Vaginal Ring Research Articles

Next-generation 3D printed multipurpose prevention intravaginal ring for prevention of HIV, HSV-2, and unintended pregnancy

Globally, nearly half of all pregnancies are unintended, ~1.3 million new human immunodeficiency virus (HIV) infections are reported every year, and more than 500 million people are estimated to have a genital herpes simplex virus (HSV-2) infection. Here we report the first 3D printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for prevention of HIV, HSV-2, and unintended pregnancy. The IVRs were fabricated using state-of-the-art Continuous Liquid Interface Production (CLIP™) 3D printing technology using a biocompatible silicone-urethane based resin. Anti-HIV drug (Dapivirine, DPV), anti-herpes drug (Pritelivir, PTV) and a contraceptive drug (Levonorgestrel, LNG) were loaded in a macaque size IVR (25 mm outer diameter, OD; 6.0 mm cross-section, CS) allometrically scaled from the human size (54 mm OD; 7.6 mm CS) IVR analogue. All three active pharmaceutical ingredients (APIs) were loaded in the IVR using a single-step drug loading process driven by absorption. DPV, PTV, and LNG elicited zero-order release kinetics in vitro in simulated vaginal fluid (SVF) at pH 4 and pH 8 relevant to human and macaque vaginal pH respectively. CLIP 3D printed MPT IVRs remained stable after 6 months of storage at 4 °C with no change in physical, dimensional, or mechanical properties and no change in drug concentration and absence of drug degradation byproducts. The MPT IVRs elicited sustained release of all three APIs in macaques for 28 days with median plasma concentrations of 138 pg/mL (DPV), 18,700 pg/mL (PTV), and 335 pg/mL (LNG). Safety studies demonstrated that the MPT IVRs were safe and well tolerated in the macaques with no observed change or abnormalities in vaginal pH and no significant changes in any of the 22 mucosal cytokines and chemokines tested including pro-inflammatory (IL-1β, IL-6, IL-8, IFN-γ, TNF-α, IL-17, IL-18) and anti-inflammatory (IL-10, IL-12) cytokines while the MPT IVR was in place or after its removal. Additionally, MPT IVRs elicited no observed alterations in systemic CD4+ and CD8+ T cells during the entire study. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls against unintended pregnancy against two highly prevalent sexually transmitted infections (STIs).

Use of an Ethinyl Estradiol/Etonogestrel Vaginal Ring Alters Vaginal Microbial Communities in Women with HIV.

HIV-1 antiretroviral therapy (ART) alters hormonal contraceptive levels delivered via intravaginal ring (IVR) in a regimen specific manner. We explored the role of the IVR on vaginal microbial communities, vaginal short chain fatty acids (SCFAs), vaginal HIV shedding, and the effect of vaginal microbes on hormone concentrations in cisgender women with HIV (WWH). Vaginal microbes were assessed by 16S RNA sequencing of weekly vaginal swabs, vaginal SCFA by mass spectrometry, HIV-1 shedding by nucleic acid amplification on vaginal aspirates, and bacterial vaginosis by Nugent scoring from 74 participants receiving an etonorgestrel/ethinyl estradiol (ENG/EE) intravaginal ring while on no ART (N=25), efavirenz-based ART (N=25), or atazanavir-based ART (N=24). At baseline, microbial communities of the 64 substudy eligible participants robustly classified as Lactobacillus crispatus--dominant (n=8), L. gasseri-dominant (n=2), L. iners-dominant (n=17), or mixed anaerobic communities (n=37). During IVR therapy, there was an increased probability of Lactobacillus-dominant community state types (CSTs) (odds-ratio=1.61, p=0.04). Vaginal CSTs were associated with Nugent scores. Bacterial vaginosis-associated bacteria were associated with significantly higher and L. iners with lower Nugent Scores (all p adj <0.1). Lactic acid levels were correlated with the relative abundance of Lactobacillus species (r2=0.574; p<0.001). Vaginal shedding of HIV-1 was less common in women with L. crispatus-dominant microbiomes (p=0.04). Mixed anaerobic vaginal communities modulated EE concentrations in a regimen-specific manner. Combined ENG/EE IVR therapy was associated with an increase in Lactobacillus-dominant vaginal microbial communities in WWH and may benefit those with bacterial vaginosis. EE levels were altered by the vaginal microbiota.

HIV Prevention Product Acceptability and Preference Among Women in Sub-Saharan Africa to Inform Novel Biomedical Options in Development: A Systematic Review.

The availability of several HIV prevention options may allow women to choose a product that suits their lifestyle and preferences. Product attributes and contextual factors influence product acceptability, which affects uptake and effective use. We conducted a systematic review of acceptability and preference for biomedical HIV prevention products among women in sub-Saharan Africa (SSA) to inform the development of novel products. We used a comprehensive strategy to search three databases for peer-reviewed literature from SSA published between January 2015 and December 2023. A two-stage review process assessed references against eligibility criteria. Data were abstracted using a standardized spreadsheet, then organized by constructs from two theoretical frameworks of acceptability. Results were synthesized based on product classes defined by route of administration. We identified 408 unique references; 100 references met eligibility criteria. References assessed oral PrEP (n = 65), vaginal ring (n = 44), long-acting systemic products (injectable, implant, microarray patch) (n = 28), and other vaginal products (film, insert, gel) (n = 20). Over two-thirds reported qualitative or mixed-methods data, primarily from adolescent girls and young women. Frequent dosing, especially noted for daily oral PrEP, and perceived/experienced side effects were notably negative influences. Most end-users preferred long-acting products (systemically or vaginally delivered), though on-demand products offering user control were also valued. Influencing factors, especially partners, shaped end-user perceptions of product attributes and acceptability. All products were linked to at least some barriers to uptake and/or use, highlighting the need to provide end-users with a range of options and assist them in identifying one that best suits their circumstances and needs. Biomedical HIV prevention development should advance products that address gaps in available options while optimizing favorable product attributes to achieve high acceptability that ultimately supports adoption and use.

A Review and Economic Analysis of the Dapivirine Vaginal Ring as HIV Pre-Exposure Prophylaxis for Women, to Inform South African Public-Sector Guidelines.

South Africa has a high HIV incidence and oral pre-exposure prophylaxis (PrEP) is available as public-sector standard of care. Access to alternative prevention methods for women may further reduce HIV acquisition. South African public sector. We performed a systematic search for high-quality up-to-date guidelines recommending dapivirine rings as PrEP using the Grading of Recommendations Assessment, Development, and Evaluation -Adolopment process. We appraised the systematic review and randomized controlled trial (RCT) evidence underpinning the selected guideline's recommendations and conducted a cost-effectiveness analysis. The Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework guided the adaptation of source guideline recommendations, according to our local context. We identified the 2021 World Health Organization PrEP Guidelines, informed by 2 placebo-controlled RCTs, which were included in a contemporaneous systematic review. There were 23 fewer HIV acquisitions per 1000 clients with dapivirine ring vs placebo (95% confidence interval: 10 to 34), with no increase in adverse events (moderate certainty evidence). We found no RCTs comparing dapivirine to oral PrEP or among adolescent/pregnant/breastfeeding clients. Dapivirine is less cost-effective than oral PrEP at $14.59/ring, at the current price. The source guideline recommendation was adapted for the local context. Dapivirine ring seems to be less efficacious than oral PrEP, although comparative studies are lacking. Data on adolescents and pregnancy are also lacking, currently limiting the use of dapivirine as an alternative for women unable to take oral PrEP. At the current price, dapivirine is not cost-effective and unaffordable for inclusion in the South African Essential Medicines List.

A REVIEW STUDY ON ROLE OF CONTRACEPTIVES AND THEIR VARIOUS TYPES.

Contraception is the process used to stop unwanted pregnancy and control birth rate. Contraceptives reduces the chances of pregnancy after sexual intercourse. Contraceptives prevent pregnancies by interfering with the procedure of fertilization. Contraceptives reduces the chances of abortion by preventing unintended pregnancies on their partners, in which 842 million (44%) are modern using modern methods of Contraceptives are accessible in huge varieties and types . Numerous contraceptives are available, 790 million (42%) are traditional method users according the statistical data of 2019. The most common contraceptive techniques that are use of contraceptives are increasing day by day, 922 million of women of reproductive age used worldwide are female sterilization and male condoms, female sterilization are used in 219 million users (24%), male condoms are used in 189 million users (21%) according the data of 2019. The use of traditional methods and IUDs has reduced worldwide since 1994. According to WHO, The only form of birth control is a condom,that can prevent both unintended pregnancies and sexually transmitted diseases. The need of family planning is increased globally up to 77% from 2015 to 2020.. Over the past 20 years, the number of women using family planning methods has grown, rising from 900 million in 2020 to 2000 million. Use of modern contraceptive methods is also increased from 663 million to 851 million with the prevalence rate of 47.7% to 49.0%. Numerous contraceptive methods exist, including hormonal methods like CHC vaginal ring, CHC transdermal patch, and combination hormonal contraceptives. Progestin-only techniques include hormonal male contraceptives, progestin-only pills, DMPA injections, implants, and progestin-only IUDs. The other approach is non-hormonal and consists of vaginal pH modulators, barrier techniques like condoms, and copper IUDs. Traditional methods, such as the LAM method, the fertile cycle method, and the withdrawal approach, comprise the third type of contraception. Herbal contraceptives, which use a variety of herbs and plant preparations, are the fourth technique of birth control.

Adolescent Girls and Young Women Overcoming Adherence Challenges with Vaginal and Oral PrEP Use: A Longitudinal Qualitative Study from a Crossover Trial in South Africa, Uganda, and Zimbabwe.

Rates of HIV acquisition remain high among adolescent girls and young women (AGYW) in sub-Saharan Africa. We explored South African, Ugandan, and Zimbabwean AGYW's experiences in a crossover trial of two HIV prevention products: Daily oral pre-exposure prophylaxis pills and a monthly dapivirine vaginal ring. A subset of participants (n = 25) across all sites completed up to three serial in-depth interviews (SIDIs). The SIDIs explored barriers to product use, coping strategies, and the resulting outcomes. Coded textual data were analyzed using a product acceptability conceptual framework. Participants in the SIDIs described managing the array of challenges they encountered through formal adherence support, strategic product disclosure, and personally adapted strategies. For both products, perceived discreetness of the product and decision-making around disclosure was an important component of participants' narratives. Participants tailored their coping strategies based on available personal resources (e.g., cell phone alarms for PrEP reminders, social support through disclosure) or study provided resources (e.g., encouragement from staff, adherence groups). Notably, challenges participants encountered with each product during the crossover period helped inform product selection during the choice period. Our findings suggest that-even in a context where AGYW have access to several options for HIV prevention-challenges to consistent product use remain, but accessible support mechanisms and informed choice can help mitigate these challenges. Enacting that choice may also empower AGYW to reach their short and long-term life goals-including for HIV prevention. (NCT03593655, 20th July 2018).

Personalization of Intravaginal rings by droplet deposition modeling based 3D printing technology

Intravaginal rings (IVRs) are long-acting drug device systems designed for controlled drug release in the vagina. Commercially available IVRs employ a one-size-fits-all development approach, where all patients receive the same drug in similar doses and frequencies, allowing no space for dosage individualization for specific patients’ needs. To allow flexibility for dosage individualization, this study explores the impact of infill-density on critical characteristics of personalized IVRs, manufactured using droplet deposition modeling three-dimensional (3D) printing technology. The model drug was dispersed on the surface of thermoplastic polyurethane pellets using an oil coating method. IVR infill-density ranged from 60 to 100 %. The compatibility of the drug and matrix was assessed using thermal and spectroscopic analyses. The IVRs were evaluated for weight, porosity, surface morphology, mechanical properties, and in vitro drug release. The results demonstrated high dimensional accuracy and uniformity of 3D-printed IVRs, indicating the robustness of the printing process. Increasing infill-density resulted in greater weight, storage modulus, Young’s modulus, Shore hardness, and compression strength, while reducing the porosity of IVRs. All IVRs showed a controlled drug release pattern when tested under accelerated conditions of temperature for 25 days. Notably, greater infill-densities were associated with a decrease in the percentage of drug released. Overall, the study demonstrated that infill-density was an important parameter for personalizing the critical characteristics of the 3D-printed IVRs to fit individual patient needs.

Perceptions of the attributes of new long-acting HIV pre-exposure prophylaxis formulations compared with a daily, oral dose among South African young women: a qualitative study

ABSTRACT Oral PrEP is highly effective against the acquisition of HIV but is underutilised by young women. New options, like the monthly dapivirine vaginal ring (DVR) and injectable long-acting cabotegravir (CAB-LA), are emerging. However, little is known about young women’s perceptions of these alternatives. This qualitative study explored perceptions of the attributes of PrEP technologies in South Africa. Young women accessing sexual health services were purposively selected to participate in 22 in-depth interviews, five focus group discussions and two workshops using the nominal group technique, between August 2022 and March 2023. A thematic approach guided by the diffusion of innovation attributes, including relative advantage, compatibility with the student's lives, complexity of the technology, and trialability, was used for data analysis. The DVR was the least preferred because of lower efficacy, the perceived complexity of inserting it in the vagina and some safety concerns. Oral PrEP, which some had tried and discontinued, was least compatible with students’ busy schedules. Integrating PrEP and contraceptives with similar return visit patterns could enhance service delivery. Intensive demand creation campaigns will be needed to increase PrEP utilisation and dispel myths about the vaginal ring.

Additive manufacturing of TPU devices for genital herpes treatment with sustained acyclovir release

The treatment of recurrent genital herpes typically involves daily doses of acyclovir for extended periods. Additive manufacturing is an intriguing technique for creating personalised drug delivery systems, which can enhance the effectiveness of treatments for various diseases. The vaginal route offers a viable alternative for the systemic administration of drugs with low oral bioavailability. In this study, we produced different grades of thermoplastic polyurethane (TPU) filaments through hot-melt extrusion, with acyclovir concentrations of 0%, 10%, and 20% by weight. We used fused filament fabrication to manufacture matrix-based devices, including intrauterine devices and intravaginal rings. Our results, obtained through SEM, FTIR, and DSC analyses, confirm the successful incorporation of acyclovir into the matrix. Thermal analysis reveals that the manufacturing process alters the organization of the TPU chains, resulting in a slight reduction in crystallinity. In our in-vitro tests, we observed an initial burst release on the first day, followed by sustained release at reduced rates for up to 145 days, demonstrating their potential for long-term applications. Additionally, cytotoxicity analysis suggests the excellent biocompatibility of the printed devices, and biological assays show a remarkable 99% reduction in HSV-1 replication. In summary, TPU printed devices offer a promising alternative for long-term genital herpes treatment, with the results obtained potentially contributing to the advancement of pharmaceutical manufacturing.

Efficacy of the Dapivirine Vaginal Ring Accounting for Imperfect Adherence.

Product adherence is critical to obtaining objective estimates of efficacy of pre-exposure prophylactic interventions against HIV-1 infection. With imperfect adherence, intention-to-treat analyses assess the collective effects of complete, sub-optimal and non-adherence, providing a biased and attenuated estimate of the averagecausal effect of an intervention. Using data from the MTN-020/ASPIRE phase III trial evaluating HIV-1 efficacy of the dapivirine vaginal ring, we conducted per-protocol, and adherence-adjusted causal inference analyses using principal stratification and marginal structural models. We constructed two adherence cut offs of ≥ 0.9mg (low cutoff) and > 4.0mg (high cutoff) that represent drug released from the ring over a 28-day period. The HIV-1 efficacy estimate (95% CI) was 30.8% (3.6%, 50.3%) (P = 0.03) from the per-protocol analysis, and 53.6% (16.5%, 74.3%) (P = 0.01) among the highest predicted adherers from principal stratification analyses using the low cutoff. Marginal structural models produced efficacy estimates (95% CIs)ranging from 48.8 (21.8, 66.4) (P = 0.0019) to 56.5% (32.8%, 71.9%) (P = 0.0002). Application of adherence-adjusted causal inference methods are useful in interpreting HIV-1 efficacy in secondary analyses of PrEP clinical trials.

Next-Generation Contraceptive Intravaginal Ring: Comparison of Etonogestrel and Ethinyl Estradiol In Vitro and In Vivo Release from 3D-Printed Intravaginal Ring and NuvaRing.

Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface production (CLIP™) (referred to as CLIPLOW for low drug loading and CLIPHIGH IVRs for high drug loading) and NuvaRing, a commercially available injection molded IVR. We conducted in vitro release studies in simulated vaginal fluid to compare the release of ENG and EE from CLIPLOW IVRs and NuvaRing. CLIPLOW IVRs had a similar hormone dose to NuvaRing and exhibited slightly slower ENG release and greater EE release in vitro compared to NuvaRing. When administered to female sheep, NuvaRing demonstrated greater ENG/EE levels in plasma, vaginal tissue and vaginal fluids compared to CLIPLOW IVR despite similar drug loadings. Leveraging observed hormones levels in sheep from NuvaRing as an effective contraceptive benchmark, we developed a long-acting CLIPHIGH IVR with increased ENG and EE doses that demonstrated systemic and local hormone levels greater than the NuvaRing for 90 days in sheep. No signs of toxicity were noted regarding general health, colposcopy, or histological analysis in sheep after CLIPHIGH IVR administration. Our results provided (1) a comparison of ENG and EE release between a 3D-printed IVR and NuvaRing in vitro and in vivo, (2) a preclinical pharmacokinetic benchmark for vaginally delivered ENG and EE and (3) the generation of a 90-day CLIP IVR that will be utilized in future work to support the development of a long-acting ENG/EE IVR combined with an antiretroviral for the prevention of HIV and unplanned pregnancy.

Sexual function, quality of life, anxiety, and depression in women of reproductive age using hormonal, nonhormonal, and no contraceptive methods.

Hormonal contraceptive use has been related to adverse effects, including impacts on sexual function and sexual satisfaction, although the difference in the effects on sexual function with the use of hormonal vs nonhormonal contraceptive methods remains controversial. In this study we sought to compare the prevalence of dyspareunia, sexual function, sexual satisfaction, quality of life, anxiety, and depression between women using hormonal, nonhormonal, or no contraceptive methods and to compare these outcomes between the most frequently used contraceptive methods. This cross-sectional study included sexually active women of reproductive age who were stratified into 3 groups: women using hormonal, nonhormonal, or no contraceptive methods. Based on the use of questionnaires administered to the study participants, we compared sexual function in the 3 groups and more specifically among users of oral contraceptives, copper and hormonal intrauterine devices, and barrier methods. Participants completed 4 questionnaires to assess sexual function (Female Sexual Function Index), sexual satisfaction (Sexual Quotient-Feminine Version), quality of life (12-item Medical Outcomes Short Form Health Survey), and anxiety and depression (Hospital Anxiety and Depression Scale). This study included 315 women classified into 3 groups on the basis of contraceptive use: 161 in the hormonal contraceptives group (median [interquartile range] age, 24 [23-28] years), 97 in the nonhormonal contraceptives group (age 26 [23-30] years), and 57 in the no contraceptive methods group (age 28 [24-35] years). Dyspareunia prevalence showed no difference between the groups. In the quality of life domain, compared with women in the nonhormonal contraceptive group, women in the hormonal contraceptive group were younger and had lower sexual function satisfaction, reduced arousal, and heightened pain (P< .05), as well as higher anxiety and depression levels (P= .03, for both), increased pain (P= .01), and poorer overall health (P= .01). No difference was found between these groups in other quality of life domains. Regarding contraceptive methods, women using copper intrauterine devices had better sexual function, including higher rates of arousal and lower anxiety, than women using oral contraceptives (P< .05). The results of this study highlight worse sexual function and sexual satisfaction and higher levels of anxiety and depression in women using hormonal contraceptive methods than in women using nonhormonal methods. The findings of this study strengthen the evidence of differences in sexual function between women using oral contraceptives and those using copper intrauterine devices. Sexual function was also compared among users of oral contraceptives, copper and hormonal intrauterine devices, and barrier methods. However, less frequently used contraceptive methods, such as hormonal injections and vaginal rings, could not be compared in this sample. Women using hormonal contraceptive methods were younger, had lower sexual function and satisfaction, and experienced higher anxiety and depression levels than women using nonhormonal contraceptive methods.

A Review of Concordance and Quality in Clinical Guidelines for Hormonal Contraceptives to Mitigate Drug-Drug Interactions in Women With Epilepsy.

Concomitant use of hormonal contraceptive agents (HCAs) and enzyme-inducting antiepileptic drugs (EIAEDs) may lead to contraceptive failure and unintended pregnancy. This review identified and evaluated concordance and quality of clinical treatment guidelines related to the use of HCAs in women with epilepsy (WWE) receiving EIAEDs. Relevant clinical guidelines were identified across four databases and were independently evaluated for quality utilizing the AGREE-II protocol instrument. Quality in this context is defined as the rigor and transparency of the methodologies used to develop the guideline. Guidelines were further assessed in terms of concordance and discordance with the latest body of knowledge concerning the use of hormonal contraception in the presence of EIAEDs. A total of n = 5 guidelines were retrieved and evaluated. Overall guideline scores ranged from 17% to 92%, while individual domain scores ranged from 0% to 100%. Contraceptive guidelines consistently recommended the use of intrauterine systems and long-acting injectables in the presence of EIAEDs, recommended against the use of oral, transdermal, and vaginal ring contraceptives, and differed regarding recommendations related to implants. Guidelines agreed regarding recommendations that women treated with EIAEDs should receive intrauterine systems and long-acting injectables; however, the suggested frequency of administration of injectable contraceptives differed. The use of intrauterine systems in this population is supported by evidence, but there is uncertainty surrounding the use of long-acting injectables and contraceptive implants. To mitigate the risk of unintended pregnancy and its consequences, recommendations related to implants and long-acting injectable contraceptives should be evidence-based.

Acceptability of the Dapivirine Vaginal Ring and Daily Oral Pre-exposure Prophylaxis (PrEP) during Pregnancy in Malawi, South Africa, Uganda, and Zimbabwe

Pregnant and lactating persons in sub-Saharan Africa face a heightened risk of HIV acquisition, due to biological and behavioral factors, combined with limited access to prevention and treatment services. Oral pre-exposure prophylaxis (PrEP) and the dapivirine vaginal ring are promising tools for HIV prevention, and the ring’s recent approval in multiple African countries represents a significant advancement in expanding access to HIV prevention. In a nested qualitative study within the MTN-042 trial, we explored the acceptability of study products among pregnant persons in the second and early third trimesters. Interviews were conducted privately, using a semi-structured guide with 77 participants, in participants’ preferred language. Topics explored included product acceptability (using the theoretical framework of acceptability), user experience, satisfaction, disclosure, community attitudes, and sexual activity during pregnancy. Interview transcripts were analyzed using Dedoose software. We observed positive attitudes among participants towards the study products, which they found generally user-friendly, despite the added complexities of using them during pregnancy. Participants recognized that consistent and correct use would provide protection for both them and their unborn children. Although initial concerns existed, most of these worries dissipated over time, with study staff support and increased product use experience. These findings emphasize the importance of continued surveillance, support, and education to ensure the successful rollout of new HIV prevention measures during pregnancy.

O-021 Magnetic Resonance Imaging (MRI) evaluation of Quinagolide Vaginal Ring (QVR) treatment on endometrioma, Deep Infiltrating Endometriosis (DIE), and adenomyosis lesion characteristics: QLARITY trial results

Abstract Study question Can MRI provide a useful assessment of changes to endometrioma, DIE, and adenomyosis lesion burden resulting from QVR treatment? Summary answer MRI successfully measured changes in the number, size, diffusion, and perfusion biomarkers of endometriotic and adenomyotic lesions enabling evaluation of QVR treatment efficacy. What is known already Endometriosis and adenomyosis are associated with chronic pelvic pain, painful menses, and infertility. Determining treatment efficacy is reliant on patient reported outcomes (PRO) which are sensitive to response style effects and may lag changes in underlying pathology. Availability of biomarkers measuring lesion burden could accelerate the development of therapies treating disease rather than managing symptoms. MRI is routinely used in oncology to provide non-invasive biomarkers of treatment effect, a paradigm adapted in this trial. Quinagolide is a dopamine D2 receptor agonist formulated in an extended-release vaginal ring in development for treatment of endometriosis based on presumed inhibition of lesion angiogenesis. Study design, size, duration QLARITY was a randomized, placebo-controlled phase 2 trial investigating the mechanism of action of QVR (1080 µg) administered for four menstrual cycles. Randomization was 1:1 QVR (n = 35) to placebo vaginal ring (n = 32). Primary endpoint was change in the sum of lesion sizes by type from baseline to end of cycle 4 as measured by MRI. Secondary endpoints included changes in lesion volume, PROs and adverse events. MRI-derived imaging biomarkers were analyzed as exploratory endpoints. Participants/materials, setting, methods Women, 18-45 years old with at least one type of lesion (endometrioma, adenomyosis, and/or DIE) visualized by MRI, were enrolled. The analyses were performed by treatment for each of the three lesion types individually and for all types combined. Change in lesion size was analyzed using ANCOVA adjusted for baseline. Number of subjects with lesion regression was analyzed using a Chi-Square test. MRI-derived diffusion and perfusion imaging biomarkers were analyzed as exploratory endpoints. Main results and the role of chance Demographics and baseline characteristics were comparable between treatment groups. Patients had a mean age of 36.1 years and had been diagnosed for 5.25 years on average. Most patients (n = 42, 62.7%) had 2-4 lesions. No statistically significant changes in the sum of lesion sizes or PROs (Numerical Rating Scale, Biberoglu and Behrman Scale, and Endometriosis Health Profile-30) after treatment were noted, when compared to placebo. However, across all lesion types, a statistically significantly higher proportion of QVR patients than placebo patients demonstrated lesion regression of ≥ 65.0% volume (61.3% vs 35.5%, p = 0.042). In the DIE group, lesion regression occurred in more patients treated with QVR than those on placebo (36.8% vs 7.7%, p = 0.016). For diffusion imaging biomarkers, a significant difference in the diffusion coefficient standard deviation of DIE lesions (p = 0.039) was found in the QVR group compared to placebo. For perfusion imaging biomarkers, a statistically significant relationship with the treatment was identified in the endometrioma group for the 25th percentile of difference in fractional volume of extravascular extracellular space (mean difference −1.69, p = 0.009) from baseline. Incidence and severity of adverse events were similar between QVR and placebo. Limitations, reasons for caution MRI cannot currently detect superficial, highly vascularized endometriosis, which may be more responsive to QVR treatment than the more advanced stage of endometriosis (indicated by relatively large endometrioma and DIE) imaged in QLARITY. Moreover, 4 cycles may not be of sufficient duration for optimal treatment of these lesions. Wider implications of the findings QLARITY provides support for the use of MRI to diagnose and characterize changes in endometriotic/adenomyotic lesions. It is also the first MRI characterization of the placebo response in this population. Imaging biomarkers show promise in generating insights. QVR is safe and well tolerated; further studies of its efficacy are warranted. Trial registration number NCT03749109

How have changes in accessibility and public funding influenced contraceptive use among Norwegian adolescents? A cohort study.

The Norwegian Government introduced in 2002 a reimbursement scheme for hormonal contraceptives to adolescents at the same time as public health nurses and midwives received authorization to prescribe hormonal contraceptives. This study examines the impact of increased accessibility and public funding on hormonal contraceptive use among adolescents. The Norwegian Prescription Database, Statistics Norway, and Norwegian Institute of Public Health served as data sources for this cohort study. The study population comprised 174 653 Norwegian women born 1989-1990, 1994-1995, and 1999-2000. We examined use of hormonal contraceptives through dispensed prescriptions from age 12 through age 19 with duration of first continuous use as primary outcome. The statistical analyses were done in SPSS using chi-squared test, survival analysis, and Joinpoint regression analysis with p-values < 0.05. By age 19, ~75% of the cohorts had used at least one hormonal method. The main providers of the first prescription were general practitioners and public health nurses. Starters of progestogen-only pills (POPs) have increased across the cohorts, while starters of combined oral contraceptives (COCs) have decreased. The use of long-acting reversible contraceptives (LARCs) has increased since its inclusion in the reimbursement scheme (2015). Most switchers shifted from COCs or POPs as a start method to implants after LARCs became part of the reimbursement scheme. There has been a significant increase across the cohorts in the number of women who continuously used hormonal contraceptives from start to the end of the calendar year they became 19 years with the same method and after switching methods. We could not correlate changes in decreasing trends for teenage births or induced abortions (Joinpoint analysis) to time for implementation or changes in the reimbursement of hormonal contraceptives from 2002. Primarily public health nurses and to a lesser extent midwives became soon after they received authorization to prescribe COCs important providers. The expansion of the reimbursement scheme to cover POPs, patches, vaginal ring, and depot medroxyprogesterone acetate in 2006 had minor impact on increasing the proportion of long-term first-time users. However, the inclusion of LARCs in 2015 significantly increased the proportion of long-term first-time hormonal contraceptive users.

Enhancing HIV pre-exposure prophylaxis outcomes among Kenyan adolescent girls and young women with a novel pharmacy-based PrEP delivery platform: protocol for a cluster-randomized controlled trial

BackgroundIn Kenya, 65% of sexually active unmarried women use modern contraceptives, a population at increased risk of HIV acquisition compared to other populations. Anchoring HIV prevention services, including pre-exposure prophylaxis (PrEP), to trusted contraceptive delivery settings offers opportunities to efficiently reach this important population. In Kenya, almost half (40%) of women accessing contraception services do so outside traditional healthcare facilities, such as retail pharmacies. Thus, integrating PrEP services into retail pharmacies may increase options for reaching adolescent girls and young women (AGYW) who could benefit from PrEP. Efforts are underway to define care pathways for pharmacy-delivered PrEP services in Kenya, including unsupported and supported models with nurse navigators.MethodsThe AGYW Pharmacy PrEP study is an unblinded 2-arm cluster-randomized controlled trial in Kisumu, Kenya. The objective is to determine the effect that unsupported versus supported pharmacy-delivered PrEP services has on PrEP initiation, persistence, and adherence among AGYW seeking contraception. Twenty retail pharmacies offering pharmacy provider-led PrEP delivery will be randomized 1:1 to either receive or not receive a nurse navigator to support PrEP delivery. Eligible AGYW (n = 1900 total, n = 950/arm) will be ≥ 15 years old, purchasing a method of contraception at the pharmacy. Trained pharmacy provider will offer eligible AGYW either daily oral PrEP or the monthly DPV vaginal ring. The primary trial outcomes are PrEP initiation (use of PrEP at 1 month), persistence (use of PrEP at 10 months), and adherence (quantified by levels of TFV or DPV in hair samples). Additionally, several secondary (STI incidence, PrEP method selection, predictors of PrEP adherence) and exploratory outcomes (HIV incidence, quality of care, contraceptive method mix) will be explored.DiscussionWe hypothesize pharmacy-delivered PrEP services supported with nurse navigator, versus delivered by pharmacy providers alone, will improve PrEP outcomes among AGYW seeking contraception. Our results will help policy makers better understand how to potentially implement this novel differentiated service model for PrEP and prime pharmacies for the delivery of new PrEP agents in the pipeline (e.g., long-acting injectables and multi-purpose technologies). The study was initiated on May 13, 2023, and is expected to be completed by February 2025.Trial RegistrationClinicalTrials.gov (NCT05467306), with registration on July 20, 2022.

Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings.

Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

Intravesical misplacement of vaginal contraceptive ring: a video report and review of the literature.

The NuvaRing®, a hormonal vaginal contraceptive device, has gained widespread usage due to its favourable efficacy and safety profiles. Exceedingly rare instances of unintended misplacement in the bladder have been reported. This study presents a review of the literature and the first video report illustrating the extraction of an intravesical NuvaRing®, discussing diagnostic and therapeutic approaches. To illustrate an effective method for intravesical NuvaRing® retrieval and raise awareness about this unusual complication. A 27-year-old patient with low urinary tract symptoms related to NuvaRing® misplacement underwent diagnostic procedures, including ultrasound and diagnostic cystoscopy. A cystoscopic extraction under general anaesthesia was performed. The effectiveness of pelvic ultrasound for diagnosing an intravesical foreign body, successful cystoscopic removal of NuvaRing® from the bladder, and symptom resolution were assessed. The intravesical NuvaRing® was identified through pelvic ultrasound. During cystoscopy, the ring was detected inside the bladder. Multiple attempts with cystoscopic alligator graspers were made; the NuvaRing® was eventually extracted using transurethral Heiss forceps. The patient experienced minimal blood loss and was discharged the following day, reporting relief from symptoms. Unintentional NuvaRing® placement in the bladder is an extremely rare event that healthcare providers should consider when patients present with urinary symptoms and pelvic pain. Pelvic ultrasound is an efficient diagnostic tool, possibly averting the need for further imaging techniques. Cystoscopy remains the preferred method for diagnosis and treatment. This video report illustrates an effective technique for NuvaRing ® extraction, especially when appropriate graspers are unavailable. Adequate instruction on NuvaRing® insertion should always be emphasised.

Self-reported removal and expulsion of the dapivirine vaginal ring: qualitative reports from female ring users and their male partners in the Ring Study (IPM 027)

Background/aimsThe dapivirine vaginal ring is a self-administered, women-initiated, discreet, long-acting HIV-1 prevention option for women. It was found to be safe and effective in healthy HIV-negative women who adhered to product use instructions, and has been approved for use in women aged 18 and older in some African countries. A qualitative study was conducted to explore participants’ and their male partners’ discussions on accidental/purposeful vaginal ring removals during The Ring Study (IPM 027 clinical trial).MethodsData were collected via in-depth interviews and focus group discussions with female trial participants and their male partners, from seven research centres in South Africa and Uganda. Data were thematically analysed using NVivo.ResultsMore participants reported purposeful ring removals than accidental expulsions. Various factors influenced purposeful ring removal – including individual (discomfort during use/sex and to clean it), partner (to show them, because of discomfort during sex, to test if partners could feel it, and concerns of harm), organisational (doctor’s request), and socio-cultural (rumours about sickness and infertility). Some described their own ring use removal, others discussed why other participants removed their rings.ConclusionsVaginal ring adherence is critical to improve and support product efficacy. Counselling on vaginal anatomy, vaginal ring insertion and importance of adherence is important to minimise vaginal ring removal. Couples counselling is also important to facilitate support and long-term vaginal ring adherence behaviour. Understanding factors influencing vaginal ring adherence is important for tailoring and targeting messages to support correct and consistent vaginal ring use as it is made available to the public.