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Background/aims: The 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). Methods: Data 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. Results: More 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. Conclusions: Vaginal 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. [ABSTRACT FROM AUTHOR]

Background Confounding introduced by individuals' sexual risk behavior is potentially a significant source of bias in HIV-1 prevention intervention studies. To more completely account for sexual behaviors when assessing the efficacy of the monthly dapivirine ring, a new longer-acting HIV-1 prevention option for women, we estimated per-sex-act risk reduction associated with product use. Methods We conducted a secondary analysis of data from MTN-020/ASPIRE, a phase 3, randomized, placebo-controlled efficacy trial of the dapivirine ring that recruited HIV-uninfected, African women aged 18–45 years. With cumulative sex acts as the time scale, we used multivariable Cox regression with inverse probability of censoring weights to estimate HIV-1 risk reduction associated with a rate of dapivirine release indicative of consistent product use. Results Women in the dapivirine ring group (n = 1187) had an estimated incidence rate of 2.3 (95% confidence interval [CI], 1.8–3.1) HIV-1 acquisition events per 10 000 sex acts versus 3.6 (95% CI, 2.9–4.4) per 10 000 acts in the placebo group (n = 1187). Dapivirine release indicative of consistent ring use was associated with a 63% (95% CI, 33%–80%) per-sex-act HIV-1 risk reduction. Conclusions These results support the efficacy of the dapivirine vaginal ring for HIV-1 prevention and help to inform decision-making for women, providers, and policymakers regarding product use. Clinical Trials Registration NCT01617096. [ABSTRACT FROM AUTHOR]

Introduction: Tenofovir‐based oral pre‐exposure prophylaxis is currently approved for HIV prevention; however, adherence in women has been low. A vaginal gel containing tenofovir (TFV) demonstrated partial protection to HIV but protection was not confirmed in additional studies. Vaginal rings offer user‐controlled long‐acting HIV prevention that could overcome adherence and protection challenges. TFV may also help prevent herpes simplex virus type 2 acquisition when delivered intravaginally. We evaluated the pharmacokinetics, safety, adherence and acceptability of a 90‐day TFV ring. Methods: Between January and June 2019, Microbicide Trials Network (MTN)‐038 enrolled 49 HIV‐negative participants into a phase 1, randomized (2:1) trial comparing a 90‐day ring containing 1.4 grams (g) TFV to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid and cervical tissue, and TFV‐diphosphate (TFV‐DP) in cervical tissue. Used rings were analysed for residual TFV. Safety was assessed by adverse events (AEs); acceptability and adherence by self‐report. Results: Mean age was 29.5; 46 identified as cisgender‐female and three gender non‐conforming. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs in the TFV versus placebo arms (p = 0.41); no grade ≥3 AEs were reported. Geometric mean TFV concentrations increased through day 34 in CVF/rectal fluid and day 59 in plasma, but declined across compartments by day 91. Geometric mean TFV‐DP tissue concentrations exceeded the 1000 fmol/mg target through day 56, but fell to 456 fmol/mg at day 91. Among 32 rings returned at the end of the study, 13 had no or low (<0.1 g) residual TFV. Residual TFV did not differ by socio‐demographics, sexual activity, Nugent Score or vaginal microbiota. Most participants reported being fully adherent to ring use: 85% and 81% in the TFV and placebo arms, respectively (p = 1.00). A majority of participants reported liking the ring (median 8 on a 10‐point Likert scale) and reported a high likelihood of using the ring in the future, if effective (median 9). Conclusions: The 90‐day TFV ring was well‐tolerated, acceptable and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use. [ABSTRACT FROM AUTHOR]

Background: Delivering contraceptive hormones through a transdermal patch or a vaginal ring might have advantages over the traditional oral route. Objectives: To compare the effectiveness, compliance, and side effect profile of oral and parenteral drug administration methods. Methods: We performed a systematic literature search in four medical databases—MEDLINE (via PubMed), Cochrane Library (CENTRAL), Embase, and Scopus—from inception to 20 November 2022. Randomized controlled trials assessing the efficacy, compliance, and adverse event profile of combined parenteral and oral hormonal contraceptives were included. Results: Our systematic search provided 3952 records; after duplicate removal, we screened 2707 duplicate-free records. A total of 13 eligible studies were identified after title, abstract, and full-text selection. We observed no significant difference in contraceptive efficacy (Pearl Index) between oral and parenteral drug administration (MD = −0.06, CI: −0.66–0.53; I2 = 0%). We found significant subgroup differences between parenteral methods in terms of compliance (χ2 = 4.32, p =0.038, I2 = 80%) and certain adverse events: breast discomfort (χ2 = 19.04, p =0.001, I2 = 80%), nausea (χ2 = 8.04, p =0.005, I2 = 75%), and vomiting (χ2 = 9.30, p =0.002; I2 = 72%). Conclusion: Both parenteral and oral contraceptives can be used as an effective contraceptive method, and the route of administration should be tailored to patient needs and adverse event occurrence. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Polymeric drug-releasing vaginal rings are useful for both local and systemic administration of drugs via the intravaginal route. Typically, they provide continuous sustained or controlled release of drug(s) over extended time periods, thereby avoiding overdose and improving adherence. This first-in-human study (EudraCT number: 2020-0050044-30) evaluated the pharmacokinetics, safety, and tolerability of a single dose of oxybutynin administered by a novel microprocessor-controlled vaginal ring (MedRing). Eight healthy female subjects received an electronically controlled single intravaginal dose of 3 mg oxybutynin hydrochloride (100 mg/mL) dissolved in 1:1 water/propylene glycol administered via MedRing. Following dosing, MedRing was kept in situ for up to 6 h. Blood samples were collected 1 h prior to oxybutynin dosing and subsequently at regular intervals post-dose for the assessment of plasma concentrations of oxybutynin and its active metabolite N-desethyloxybutynin. The results showed that MedRing efficiently administered oxybutynin via the intravaginal route, resulting in plasma oxybutynin levels comparable to orally administered oxybutynin. The mean ± standard deviation pharmacokinetic parameters for oxybutynin were Cmax 5.4 ± 2.7 ng/mL, AUCinf 34.9 ± 17.4 h ng/mL, t1/2 8.5 ± 3.5 h and for N-desethyloxybutynin were Cmax 3.9 ± 2.5 ng/mL, AUCinf 51.1 ± 43.1 h ng/mL, t1/2 7.7 ± 5.9 h. No serious adverse events were reported. The study demonstrates that intravaginal administration of oxybutynin hydrochloride using the MedRing device was well tolerated. [ABSTRACT FROM AUTHOR]

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. 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. 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. Both IVR1 and IVR2 were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen. [ABSTRACT FROM AUTHOR]

Three-dimensional printing technologies can be implemented for the fabrication of personalized vaginal rings (VRs) as an alternative approach to traditional manufacturing. Although several studies have demonstrated the potential of additive manufacturing, there is a lack of knowledge concerning the opinions of patients and clinicians. This study aimed to investigate the perception of women and gynecologists regarding VRs with personalized shapes. The devices were printed with different designs (traditional, "Y", "M", and flat circle) by Fused Deposition Modeling for a cross-sectional survey with 155 participants. Their anticipated opinion was assessed through a questionnaire after a visual/tactile analysis of the VRs. The findings revealed that most women would feel comfortable using some of the 3D-printed VR designs and demonstrated good acceptability for the traditional and two innovative designs. However, women presented multiple preferences when the actual geometry was assessed, which directly related to their age, previous use of the vaginal route, and perception of comfort. In turn, gynecologists favored prescribing traditional and flat circle designs. Overall, although there was a difference in the perception between women and gynecologists, they had a positive opinion of the 3D-printed VRs. Finally, the personalized VRs could lead to an increase in therapeutic adherence, by meeting women's preferences. [ABSTRACT FROM AUTHOR]

Combined hormonal contraceptives (CHC) are a valuable and highly effective option in contraceptive counseling. Methods and preparations available in Switzerland are combined oral contraceptives (COC), vaginal rings and transdermal patches. All preparations contain an estrogen and a progestin component. The estrogen component mainly consists of the synthetically produced ethinylestradiol (EE), although newer COC may contain natural estrogens such as estradiol (E2) and estetrol (E4). For the progestin component, a variety of luteal body hormones are available, which enable the health care professional to prescribe a "tailored" product for the patient due to their different partial effects. The individual thromboembolism (TE) risk should always be considered and taken into account when prescribing CHC. [ABSTRACT FROM AUTHOR]

There are controversial debates regarding the effects of contraceptive vaginal ring devices on females' sexual function. Therefore, the meta-analysis of before-after was conducted on the intervention studies published in the past years to clarify these contradictions. The existing literature on the subject was reviewed by searching through such databases as PubMed, Scopus, ISI Web of Sciences, Embase, Cochrane Library and Google Scholar up to July 2021. Before-after intervention studies that had examined the effect of vaginal rings on females' sexual function were collected as well. In total, five studies with 369 participants were included in quantitative syntheses. Pooled results from the random-effect model showed that NuvaRing had a positive effect on females' sexual function three months after insertion (WMD: 2.48; 95% CI: 0.30, 4.67; P = 0.026); however, this effect was not significant after 6 months (WMD: 4.38; 95% CI: -4.95, 13.72; P = 0.357). Meta-regression analysis suggested that the effect of this device is associated with users' age and body mass index 3 months after insertion. No publication bias was found by Egger's test or funnel plots. Overall, the results of this meta-analysis support the view that vaginal ring use is associated with a positive effect on the sexual function of women 3 months after insertion, while the effect of this device on the sexual function of women was insignificant after 6 months. However, given the dearth of available data, it is not possible to reach a definite conclusion on the effect of vaginal rings on females' sexual function. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Persistent use of HIV prevention methods can be a challenge, particularly for some younger women. The long-acting, discreet, woman-centric dapivirine vaginal ring offers promise as a prevention method with less user burden, which could support continued use. We assessed dapivirine vaginal ring use to understand adherence patterns and identify characteristics influencing patterns. Setting: Participants enrolled in South Africa in the MTN-020/ASPIRE randomized placebo-controlled trial. Methods: We used group-based trajectory modeling to identify clusters of participants with similar longitudinal patterns of adherence in the last year of participation and potential predictors of group membership. Women with at least 1 year of follow-up were included (n = 626). Results: Five adherence patterns were identified: (1) consistently high, 34%, (2) consistently moderate, 34%, (3) consistently low, 16%, (4) decreasing, 9%, and (5) increasing, 7%. Women younger than 22 years [adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI): 1.0 to 3.0], using an intrauterine device (AOR 3.3, 95% CI: 1.4 to 7.8) or oral contraceptives (AOR 3.9, 95% CI: 1.7 to 8.9), experiencing menses (AOR 1.8, 95% CI: 1.1 to 3.0), and who reported inconsistent condom use (AOR 1.8, 95% CI: 1.0 to 3.3) were more likely to be classified as consistently low compared to consistently high (referent). Conclusions: Most South African women successfully persisted with a moderate or high level of use. Encouraging ring replacement with completion of menses may help to decrease concerns about hygiene and improve persistence. Associations between contraception and persistent low adherence suggest efforts may be needed to ensure contraceptive method choice does not interfere with ring use. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Objective: This study aims to assess the product-related, relationship-related, and sex-related factors that act as facilitators and barriers to the acceptability of a vaginal ring (VR) for HIV prevention among adolescent girls. Design: Qualitative study. Methods: Ninety-six girls aged 15–17 years from 6 urban US sites were enrolled in MTN-023/IPM 030, a 24-week randomized controlled trial, for assessing the safety and acceptability of a dapivirine VR for HIV prevention. At week 24, 21 girls were randomly selected to participate in in-depth interviews. Interviews were transcribed verbatim and data analyzed using a thematic analysis approach. Facilitators and barriers to VR acceptability related to participants' relationships, sexual activity, and characteristics of the VR product were identified. Results: Factors related to relationships rarely seemed to act as barriers to VR acceptability; most participants disclosed VR use to sexual partners, and positive reactions from sexual partners, which were common, seemed to facilitate VR acceptability. Emotional and/or physical discomfort surrounding VR use during sex was mentioned occasionally as a barrier to VR acceptability. Product characteristics were most frequently mentioned as barriers to VR acceptability. Many participants reported concerns about the large size of the VR on first impression. Although most found the VR comfortable, some reported pain with VR insertion. Several participants were concerned about VR cleanliness, particularly during menstruation. Conclusion: Product considerations, specifically size and use during menstruation, were the most commonly reported barriers to VR acceptability in this study. Adolescent girls may require additional counseling to assuage product concerns regarding a VR for HIV prevention. [ABSTRACT FROM AUTHOR]

Background: A 25-mg dapivirine vaginal ring has been demonstrated to reduce risk of human immunodeficiency virus (HIV) acquisition in nonpregnant adult women. In this secondary analysis of studies conducted in US adolescent, lactating, and postmenopausal females, vaginal microbiota was assessed prior to and after ring use, and between dapivirine and placebo ring users.Methods: Vaginal fluid swabs were collected before and after product use for the evaluation of microbiota using Nugent criteria, quantitative culture, and quantitative polymerase chain reaction.Results: Vaginal ring use did not impact bacterial vaginosis prevalence among the 3 populations and was associated with minimal shifts in microbiota. Adolescents in both arms demonstrated an increased prevalence of Lactobacillus crispatus and a decrease in quantity of Megasphaera lornae. Postmenopausal active and placebo ring users demonstrated an increased prevalence of lactobacilli and non-albicans yeast, while dapivirine ring users demonstrated an increased prevalence of Candida albicans and increased quantity of group B Streptococcus and non-albicans yeasts. Prevotella species were increased in lactating women, whereas Prevotella timonensis increased in prevalence and concentration among adolescent and postmenopausal females and Prevotella bivia increased in prevalence among adolescent dapivirine ring users.Conclusions: Dapivirine vaginal ring use was associated with minimal changes in the vaginal microbiota that are likely not clinically significant. [ABSTRACT FROM AUTHOR]

Family planning enables society to prevent unintended pregnancies and helps in attaining desired spacing between the pregnancies. It is done with the use of contraceptive methods and infertility treatments. The use of contraceptives serves to ease maternal ill-health and reduce pregnancy-related deaths and helps to decrease the number of unsafe abortions and HIV transmission from mothers to newborns. The most popular contraception method is a daily dose of combined oral contraceptives pills. However, poor compliance and various adverse effects are common problems of oral contraceptives that considerably reduce their long-term use. Thus, several non-oral contraceptive options have been developed for better compliance, reduced side effects and improved therapeutic efficacy. This review presented the non-oral contraceptive formulations given by different routes such as transdermal, nasal, subcutaneous, intramuscular, intrauterine and vaginal routes. These formulations delivering contraceptives, mainly through devices, include transdermal patches and microneedles, nasal sprays, intrauterine devices and intrauterine systems, vaginal rings, contraceptive implants and contraceptive injections, which are unique in their specific advantages and drawbacks. [Display omitted] [ABSTRACT FROM AUTHOR]

Oral Pre-Exposure Prophylaxis (PrEP) is an established option, and the dapivirine vaginal ring is emerging as a promising strategy for HIV prevention option for women. Because of this, understanding the contextual and cultural factors that will support the increased uptake of these products is crucial. In sub-Saharan Africa, religious leaders may be important stakeholders to involve in product information, education and roll-out. We conducted a sub-analysis of data from 232 participants taking part in the MTN-041/MAMMA study to explore religious leaders' involvement in pregnant and breastfeeding women's health. Study participants viewed biomedicine and spirituality as interlinked and believed that women could seek health-related care from medical experts and turn to faith-based organisations for religious or spiritual needs. Religious leaders were invested in the health of their congregations, endorsed a variety of sexual health strategies, and were eager to learn more about emerging HIV prevention technologies. These data signal the role of religious leaders in supporting their communities, and the importance of involving religious leaders in efforts to roll out new HIV prevention products to facilitate uptake. [ABSTRACT FROM AUTHOR]

Objective: The vaginal ring (ring) is a female-initiated, long-acting drug delivery system for different indications, including HIV prevention. Our aim was to provide evidence for acceptability of the vaginal ring across indications to support dapivirine and multipurpose prevention technology ring introduction and roll out.Study Design: This systematic review and meta-analysis followed PRISMA guidelines. We searched PubMed, Web of Science, Embase, and grey literature for publications reporting favorable ring acceptability and secondary outcomes involving actual ring use (comfort, ease of ring use, ring comfort during sex, expulsions, and vaginal symptoms) or hypothetical acceptability for any indication published January 1, 1970-June 15, 2021. We estimated random-effects pooled prevalence, assessing between-study variation using meta-regression.Results: Of 2,234 records, we included 123 studies with 40,434 actual and hypothetical ring users. The primary outcome assessment included 50 studies with 60 ring subgroups totaling 19,271 ring users. The favorable acceptability pooled prevalence was 85.6% (95%CI 81.3, 89.0), while hypothetical acceptability among non-ring users was 27.6% (95%CI 17.5, 40.5). In meta-regression, acceptability was higher in menopause (95.4%; 95%CI 88.4, 98.2) compared to contraceptive rings (83.7%; 95%CI 75.6, 89.5). Acceptability was lower in pharmacokinetic studies (50%; 95%CI 22.1, 77.9) compared to RCTs (89.5%; 95%CI 85.8.92.4) and in studies assessing acceptability at ≥12 months (78.5%; 95%CI 66.5, 87.1) versus studies assessing acceptability at <3 months (91.9%; 95%CI 83.7, 96.1). European (90.6%; 95%CI 83.9, 94.7), Asian (97.1%; 95%CI 92.0, 99.0), and multi-region studies (93.5%; 95%CI 84.6, 97.4) reported more favorable acceptability compared to African studies (59.4%; 95%CI 38.3, 77.5). Secondary outcomes were similarly favorable, including ring comfort (92.9%; 95%CI 89.2, 95.4), ease of use (90.9%; 95%CI 86.5, 94.0), and comfort during sex (82.7%; 95%CI 76.4, 87.6). Limitations include inconsistent outcome definitions and unmeasured factors affecting acceptability.Conclusions: Women who used vaginal rings reported they were acceptable across indications geographic regions and indications. Policy makers should consider the ring as an important option for pregnancy and HIV prevention drug development.Implications: This review found favorable acceptability among vaginal ring users across indications and geographic areas, in contrast to low hypothetical acceptability among non-users. Vaginal rings are an important drug delivery system for pregnancy and HIV preventions, and scale-up should plan to address initial hesitancy among new users. [ABSTRACT FROM AUTHOR]

The aim was to assess the pharmacokinetics of tolterodine released from vaginal rings and of its active metabolite 5‐hydroxymethyl tolterodine (5‐HMT) compared to the respective pharmacokinetics resulting from oral administration of extended‐release tolterodine in healthy, postmenopausal women. In this single‐center, open‐label trial, subjects received 4 treatments in a fixed sequence: fasted oral extended‐release tolterodine 2.74 mg/d (reference, 5 days), single vaginal rings; tolterodine releasing rates: 0.95 mg/d (test 1, 13 days), 1.40 mg/d (test 2, 28 days), 1.90 mg/d (test 3, 28 days). Systemic exposure of tolterodine, 5‐HMT, and the molar sum of unbound tolterodine/5‐HMT (active moiety [AM]) in steady state was determined. Sixteen of 18 included women completed the study. For the oral formulation, peak‐trough fluctuations of tolterodine, 5‐HMT, and AM plasma concentrations (AM: mean maximum/minimum concentration, 2580/574 pmol/L = 4.5) were large. Intravaginal application led to steadier plasma concentrations (AM, test 3: mean maximum/minimum concentration, 1880/814 pmol/L = 2.3; fluctuation due to initial peak), which is the result of constant releasing rates after ring insertion over the 28‐day application period. The vaginal rings demonstrated a favorable local tolerability. The most common adverse events with oral and vaginal tolterodine were headache (n = 11) and dry mouth (n = 8). Vaginal rings releasing tolterodine represent a promising new formulation for overactive bladder treatment with little fluctuation of drug plasma levels. This is expected to lead to a more predictable and continuous therapeutic effect and a reduced frequency of side effects compared to oral tolterodine. [ABSTRACT FROM AUTHOR]

Objective: This study aims to assess the product-related, relationship-related, and sex-related factors that act as facilitators and barriers to the acceptability of a vaginal ring (VR) for HIV prevention among adolescent girls. Design: Qualitative study. Methods: Ninety-six girls aged 15-17 years from 6 urban US sites were enrolled in MTN-023/IPM 030, a 24-week randomized controlled trial, for assessing the safety and acceptability of a dapivirine VR for HIV prevention. At week 24, 21 girls were randomly selected to participate in in-depth interviews. Interviews were transcribed verbatim and data analyzed using a thematic analysis approach. Facilitators and barriers to VR acceptability related to participants' relationships, sexual activity, and characteristics of the VR product were identified. Results: Factors related to relationships rarely seemed to act as barriers to VR acceptability; most participants disclosed VR use to sexual partners, and positive reactions from sexual partners, which were common, seemed to facilitate VR acceptability. Emotional and/or physical discomfort surrounding VR use during sex was mentioned occasionally as a barrier to VR acceptability. Product characteristics were most frequently mentioned as barriers to VR acceptability. Many participants reported concerns about the large size of the VR on first impression. Although most found the VR comfortable, some reported pain with VR insertion. Several participants were concerned about VR cleanliness, particularly during menstruation. Conclusion: Product considerations, specifically size and use during menstruation, were the most commonly reported barriers to VR acceptability in this study. Adolescent girls may require additional counseling to assuage product concerns regarding a VR for HIV prevention. [ABSTRACT FROM AUTHOR]

Introduction: Vaginal rings are a promising approach to provide a woman‐centred, long‐acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV‐1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three‐month rings with different DPV dosages, compared with the monthly DPV ring. Methods: From December 2017 to October 2018, MTN‐036/IPM‐047 enrolled 49 HIV‐negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three‐month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow‐up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. Results: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs in the extended duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations/outages) with no differences between the monthly versus three‐month rings. Most participants found the ring acceptable (median = 8 on 10‐point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms (p = 0.01 and p = 0.15 respectively). Conclusions: The extended duration DPV rings were well‐tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three‐month DPV rings for HIV prevention. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the pharmacokinetics and pharmacodynamics of oestriol (E3) and trimegestone (TMG) in healthy women after application of three different vaginal rings over 21 days. The vaginal rings had a nominal delivery rate of 0.413/0.050 mg/day (Test 1), 0.311/0.090 mg/day (Test 2) and 0.209/0.137 mg/day (Test 3) E3/TMG.Methods: Thirty-five healthy women were randomised to receive a single application of Test 1, 2 or 3 (Clinical Trial NCT03343912). The E3 and TMG plasma concentration was determined by LC-MS/MS. Oestradiol (E2) and progesterone (PG) serum concentrations, and bleeding patern were determined as pharmacodynamic parameters. Safety was assessed by evaluation of adverse events and local tolerability.Results: The total and maximum exposure of E3 and TMG increased in a proportional ratio to dose. However, not in a magnitude which was expected from the dose differences for E3. During Test 2 and 3 treatment all E2 and PG values remained on a well suppressed level until end of treatment. E2 and PG serum levels increased distinctly earlier after ring removal with Test 1 compared to Test 2 and 3. Test 3 achieved 95.24% of "no bleeding" days under treatment followed by Test 1 (91.67%), and Test 2 (86.15%).Conclusions: The Test 3 formulation presented the best dose combination of E3/TMG for contraception. Moreover, all vaginal rings were well tolerated. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have found that a monthly dapivirine vaginal ring was well-tolerated and reduced HIV-1 risk among women in sub-Saharan Africa. However, in order for the ring or other novel prevention methods to have optimal impact, it is necessary to understand and address women's challenges to uptake and adherence. This paper provides insight into a few key challenges noted by women using the ring and contraceptives simultaneously.Methods: The qualitative portion of the MTN-020/ASPIRE study consisted of data collection using single in-depth interviews, serial in-depth interviews, and focus group discussions, conducted with 214 participants across 15 sites in Malawi, South Africa, Uganda and Zimbabwe. A coding team used qualitative analysis software to identify themes within the interviews.Results: The primary qualitative themes among participant data pertained to side effects. Participants reported negative side effects related to menses, in some cases attributing these effects to their contraceptives and in others to the vaginal ring. Participants also expressed concern over the long-term impact of contraception and ring use on fertility, including the reversibility of the contraceptive, especially among nulliparous women.Conclusions: Women's attitudes toward contraceptives can impact their willingness to concurrently use and adhere to a novel HIV prevention product. To optimize the potential of both prevention products, researchers should pre-emptively address concerns about contraceptive impact on fertility and counsel women about the expected side effects of contraceptives versus the ring. Clinical trials identifier NCT01617096. Registered on 6-12-2012 at clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT01617096. [ABSTRACT FROM AUTHOR]

Objectives: The primary objective was to determine the lowest trimegestone (TMG) dose, administered via a vaginal ring, that effectively inhibited ovulation.Study Design: Single-centre, open-label, single-dose, parallel-group clinical trial with adaptive design. Eighty healthy female volunteers with proven ovulatory cycles were allocated to treatment with a vaginal ring during 28 days, with an average daily release rate of either 46 µg, 94 µg, 147 µg, or 184 µg TMG (20 women/group). Ultrasound measurements of follicular growth and endometrial thickness, and blood sampling for follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone determinations were performed every 3rd (±1) day from treatment day 4 (±1) until day 28 (±1), and in a follow-up phase after ring removal, until study day 39 (±1). Trimegestone concentrations were measured at each visit in the treatment phase.Results: Mean age and body mass index were 28.8 years and 23.15 kg/m2. One subject in the lowest dose group (46 µg/day) ovulated, no ovulations were seen in the higher dose groups. The degree of ovarian suppression increased with the dose. Median estradiol levels were 119, 36.5, 33.2 and 27.2 pg/mL in the 46, 94, 147 and 184 µg/day groups, respectively. Ovarian activity was resumed in the follow-up phase. Plasma TMG levels gradually declined over the treatment period and showed dose proportionality. The study treatment was safe and well tolerated.Conclusion: The release rate of 94 µg TMG per day was the lowest effective dose for ovulation inhibition. The study results justify further development of the TMG-ring as progestogen-only contraceptive.Implications: The vaginal ring releasing TMG seems to be an effective new progestogen-only contraceptive preparation, having the advantage of once-a-month vaginal insertion. [ABSTRACT FROM AUTHOR]

Objective: To evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism.Study Design: We conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40 pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information.Results: Sixty-five participants enrolled in E2 75 (n = 22), 100 (n = 21), and 200 (n = 22) mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100 mcg/day groups were <40 pg/mL. In the 200 mcg/day group, median E2 concentrations peaked on days 4-5 of CVR use at 194 pg/mL (range 114-312 pg/mL) and remained >40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28-62 pg/mL) on days 88-90 (n = 11). Among the E2 200 mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0-16) and three (range 0-19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days.Conclusions: Estradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use.Implications: A 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation. [ABSTRACT FROM AUTHOR]

Background: The silicone Dapivirine Vaginal Ring 25 mg, has been developed to provide an additional HIV prevention option for women. If approved for use, women will always be counselled to use condoms when using the vaginal ring for maximum protection. This paper evaluates the compatibility of female condoms with the ring. Methods: This was a 2-period crossover, randomized noninferiority trial. Couples in 2 sites in the United States of America were randomized to FC2 Female Condom (FC2) with and without a placebo silicone ring and asked to use 4 female condoms in each period. The primary noninferiority endpoint was the clinical failure rate during intercourse or withdrawal (self-reported clinical breakage, slippage, misdirection, and invagination). Frequencies and percentages were calculated for each failure mode and differences in performance of the 2 periods, using the female condom without the ring as reference. Noninferiority was defined using an 8% margin at the 5% significance level. Safety and tolerability were also assessed. Results: Eighty-one couples were enrolled and 79 completed the trial using a total of 596 female condoms (297 and 299 with/without a ring inserted, respectively). Total female condom clinical failure was 14.1% and 15.7% in the presence and absence of a ring, respectively, with a difference of -2.1% (95% confidence interval: -7.8% to 3.6%), thereby demonstrating noninferiority when used with the ring. There were no differences in safety and tolerability between the 2 periods. Discussion: Concurrent use of the placebo silicone vaginal ring had no significant effect on female condom functionality or safety outcomes. [ABSTRACT FROM AUTHOR]

Background: The dapivirine vaginal ring reduced the risk of HIV infection by approximately 30% in Phase III trials. To ensure higher levels of protection against HIV and sexually transmitted infections, women should be counseled to use condoms when using the vaginal ring. This article evaluates the compatibility of male condoms with a placebo vaginal ring. Methods: This was a 2-period crossover, randomized, noninferiority trial. Couples in 2 sites in the United States were randomized to male condom use, with and without a placebo silicone vaginal ring, and asked to use 4 male condoms in each period. The primary noninferiority end points were total clinical failure and their component failure events (clinical breakage or slippage). Frequencies and percentages were calculated for each failure mode and differences in performance of the 2 periods using the male condom without the ring as reference. Noninferiority was defined using a 3% margin at the 5% significance level. Safety and acceptability were also assessed. Results: Seventy couples were enrolled, and 68 completed the trial with a total of 275 male condoms used in each period. Total condom clinical failure rates were 2.2% and 4.0% in the presence and absence of the vaginal ring, respectively, with a difference of -1.9% (95% confidence interval: -5.3% to 1.5%), thereby demonstrating noninferiority when used with the ring. There was no difference in safety between the 2 periods. Discussion: Concurrent use of the placebo silicone vaginal ring had no significant effect on male condom functionality or safety outcomes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the evidence on the effectiveness of vaginal microbicides in preventing HIV transmission in women.Methods: Systematic review through a comprehensive search of relevant electronic databases for eligible randomised controlled trials (RCTs) published through June 2019. Two authors independently screened titles and abstracts according to eligibility criteria, then extracted data and assessed risk of bias of included studies. We conducted a random-effects meta-analysis of risk ratios (RR) of HIV infection and assessed heterogeneity using chi-squared and I2 tests. Sources of heterogeneity were investigated through subgroup analysis, publication bias was assessed using funnel plots, and certainty of evidence was graded using GRADEPro software.Results: We included 18 RCTs which enrolled 40,048 sexually active, HIV-negative, non-pregnant women, aged 16 years and older, mainly from sub-Saharan Africa. The intravaginal ring containing dapivirine significantly reduced HIV risk by 29% (RR 0.71, 95% CI: 0.57-0.89; 2 RCTs, 4,564 women, moderate certainty of evidence). Estimates of effect of tenofovir 1% (RR 0.83, 95% CI: 0.65-1.06), nonoxynol-9 (RR 1.15, 95% CI: 0.93-1.42), cellulose sulphate (RR 1.16, 95% CI: 0.61-2.21), SAVVY (RR 1.34, 95% CI: 0.69-2.59), Carraguard (RR 0.89, 95% CI: 0.71-1.10), BufferGel (RR 1.02, 95% CI: 0.71-1.46), 0.5% PRO2000 (RR 0.88, 95% CI: 0.60-1.28) and 2% PRO2000 (RR 0.81, 95% CI: 0.58-1.12) failed to reach statistical significance; each had low certainty of evidence.Conclusion: The long-acting intravaginal ring containing dapivirine significantly reduced risk of HIV transmission in women by 29%. The remaining microbicides had no evident effect. [ABSTRACT FROM AUTHOR]

Combined vaginal rings (ethinylestradiol (EE)/desogestrel), indicated for contraception, are highly effective, comparable to other combined hormonal contraceptives, such as pills. In addition to this benefit, vaginal rings are easy to use, with a probable lower risk of forgetting, due to their non-daily, monthly schedule. Besides, for users with poor gastric tolerance to oral formulations, they represent a method with safety and comparable extraconceptive benefits. The latest generation rings have a novel polymeric structure, do not need special storage methods and do not generate accelerated initial release of EE, reducing the early increased systemic exposure to the synthetic steroids they contain. This review describes main aspects related to its use, efficacy, and safety for contraceptive purposes. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate whether the compositions of the ethylene vinyl acetate (EVA) membrane of two different contraceptive vaginal rings could influence the surface roughness, which is associated with the possible accumulation of vaginal biomass on the rings during use.Methods: We measured and compared the surface roughness of unused vaginal rings, NuvaRing and Ornibel, using a scanning electron microscope (SEM) and dedicated software that can convert SEM images into 3D models. Average roughness (Ra), average quadratic roughness (Rq) and mean height of the irregularities at 10 points (Rz) were calculated.Results: Different thicknesses of the EVA membranes between the two rings were noted. No significant differences were found between the two rings in the three evaluated values of surface roughness (NuvaRing vs Ornibel, respectively: Ra, 1.53 ± 0.14 vs 1.61 ± 0.14 µm, p = 0.141; Rq, 2.03 ± 0.25 vs 2.07 ± 0.16 µm, p = 0.688; Rz, 11.4 ± 3.1 vs 11.4 ± 2.4 µm, p = 0.987).Conclusion: The different composition of the vaginal rings' EVA membrane is not associated with different surface roughness. Ornibel is equivalent to NuvaRing in terms of surface roughness, despite the different composition of the membrane polymers. [ABSTRACT FROM AUTHOR]

Rumours may influence health-related behaviours, including the uptake of and adherence to HIV prevention products. This study assessed the safety and effectiveness of a vaginal ring delivering the antiretroviral dapivirine for HIV prevention in Africa. We explored negative rumours about study participation and the vaginal ring amongst study participants and their communities in Malawi, Uganda, South Africa and Zimbabwe. In total 214 women participated in either single or serial in-depth interviews, or a focus group discussion. Three key findings emerged in the data. Firstly, rumours reflected fears concerning the ring and trial participation. Given the historical-political context of the countries in which the trial was conducted, the ring's investigational nature and its foreign origin, ring use was rumoured to cause negative health outcomes such as cancer and infertility and to be associated with practices such as witchcraft or Satanism. The salience of these rumours varied by country. Secondly, rumours reportedly affected participants' adherence to the ring, and other women's willingness to participate in the study. Finally, participants reported that participant engagement activities helped address rumours, resulting in enhanced trust and rapport between staff and participants. [ABSTRACT FROM AUTHOR]

Introduction: A vaginal ring containing dapivirine is effective for HIV prevention as pre‐exposure prophylaxis (PrEP). We evaluated the potential epidemiological impact and cost‐effectiveness of dapivirine vaginal ring PrEP among 22‐ to 45‐year‐old women in KwaZulu‐Natal, South Africa. Methods: Using mathematical modelling, we studied dapivirine vaginal ring PrEP implementation, either unprioritized, or prioritized based on HIV incidence (≥3% per year), age (22 to 29 years) or female sex worker status, alongside the implementation of voluntary medical male circumcision and antiretroviral therapy scaled‐up to UNAIDS Fast‐Track targets. Outcomes over the intervention (2019 to 2030) and lifetime horizons included cumulative HIV infections, life‐years lived, costs and cost‐effectiveness. We assessed the incremental cost‐effectiveness ratios against the revealed willingness to pay ($500) and the standard (2017 per capita gross domestic product; $6161) cost‐effectiveness thresholds for South Africa. Results: Compared to a reference scenario without PrEP, implementation of dapivirine vaginal ring PrEP, assuming 56% effectiveness and covering 50% of 22 to 29‐year‐old or high‐incidence women, prevented 10% or 11% of infections by 2030 respectively. Equivalent, unprioritized coverage (30%) prevented fewer infections (7%), whereas 50% coverage of female sex workers had the least impact (4%). Drug resistance attributable to PrEP was modest (2% to 4% of people living with drug‐resistant HIV). Over the lifetime horizon, dapivirine PrEP implementation among female sex workers was cost‐saving, whereas incidence‐based PrEP cost $1898 per life‐year gained, relative to PrEP among female sex workers and $989 versus the reference scenario. In a scenario of 37% PrEP effectiveness, PrEP had less impact, but prioritization to female sex workers remained cost‐saving. In uncertainty analysis, female sex worker PrEP was consistently cost‐saving; and over the lifetime horizon, PrEP cost less than $6161 per life‐year gained in over 99% of simulations, whereas incidence‐ and age‐based PrEP cost below $500 per life‐year gained in 61% and 49% of simulations respectively. PrEP adherence and efficacy, and the effectiveness of antiretroviral therapy for HIV prevention, were the principal drivers of uncertainty in the cost‐effectiveness of PrEP. Conclusions: Dapivirine vaginal ring PrEP would be cost‐saving in KwaZulu‐Natal if prioritized to female sex workers. PrEP's impact on HIV prevention would be increased, with potential affordability, if prioritized to women by age or incidence. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of investigational vaginal rings containing nomegestrol acetate (NOMAC) plus 17β-estradiol (E2) or etonogestrel (ENG) plus E2 in women with moderate to severe primary dysmenorrhea.Study Design: This was a Phase 2b randomized, placebo-controlled, multicenter, double-blind study. We randomized participants to one of five treatment groups: four hormonal rings and one placebo ring. The investigational vaginal rings released 300 μg of E2 daily along with 700 μg or 900 μg of NOMAC or 100 μg or 125 μg of ENG. Each participant received 2 identical rings and was to insert each for 21 days followed by a 7-day ring-free period. The primary endpoint, as assessed by a daily electronic diary (e-Diary), was the change in menstrual pain score from baseline to the second in-treatment withdrawal bleeding episode (Cycle 2). The pain score was the mean of the three highest scores for menstrual cramping pain (0-4 point scale) recorded from the day before menses to the third day of bleeding. The primary hypothesis was that at least one investigational vaginal ring would demonstrate a statistically significant larger reduction from baseline in pain score compared to placebo. Secondary endpoints included total mean impact score (which assessed the negative impact on work/school, physical activities, leisure/social activities) and the amount and days of rescue medication (ibuprofen) used.Clinical Trial Registration Number: NCT01670656.Results: We randomized 439 participants. The mean pain score decreased from baseline to Cycle 2 in all groups; the decrease in all four treatment groups compared to placebo was statistically significant (p-values ≤0.002). All treatment groups had greater reductions than placebo in ibuprofen intake and greater improvement in impact scores; these differences were statistically significant for both endpoints for the ENG-E2 100/300 μg/day group, while the other groups were not statistically significant for one or both endpoints.Conclusion: All four investigational rings produced a statistically significantly larger reduction from baseline in mean menstrual pain score compared to placebo while pain medication use decreased.Implications: This placebo-controlled study provides evidence that vaginal contraceptive rings containing NOMAC-E2 or ENG-E2 improve moderate to severe dysmenorrhea, across all of doses studied. This adds to the evidence that hormonal contraceptives are effective treatments for dysmenorrhea. [ABSTRACT FROM AUTHOR]

Objective: In this study we aimed to investigate the content and process of contraceptive counseling surrounding combined hormonal contraceptive (CHC) methods (combined oral contraceptives, the ring, and the patch).Study Design: We performed a mixed methods analysis of data collected as part of the Patient-Provider Communication about Contraception study, in which reproductive age women and their providers were recruited at several San Francisco Bay Area clinics from 2009-2012. Participants completed pre- and post-visit surveys, and had their visits audio recorded and transcribed. We performed descriptive and bivariate analyses of the entire cohort to examine associations between demographic characteristics and pre-existing method preferences with method selection and counseling content, and coded transcripts of a subset of the sample for salient themes related to content and process of counseling about combined hormonal contraceptive methods using a directed content analysis approach.Results: The overall sample included 342 women, with 152 women (44%) having a preference for a specific CHC prior to their visit, 127 women (37%) had a preference for a non-CHC method, and 63 (18%) having no existing method preference. Of the women who reported preferring a CHC in their pre-visit survey, the majority (72%) chose that method. We found that women were inconsistently counseled about the range of CHC methods. For example, women who had no pre-visit method preference (52%) or who preferred the ring (54%) or the patch (73%) were more likely to receive comprehensive counseling about the three CHC methods than were women who preferred combined oral contraceptives (35%) or non-CHC methods (33%). Providers mentioned the patch the least often, and in qualitative analysis indicated discomfort with prescribing this method. Side effects and benefits of methods, as well as strategies to enhance successful use of the chosen method, were inconsistently discussed. In only 73% of visits in which a woman chose a CHC did the provider assess the patient's ability to use the chosen method correctly, and in 66% of all visits in which women chose a CHC method, providers discussed what to do if she was dissatisfied with the method.Conclusions: Counseling about combined hormonal contraceptive methods often does not include information about all available methods, or comprehensive information about side effects, benefits, or logistics of use. As this counseling can impact patient's satisfaction with and continuation of their chosen method of contraception, future work should focus on designing interventions to improve providers' ability to meet patients' needs.Implications: Short acting hormonal contraception is widely used, but counseling for these methods often neglects key features. Comprehensive counseling about all methods and their individual features can improve contraceptive selection and use. [ABSTRACT FROM AUTHOR]

Objective: A systematic review was carried out of studies of women with endometriosis, to examine the evidence for efficacy of the use of hormonal contraception to improve disease-related pain and decrease postoperative risk of disease recurrence.Methods: A search of the Medline/PubMed and Embase databases was performed to identify all published English language studies on hormonal contraceptive therapies (combined hormonal contraceptives [CHCs], combined oral contraceptives [COCs], progestin-only pills [POPs] and progestin-only contraceptives [POCs]) in women with a validated endometriosis diagnosis, in comparison with placebo, comparator therapies or other hormonal therapies. Main outcome measures were endometriosis-related pain (dysmenorrhoea, pelvic pain and dyspareunia), quality of life (QoL) and postoperative rate of disease recurrence during treatment.Results: CHC and POC treatments were associated with clinically significant reductions in dysmenorrhoea, often accompanied by reductions in non-cyclical pelvic pain and dyspareunia and an improvement in QoL. Only two COC preparations (ethinylestradiol [EE]/norethisterone acetate [NETA] and a flexible EE/drospirenone regimen) demonstrated significantly increased efficacy compared with placebo. Only three studies found that the postoperative use of COCs (EE/NETA, EE/desogestrel and EE/gestodene) reduced the risk of disease recurrence. There was no evidence that POCs reduced the risk of disease recurrence.Conclusions: CHCs and POCs are effective for the relief of endometriosis-related dysmenorrhoea, pelvic pain and dyspareunia, and improve QoL. Some COCs decreased the risk of disease recurrence after conservative surgery, but POCs did not. There is insufficient evidence, however, to reach definitive conclusions about the overall superiority of any particular hormonal contraceptive. [ABSTRACT FROM AUTHOR]

Objectives: We sought to identify factors associated with nonadherence to instructions for using a novel contraceptive providing 1 year of protection.Study Design: Data from a multicountry Phase 3 trial of the Nestorone® (segesterone acetate)/ethinyl estradiol (NES/EE) contraceptive vaginal ring (CVR) were analyzed. Participants were instructed to use the CVR over 13 cycles and follow a 21/7 regimen. Their reports of CVR removals >2 h outside scheduled removal periods served as a proxy for nonadherence. We used multivariate logistic regression to determine factors associated with such use.Results: Of 905 participants, 120 (13%) reported CVR removals >2 h. Removals for washing [odds ratio (OR) 3.96, 95% confidence interval (CI) 2.50-6.27] or sexual intercourse (OR 3.19, 95% CI 2.03-4.99), and finding CVR insertion difficult (OR 2.80, 95% CI 1.36-5.80) were factors associated with removals >2 h. Lower educational attainment also predicted ring removal >2 h (OR 3.23, 95% CI 1.55-6.75). Women residing in Europe or Australia were less likely to remove the ring for >2 h compared with women in the United States (OR 0.44, 95% CI 0.24-0.83 and OR 0.13, 95% CI 0.02-0.98, respectively). Participants who reported removals >2 h were more likely to discontinue CVR use (OR 1.93, 95% CI 1.24-2.95), report dissatisfaction (OR 2.20, 95% CI 1.32-3.69) and become pregnant during the study (OR 4.07, 95% CI 1.58-10.50).Conclusions: Removing the CVR for washing and removing it before intercourse are factors associated with nonadherence to ring use. These are important topics for counseling women who are considering or using vaginal rings, including the NES/EE CVR.Implications: Findings from this study may be useful in guiding counseling for current and prospective vaginal ring users. Anticipatory guidance should focus on how the ring feels in the vagina and during sex. Asking about ring removals may help identify women who are at increased risk for having an unplanned pregnancy. [ABSTRACT FROM AUTHOR]

Vaginal rings are gynecological drug delivery devices with fixed shapes, sizes and drug doses. Here 3D printed personalized progesterone-loaded vaginal rings were prepared. Progesterone was mixed with polyethylene glycol (PEG) 4000 to form a solid dispersion that was cut into pieces. The mixture of poly(lactic acid) (PLA)/polycaprolactone (PCL) (8:2) and Tween 80 were mixed with the above pieces and hot-melted to form filaments. A fused deposition modeling (FDM) printer was used to prepare “O”, “Y” or “M”-shaped vaginal rings with the filaments. Differential scanning calorimetry and X-ray powder diffraction showed that amorphous progesterone existed in the rings. Moreover, progesterone did not decompose in the preparation according to the thermal gravimetric analysis. Surface pores and inner channels appeared in the rings due to PEG 4000 dissolution and Tween 80 made the rings wettable. The “O” ring had higher dissolution than the “Y” and “M” rings due to its higher surface area/volume ratio and special shape. The vaginal rings showed the long-term sustained release of progesterone for more than 7 days with diffusion-controlled release behavior. The 3D printed vaginal rings are promising local gynecological medications. 3D printing is an effective strategy for preparation of personalized and customized medications. [ABSTRACT FROM AUTHOR]

The parasitism by Trichomonas vaginalis is complex and in part is mediated by cytoadherence accomplished via five surface proteins named adhesins and a glycoconjugate called lipophosphoglycan (TvLPG). In this study, we evaluated the ability of T. vaginalis isolates to adhere to cells, plastic (polystyrene microplates), intrauterine device (IUD), and vaginal ring. Of 32 T. vaginalis isolates, 4 (12.5%) were strong adherent. The T. vaginalis isolates TV-LACM6 and TV-LACM14 (strong polystyrene-adherent) were also able to adhere to IUD and vaginal ring. Following chemical treatments, results demonstrated that the T. vaginalis components, lipophosphoglycan, cytoskeletal proteins, and surface molecules, were involved in both adherence to polystyrene and cytoadherence. The gene expression level from four adhesion proteins was highest in trophozoites adhered to cells than trophozoites adhered to the abiotic surface (polystyrene microplate). Our data indicate the major involvement of TvLPG in adherence to polystyrene, and that adhesins are important for cytoadherence. Furthermore, to our knowledge, this is the first report showing the T. vaginalis adherence to contraceptive devices, reaffirming its importance as pathogen among women in reproductive age. [ABSTRACT FROM AUTHOR]

Purpose: We aim to provide a comprehensive overview of the role of the vagina as a route for drug delivery and absorption, with a particular focus on the use of vaginal hormonal compounds for the treatment of deep infiltrating symptomatic endometriosis.Methods: A MEDLINE search through PubMed was performed to identify all published studies in English language on vaginal hormonal treatments for symptomatic endometriosis.Results: Main advantages of the vaginal route include avoidance of the hepatic-first pass metabolic effect, the possibility of using lower therapeutic dosages, and the reduction of side effects compared with the oral administration. Studies on endometriosis treatment mainly focused on the use of vaginal danazol (n = 6) and the contraceptive vaginal ring (n = 2). One pilot study evaluated the efficacy of vaginal anastrozole in women with rectovaginal endometriosis. Most investigations evaluated the vaginal use of hormonal agents in women with deep infiltrating endometriosis/rectovaginal endometriosis. Overall, a substantial amelioration of pelvic pain symptoms associated with endometriosis was observed, particularly of dysmenorrhea. A significant reduction in rectovaginal endometriotic nodule dimensions measured at ultrasound examination was detected by some but not all authors.Conclusions: The vaginal route represents a scarcely explored modality for drug administration. High local hormonal concentrations might achieve a greater effect on endometriotic lesions compared with alternative routes. Future studies should focus on the use of the vagina for delivering target therapies particularly in patients with deeply infiltrating rectovaginal lesions. [ABSTRACT FROM AUTHOR]

Introduction:Oral contraceptives could induce mood changes. As far as our knowledge, there are no studies in literature that have examined the role of vaginal contraception in self-perceived body image. Aim: To evaluate the effects of intravaginal contraception on weight gain and perceived body image in relation with the Beck’s Depression Inventory questionnaire (BDI) and the McCoy Female Sexuality Questionnaire (MFSQ). Methods: Twenty-one adult (18–35 years old) eumenorrheic (menstrual cycle of 25–35 days), lean (body mass index – BMI – of 19–25 kg/m2) women who were referred for hormonal contraception were administered the Stunkard Figure Rating Scale (FRS), BDI and MFSQ. Subjects were studied in basal condition and after 6 months of therapy with vaginal contraception (NuvaRing®; Organon-Schering-Plough Italia, Milan, Italy). Main outcome measures: BMI, FRS, MFSQ and BDI. Results: After 6 months of therapy with NuvaRing®, both body weight (60.0 ± 8.3;p = 0.050) and BMI (22.1 ± 3.1;p = 0.028) slightly, but statistically, increased. FRS and BDI showed no differences after the vaginal contraception. Hormonal contraception was associated with a significant decrease in the two-factor Italian MFSQ score. Conclusions: Vaginal ring seems a good alternative to other hormonal contraceptive not significantly altering the female sexuality and not influencing the FRS and BDI. [ABSTRACT FROM AUTHOR]

Several formulations of HIV pre-exposure prophylaxis (PrEP) have shown varying levels of effectiveness in women. Little information is known about preference across formulations, especially among product experienced women. Seventy-one women (48% married; median age 26; range 18-45) who were participating in a vaginal ring trial for HIV prevention in Malawi, South Africa, Uganda, and Zimbabwe underwent an in-depth interview at their last study visit, during which they were presented with pictures and descriptions of nine possible product formulations (male and female condoms, oral tablets, injectables, implants, and a vaginal gel, ring, insert, and film). Each formulation was discussed, highlighting salient attribute(s) and contextual factors that may have informed stated preferences. Participants expressed most interest for long-acting PrEP formulations (rings, 94%; implants, 39%; injections, 34%), which were generally favored over short-acting ones. Participants appreciated the continuous protection offered, discreet usage, and the advantage of 'peace of mind' imparted by simplified use and infrequent dosing, alleviating worries around forgetting doses. Preferred attributes of short-acting formulations included reversibility, user control, ease of administration, and low toxicity. Participants were least interested in the oral tablets (due to the daily dosing, difficulty swallowing pills, and HIV-related stigma), and the vaginal gel and film (due to vaginal insertion, coital dosing, effect on sex. and unfamiliarity with the method). Dislike for vaginally administered products was more pronounced among young women. Multiple factors played into potential users' considerations for preferred formulations, emphasizing how a suite of options for prevention might best respond to women's needs and wants. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to examine, in a sample of Italian women, the rate of discontinuation of use of hormonal contraception.Methods: In a retrospective cross-sectional study, data were collected from a chart review of 1809 women using or stopping the hormonal contraceptive prescribed by their physician. The name of the contraceptive and the reason for discontinuation were taken from the charts. The differences between the methods regarding reasons for discontinuation were analysed.Results: Of the 1809 women examined, 34.9% had discontinued their hormonal contraception: 6.9% did so for non-method-related reasons, 20.5% due to minor side effects, 4.4% due to major side effects and 3.8% due to difficulties with compliance. Irregular bleeding, weight gain and headache were the main reasons reported for discontinuation. Pills containing 30 μg or 20 μg ethinylestradiol (EE) and the vaginal ring were the most used contraceptive methods. Women using the vaginal ring discontinued less frequently compared with pill users (p < .005). Pills containing 20 μg and 30 μg EE had the same discontinuation rate. Venous thrombosis was the most frequently reported major side effect leading to discontinuation.Conclusion: About one-third of women who used modern hormonal contraceptives discontinued the method. Although the percentage of women who gave up as a result of minor side effects was lower than it used to be, and the use of low doses of EE by the vaginal route has decreased the rate of discontinuation, physicians should counsel women about the possibility of side effects and encourage them to seek advice before stopping. [ABSTRACT FROM AUTHOR]

Microbicides are being developed in order to prevent sexual transmission of HIV. Dapivirine, a non-nucleoside reverse transcriptase inhibitor, is one of the leading drug candidates in the field, currently being tested in various dosage forms, namely vaginal rings, gels, and films. In particular, a ring allowing sustained drug release for 1 month is in an advanced stage of clinical testing. Two parallel phase III clinical trials are underway in sub-Saharan Africa and results are expected to be released in early 2016. This article overviews the development of dapivirine and its multiple products as potential microbicides, with particular emphasis being placed on clinical evaluation. Also, critical aspects regarding regulatory approval, manufacturing, distribution, and access are discussed. [ABSTRACT FROM AUTHOR]

Despite a long history of incorporating steroids into silicone elastomers for drug delivery applications, little is presently known about the propensity for irreversible drug binding in these systems. In this study, the ability of the contraceptive progestin levonorgestrel to bind chemically with hydrosilane groups in addition-cure silicone elastomers has been thoroughly investigated. Cure time, cure temperature, levonorgestrel particle size, initial levonorgestrel loading and silicone elastomer type were demonstrated to be key parameters impacting the extent of levonorgestrel binding, each through their influence on the solubility of levonorgestrel in the silicone elastomer. Understanding and overcoming this levonorgestrel binding phenomenon is critical for the ongoing development of a number of drug delivery products, including a multi-purpose technology vaginal ring device offering simultaneous release of levonorgestrel and dapivirine – a lead candidate antiretroviral microbicide – for combination HIV prevention and hormonal contraception. [ABSTRACT FROM AUTHOR]

Objectives: Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150mcg Nestorone® (NES) and 15mcg ethinyl estradiol (EE).Study Design: A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers).Results: Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen.Conclusion: NES/EE CVR for up to 13cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure.Implications: Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC. [ABSTRACT FROM AUTHOR]

Objective To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles. Study Design This was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 μg/day) or a high-dose (2500 μg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns. Results All subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding. Conclusion The 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-μg/day ring. Implications The 3-month CVR delivering UPA 2500 μg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment. [ABSTRACT FROM AUTHOR]

Composites of low-density polyethylene (LDPE), poly(ethylene-co-vinyl acetate) (EVA), poly(ethylene-co-octadecene), and an LDPE/EVA blend were prepared with different amounts of meloxicam (1, 3 and 5 wt %) by the melt blending process. Meloxicam was homogenously dispersed in polymer matrices. The polymer-meloxicam composites showed thermal behavior and thermal characteristics similar to those of the original polymers. Meloxicam release from the composites was examined in vitro for 50 days. The composites were incubated in phosphate-buffered solution and meloxicam concentration was determined by high-performance liquid chromatography. The prolonged release of the drug indicates that meloxicam-loaded plastic rings offer potential for control of reproduction and chronic inflammatory conditions. [ABSTRACT FROM AUTHOR]

Cervical cancer is the third most prevalent cancer in women and disproportionately affects those in low resource settings due to limited programs for screening and prevention. In the developed world treatment for the disease in the non-metastasised state usually takes the form of surgical intervention and/or radiotherapy. In the developing world such techniques are less widely available. This paper describes the development of an intravaginal ring for the localised delivery of a chemotherapeutic drug to the cervix that has the potential to reduce the need for surgical intervention and will also provide a novel anti-cancer therapy for women in low resource settings. Disulfiram has demonstrated antineoplastic action against prostate, breast and lung cancer. Both PEVA and silicone elastomer were investigated for suitability as materials in the manufacture of DSF eluting intravaginal rings. DSF inhibited the curing process of the silicone elastomer, therefore PEVA was chosen as the material to manufacture the DSF-loaded vaginal rings. The vaginal rings had an excellent content uniformity while the DSF remained stable throughout the manufacturing process. Furthermore, the rings provided diffusion controlled release of DSF at levels well in excess of the IC50 value for the HeLa cervical cancer cell line. [ABSTRACT FROM AUTHOR]

Objectives Develop and test a theoretical acceptability model for the Nestorone®/ethinyl estradiol contraceptive vaginal ring (CVR); explore whether domains of use within the model predict satisfaction, method adherence and CVR continuation. Study Design Four domains of use were considered relative to outcome markers of acceptability, that is, method satisfaction, adherence and continuation. A questionnaire to evaluate subjects' experiences relative to the domains, their satisfaction (Likert scale) and adherence to instructions for use was developed and administered to 1036 women enrolled in a 13-cycle Phase 3 trial. Method continuation was documented from the trial database. Stepwise logistic regression (LR) analysis was conducted and odds ratios (ORs) calculated to assess associations of satisfaction with questions from the four domains. Fisher's Exact Test was used to determine the association of satisfaction with outcome measures. Results A final acceptability model was developed based on the following determinants of CVR satisfaction: ease of use, side effects, expulsions/feeling the CVR and sexual activity including physical effects during intercourse. Satisfaction was high (89%) and related to higher method adherence [OR, 2.6 (1.3, 5.2)] and continuation [OR, 5.5 (3.5, 8.4)]. According to the LR analysis, attributes of CVR use representing items from the four domains — finding it easy to remove, not complaining of side effects, not feeling the CVR while wearing it and experiencing no change or an increase in sexual pleasure and/or frequency — were associated with higher odds of satisfaction. Conclusion Hypothesized domains of CVR use were related to satisfaction, which was associated with adherence and continuation. Results provide a scientific basis for introduction and future research. Implications Statement Acceptability research is important when introducing a new method of contraception and determining whether it can be a successful option in meeting the reproductive health needs of women and men. This study was designed to test a conceptual model of acceptability and identify factors associated with successful use of a new contraceptive delivery modality. Original research was conducted for this publication. [ABSTRACT FROM AUTHOR]

Objective This study sought to measure residual contraceptive hormone levels in vaginal rings as an adherence marker for monitoring product use in clinical trials. Study design Residual etonogestrel and ethinyl estradiol levels from used NuvaRings® of 26 self-reported adherent women enrolled in a clinical trial of vaginal ring acceptability were compared to those from 16 women who used NuvaRing® as their contraceptive choice. Results Twenty-one (81%) clinical trial rings had contraceptive hormone levels within the range of those used as a contraceptive choice. Five returned rings had unused or discordant levels of residual contraceptive hormones. Conclusion Residual vaginal ring drug levels could help assess adherence in clinical trials. [ABSTRACT FROM AUTHOR]

Introduction Product adherence and its measurement have emerged as a critical challenge in the evaluation of new HIV prevention technologies. Long-acting ARV-based vaginal rings may simplify use instructions and require less user behaviour, thereby facilitating adherence. One ARV-based ring is in efficacy trials and others, including multipurpose rings, are in the pipeline. Participant motivations, counselling support and measurement challenges during ring trials must still be addressed. In previous HIV prevention trials, this has been done largely using descriptive and post-hoc methods that are highly variable and minimally evaluated. We outline an interdisciplinary framework for systematically investigating promising strategies to support product uptake and adherence, and to measure adherence in the context of randomized, blinded clinical trials. Discussion The interdisciplinary framework highlights the dual use of adherence measurement (i.e. to provide feedback during trial implementation and to inform interpretation of trial findings) and underscores the complex pathways that connect measurement, adherence support and enacted adherence behaviour. Three inter-related approaches are highlighted: 1) adherence support - sequential efforts to define motivators of study product adherence and to develop, test, refine and evaluate adherence support messages; 2) self-reported psychometric measures - creation of valid and generalizable measures based in easily administered scales that capture vaginal ring use with improved predictive ability at screening, baseline and follow-up that better engage participants in reporting adherence; and 3) more objective measurement of adherence - real-time adherence monitoring and cumulative measurement to correlate adherence with overall product effectiveness through innovative designs, models and prototypes using electronic and biometric technologies to detect ring insertion and/or removal or expulsion. Coordinating research along these three pathways will result in a comprehensive approach to product adherence within clinical trials. Conclusions Better measurement of adherence will not, by itself, ensure that future effectiveness trials will be able to address the most basic question: if the product is used per instructions, will it prevent HIV transmission? The challenges to adherence measurement must be addressed as one component of a more integrated system that has as its central focus adherence as a behaviour emerging from the social context of the user. [ABSTRACT FROM AUTHOR]