Amygdalobacter indicium gen. nov., sp. nov., and Amygdalobacter nucleatus sp. nov., gen. nov.: novel bacteria from the family Oscillospiraceae isolated from the female genital tract.

Four obligately anaerobic Gram-positive bacteria representing one novel genus and two novel species were isolated from the female genital tract. Both novel species, designated UPII 610-JT and KA00274T, and an additional isolate of each species were characterized utilizing biochemical, genotypic and phylogenetic analyses. All strains were non-motile and non-spore forming, asaccharolytic, non-cellulolytic and indole-negative coccobacilli. Fatty acid methyl ester analysis for UPII 610-JT and KA00274T and additional isolates revealed C16 : 0, C18 : 0, C18:1ω9c and C18:2ω6,9c to be the major fatty acids for both species. UPII 610-JT had a 16S rRNA gene sequence similarity of 99.4 % to an uncultured clone sequence (AY724740) designated as Bacterial Vaginosis Associated Bacterium 2 (BVAB2). KA00274T had a 16S rRNA gene sequence similarity of 96.5 % to UPII 610-JT. Whole genomic DNA mol% G+C content was 42.2 and 39.3 % for UPII 610-JT and KA00274T, respectively. Phylogenetic analyses indicate these isolates represent a novel genus and two novel species within the Oscillospiraceae family. We propose the names Amygdalobacter indicium gen. nov., sp. nov., for UPII 610-JT representing the type strain of this species (=DSM 112989T, =ATCC TSD-274T) and Amygdalobacter nucleatus gen. nov., sp. nov., for KA00274T representing the type strain of this species (=DSM 112988T, =ATCC TSD-275T).

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.

Impact of contraceptive initiation on vaginal microbiota.

BACKGROUND: Data evaluating the impact of contraceptives on the vaginal microbiome are limited and inconsistent. OBJECTIVE: We hypothesized that women initiating copper intrauterine device use would have increased bacterial vaginosis and bacterial vaginosis-associated microbes with use compared to women initiating and using hormonal contraceptive methods. STUDY DESIGN: Vaginal swabs (N = 1047 from 266 participants seeking contraception) for Nugent score determination of bacterial vaginosis and quantitative polymerase chain reaction analyses for assessment of specific microbiota were collected from asymptomatic, healthy women aged 18-35 years in Harare, Zimbabwe, who were confirmed to be free of nonstudy hormones by mass spectrometry at each visit. Contraception was initiated with an injectable (depot medroxyprogesterone acetate [n = 41], norethisterone enanthate [n = 44], or medroxyprogesterone acetate and ethinyl estradiol [n = 40]), implant (levonorgestrel [n = 45] or etonogestrel [n = 48]), or copper intrauterine device (n = 48) and repeat vaginal swabs were collected after 30, 90, and 180 days of continuous use. Self-reported condom use was similar across all arms at baseline. Quantitative polymerase chain reaction was used to detect Lactobacillus crispatus, L jensenii, L gasseri/johnsonii group, L vaginalis, L iners, Gardnerella vaginalis, Atopobium vaginae, and Megasphaera-like bacterium phylotype I from swabs. Modified Poisson regression and mixed effects linear models were used to compare marginal prevalence and mean difference in quantity (expressed as gene copies/swab) prior to and during contraceptive use. RESULTS: Bacterial vaginosis prevalence increased in women initiating copper intrauterine devices from 27% at baseline, 35% at 30 days, 40% at 90 days, and 49% at 180 days (P = .005 compared to marginal prevalence at enrollment). Women initiating hormonal methods had no change in bacterial vaginosis prevalence over 180 days. The mean increase in Nugent score was 1.2 (95% confidence interval, 0.5-2.0; P = .001) in women using copper intrauterine devices. Although the frequency and density of beneficial lactobacilli did not change among intrauterine device users over 6 months, there was an increase in the log concentration of G vaginalis (4.7, 5.2, 5.8, 5.9; P = .046) and A vaginae (3.0, 3.8, 4.6, 5.1; P = .002) between baseline and 30, 90, and 180 days after initiation. Among other contraceptive groups, women using depot medroxyprogesterone acetate had decreased L iners (mean decrease log concentration = 0.8; 95% confidence interval, 0.3-1.5; P = .004) and there were no significant changes in beneficial Lactobacillus species over 180 days regardless of contraceptive method used. CONCLUSION: Copper intrauterine device use may increase colonization by bacterial vaginosis-associated microbiota, resulting in increased prevalence of bacterial vaginosis. Use of most hormonal contraception does not alter vaginal microbiota.

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 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.

Meeting report: Considerations for trial design and endpoints in licensing therapeutic HPV16/18 vaccines to prevent cervical cancer.

Cervical cancer is a major cause of morbidity and mortality globally with a disproportionate impact on women in low- and middle-income countries. In 2021, the World Health Organization (WHO) called for increased vaccination, screening, and treatment to eliminate cervical cancer. However, even with widespread rollout of human papillomavirus (HPV) prophylactic vaccines, millions of women who previously acquired HPV infections will remain at risk for progression to cancer for decades to come. The development and licensing of an affordable, accessible therapeutic HPV vaccine, designed to clear or control carcinogenic HPV and/or to induce regression precancer could significantly contribute to the elimination efforts, particularly benefiting those who missed out on the prophylactic vaccine. One barrier to development of such vaccines is clarity around the regulatory pathway for licensure. In Washington, D.C. on September 12-13, 2023, a meeting was convened to provide input and guidance on trial design with associated ethical and regulatory considerations. This report summarizes the discussion and conclusions from the meeting. Expert presentation topics included the current state of research, potential regulatory challenges, WHO preferred product characteristics, modeling results of impact of vaccine implementation, epidemiology and natural history of HPV infection, immune responses related to viral clearance and/or precancer regression including potential biomarkers, and ethical considerations. Panel discussions were held to explore specific trial design recommendations to support the licensure process for two vaccine indications: (1) treatment of prevalent HPV infection or (2) treatment of cervical precancers. Discussion covered inclusion/exclusion criteria, study endpoints, sample size and power, safety, study length, and additional data needed, which are reported here. Further research of HPV natural history is needed to address identified gaps in regulatory guidance, especially for therapeutic vaccines intended to treat existing HPV infections.

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.

Development of My Decision/Mi Decisión, a web-based decision aid to support permanent contraception decision making.

Objective: To develop a patient-centered, web-based decision aid to support informed and value-concordant decision making among Medicaid enrollees considering tubal sterilization. Methods: We used the Ottawa Decision Support Framework and the International Patient Decision Aids Standards (IPDAS) to guide systematic development of our decision aid. We interviewed 15 obstetrician-gynecologists and 40 women, who had considered or were considering tubal sterilization. A Steering Committee-comprising healthcare providers, social scientists, reproductive health and justice advocates, and people with lived experience-provided feedback and direction. We developed English and Spanish prototypes, which were beta tested with 24 women. Results: The resulting web-based My Decision/Mi Decisión tool (English/Spanish) includes written and video information about tubal sterilization procedures; an interactive table of contraception options; values clarification exercises; reflection and deliberation; knowledge checks; and a summary report to share with one's provider. Users found the decision aid to be informative, engaging, easy to use, and helpful in informing contraception decision making. Conclusion: My Decision/Mi Decisión is a scalable tool that could be implemented widely to support informed decision making about tubal sterilization. Innovation: This is a novel and timely web-based decision tool for tubal sterilization, when demand for permanent contraception is rapidly increasing post-Dobbs. While designed for Medicaid enrollees, further investigation will explore more generalized use.

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.

Vaginal ring acceptability: A systematic review and meta-analysis of vaginal ring experiences from around the world.

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.

Spatiotemporal regulation of human IFN-ε and innate immunity in the female reproductive tract.

Although published studies have demonstrated that IFN-ε has a crucial role in regulating protective immunity in the mouse female reproductive tract, expression and regulation of IFN-ε in the human female reproductive tract (hFRT) have not been characterized to our knowledge. We obtained hFRT samples from a well-characterized cohort of women to enable us to comprehensively assess ex vivo IFN-ε expression in the hFRT at various stages of the menstrual cycle. We found that among the various types of IFNs, IFN-ε was uniquely, selectively, and constitutively expressed in the hFRT epithelium. It had distinct expression patterns in the surface and glandular epithelia of the upper hFRT compared with basal layers of the stratified squamous epithelia of the lower hFRT. There was cyclical variation of IFN-ε expression in the endometrial epithelium of the upper hFRT and not in the distal FRT, consistent with selective endometrial expression of the progesterone receptor and regulation of the IFNE promoter by progesterone. Because we showed IFN-ε stimulated important protective IFN-regulated genes in FRT epithelium, this characterization is a key element in understanding the mechanisms of hormonal control of mucosal immunity.

Tolerability and safety of the estetrol/drospirenone combined oral contraceptive: Pooled analysis of two multicenter, open-label phase 3 trials.

OBJECTIVES: To evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials. STUDY DESIGN: The two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings. RESULTS: Of 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment. CONCLUSIONS: E4/DRSP is associated with a favorable tolerability and safety profile. IMPLICATIONS STATEMENT: Pooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks.

Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials.

OBJECTIVE: To evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen. STUDY DESIGN: We pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors. RESULTS: Analyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI <25 kg/m2, 25 to 29.9 kg/m2, and ≥30 kg/m2 of 1.14 (0.64-1.88), 2.19 (1.05-4.03), and 2.27 (0.83-4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] 3.61[1.56-8.38]), Black race (HR 4.61[1.97-10.80]), age 16 to 25 years (HR 2.37[1.09-5.15]) and compliance <99% of expected pills (HR 4.21[2.04-8.66]) with conception. CONCLUSION: E4/DRSP is an effective oral contraceptive overall and across subgroups stratified by age, contraceptive history, and BMI. Other than compliance, predictors of contraceptive failure are nonmodifiable. IMPLICATIONS STATEMENT: Pooled results from two phase 3 trials demonstrate high contraceptive efficacy of the novel estetrol-drospirenone oral contraceptive. Several non-modifiable risk factors, including prior pregnancy, race, and age, are associated with higher pregnancy risk. Additional research is needed to better understand predictors of combined oral contraceptive failure.

Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women.

OBJECTIVE: To evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen. STUDY DESIGN: We pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes. RESULTS: We included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event. CONCLUSION: E4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns. IMPLICATIONS STATEMENT: Most estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

A Randomized, Open-Label, Crossover Phase 1 Safety and Pharmacokinetic Study of Oral Maraviroc and Maraviroc 1% Gel (the CHARM-03 Study).

The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral maraviroc (MVC) and MVC 1% gel. At a single site, healthy HIV-uninfected men and women were enrolled and randomized to an open label crossover sequence of eight consecutive daily exposures to MVC 300 mg dosed orally, MCV 1% gel dosed rectally, and MVC 1% gel dosed vaginally. Male participants received oral and rectal dosing and female participants received oral, rectal, and vaginal dosing. Assessments were undertaken at baseline and following each 8-day period and included collection of plasma, rectal/cervical tissue (CT), and rectal/endocervical/vaginal fluids. Eleven men and nine women were enrolled. Two participants withdrew from the study before receiving study product. There were 25 adverse events, of which 24 were Grade 1 (G1) and one was G2 (unrelated). After eight doses, MVC was quantifiable in all samples following oral, rectal, or vaginal product administration. The highest drug concentrations in plasma, rectal tissue (RT), and CT were associated with oral, rectal, and vaginal drug delivery, respectively. There were significant reductions in tissue drug concentrations when rectal and cervical biopsies were incubated in media before tissue processing for PK (p < .0001). Only oral MVC was associated with limited protection in the rectal explant HIV challenge model (p < .05). There were no immunological changes in RT, and all products were acceptable to participants. In conclusion, all products were found to be safe and acceptable and did not induce local inflammation. The lack of ex vivo efficacy demonstrated in study samples may be due to rapid disassociation of MVC from the explant tissue. ClinicalTrials.gov Identifier: NCT02346084.

Understanding the public health value and defining preferred product characteristics for therapeutic human papillomavirus (HPV) vaccines: World Health Organization consultations, October 2021-March 2022.

The World Health Organization (WHO) global strategy to eliminate cervical cancer (CxCa) could result in >62 million lives saved by 2120 if strategy targets are reached and maintained: 90% of adolescent girls receiving prophylactic human papillomavirus (HPV) vaccine, 70% of women receiving twice-lifetime cervical cancer screening, and 90% of cervical pre-cancer lesions and invasive CxCa treated. However, the cost and complexity of CxCa screening and treatment approaches has hampered scale-up, particularly in low- and middle-income countries (LMICs), and new approaches are needed. Therapeutic HPV vaccines (TxV), which could clear persistent high-risk HPV infection and/or cause regression of pre-cancerous lesions, are in early clinical development and might offer one such approach. During October 2021 to March 2022, WHO, in collaboration with the Bill and Melinda Gates Foundation, convened a series of global expert consultations to lay the groundwork for understanding the potential value of TxV in the context of current CxCa prevention efforts and for defining WHO preferred product characteristics (PPCs) for TxV. WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper reports on the main discussion points and findings from the expert consultations. Experts identified several ways in which TxV might address challenges in current CxCa prevention programmes, but emphasized that the potential value of TxV will depend on their degree of efficacy and how quickly they can be developed and implemented relative to ongoing scale-up of existing interventions. Consultation participants also discussed potential use-cases for TxV, important PPC considerations (e.g., vaccine indications, target populations, and delivery strategies), and critical modelling needs for predicting TxV impact and cost-effectiveness.

Management of heterotopic pregnancy with uterine aspiration and systemic two-dose methotrexate.

The expected trend in serum beta-human chorionic gonadotropin (ß-hCG) following treatment of an undesired heterotopic pregnancy with uterine aspiration and systemic methotrexate is not known. Thus, monitoring for treatment success is challenging. We describe an undesired heterotopic pregnancy treated with aspiration and two-dose methotrexate and report the observed ß-hCG trend.