Vaginal Ring Research Articles

O-044 The future of contraception

Abstract In 1960, the first hormonal contraceptive agent, Enovid approved by the Food and Drug Administration in the United States. The pill contained mestranol 150 mcg and norethynodrel 10 mg. High dose pills containing >50 mcg of estrogen were discontinued in 1988 due to a higher risk of myocardial infraction and stroke secondary to thrombosis. Until recently, the only estrogens used in combination OCPs were mestranol and ethinyl estradiol (EE). Estetrol (E4) and 17-beta estradiol have been added to newer pill and intravaginal ring (IVR) formulations in order to reduce the risk of thrombosis. Progestins confer the primary contraceptive effect in combination agents and can be used without estrogens. First generation progestins include norethynodrel, ethynodiol diacetate, norethindrone and norethindrone acetate (estranes). Second generation progestins include norgestrel and levonorgestrel (gonanes). Third generation include gestoden, desogrestrel and norgestimate, which are less androgen versions of the second generation progestins. Fourth generation progestins have no androgenicity include drospirenone. The fourth generation progestin is a 17 carbon compound which separates it from the other progestins that are primarily 19 carbon derivatives of androgens. Segesterone acetate (SA) is a newer progestin that is less potent and has no androgenic properties. SA, combined with EE, is currently being used in an IVR. However, clinical trials are ongoing using SA with 17-beta estradiol in an IVR and another with EE as a contraceptive gel. Other new methods of hormonal contraception include progestins in a biodegradable implant, longer acting injectables that can last 6-12 months, transdermal patches that are imbedded with an array of microneedles where either the contraceptive agent is in a reservoir or in the needles themselves. Microchip technology is being developed by the Gates Foundation that would allow levonorgestrel to be released systemically at will over a 16-year period using a remote device. Multipurpose technologies are being developed utilizing contraceptive pills, injectables and IVRs containing hormonal agents as well as medications to prevent STI/HIV acquisition.

A phase 1/2, open-label, parallel group study to evaluate the safety and pharmacokinetics of DARE-HRT1 (80 μg estradiol/4 mg progesterone and 160 μg estradiol/8 mg progesterone intravaginal rings) over 12 weeks in healthy postmenopausal women.

Primary objectives were to evaluate the safety and systemic pharmacokinetics (PK) of DARE-HRT1, an intravaginal ring (IVR), which releases 17β2-Estradiol (E2) with progesterone (P4) for 28 days in healthy postmenopausal women. This was a randomized, open-label, 2-arm, parallel group study in 21 healthy postmenopausal women with an intact uterus. Women were randomized (1:1) to either DARE-HRT1 IVR1 (E2 80 μg/d with P4 4 mg/d) or DARE-HRT1 IVR2 (E2 160 μg/d with P4 8 mg/d). They used the IVR for three 28-day cycles, inserting a new IVR monthly. Safety was measured by treatment emergent adverse events and changes in systemic laboratories and the endometrial bilayer width. Baseline adjusted plasma PK of E2, P4, and estrone (E1) was described. Both DARE-HRT1 IVR were safe. All treatment emergent adverse events were mild or moderate and were distributed similarly among IVR1 versus IVR2 users. Month 3 median maximum plasma (Cmax) P4 concentrations were 2.81 and 3.51 ng/mL and Cmax E2 was 42.95 and 77.27 pg/mL for IVR1 and IVR2 groups, respectively. Month 3 median steady state (Css) plasma P4 concentrations were 1.19 and 1.89 ng/mL, and Css E2 was 20.73 and 38.16 pg/mL for IVR1 and IVR2 users, respectively. Both DARE-HRT1 IVRs were safe and released E2 in systemic concentrations, which were in the low, normal premenopausal range. Systemic P4 concentrations predict endometrial protection. Data from this study support further development of DARE-HRT1 for the treatment of menopausal symptoms.

Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya.

Globally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies. Healthy women ages 18-34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition. Among 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36-90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10 ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and -27.1% to -20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml [95% CI 473, 726] and 87 pg/ml [95% CI 64, 119], respectively). TFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR. NCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382].

Pharmacokinetic and pharmacodynamic studies of an altrenogest diffusing intravaginal ring for estrus suppression in the mare

Managing mares through unpredictable behaviors associated with fluctuating hormones is frustrating, particularly during performance. A variety of solutions have been explored, but without reliable success. The synthetic progestin altrenogest, marketed for estrus suppression in the mare, is the current industry paradigm. Commonly administered orally or sustained release injectable formulations, both pose risks, leading to poor owner compliance. We investigated the ability of a novel biomedical device to deliver altrenogest through the vaginal mucosa directly compared with conventional oral administration. In total, 12 grade mares were utilized for this study during the physiologic breeding season. Mares were enrolled within a treatment group spanning three estrous cycles in a crossover design. Intravaginal ring altrenogest (IVRA), oral altrenogest (OA) and a control placebo vaginal ring (IVRP). Group IVRA: 14.2cm diameter silicone ring containing 1% powder altrenogest placed into the cranial vaginal vault day 5 of diestrus (0d = ovulation). Group OA: administered commercially available altrenogest (Regu-Mate®, Merck & Co., Inc., Rahway, NJ) orally daily at 0.044 mg/kg. Group IVRP: insertion of a silicone vaginal ring without altrenogest into the vaginal vault. Blood was collected at each trial initiation (T0) and at 2h, 24h, 72h, 10 days and plasma stored at -80°C until pharmacokinetic (PK) evaluation utilizing modern liquid chromatography tandem mass spectrometry(LC/MS/MS). Blood samples were also collected (days 5, 11, 15, 22) to determine native progesterone levels. Transrectal ultrasonographic evaluation was performed every five days following ovulation. Controlled exposure to a stallion occurred every other day. Values are given as mean ± standard error of mean. IVRA peak plasma levels: 1.45 ng/ml following ring insertion; average steady state level: 0.3 ng/ml. OA peak plasma levels: 1.8 ng/ml following administration; average steady state: 0.55 ng/ml. IVRP: no altrenogest detected. Cmax for IVRA and OA groups was reached within 2 hours. IVRA eliminated peaks/troughs identified in group OA, demonstrating a steady state. Transrectal ultrasonography revealed group IVRA maintained a CL an average of 20.8 ± 1.3, group OA for 21.4 ± 0.75 and IVRP for 14.4 ± 1.2 days. There was no difference in native progesterone levels amongst groups. Groups IVRA and OA maintained significantly longer luteal phases than IVRP (p<0.0001 and p<0.002, respectively). Mares in group IVRA displayed significantly lower teasing scores than IVRP (p<0.009). Groups IVRA and OA were not significantly different (p<0.188). Previous studies determined therapeutic levels of altrenogest at or above 0.5 ng/ml but our observations with mare behavior and PK data suggest efficacy at lower limits of quantification (0.1 ng/ml). An equine intravaginal ring represents a novel medical device for effective delivery of therapeutics and future applications.

3D printing fabrication of Ethylene-Vinyl Acetate (EVA) based intravaginal rings for antifungal therapy

3D printing fabrication of Ethylene-Vinyl Acetate (EVA) based intravaginal rings for antifungal therapy

Synthesis of end-user research to inform future multipurpose prevention technologies in sub-Saharan Africa: a scoping review.

Women in sub-Saharan Africa (SSA) experience disproportionately high rates of HIV infection and unintended pregnancy compared to their age-matched counterparts in other regions of the world. Multipurpose prevention technologies (MPTs) that offer protection against HIV and unintended pregnancy in a single product stand to address these dual sexual and reproductive health needs simultaneously. The aim of this scoping review is to identify factors that are important for optimizing the likelihood of MPT adoption by end users in SSA. Study inclusion criteria included MPT research (HIV and pregnancy prevention dual indication) published or presented in English from 2000 to 2022 and conducted in SSA amongst end-users (women aged 15-44), male partners, health care providers, and community stakeholders. References were identified by searching peer reviewed literature, grey literature, conference presentations (2015-2022), grant databases, and outreach to MPT subject matter experts. Of 115 references identified, 37 references met inclusion criteria and were extracted for analysis. A narrative synthesis approach was used to summarize findings within and across MPT products. Studies were identified from six countries in SSA and a substantial proportion included a South African (n = 27) and/or Kenyan (n = 16) study site. Most studies utilized a qualitative study design (n = 22) and evaluated MPT acceptability and preferences by presenting hypothetical products through images or a list of product attributes (n = 21). The vaginal ring (n = 20), oral tablet (n = 20), and injection (n = 15) were examined most frequently. Across studies, there was high acceptability and demand for an HIV and pregnancy prevention MPT. End users valued choice in prevention product type as well as discreetness and long-acting options. Provider counseling and community sensitization were reported as essential for future introduction of novel MPT delivery forms. Recognizing the heterogeneity of women's preferences and changing reproductive and sexual health needs over the life course, choice is important in the delivery of pregnancy and HIV prevention products as well as amongst MPT products with distinct product profiles. End user research with active MPTs, vs. hypothetical or placebo MPTs, is necessary to advance understanding of end-user preferences and acceptability of future products.

(117) Postpartum Vulvovaginal Dryness: Disparities in Adequate Treatment for Postpartum Patients’ Sexual Health

Abstract Introduction Vaginal estrogen therapy (VET) use and efficacy is well established for genitourinary symptoms commonly seen in menopause. Despite the similar symptom profile and dramatic hormonal shifts in postpartum (PP) patients, they are not routinely offered the same therapies. The pathophysiology of these symptoms PP is multifactorial and frequently dismissed as “normal,” even with the subsequent negative effect on their quality of life. Concerns regarding potential harm on lactation and infant development further decreases utilization. However, these apprehensions may be outdated due to evolution of VET, warranting review of available literature. Objective To review the efficacy, concerns, and barriers of utilization of VET for vulvovaginal symptoms in PP patients. Methods A systematic review in the PubMed database spanning from January 1990 – June 2022 was performed to assess the relevant medical literature on the utilization of VET for vulvovaginal symptoms in PP patients. MeSH terms used to narrow the search include: [“dyspareunia” OR “vulvovaginal atrophy” OR “genitourinary”] AND [“hypoestrogenic state” OR “estrogenic endocrine disrupting compounds” OR “estrogen responsive tissues”] AND [“postpartum” OR “menopausal” OR “infant”] AND [“estrogen preparations” OR “vaginal estrogen”]. Results The published literature (n=33) was analyzed by relevant key terms. FDA has approved a number of estrogen-based formulations for vulvovaginal atrophy and dysparenuia in menopausal patients, including: 7.5ug/day (vaginal ring), ultra low dose 10ug (vaginal tablet), 0.01% estradiol creams, premarin (conjugated estrogen) cream, and vaginal DHEA. Data for PP patients is limited with varying results. Nonetheless, drastic improvement in tissue thickening, lubrication, and baseline elasticity within a few weeks of minimal applied dosage of VET has been shown. Addressing primary worries, while higher doses (&amp;gt;50mcg) of estrogen in the early PP period may negatively affect lactation, initiating VET after supply is well established (at 6-8 weeks) or using lower dose estrogen (≤50mcg) has no changes in lactation. In fact, the ultra-low-dose combined oral contraceptive pill (20mcg of ethinyl estradiol with progestins) is approved PP for contraception after 30 days with no adverse impact on breastfeeding. VET concentrations are smaller, and locally applied, implying even less risk of systemic effects. Tolerability is further enhanced with a personalized approach, prescribing the smallest effective dose for the shortest duration of time. Additionally, data suggests that if lactation is affected, there is no significant alteration to the infant’s growth, no to minimal increase of estradiol or estriol in breastfed infants, nor significant evidence of long-term prolongation of physiologic estrogenization. PP patients face numerous barriers, further limiting access to effective treatment, such as: varied clinical presentations, relatively high cost of therapies, minimal time and access to providers resulting in poor communication and hesitation, and limited research focused on therapeutic options for health concerns. Conclusions This review outlines the proven therapeutic uses, indications, and safety of VET, along with the scarcity of current literature for the PP population. The concurrent sexual dysfunction and discomfort can be devastating, supporting the need for focused research on the efficacy of VET connected to the specific needs and concerns of PP patients. Disclosure No

(195) Postpartum Vulvovaginal Dryness: Disparities in Adequate Treatment for Postpartum Patients’ Sexual Health

Abstract Introduction Vaginal estrogen therapy (VET) use and efficacy is well established for genitourinary symptoms commonly seen in menopause. Despite the similar symptom profile and dramatic hormonal shifts in postpartum (PP) patients, they are not routinely offered the same therapies. The pathophysiology of these symptoms PP is multifactorial and frequently dismissed as “normal,” even with the subsequent negative effect on their quality of life. Concerns regarding potential harm on lactation and infant development further decreases utilization. However, these apprehensions may be outdated due to evolution of VET, warranting review of available literature. Objective To review the efficacy, concerns, and barriers of utilization of VET for vulvovaginal symptoms in PP patients. Methods A systematic review in the PubMed database spanning from January 1990 – June 2022 was performed to assess the relevant medical literature on the utilization of VET for vulvovaginal symptoms in PP patients. MeSH terms used to narrow the search include: [“dyspareunia” OR “vulvovaginal atrophy” OR “genitourinary”] AND [“hypoestrogenic state” OR “estrogenic endocrine disrupting compounds” OR “estrogen responsive tissues”] AND [“postpartum” OR “menopausal” OR “infant”] AND [“estrogen preparations” OR “vaginal estrogen”]. Results The published literature (n=33) was analyzed by relevant key terms. FDA has approved a number of estrogen-based formulations for vulvovaginal atrophy and dysparenuia in menopausal patients, including: 7.5ug/day (vaginal ring), ultra low dose 10ug (vaginal tablet), 0.01% estradiol creams, premarin (conjugated estrogen) cream, and vaginal DHEA. Data for PP patients is limited with varying results. Nonetheless, drastic improvement in tissue thickening, lubrication, and baseline elasticity within a few weeks of minimal applied dosage of VET has been shown. Addressing primary worries, while higher doses (&amp;gt;50mcg) of estrogen in the early PP period may negatively affect lactation, initiating VET after supply is well established (at 6-8 weeks) or using lower dose estrogen (≤50mcg) has no changes in lactation. In fact, the ultra-low-dose combined oral contraceptive pill (20mcg of ethinyl estradiol with progestins) is approved PP for contraception after 30 days with no adverse impact on breastfeeding. VET concentrations are smaller, and locally applied, implying even less risk of systemic effects. Tolerability is further enhanced with a personalized approach, prescribing the smallest effective dose for the shortest duration of time. Additionally, data suggests that if lactation is affected, there is no significant alteration to the infant’s growth, no to minimal increase of estradiol or estriol in breastfed infants, nor significant evidence of long-term prolongation of physiologic estrogenization. PP patients face numerous barriers, further limiting access to effective treatment, such as: varied clinical presentations, relatively high cost of therapies, minimal time and access to providers resulting in poor communication and hesitation, and limited research focused on therapeutic options for health concerns. Conclusions This review outlines the proven therapeutic uses, indications, and safety of VET, along with the scarcity of current literature for the PP population. The concurrent sexual dysfunction and discomfort can be devastating, supporting the need for focused research on the efficacy of VET connected to the specific needs and concerns of PP patients. Disclosure No

A Review on Physicochemical Properties of Polymers Used as Filaments in 3D-Printed Tablets.

Three-dimensional (3D) printing technology has presently been explored widely in the field of pharmaceutical research to produce various conventional as well as novel dosage forms such as tablets, capsules, oral films, pellets, subcutaneous implants, scaffolds, and vaginal rings. The use of this innovative method is a good choice for its advanced technologies and the ability to make tailored medicine specifically for individual patient. There are many 3D printing systems that are used to print tablets, implants, and vaginal rings. Among the available systems, the fused deposition modeling (FDM) is widely utilized. The FDM has been regarded as the best choice of printer as it shows high potential in the production of tablets as a unit dose in 3D printing medicine manufacturing. In order to design a 3D-printed tablet or other dosage forms, the physicochemical properties of polymers play a vital role. One should have proper knowledge about the polymer's properties so that one can select appropriate polymers in order to design 3D-printed dosage form. This review highlighted the various physicochemical properties of polymers that are currently used as filaments in 3D printing. In this manuscript, the authors also discussed various systems that are currently adopted in the 3D printing.

Modern women choose contraceptive vaginal ring

This survey introduces up-to-date statistic data on women’s reproductive health considering current control methods. It includes literature analysis on the contraceptive vaginal ring (CVR) use. Evidential medicine proves that CVR is a long-standing, safe and effective birth control method. CVR usage definitely wins the battle against oral contraception and prolonged contraception methods. The survey includes current patients’ survey results concerning CVR usability particularly during sex. VR’s effect on vagina microbiota and cervix epithelium is also covered, considering the discussions on cervix cancer increase caused by long-term use of combined hormonal contraceptives. Recently, there has been some positive trend towards the protection of reproductive health. However, we have to admit that there are still many unresolved issues, in particular, unavailability of adequate family planning counselling services and advanced effective birth control methods. The pharmaceutical market is saturated with various birth control methods. A careful analysis of medical history details and test results makes it easy to choose the best possible and safe birth control method with due regard of the patients’ wishes. Bearing in mind the less pronounced systemic effect, ease of use, and a favourable safety profile, the choice of CVR as a birth control method seems to be the best solution for women

Physician Characteristics Associated With Bias in Contraceptive Recommendations [ID: 1349236

INTRODUCTION: We sought to determine the effect of obstetrician–gynecologist characteristics on contraceptive recommendations for patients of various racial and socioeconomic backgrounds. METHODS: U.S. obstetrician–gynecologists were administered an online survey depicting photographic scenarios of reproductive-aged women of differing races (White, Black, Latina, Asian) and described socioeconomic status (SES) (high versus low), with all other factors identical, and asked to provide contraceptive recommendations. We used logistic regression to analyze recommendation differences based on physician and patient characteristics. Institutional review board approval was obtained. RESULTS: One hundred thirty-five total respondents were included: 55% attending physicians, 45% trainees (residents/fellows); 73% White, 27% non-White. Among all patients: Non-White physicians had significantly lower odds of recommending tubal (odds ratio [OR] 0.493), vaginal ring (OR 0.401), and patch (OR 0.513) compared to White physicians. Non-White physicians had significantly higher odds of recommending any long-acting reversible contraception (LARC) (OR 1.846) and condoms (OR 1.438) compared to White physicians. Trainees had significantly lower odds of recommending tubal (OR 0.632), condoms (OR 0.595), pills (OR 0.428), vaginal ring (OR 0.326), and patch (OR 0.536) compared to attendings. Trainees had significantly higher odds of recommending any LARC (OR 18.374) and medroxyprogesterone injection (OR 1.797) compared to attendings. All physicians had a significantly lower odds of recommending any self-administered contraceptive method to Black high-SES patients compared to White high-SES patients (OR 0.418). Other variations were noted but did not reach statistical significance. CONCLUSION: In our study, contraceptive recommendations differed by race and training level of the recommending physician and by patients' perceived race and SES. This suggests that physician bias contributes to contraceptive recommendations.

Preferences and acceptability for long-acting PrEP agents among pregnant and postpartum women with experience using daily oral PrEP in South Africa and Kenya.

Long-acting pre-exposure prophylaxis (PrEP) options could overcome barriers to oral PrEP persistence during pregnancy and postpartum. We evaluated long-acting PrEP preferences among oral PrEP-experienced pregnant and postpartum women in South Africa and Kenya, countries with high PrEP coverage with pending regulatory approvals for long-acting injectable cabotegravir and the dapivirine vaginal ring (approved in South Africa, under review in Kenya). From September 2021 to February 2022, we surveyed pregnant and postpartum women enrolled in oral PrEP studies in South Africa and Kenya. We evaluated oral PrEP attitudes and preferences for long-acting PrEP methods in multivariable logistic regression models adjusting for maternal age and country. We surveyed 190 women in South Africa (67% postpartum; median age 27 years [IQR = 22-32]) and 204 women in Kenya (79% postpartum; median age 29 years [IQR = 25-33]). Seventy-five percent of participants reported oral PrEP use within the last 30 days. Overall, forty-nine percent of participants reported negative oral PrEP attributes, including side effects (21% South Africa, 30% Kenya) and pill burden (20% South Africa, 25% Kenya). Preferred PrEP attributes included long-acting method, effectiveness, safety while pregnant and breastfeeding, and free medication. Most participants (75%, South Africa and Kenya) preferred a potential long-acting injectable over oral PrEP, most frequently for a longer duration of effectiveness in South Africa (87% South Africa, 42% Kenya) versus discretion in Kenya (5% South Africa, 49% Kenya). Eighty-seven percent of participants preferred oral PrEP over a potential long-acting vaginal ring, mostly due to concern about possible discomfort with vaginal insertion (82% South Africa, 48% Kenya). Significant predictors of long-acting PrEP preference included past use of injectable contraceptive (aOR = 2.48, 95% CI: 1.34, 4.57), disliking at least one oral PrEP attribute (aOR = 1.72, 95% CI: 1.05, 2.80) and preferring infrequent PrEP use (aOR = 1.58, 95% CI: 0.94, 2.65). Oral PrEP-experienced pregnant and postpartum women expressed a theoretical preference for long-acting injectable PrEP over other modalities, demonstrating potential acceptability among a key population who must be at the forefront of injectable PrEP rollout. Reasons for PrEP preferences differed by country, emphasizing the importance of increasing context-specific options and choice of PrEP modalities for pregnant and postpartum women.

Contraceptive vaginal ring (MyRing®): multicenter study in Venezuelan women.

Objective: To evaluate the factors associated with the use of the vaginal ring in Venezuelan women of reproductive age, with a desire for contraception and with an active sexual life. Methods: Observational - descriptive, multicenter study. The sample was non-probabilistic, deliberate and voluntary. The vaginal ring was provided for three cycles and follow-up visits were made at the end of the first and third menstrual cycles. Acceptability, tolerability, compliance, menstrual cycle control, and the presence of adverse effects were evaluated. Results: A total of 140 women were included, whose mean age was 31.01 ± 8.14 years. The reasons for selecting the vaginal ring were: effectively prevents pregnancy (69.29 %), easy to use (68.57 %), method of monthly use (65.71 %). The bleeding pattern was reported as regular in 95% of the women in the second consultation and in 92.8% in the third; 88.57% reported absence of intermenstrual bleeding. There was adequate compliance in 97.86%; 96.43% expressed that it was easy to use and 92.86% comfortable at a sexual level. There were no statistically significant differences in the average weight at the second and third consultation (p &gt; 0.05), nor in systolic and diastolic blood pressure (p &gt; 0.05). There were no adverse events in 77%, when there were, the most frequent were headache, nausea and mastodynia; there were no serious adverse events or pregnancy. Conclusion: The contraceptive vaginal ring is a well-tolerated option with excellent acceptance, sexual and general satisfaction, safe, with few adverse events.

Safety and acceptability of intravaginal rings releasing estradiol and progesterone

Objective This study aimed to evaluate the safety and acceptability of two fixed-dose 28-day vaginal ring formulations of 17β-estradiol (E2) and progesterone (P4) to treat vasomotor symptoms (VMS) and the genitourinary syndrome of menopause. Design DARE HRT1-001 was the first-in-woman study of 28-day exposure to two 28-day intravaginal rings (IVRs) designed to release 80 µg/day E2 + 4 mg/day P4 (IVR1) or 160 µg/day E2 + 8 mg/day P4 (IVR2) compared with oral E2 1 mg/day + oral P4 100 mg/day. To assess safety, participants completed a daily diary to record treatment emergent adverse events (TEAEs). To determine acceptability, at the end of treatment IVR users completed a questionnaire assessing tolerability and usability. Results Enrolled women (n = 34) were randomized to use IVR1 (n = 10), IVR2 (n = 12) or oral (n = 12). Thirty-one participants (IVR1 = 10, IVR2 = 10, oral = 11) completed the study. The TEAE profile of those in the IVR groups were similar to the referent oral regimen. TEAEs related to the study product were more common with IVR2 use. Endometrial biopsies were not performed unless endometrial thickness was >4 mm or for clinically significant postmenopausal bleeding. One IVR1 participant had an endometrial stripe increase from 4 mm at screening to 8 mm at the end of treatment. The biopsy indicated no evidence of plasma cells or endometritis and no evidence of atypia, hyperplasia or malignancy. Two other endometrial biopsies were performed for postmenopausal bleeding with similar findings. There were no clinically meaningful laboratory or vital sign abnormalities or trends identified in observed values or changes from baseline. Pelvic speculum examination identified no clinically significant abnormalities in any participant at any visit. Tolerability and usability data demonstrated that both IVRs were generally highly acceptable. Conclusions Both IVR1 and IVR2 were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen.

A novel anastrozole intravaginal ring for endometriosis: Pharmacokinetic characteristics and mucosal irritation.

In order to achieve the long-term management of endometriosis, a more economical and environmentally friendly material, ethylene vinyl acetate (EVA), was used to prepare a intravaginal ring with anastrozole (ATZ). This paper has compared the pharmacokinetic parameters with oral tablets (Aida®) in mini pigs and evaluated the uterine targeted effect and mucosal irritation of the ring. A bioassay method was developed and validated for the determination of ATZ in mini pigs. The determination of ATZ was achieved by LC-MS/MS using terfenadine as the internal standard. Separation was achieved on a Kinetex-C18 110A chromatographic column (3 × 30 mm, 2.6μm; Phenomenex) with a gradient mobile phase consisting of methanol (0.1% formic acid) and water (0.1% formic acid). The method has been proved to be scientific and sensitive through methodological validation and can be easily and quickly applied to the determination of the content of anastrozole in mini pigs. The pharmacokinetic test results show that there was no significant difference in pharmacokinetic parameters between the two formulations. The intravaginal ring has a passive targeting effect on the uterus, and its mucosal irritation is acceptable. The intravaginal ring provides a new method for long-term management of endometriosis.

Acceptability of the dapivirine vaginal ring for HIV-1 prevention among women reporting engagement in transactional sex

ABSTRACT We assessed if acceptability of the dapivirine vaginal ring for HIV prevention differed among the subgroup of women who reported engaging in transactional sex prior to enrollment in MTN-020/ASPIRE (phase III trial in Malawi, South Africa, Uganda, and Zimbabwe, 2012-2015; n = 2629). Transactional sex was defined as receipt of money, goods, gifts, drugs, or shelter in exchange for sex in the past year. Dimensions of acceptability included: ease of use and physical sensation in situ, impacts on sex, partner’s opinion, and likelihood of future use. We used Poisson regression models with robust standard errors to compare risk of acceptability challenges by baseline history of transactional sex. At product discontinuation, women exchanging sex found the ring comfortable (90%), easy to insert (92%) and nearly all (96%) were likely to use the ring in the future. Women who had exchanged sex were more likely to report feeling the ring during sex (ARR 1.43, 95% CI: 1.09, 1.89; p = 0.01) and slightly more likely to mind wearing the ring during menses (ARR 1.22, 95% CI: 1.01, 1,46; p = 0.04) and during sex (ARR 1.22, 95% CI: 1.02, 1.45; p = 0.03). Messaging and counseling should include enhanced support for use during sex and menses to support optimal use.

Defining principles for a choice-based approach to HIV prevention

The HIV prevention landscape is on the cusp of an unprecedented era of multiple biomedical prevention products available for distribution. Several HIV prevention options, such as oral pre-exposure prophylaxis (PrEP), dapivirine vaginal rings, and injectable cabotegravir for PrEP, are becoming more widely available. Although the future HIV prevention market promises to be rich in options, it would benefit from a core set of principles that uphold choice in all phases of product development, assessment, and introduction. These principles, as presented in this Viewpoint, show the applicability, opportunities, and challenges of choice in different contexts of HIV prevention and provide checkpoints of accountability. By committing to these principles, stakeholders at national and global levels can advance choice across all phases of the HIV prevention market, thereby ensuring that individuals can realise their right to choose when and how to prevent HIV in their own lives.

Personalizing prevention: Advances in pharmacotherapy for HIV prevention.

The HIV epidemic continues to pose a significant burden on the healthcare system. Although the incidence of annual new infections is decreasing, health disparities persist and most new infections remain concentrated into different racial, ethnic, and minority groups. Pre-exposure prophylaxis (PrEP), which involves those at high risk of acquiring HIV to take chronic medications to prevent acquisition of the virus, is key to preventing new HIV infections. The purpose of this article is to review medication therapies for PrEP and examine their role in personalizing PrEP in different patient populations. Additionally, new medications currently under development for PrEP are reviewed, as well as treatment as prevention (TasP) and post-exposure prophylaxis (PEP). There are currently four medications available for PrEP: the oral options of co-formulated emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or emtricitabine/tenofovir alafenamide (FTC/TAF); injectable long-acting cabotegravir (CAB-LA); and the vaginal ring dapivirine (DPV-VR). FTC/TAF is not currently indicated for persons at risk for HIV through vaginal sex due to lack of studies, but trials are currently ongoing. DPV-VR is available in Zimbabwe and South Africa and has been endorsed by the World Health Organization but is not currently available in the United States. Several agents are also in development for use in PrEP: the novel long-acting injectable lenacapavir, a first-in-class capsid inhibitor, which has no cross-resistance to any existing HIV drug class; the subdermal implant islatravir, a first-in-class translocation inhibitor; and VRC01, a broadly neutralizing antibody (bnAb) which has been evaluated in proof-of-concept studies that may lead to the development of more potent bnAbs. Overall, PrEP is highly effective at preventing HIV infection in high-risk populations. Identifying optimal PrEP regimens in different patient populations is complex and must consider patient-specific factors and medication cost and access considerations. Lastly, providers should consider individual patient preferences with regard to prevention to improve access, retention in care, and adherence.

Preferred product attributes of a multipurpose vaginal ring: Findings from a phase 1 trial.

Most women face multiple and co-occurring risks from unwanted pregnancy, human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) at some point during their lifetime. While a range of contraceptive methods exist and options for HIV prevention are increasing, to date, only male and female condoms provide multipurpose protection from both pregnancy and disease. From September 2017 to December 2018, 60 women from the United States and the Dominican Republic, randomized 1:1 to continuous or interrupted use and 4:1 to active vs. placebo ring, participated in a Phase I trial to assess the safety and tolerability of a three-month multipurpose intravaginal ring (IVR) containing the antiviral tenofovir and the contraceptive levonorgestrel. This study examines survey responses from all participants and qualitative data from a subset of 17 women to assess acceptability of and preferences for IVR characteristics. Overall, women liked the concept of a multipurpose IVR and found it easy to insert and remove. Initial concerns about the size or thickness of the ring generally disappeared with use experience. Women weighed trade-offs between the ease of continuous use for a longer duration against concerns about hygiene and discoloration of the ring when left in place during menses. Whether randomized to continuous or interrupted use, most women found ring attributes (size, thickness, flexibility) very acceptable. They provided recommendations via survey and qualitative interviews for ring modifications that would further increase acceptability. Insights into women's use experiences also suggest the need for clear counseling messages and introduction strategies that can facilitate women's choice and use of prevention methods. Study findings suggest that a multipurpose IVR would make a valuable contribution to women's sexual and reproductive health options, and that both continuous and interrupted use strategies may be preferred.

LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity.

High rates of unintended pregnancies worldwide indicate a need for more accessible and acceptable methods of contraception. We have developed a monoclonal antibody, the Human Contraception Antibody (HCA), for use by women in vaginal films and rings for contraception. The divalent F(ab')2 region of HCA binds to an abundant male reproductive tract-specific antigen, CD52g, and potently agglutinates sperm. Certain other antibody activities mediated by the Fc region such as mucus trapping, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) could have beneficial or negative effects. The purpose of this study was to document HCA Fc effector functions and determine whether an engineered variant of HCA with a modified Fc region, HCA-LALAPG, retains desirable contraceptive activity while minimizing Fc-mediated effects. Fab and Fc functions were compared between HCA and HCA-LALAPG. Fab activity was assessed using sperm agglutination and modified swim-up ("sperm escape") assays. Fc functions were assessed by CDC (sperm immobilization), ADCP, and cervical mucus penetration assays. HCA and HCA-LALAPG showed equivalent activity in assays of Fab function. In the assays of Fc function, HCA supported strong CDC, ADCP, and sperm trapping in cervical mucus whereas HCA-LALAPG demonstrated little to no activity. HCA and the HCA-LALAPG variant were both highly effective in the sperm agglutination assays but differed in Fc mediated functions. Use of the HCA-LALAPG variant for contraception in women could reduce antibody-mediated inflammation and antigen presentation but may have reduced contraceptive efficacy due to much weaker sperm trapping in mucus and complement-dependent sperm immobilization activity.