, which also showed 100% resumption of fecundity. In contrast, VCF-injected mice showed histological abnormalities in the vagina/cervix/uterus and only 50% of them resumed fecundity. Similarly, LL-37 multiply administered intravaginally caused no damage to FRT tissues. While our results indicate the safety of multiple treatments of LL-37 in the mouse model, similar studies have to be conducted in non-human primates and then humans. Regardless, our study provides an experimental model for studying in vivo safety of other vaginal MPT/spermicide candidates.

Innovations in monoclonal antibody-based multipurpose prevention technology (MPT) for the prevention of sexually transmitted infections and unintended pregnancy.

Monoclonal antibodies (mAbs) are currently being produced for a number of clinical applications including contraception and the prevention of sexually transmitted infections (STIs). Combinations of contraceptive and anti-STI mAbs, including antibodies against HIV-1 and HSV-2, provide a powerful and flexible approach for highly potent and specific multipurpose prevention technology (MPT) products with desirable efficacy, safety and pharmacokinetic profiles. MAbs can be administered systemically by injection, or mucosally via topical products (e.g., films, gels, rings) which can be tailored for vaginal, penile or rectal administration to address the needs of different populations. The MPT field has faced challenges with safety, efficacy, production and cost. Here, we review the state-of-the-art of mAb MPTs that tackle these challenges with innovative strategies in mAb engineering, manufacturing, and delivery that could usher in a new generation of safe, efficacious, cost-effective, and scalable mAb MPTs.

17BIPHE2, an engineered cathelicidin antimicrobial peptide with low susceptibility to proteases, is an effective spermicide and microbicide against Neisseria gonorrhoeae.

STUDY QUESTION: Is 17BIPHE2, an engineered cathelicidin antimicrobial peptide with low susceptibility to proteases, a better spermicide in cervicovaginal fluid (CVF) than its parental peptides, LL-37 and GF-17? SUMMARY ANSWER: At the same mass concentration, 17BIPHE2 exhibited the highest spermicidal activity on human sperm resuspended in CVF-containing medium. WHAT IS KNOWN ALREADY: LL-37 and its truncated peptide GF-17 exert both spermicidal and microbicidal activities, although they are prone to proteolytic degradation in body fluids. STUDY DESIGN, SIZE, DURATION: Spermicidal activities of 17BIPHE2 were evaluated in vitro in mouse and human sperm, both resuspended in medium, and then on human sperm incubated in CVF-containing medium; in the latter condition, the spermicidal activity and peptide stability in CVF of 17BIPHE2 were compared with that of LL-37 and GF-17. The in vivo contraceptive effects of 17BIPHE2 and the reversibility thereof were then assessed in mice. Finally, in vitro microbicidal effects of 17BIPHE2 on Neisseria gonorrhoeae were determined. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm motility and plasma membrane integrity were assessed by videomicroscopy and exclusion of Sytox Green, a membrane-impermeable fluorescent dye, respectively. Successful in vitro fertilization (IVF) was determined by the presence of two pronuclei in oocytes following their coincubation with capacitated untreated or 17BIPHE2-treated sperm. Sperm alone or with 17BIPHE2 were transcervically injected into female mice and successful in vivo fertilization was indicated by the formation of two-cell embryos 42-h postinjection, and by pregnancy through pup delivery 21-25 days afterwards. Peptide intactness was assessed by immunoblotting and HPLC. Reversibility of the contraceptive effects of 17BIPHE2 was evaluated by resumption of pregnancy of the female mice, pretranscervically injected with 17BIPHE2, following natural mating with fertile males. Minimum inhibitory/bactericidal concentrations of 17BIPHE2 on N. gonorrhoeae were obtained through microdilution broth assay. MAIN RESULTS AND THE ROLE OF CHANCE: At the same mass concentration, 17BIPHE2 was a more effective spermicide than LL-37 or GF-17 on human sperm resuspended in CVF-containing medium, with the spermicidal concentration of 32.4 µM. This was mainly due to lower susceptibility of 17BIPHE2 to CVF proteases. Importantly, the reproductive tract of mouse females treated three times with 32.4 µM 17BIPHE2 remained normal and their fecundity resumed after stopping 17BIPHE2 treatment. LIMITATIONS, REASONS FOR CAUTION: For ethical reasons, the inhibitory effects of 17BIPHE2 on fertilization and pregnancy cannot presently be performed in women. Also, while our study has proven the effectiveness of 17BIPHE2 as a spermicide for mouse and human sperm in vitro, dosage formulation (e.g. in hydrogel) of 17BIPHE2 still needs to be developed to allow 17BIPHE2 to remain in the vagina/uterine cavity with controlled release for its spermicidal action. WIDER IMPLICATIONS OF THE FINDINGS: Since 17BIPHE2 also exerted bactericidal activity against N. gonorrhoeae at its spermicidal concentration, it is a promising candidate to be developed into a vaginal multipurpose prevention technology agent, thus empowering women against unplanned pregnancies and sexually transmitted infections. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Canadian Institutes of Health Research (PJT 173268 to N.T.). There are no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Couples' Preferences for "2 in 1" Multipurpose Prevention Technologies to Prevent Both HIV and Pregnancy: Results of a Discrete Choice Experiment in Uganda and Zimbabwe.

End-user input early in biomedical product development may optimize design to support high uptake and adherence. We interviewed 400 couples (800 total participants) in Uganda and Zimbabwe to assess their preferences for multipurpose prevention technologies (MPTs) for HIV and pregnancy prevention. Using a discrete choice experiment, couples made a series of choices between hypothetical MPTs, including oral tablets and vaginal rings, inserts, and films and completed an interviewer-administered questionnaire assessing sociodemographic and behavioral measures. Most couples preferred presented MPTs over male condoms. Couples' MPT choices in both countries were influenced most by the combination of product form and dosing frequency, with monthly dosing preferred over daily. Analysis highlighted differences by country as to which side effects were most important: Ugandan couples placed greater importance on effects on the vaginal environment during sex, whereas Zimbabwean couples placed more importance on changes to menstruation and other side effects (headache, cramps). Couples' preferences signaled an openness to new product forms and more frequent dosing if preferred characteristics of other attributes were achieved.

Acceptability of a Long-Acting, Multipurpose Vaginal Ring: Findings from a Phase I Trial in the U.S. and Dominican Republic.

Background: Women worldwide face risks from pregnancy, HIV, and other sexually transmitted infections (STIs). To date, highly effective contraceptive methods provide no HIV/STI protection, and HIV prevention products, excluding condoms, provide no pregnancy protection. Intravaginal rings (IVRs) delivering antiretrovirals and contraceptives are a promising multipurpose prevention technology (MPT). Methods: Embedded within a Phase I randomized, placebo-controlled trial, we examined acceptability of continuous versus interrupted use of a 90-day MPT IVR among 47 low-risk women in Norfolk, Virginia and the Dominican Republic. A baseline survey assessed menstruation attitudes, risk perceptions and trial-related motivations. Follow-up surveys (M1/M3) examined user experiences with and preferences for IVR attributes; 18 women also participated in two in-depth interviews. Results: Most women rated the IVR's flexibility and smoothness (86%) and ease of insertion/removal (76%) as very acceptable. Fewer women similarly rated the IVR size (57%) and changes in color from menstruation (52%). Most participants experienced no changes or less bleeding. Those reporting more/heavier bleeding (20% M1, 15% M3) disliked the change. Overall, women preferred a 3-month (75%) to a 1-month IVR (7.5%) or a bimonthly injectable (10%). In qualitative interviews, women were willing to continuously use an IVR for 6-12 months, providing it did not "degrade" inside the body. Reasons for trial participation and prevention preferences, menstrual attitudes, and perceived IVR benefits and doubts varied by site. Conclusions: Findings provide strong evidence of demand for an MPT IVR that protects from pregnancy and HIV/STIs, lasts longer than 1 month, minimally disrupts menstrual bleeding, and is in women's control. numberClinicalTrials.gov: #NCT03279120.

Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring.

Background: A relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported. Objective: CONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK. Methods: The study screened 68 participants and randomized 47 (37 TFV/LNG, 10 placebo), assessing the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and monthly for 3 months. Concentrations of TFV in vaginal fluid (VF), and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue, and modeled PD against HIV-1 in vitro were measured before and after treatment. Results: There were no clinically significant changes in relative abundance of vaginal bacterial phylotypes from pre-insertion baseline at any month among active and placebo IVR users. There were no significant changes in community state type (CST) with IVR use. Participants with diverse, anaerobic CST IVA/B microbiota had higher in vivo release of TFV from the IVR compared to women with Lactobacillus-dominated (LbD) microbiota, who had expected in vivo TFV release rates. Median VF TFV concentrations were significantly higher among women with CST IVA/B microbiota in months 1 (3,135 ng/mg VF) and 2 (3,800 ng/mg). Women with LbD microbiota had significantly higher median VF TFV concentration (1,423 ng/mg) and median TFV (103 ng/mg) and TFV-DP (5,877 fmol/mg) tissue concentrations versus women with CST IVA/B microbiota at month 3. All women demonstrated a significant increase from pre-insertion baseline of in vitro HIV-1 inhibition by VF (p values <0.05). PD differences in tissue according to CST, however, were not statistically significant. Conclusion: TFV/LNG IVR use did not change the vaginal microbiota nor increase the incidence of CST IVA/B. Vaginal microbiota, and in particular CST IVA/B, possibly through increased vaginal pH, impacted in vivo TFV release and cervicovaginal (CV) PK, but both PK and PD data suggest CV protection against HIV-1. Clinical Trial Registration: ClinicalTrials.gov (#NCT03279120).

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

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.

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

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 (H2O2), 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.

Silicone elastomer formulations for improved performance of a multipurpose vaginal ring releasing dapivirine and levonorgestrel.

A dapivirine-releasing silicone elastomer vaginal ring for reducing women's risk of HIV acquisition has recently been approved. A next-generation multipurpose vaginal ring releasing dapivirine and levonorgestrel is currently in development, offering hormonal contraception and HIV prevention from a single device. Previously, we reported challenges with incorporating levonorgestrel into rings manufactured from addition-cure silicone elastomers due to an irreversible chemical reaction between the levonorgestrel molecule and the hydride-functionalised crosslinker component of the silicone elastomer formulation, leading to low drug content assay, cure inhibition, and reduced ring mechanical properties (which may account for the increased incidence of ring expulsion in vivo). Here, we report on the development and testing of various custom silicone elastomer materials specifically formulated to circumvent these issues. After extensive testing of the custom silicones and subsequent manufacture and testing (Shore M hardness, pot life, content assay, oscillatory rheology, mechanical testing) of rings containing both dapivirine and levonorgestrel, a lead candidate formulation was selected that was amenable to practical ring manufacture via injection molding, exhibited no substantial levonorgestrel binding, and offered suitable mechanical properties.

Engineering monoclonal antibody-based contraception and multipurpose prevention technologies†.

Sexually transmitted infections are highly prevalent, and over 40% of pregnancies are unplanned. We are producing new antibody-based multipurpose prevention technology products to address these problems and fill an unmet need in female reproductive health. We used a Nicotiana platform to manufacture monoclonal antibodies against two prevalent sexually transmitted pathogens, HIV-1 and HSV-2, and incorporated them into a vaginal film (MB66) for preclinical and Phase 1 clinical testing. These tests are now complete and indicate that MB66 is effective and safe in women. We are now developing an antisperm monoclonal antibody to add contraceptive efficacy to this product. The antisperm antibody, H6-3C4, originally isolated by Shinzo Isojima from the blood of an infertile woman, recognizes a carbohydrate epitope on CD52g, a glycosylphosphatidylinositol-anchored glycoprotein found in abundance on the surface of human sperm. We engineered the antibody for production in Nicotiana; the new antibody which we call "human contraception antibody," effectively agglutinates sperm at concentrations >10 µg/ml and maintains activity under a variety of physiological conditions. We are currently seeking regulatory approval for a Phase 1 clinical trial, which will include safety and "proof of principle" efficacy endpoints. Concurrently, we are working with new antibody production platforms to bring the costs down, innovative antibody designs that may produce more effective second-generation antibodies, and delivery systems to provide extended protection.

Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers.

With a dapivirine-releasing vaginal ring having successfully completed late-stage clinical testing for HIV prevention and currently undergoing regulatory review, there is now growing interest in next-generation multipurpose prevention technologies that seek to combine antiretroviral and contraceptive drugs within a single product. Here, we focus on ongoing efforts to develop a silicone elastomer vaginal ring releasing both dapivirine and levonorgestrel. Specifically, we evaluate various strategies aimed at both better understanding and reducing the tendency of levonorgestrel to bind with the elastomer, including: (i) formulation and post-manufacturing strategies aimed at reducing the extent of levonorgestrel reaction with addition-cure silicone elastomers; (ii) evaluation of a simple silicone system to model the complex elastomer; (iii) use of model compounds representing the enone and ethinyl moieties of levonorgestrel to probe the mode of addition of levonorgestrel to addition-cure silicone elastomers; and (iv) solution and solid-state 13C NMR analysis to probe the structural features of the levonorgestrel-silicone system. The results demonstrate that both the enone and ethinyl groups within levonorgestrel undergo hydrosilylation reactions with the hydrosiloxane groups in the silicone elastomer leading to covalent binding. The results also highlight potential strategies for further optimising the dapivirine + levonorgestrel silicone vaginal ring formulation to ensure that the levonorgestrel is available for release.

Preferred Product Attributes of Potential Multipurpose Prevention Technologies for Unintended Pregnancy and Sexually Transmitted Infections or HIV Among U.S. Women.

Background: Multipurpose prevention technologies (MPTs) are being developed to simultaneously protect women from unintended pregnancy and sexually transmitted infections (STIs) or human immunodeficiency virus. This study aims to determine MPT characteristics desired by young women in the United States (U.S.). Materials and Methods: This is a cross-sectional national survey administered online by MTurk. Eligibility criteria included female sex, age 18-29 years, U.S. residence, and sexual activity with a male partner in the past 3 months. MPT characteristics were rated for importance. Odds ratios were generated to explore associations between demographics, sexual behaviors, and prior contraceptive use and likelihood of using various MPT formulations. Results: Of 835 women, the largest proportion reported being likely to use MPTs in the form of injectables (45.6%), followed by vaginal gels (33.7%), vaginal rings (26.3%) and diaphragms (17.3%). Women with prior experience using a specific method of contraception appeared more likely to try an MPT of the same form. Women concerned about STIs and unwanted pregnancy, or with a history of such undesirable outcomes, expressed higher likelihood of use for a broad range of products. Women indicated that safety and efficacy at preventing pregnancy were the most important product characteristics when choosing an MPT. Conclusions: MPTs in the form of injectables are most highly desired, but many women would use vaginal methods, highlighting the importance of developing different delivery methods. Women desire safety and emphasize contraceptive efficacy over infection prevention. MPT preferences must be considered during product development to promote future acceptance among young women in the U.S.