Risk factors for and outcomes of ring expulsions with a 1-year contraceptive vaginal system.

BACKGROUND: The US Food and Drug Administration-approved segesterone acetate and ethinyl estradiol ring-shaped contraceptive vaginal system, known as Annovera (Sever Pharma Solutions/QPharma, Malmö, Sweden), was inserted and removed under a woman's control for a 21 day in and 7 day out regimen for up to 13 cycles of use. OBJECTIVE: We aimed to describe the patterns of ring expulsion over time, to identify potential predictors of expulsion, and to evaluate the impact of expulsions on method discontinuation and pregnancy risk. STUDY DESIGN: Using data from 2064 participants who were enrolled in 2 multinational phase 3 clinical trials on the use of this contraceptive vaginal system, we examined data from participants' daily diaries for documentation of complete ring expulsion. We modeled the odds of reported expulsions over time with adjustment for background and demographic characteristics using mixed-effects logistic regression models with random intercepts. We compared the probability of continuation between those who did and those who did not report expulsions in the first cycle of use using survival analysis and hazards modeling. To determine if expulsions during the first cycle of use affected the risk for pregnancy, we calculated Pearl Indices. RESULTS: Most participants (75%) never experienced any expulsions during any cycle of use, and 91% to 97% did not experience an expulsion during any 1 cycle. The incidence of expulsion was highest in cycle 1 (9%). The odds of experiencing expulsions decreased by half in cycles 2 to 8 when compared with cycle 1 (0.48; 95% confidence interval, 0.40-0.58), and in cycles 9 to 13, expulsions were about a third of that in cycle 1 (0.32; 95% confidence interval, 0.26-0.41). Of those who did experience expulsions, most (62%-84%) experienced ≤2 expulsions per cycle. Participants from study sites in Latin America vs those in the United States had higher odds of not experiencing an expulsion (odds ratio, 1.95; 95% confidence interval, 1.45-2.63). Women with a higher education level had higher odds of experiencing an expulsion. Notably, parity, age, and body mass index were not associated with expulsion. Participants who experienced any expulsions in cycle 1 were more likely to discontinue use early (hazard ratio, 1.28; 95% confidence interval, 1.14-1.43) than participants who did not have an expulsion. The Pearl Index for participants who had expulsions during cycle 1 was 3.99 (95% confidence interval, 1.29-9.31), which was higher than that among participants who reported no expulsions (Pearl Index, 2.39; 95% confidence interval, 1.61-3.41), but the overlapping confidence intervals indicate that there is not sufficient evidence to demonstrate an association between expulsions and pregnancy risk. CONCLUSION: Expulsions were infrequent overall, decreased with subsequent cycles of use, and were not associated with body mass index or parity. Early discontinuation of product use was higher among participants who experienced an expulsion during cycle 1. Although it is unclear whether pregnancy risk was associated with expulsions, early recognition of expulsions among users may identify those at higher risk for discontinuation and may highlight when enhanced anticipatory counselling and guidance may be advantageous.

Assessing the acceptability of, adherence to and preference for a dual prevention pill (DPP) for HIV and pregnancy prevention compared to oral pre-exposure prophylaxis (PrEP) and oral contraception taken separately: protocols for two randomised, controlled, cross-over studies in South Africa and Zimbabwe.

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is a highly effective HIV prevention method; however, uptake and persistence have been low among southern African women. A dual prevention pill (DPP) that combines PrEP with oral contraception (OC) may increase PrEP use and better meet women's sexual and reproductive health needs. We will gauge the DPP's acceptability in two cross-over clinical trials. METHODS AND ANALYSIS: PC952 (Zimbabwe) and PC953 (South Africa) will compare acceptability, adherence and preference for an over-encapsulated DPP versus PrEP and OCs taken separately. HIV-negative, non-pregnant cisgender females in Johannesburg, South Africa (n=96, 16-40 years) and Harare, Zimbabwe (n=30, 16-24 years) will be randomised 1:1 to the order of regimens-DPP or two separate tablets-each used for three 28-day cycles, followed by a 6-month choice period in South Africa. Monthly clinic visits include HIV and pregnancy testing; safety assessments and risk reduction and adherence counselling. We will assess adherence (monthly) based on tenofovir diphosphate drug levels in dried blood spots and by self-report. We will evaluate acceptability (monthly) and preference (end of cross-over) via computer-assisted self-interviewing and in-depth interviews with a subset of participants. Data collection started in September 2022 and ended in January 2024. ETHICS AND DISSEMINATION: PC952 was approved by the Ministry of Health and Child Care, Medical Research Council, Research Council and Medicines Control Authority of Zimbabwe; the Chitungwiza City Health Ethics Committee; and the Joint Research Ethics Committee for the University of Zimbabwe Faculty of Medicine and Health Sciences and Parirenyatwa Group of Hospitals. PC953 was approved by the South African Health Products Regulatory Authority and the University of the Witwatersrand's Human Research Ethics Committee. The Population Council IRB approved both studies. We will disseminate results in open-access journals, clinical trials registries, and at local and international meetings and conferences. TRIAL REGISTRATION NUMBERS: NCT04778514, NCT04778527.

Results of a phase 1, randomized, placebo-controlled first-in-human trial of griffithsin formulated in a carrageenan vaginal gel.

HIV pre-exposure prophylaxis (PrEP) is dominated by clinical therapeutic antiretroviral (ARV) drugs. Griffithsin (GRFT) is a non-ARV lectin with potent anti-HIV activity. GRFT's preclinical safety, lack of systemic absorption after vaginal administration in animal studies, and lack of cross-resistance with existing ARV drugs prompted its development for topical HIV PrEP. We investigated safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PC-6500 (0.1% GRFT in a carrageenan (CG) gel) in healthy women after vaginal administration. This randomized, placebo-controlled, parallel group, double-blind first-in-human phase 1 study enrolled healthy, HIV-negative, non-pregnant women aged 24-45 years. In the open label period, all participants (n = 7) received single dose of PC-6500. In the randomized period, participants (n = 13) were instructed to self-administer 14 doses of PC-6500 or its matching CG placebo (PC-535) once daily for 14 days. The primary outcomes were safety and PK after single dose, and then after 14 days of dosing. Exploratory outcomes were GRFT concentrations in cervicovaginal fluids, PD, inflammatory mediators and gene expression in ectocervical biopsies. This trial is registered with ClinicalTrials.gov, number NCT02875119. No significant adverse events were recorded in clinical or laboratory results or histopathological evaluations in cervicovaginal mucosa, and no anti-drug (GRFT) antibodies were detected in serum. No cervicovaginal proinflammatory responses and no changes in the ectocervical transcriptome were evident. Decreased levels of proinflammatory chemokines (CXCL8, CCL5 and CCL20) were observed. GRFT was not detected in plasma. GRFT and GRFT/CG in cervicovaginal lavage samples inhibited HIV and HPV, respectively, in vitro in a dose-dependent fashion. These data suggest GRFT formulated in a CG gel is a safe and promising on-demand multipurpose prevention technology product that warrants further investigation.

Bleeding profile associated with 1-year use of the segesterone acetate/ethinyl estradiol contraceptive vaginal system: pooled analysis from Phase 3 trials.

OBJECTIVES: To describe bleeding patterns among users of the segesterone acetate (SA) and ethinyl estradiol (EE) contraceptive vaginal system (CVS), and identify factors associated with unscheduled bleeding/spotting (B/S). STUDY DESIGN: We pooled results from two multicenter, single-arm, open-label, pivotal, phase 3 studies of the SA/EE CVS conducted in 17 US and 7 international sites. Participants (age 18-40 years; BMI ≤29 kg/m2) followed a 21/7-day in/out schedule of CVS use for up to 13 cycles and recorded vaginal bleeding daily in paper diaries. Scheduled and unscheduled B/S were summarized by cycle. We used multiple logistic regression to identify factors associated with unscheduled bleeding/spotting, based on the first 4 cycles only. RESULTS: Analysis included data from 2070 participants (16,408 cycles). Ninety-eight percent documented scheduled B/S [mean (SD): 4.9 (1.1) days/cycle)]. Absence of scheduled B/S was 5-8% of women/cycle. Unscheduled B/S ranged from 13.2% to 21.7% of women per cycle. Few women (1.8%) discontinued prematurely due to unacceptable bleeding. Black women were more likely to report unscheduled B/S than White women [Adjusted odds ratio (AOR) = 1.49, 95% confidence interval (CI) = 1.14-1.94]. Women with fewer years of schooling [