Impact of Dapivirine and Placebo Vaginal Rings on the Microbiota of Adolescent, Lactating, and Postmenopausal Females.

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.

Levonorgestrel 52 mg intrauterine system efficacy and safety through 8 years of use.

BACKGROUND: Extending hormonal intrauterine system duration will allow users to have less need for procedures to provide long-term contraception. OBJECTIVE: This study aimed to evaluate the efficacy and safety of the levonorgestrel 52 mg intrauterine system during years 7 and 8 of use. STUDY DESIGN: A total of 1751 nulliparous and multiparous participants aged 16 to 45 years enrolled in a phase 3, multicenter trial to evaluate the efficacy and safety of the use of the Liletta levonorgestrel 52 mg intrauterine system for up to 10 years. Participants aged 36 to 45 years at enrollment underwent safety evaluation only. After the first year, we evaluated participants every 6 months for intrauterine system location confirmation and urine pregnancy testing at each visit. We assessed the Pearl Indices in years 7 and 8 and the life-table analysis for cumulative pregnancy rates through 8 years of use. For the primary efficacy analyses, all participants aged 16 to 35 years at enrollment were included through year 6; years 7 and 8 included only users aged ≤39 years at the start of each use year. Safety outcomes were assessed in all participants regardless of duration of use. We assessed amenorrhea rates, defined as no bleeding or spotting in the 90 days before the end of the year. RESULTS: After intrauterine system placement, we followed 1568 participants aged 16 to 35 years and 146 participants aged 36 to 45 years. The 16- to 35-year-old participants included 986 (57.5%) nulliparous and 433 (25.3%) obese users. Overall, 569 participants started year 7, 478 completed year 7 (380 aged ≤39 years at beginning of year) and 343 completed year 8 (257 aged ≤39 years at beginning of year); 77 completed 10 years of use. Eleven pregnancies occurred over 8 years, 7 (64%) of which were ectopic. Two pregnancies occurred in year 7 (Pearl Index, 0.49; 95% confidence interval, 0.06-1.78), 1 in a participant with implantation 4 days after a desired removal; no pregnancies occurred in year 8. The cumulative life-table pregnancy rate in the primary efficacy population through year 8 was 1.32 (95% confidence interval, 0.69-2.51); without the postremoval pregnancy, the rate was 1.09 (95% confidence interval, 0.56-2.13). Two perforations (0.1%) occurred, none noted after year 1. Expulsion occurred in 71 (4.1%) participants overall, with 3 in year 7 and 2 in year 8. Pelvic infection was diagnosed in 16 (0.9%) participants during intrauterine system use, 1 each in years 7 and 8. Only 44 (2.6%) participants overall discontinued because of bleeding complaints (4 total in years 7 and 8) with rates per year of 0.1% to 0.5% for years 3 to 8. Amenorrhea rates were 39% at both years 7 and 8. CONCLUSION: The levonorgestrel 52 mg intrauterine system is highly effective over 8 years of use and has an excellent extended safety profile. This report details the longest period of efficacy and safety data for continuous use of a levonorgestrel 52 mg intrauterine system for contraception.

Increasing access to immediate postpartum contraceptive implants: a prospective clinical trial among patients with opioid use disorder.

OBJECTIVE: To evaluate the effects of increased access to immediate postpartum contraceptive implants (IPI) on repeat pregnancy and contraceptive use rates among patients with opioid use disorder (OUD). MATERIALS AND METHODS: Between 2016 and 2018, 194 postpartum patients with OUD were offered the option of IPI placement at an institution with limited immediate postpartum long-acting reversible contraception availability and followed for one-year postpartum. Differences in pregnancy rates between participants who did and did not choose IPI were examined using logistic regression with inverse probability of treatment weighting from propensity scores accounting for differences between the two groups. RESULTS: Among 194 participants, 96 (49.5%) chose an IPI and 98 (50.5%) chose an alternative method or no contraception (non-IPI). Among IPI participants, 76 (80.9%) continued to use their implant at one-year postpartum. Overall, 19 participants had a repeat pregnancy and 11 (57.9%) were unintended. In multivariable analyses, repeat pregnancy was more likely among those who did not choose IPI (OR 9.90; 95% CI 3.58-27.03) than those who did. Participants with OUD and who used alcohol (11.66; 1.38, 98.20) or cocaine (2.72; 1.23, 5.99) during pregnancy were more likely to choose IPI. Participants who were married (0.28; 0.09, 0.89), engaged in OUD treatment prior to pregnancy (0.48; 0.25, 0.93), and happier when they found out about their pregnancy (0.87; 0.77, 0.98) were less likely to choose IPI. CONCLUSION: Offering patients with OUD the option of IPI is associated with high utilisation and continuation rates, and low rates of repeat pregnancy within one-year postpartum.

Bleeding changes after levonorgestrel 52-mg intrauterine system insertion for contraception in women with self-reported heavy menstrual bleeding.

BACKGROUND: The levonorgestrel 52-mg intrauterine system has proven efficacy for heavy menstrual bleeding treatment in clinical trials, but few data exist to demonstrate how rapidly the effects occur and the effects in women with self-reported heavy bleeding, as seen commonly in clinical practice. OBJECTIVE: Evaluate changes in bleeding patterns in women with self-reported heavy menstrual bleeding before levonorgestrel 52-mg intrauterine system insertion. STUDY DESIGN: A total of 1714 women aged 16-45 years old received a levonorgestrel 52-mg intrauterine system in a multicenter trial evaluating contraceptive efficacy and safety for up to 10 years. At screening, participants described their baseline menstrual bleeding patterns for the previous 3 months. Participants completed daily diaries with subjective evaluation of bleeding information for the first 2 years. For this analysis, we included women with at least 1 complete 28-day cycle of intrauterine system use and excluded women using a hormonal or copper intrauterine contraception in the month prior to study enrollment. We evaluated changes in menstrual bleeding and discontinuation for bleeding complaints per 28-day cycle over 26 cycles (2 years) in women who self-reported their baseline pattern as heavy. We also compared rates of amenorrhea, defined as no bleeding or spotting, within the entire study population in women with subjective heavy menstrual bleeding at baseline compared with those who did not complain of heavy menstrual bleeding. RESULTS: Of the 1513 women in this analysis, 150 (9.9%) reported baseline heavy menstrual bleeding. The majority of women reported no longer experiencing heavy menstrual bleeding by the end of cycle 1 (112/150, 74.7%) with even greater rates by cycle 2 (124/148, 83.8%). At the end of cycles 6, 13, and 26, 129 of 140 (92.1%; 95% confidence interval, 87.7%-96.6%), 114 of 123 (92.7%; 95% confidence interval, 88.1%-97.3%), and 100 of 103 (97.1%; 95% confidence interval, 93.8%-100%) women reported no heavy menstrual bleeding, respectively. After cycles 13 and 26, 63 of 123 (51.2%; 95% confidence interval, 42.4%-60.1%) and 66 of 103 (64.1%; 95% confidence interval, 54.8%-73.3%), respectively, reported their bleeding as amenorrhea or spotting only. A lower proportion of women with baseline self-reported heavy menstrual bleeding reported amenorrhea as compared with women in the overall study cohort without heavy menstrual bleeding at the end of 6 cycles (319 [25.5%] vs 21 [15.0%], P=.005) and 13 cycles (382 [34.4%] vs 26 [21.1%], P=.003); differences were not significant after 19 cycles (367 [37.2%] vs 36 [31.0%], P=.022) and 26 cycles (383 [43.5%] vs 38 [36.9%], P=.21). Only 4 (2.7%) women with baseline heavy menstrual bleeding discontinued for bleeding complaints (2 for heavy menstrual bleeding and 2 for irregular bleeding), all within the first year. CONCLUSION: Most women who self-report heavy menstrual bleeding experience significant improvement quickly after levonorgestrel 52-mg intrauterine system insertion. Discontinuation for bleeding complaints among women with baseline heavy menstrual bleeding is very low.

A Mixed-Methods Study Examining Adherence to and Acceptability of Intravaginal Rings for HIV Prevention: Behavioral Results of MTN-027.

Intravaginal rings (IVR) containing antiretroviral drugs are a promising method for HIV prevention. We triangulated quantitative and qualitative assessments to evaluate the acceptability of four IVRs used continuously for 28 days as part of a Phase I trial (N = 48 HIV-negative women; ages 18-45). Adherence was high throughout the trial, yet 30% of participants reported involuntary IVR expulsions followed by re-insertion. Most participants (93.6%) felt comfortable with the IVR being inside their body. Participants reported liking the IVR more (36.2%) or the same amount (55.3%) since starting the study. When given the option of choosing between the IVR and/or a male condom for HIV-prevention, most reported preferring the IVR (n = 29, 63.0%), and over a quarter of the sample reported liking them equally (n = 12, 26.1%). We observed no differences in IVR acceptability across the study arms. High adherence and acceptability underscores the promise of an IVR as a female-controlled, sustained mechanism for HIV prevention.

Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings.

BACKGROUND: Vaginal rings (VR) containing antiretroviral (ARV) drugs can be utilized for prevention of human immunodeficiency virus (HIV) with potential for improved adherence compared to daily pills. Combination ARV VRs could improve efficacy. METHODS: MTN-027, a single-blind, randomized, placebo-controlled trial in 48 women, evaluated VRs containing MK-2048 (30 mg) and vicriviroc (VCV, 182 mg), alone or in combination, and placebo used continuously for 28 days. Safety was assessed by recording adverse events. Drug concentrations were quantified in plasma, vaginal fluid, cervical tissue, and rectal fluid. Cervical tissue was utilized for ex vivo HIV inhibition analysis. RESULTS: There was no difference in related genitourinary adverse events between treatment arms compared to placebo. VCV and MK-2048 released from single or combination VRs both achieved peak concentrations in vaginal fluids, which were substantially higher compared to plasma (200× for VCV, 30× for MK-2048) and rectal fluid. In an ex vivo challenge assay, the antiviral activity of VCV and/or MK-2048 was not correlated with tissue-associated drug concentrations. Most women (77%) were fully adherent to 28 days of continuous VR use and found the VR acceptable. CONCLUSIONS: VCV and/or MK-2048 containing VRs were safe and acceptable. Both VCV and MK-2048 were quantifiable in all matrixes tested with peak compartmental drug concentrations similar for single and combination drug VRs. Tissue-associated VCV and/or MK-2048 did not correlate with inhibition of HIV infection. These data highlight the need to assess adequacy of drug dosing in the VR and measuring genital tissue drug concentrations to develop more precise concentration-response relationships.

Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women.

BACKGROUND: Postmenopausal women have unique sociobiological human immunodeficiency virus (HIV) risks. We evaluated the safety, pharmacokinetics, and acceptability of a microbicide dapivirine (DPV) vaginal ring (VR) versus placebo in postmenopausal women. METHODS: We enrolled 96 HIV-negative postmenopausal US women in a phase 2a double-blind, randomized (3:1) trial of monthly VRs containing 25 mg DPV or placebo used continuously for 12 weeks. We assessed safety by adverse events (AEs). DPV concentrations were quantified in plasma and vaginal fluid. Steady-state concentrations were analyzed at 4, 8, and 12 weeks using repeated measures ANOVA. We assessed acceptability by self-report. RESULTS: We found no differences in the proportion of women with related grade 2 or higher reproductive system AEs (DPV: 6/72 (8%), placebo: 3/24 (13%), P = .68) or grade 3 or higher AEs (DPV: 4/72 (6%), placebo: 0/24 (0%), P = .57). In the DPV arm, 2/72 (3%) declined to resume product use due to AEs. Median DPV concentrations in plasma (262.0 pg/mL at week 12) and vaginal fluid (40.6 ng/mg at week 12) were constant over 12 weeks and exceeded the in vitro 50% effective concentration by 5000-fold in vaginal fluid by week 4. VR acceptability was high; 84/93 (90%) "very much liked or liked" the VR. CONCLUSIONS: DPV VRs were safe, well tolerated, and acceptable in postmenopausal women. Plasma concentrations were comparable to published data on DPV use in reproductive-age women (median plasma concentration: 264 pg/mL). Given the reassuring safety and pharmacokinetic data, the DPV VR is promising for preexposure prophylaxis in postmenopausal women. CLINICAL TRIALS REGISTRATION: NCT02010593.

Effect of patient genetics on etonogestrel pharmacokinetics when combined with efavirenz or nevirapine ART.

BACKGROUND: We previously demonstrated that etonogestrel concentrations were 82% lower in women using etonogestrel contraceptive implants plus efavirenz-based ART compared with women not receiving ART. OBJECTIVES: To investigate the genetic contribution to this previously observed drug-drug interaction through studying SNPs in genes known to be involved in efavirenz, nevirapine or etonogestrel metabolism in the same group of women. PATIENTS AND METHODS: Here, we present a secondary analysis evaluating SNPs involved in efavirenz, nevirapine and etonogestrel metabolism and associated etonogestrel pharmacokinetics among 57 women, 19 not receiving ART (control group), 19 receiving efavirenz- (600 mg daily) based ART and 19 receiving nevirapine- (200 mg twice daily) based ART. Associations between patient genotype and etonogestrel pharmacokinetic parameters were determined through univariate and multivariate linear regression. This study was registered at clinicaltrials.gov (NCT02082652). RESULTS: Within the control group, CYP2B6 983 T>C was associated with 27% higher etonogestrel Cmax and 28% higher AUC0-24weeks. In the efavirenz group CYP2B6 516 G>T was associated with 43% lower etonogestrel Cmin and 34% lower AUC0-24weeks. For participants receiving nevirapine, NR1I2 63396 C>T was associated with 39% lower etonogestrel Cmin and 37% lower AUC0-24weeks. CONCLUSIONS: This study demonstrates the influence of pharmacogenetics on the extent of drug-drug interactions between etonogestrel and efavirenz- or nevirapine-based ART. Efavirenz plus the etonogestrel contraceptive implant results in a detrimental drug-drug interaction irrespective of patient genetics, which is worsened in women possessing variant alleles for these CYP2B6 SNPs.

Investigating Pregnancy Outcomes After Abnormal Cell-Free DNA Test Results.

Cell-free DNA (cfDNA) testing has increased sensitivity and specificity compared to other prenatal screening methods, but invasive diagnostic testing (IDT) is recommended for confirmation. We performed a retrospective chart review of 39 women with abnormal cfDNA results between March 2012 and September 2015 at an urban academic hospital to evaluate patient choice and pregnancy outcomes. We analyzed data using descriptive statistics, Fisher's exact tests, and Wilcoxon rank-sum tests. Median maternal age was 36.0 years [interquartile range (IQR) 31, 39]; 64.1% of women (25/39) were advanced maternal age and 69.2% (27/39) had abnormal ultrasounds. Median gestational age at time of cfDNA testing was 18 3/7 weeks [IQR 12 2/7, 20 5/7]. cfDNA results included trisomy 21 (89.7%, 35/39), trisomy 18 (7.7%, 3/39), and both trisomy 21/monosomy X (2.6%, 1/39). Of 39 women, 22 (56.4%) continued and 10 (25.6%) terminated the pregnancy; six (15.4%) had fetal demises, and one was lost to follow-up. Of women continuing their pregnancies, 54.6% (12/22) declined further genetic counseling, and 77.3% (17/22) declined IDT. Only 14 women pursued IDT; not pursuing IDT was associated with continuing the pregnancy (Fisher's exact test, p = .001). All women terminating their pregnancy (90.0%, 9/10) pursued IDT or had major anomalies on ultrasound, suggesting that women considering termination undergo more confirmatory tests or already have high suspicion for an abnormal pregnancy.

Impact of Sex on the Pharmacokinetics and Pharmacodynamics of 1% Tenofovir Gel.

BACKGROUND: Tenofovir (TFV) gel partially protected against human immunodeficiency virus (HIV) in one but not subsequent trials. The disappointing results were attributed largely to poor adherence. However, timing of gel application relative to sex may impact pharmacokinetics and contribute to outcomes. Thus, we conducted a single-dose pharmacokinetic study of TFV gel applied 1 or 24 hours before or 1 hour before and 1 hour after (BAT) sex and compared results with dosing without sex. METHODS: Twenty-four couples were enrolled; cervicovaginal lavage (CVL) and tissue were collected 2 hours after sex with matching timed collections at no sex visits and assayed for drug concentrations and CVL anti-HIV activity. RESULTS: Compared with dosing without sex, median TFV concentrations after sex decreased 72% and 78% (P < .001) in CVL, 75% and 71% (P < .001) in vaginal tissue, and 75% (P = .06) and 55% (P < .001) in cervical tissue with -1 hour and -24 hour dosing, respectively. Median concentration of TFV-diphosphate also decreased significantly in cervical tissue with -1 hour, dosing. BAT dosing resulted in drug levels at least as great as those in the absence of sex. Percent inhibition of HIV infection by post-coital CVL increased significantly from median (interquartile range) of 55% (54%) in the absence of gel to 99% (7%), 77% (57%), and 100% (0.4%) with -1 hour, -24 hour, or BAT dosing, respectively, and correlated significantly with drug concentration. CONCLUSIONS: Timing of TFV gel application relative to sex significantly impacts drug levels. BAT dosing or sustained delivery may be optimal for preexposure prophylaxis.

Adherence and Acceptability of a Multidrug Vaginal Ring for HIV Prevention in a Phase I Study in the United States.

We evaluated the adherence and acceptability of a vaginal ring containing dapivirine, maraviroc, or both drugs for 28 days during a Phase I placebo-controlled trial in 48 HIV-negative sexually abstinent U.S. women aged 18-40. Adherence was assessed weekly by clinical interview and computer-assisted self-interviewing; acceptability assessment occurred at the last product-use visit. Study retention was 98 % (47/48); 94 % (45/48) reported being fully adherent with ring use during the 28-day period. Two participants experienced the ring partially coming out. Analysis was blinded and behavioral data were combined across study groups. Most women reported being very comfortable having the ring in their vagina; 44 % preferred continuous use, whereas 51 % had no preference compared to episodic use. Although a range of minor ring concerns were expressed, few were actually experienced. High adherence to and acceptability of this vaginal ring in this Phase I trial contributes to its promise as a sustained mechanism for multidrug vaginal microbicide delivery.

Changes in genital tract immune cell populations after initiation of intrauterine contraception.

OBJECTIVE: The primary target cells for the human immunodeficiency virus (HIV) infection in the genital tract are CD4 T cells that express CCR5 on the surface. Alterations in genital tract T cells that express CCR5 could impact HIV acquisition risk. We hypothesized that, when compared with baseline, the use of a hormonal intrauterine device (IUD) would alter HIV target cells (primarily CCR5+ CD4 cells) in the female genital tract more than a nonhormonal IUD. STUDY DESIGN: Thirty-four healthy HIV-negative women aged 18-40 years who were seeking an IUD for contraception were assigned randomly to receive a levonorgestrel IUD or a copper T380A IUD. A parallel group of 8 control women who did not need contraception was also enrolled. Genital tract mucosal immune cell populations that were collected by cervical cytobrush and endometrial biopsy before and 2 months after IUD placement were analyzed by flow cytometry. Mean differences in cell number and percent that expressed receptors from baseline to follow-up examination were evaluated with the use of paired Student t tests. RESULTS: Neither IUD altered the number of T cells within the upper and lower genital tracts. Levonorgestrel IUD users had a decrease in T cells that expressed the HIV coreceptor CCR5 in the endometrium and cervix after 2 months of use compared with baseline. There was a decrease in activated endometrial T cells in levonorgestrel IUD users and a decrease in activated cervical T cells in copper IUD users after 2 months of IUD use, compared with baseline. CONCLUSION: Women who use IUDs have reduced expression of the CCR5 HIV coreceptor on T cells in the endometrium and cervix compared with expression before IUD placement. These findings suggest that susceptibility to HIV infection would not be increased by IUD use.

Phase 1 randomized pharmacokinetic and safety study of a 90-day tenofovir vaginal ring in the United States.

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.

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

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

Adherence and acceptability in MTN 001: a randomized cross-over trial of daily oral and topical tenofovir for HIV prevention in women.

We compared adherence to and acceptability of daily topical and oral formulations of tenofovir (TFV) used as pre-exposure prophylaxis (PrEP) for HIV prevention among women in South Africa, Uganda and the United States. 144 sexually active, HIV-uninfected women participated in a cross-over study of three regimens: oral tablet, vaginal gel, or both. We tested for differences in adherence and evaluated product acceptability. Self-reported adherence for all regimens was high (94 %), but serum TFV concentrations indicated only 64 % of participants used tablets consistently. Most women in the U.S. (72 %) favored tablets over gel; while preferences varied at the African sites (42 % preferred gel and 40 % tablets). Findings indicate a role for oral and vaginal PrEP formulations and highlight the importance of integrating pharmacokinetics-based adherence assessment in future trials. Biomedical HIV prevention interventions should consider geographic and cultural experience with product formulations, partner involvement, and sexual health benefits that ultimately influence use.

Early pregnancy confirmation availability at crisis pregnancy centers and abortion facilities in the United States.

OBJECTIVES: Crisis pregnancy centers (CPCs) seek to dissuade people from having abortions. Twenty-five states have policies supporting CPCs. We aimed: (1) to characterize access to early pregnancy confirmation at CPCs compared to abortion facilities nationwide and (2) to understand the role of state CPC policy in service access. STUDY DESIGN: We conducted a national mystery caller study of 445 CPCs and geographically paired abortion facilities, posing as patients seeking pregnancy confirmation. Facility type (CPC vs abortion facility) was the primary exposure in Aim 1. Wait time to first available early pregnancy appointment was the primary outcome. In Aim 2, state-level CPC policy designation (supportive vs not supportive of CPCs) was the primary exposure. Difference in wait time ≥7 days to first available appointment between CPCs and paired abortion facilities was the primary outcome. RESULTS: CPCs were more likely than abortion facilities to provide same-day appointments (68.5% vs 37.2%, p < 0.0001), and free pregnancy testing (98.0% vs 16.6%, p < 0.0001). The median wait to first available appointment at a CPC was 0 days (IQR 0,1), compared to 1 day at abortion facilities (IQR 0, 5), p < 0.0001. In states with supportive CPC policy environments, abortion facilities were less likely to have wait times exceeding their paired CPC by a week or more, compared to paired facilities in states with non-supportive CPC policy environments (p = 0.033). This remained true after adjusting for state abortion policy environment (p = 0.011). CONCLUSIONS: Pregnancy confirmation is more accessible at CPCs compared to abortion facilities. Factors other than state-level CPC policies likely influence service accessibility. There is a need for improved access to pregnancy confirmation in medical settings. IMPLICATIONS: Our findings demonstrating that pregnancy confirmation is more accessible at crisis pregnancy centers than at abortion facilities are predicted to be exacerbated in the wake of abortion clinic closures following the Dobbs v Jackson Women's Health Organization Supreme Court decision. This highlights the need for improved funding and support for pregnancy confirmation service delivery in medical settings, including abortion facilities.

Dextromethorphan as a novel nonopioid adjunctive agent for pain control with medication abortion: A randomized controlled trial.

OBJECTIVES: To evaluate efficacy and satisfaction of dextromethorphan as a non-narcotic adjuvant to current analgesic regimens for medication abortion. STUDY DESIGN: We conducted a randomized, double-blinded, placebo-controlled trial. We randomized eligible participants (N = 156) 1:1 to adjunctively take dextromethorphan (loading dose 60 mg and two subsequent 30 mg doses at 2 and 5 hours after misoprostol administration) or placebo combined with usual-care nonsteroidal anti-inflammatory medications ± opioids for pain. Participants reported pain scores and satisfaction using a secure texting application at 2, 5, 8, and 24 hours after misoprostol administration. Our primary outcome was worst pain score and total analgesic use. RESULTS: Baseline demographics of enrolled participants were similar between randomization arms. Worst pain scores for participants receiving dextromethorphan versus placebo (8.0 vs 7.0, p = 0.06) did not differ. Total milligram usage of ibuprofen (800 mg vs 610 mg, p =.62), acetaminophen (1000 mg vs 1300 mg, p = 0.62), and opioids (10 mg vs 15 mg, p = 0.51) did not differ between the randomization groups. Participants randomized to placebo were significantly more likely to be satisfied with their pain control (91% vs 75%, p = 0.02). CONCLUSION: Dextromethorphan used adjunctively with standard analgesics did not reduce pain associated with medication abortion. Participants who received dextromethorphan reported decreased satisfaction with their pain control. IMPLICATIONS: Dextromethorphan used adjunctively with commonly used analgesic regimens did not reduce medication abortion associated pain. Many participants did not use analgesics as counseled, and nearly 25% used no analgesia during medication abortion.

Levonorgestrel 52-mg Intrauterine Device Efficacy and Safety After More Than 8 Years of Use.

FUNDING SOURCE: Medicines360. The Sponsor, Medicines360, designed the study and oversaw its conduct, including funding the trial and providing all study product free of charge to participants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00995150.

Participant experiences with a multipurpose vaginal ring for HIV and pregnancy prevention during a phase 1 clinical trial: learning from users to improve acceptability.

Introduction: With high concurrent global rates of HIV incidence and unintended pregnancy, there is a need to provide options beyond condoms to enable users to simultaneously prevent HIV acquisition and pregnancy. Multiple vaginal rings are in development as "MPTs" (multipurpose prevention technologies) as they are shown to provide several co-occurring benefits such as discretion, convenience, reversibility and user control. Methods: In this Phase 1 trial of a 3-month MPT ring in the U.S., 25 participants (low-risk for HIV and pregnancy) were randomized to use the study ring for 90 days continuously or in 28-day cycles with 2-day removal periods in between. All participants completed in-depth interviews at the end of their study participation. Results: Overall, the ring was well tolerated. Participants resoundingly endorsed the concept of an extended-use, dual-purpose vaginal ring, but reported too many functional challenges and side effects to endorse this particular ring. Participants assigned to the continuous regimen reported more positive experiences with ring use than those in the cyclic group. A minority of participants who experienced minimal side effects and did not experience challenges with vaginal retention of the ring found it appealing. However, the majority of participants experienced challenges (ring slippage, expulsions, side effects, vaginal bleeding changes) with product use that outweighed the potential benefits and led them to report that - in the future - they would not be interested in using this specific version of the ring in its current form. A subset expressed interest in using the current MPT ring under certain conditions (e.g., if fewer expulsions, less bleeding, higher risk for HIV/pregnancy). Discussion: User feedback regarding participant experiences and challenges with the study ring was continuously shared with the product developer, underscoring the value of early-stage end-user feedback in product development.