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.

Baseline Predictors of High Adherence to a Coitally Dependent Microbicide Gel Based on an Objective Marker of Use: Findings from the Carraguard Phase 3 Trial.

A randomized, placebo-controlled, efficacy trial of Carraguard was unable to demonstrate a reduction in women's risk of HIV infection, which may have been due, in part, to low adherence (gel used in 42 % of vaginal sex acts, on average). A secondary analysis was undertaken to understand baseline factors associated with high adherence (gel used in ≥85 % of sex acts). Women who reported ≥1 vaginal sex act, returned ≥1 opened applicator, and had ≥1 conclusive post-enrollment HIV test (N = 5990) were included. Adherence was estimated as the ratio of average weekly applicator insertions (based on a dye stain assay indicating vaginal insertion)/average weekly sex acts (by self-report). Multivariate logistic regression modeling indicated that coital frequency, site, contraception, and partner age difference had a significant impact on adherence. Women reporting >1 and ≤2 vaginal sex acts per week, on average, were half as likely to be adherent as those reporting 1 vaginal sex act per week or less [adjusted odds ratio (AOR): 0.48; 95 % CI 0.38-0.61]; women from the Western Cape had one-third the odds of being adherent compared to women from KZN (AOR: 0.31; 95 % CI 0.23-0.41); compared to women using injectable contraception, women using any other or no method were more likely to be adherent (AOR: 1.30; 95 % CI 1.04-1.63); and women who had a larger age gap from their partners were more likely to be adherent (AOR: 1.03; 95 % CI 1.01-1.05; p = 0.001). Despite low adherence, overall, 13 % of participants achieved nearly perfect adherence, indicating a potential niche for a coitally dependent microbicide. More research is needed on the impact of sexual patterns and HIV risk perception on product acceptability and adherence to improve counseling in ongoing trials and when products are eventually introduced.

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.

Evaluation of a pilot respiratory virus surveillance system linking electronic health record and diagnostic data.

CONTEXT: During the onset of 2009 pandemic influenza A (H1N1) (pH1N1), the New York City Department of Health and Mental Hygiene implemented a pilot respiratory virus surveillance system. OBJECTIVES: We evaluated the performance of this pilot system, which linked electronic health record (EHR) clinical, epidemiologic, and diagnostic data to monitor influenza-like illness (ILI) in the community. DESIGN: Surveillance was conducted at 9 community health centers with EHRs. Clinical decision support system alerts encouraged diagnostic testing of patients. Rapid influenza diagnostic testing (RIDT) and multiplex polymerase chain reaction assay (MassTag PCR) were performed sequentially. SETTING: Nine Institute for Family Health (IFH) clinics in Manhattan and the Bronx during May 26 to June 30, 2009, the pH1N1 outbreak peak. PARTICIPANTS: Adult and pediatric patients presenting to IFH clinics during May 26 to June 30, 2009. MAIN OUTCOME MEASURES: By using Centers for Disease Control and Prevention guidelines, we evaluated the system's completeness, sensitivity, timeliness, and epidemiologic usefulness. RESULTS: Of 537 ILI visits (5.7% of all visits), 17% underwent diagnostic testing. Of the 132 specimens with both a RIDT and MassTag PCR result, 90 (68%) had a MassTag PCR-identified respiratory virus, most commonly pH1N1 (n = 69; 77%). Of the 81 specimens that met the ILI case definition, 58 (72%) were positive for a respiratory virus tested for by MassTag PCR; 48 (59%) were positive for pH1N1. Ninety-four percent of ILI patients positive for pH1N1 were 45 years or younger. Sensitivity and specificity of RIDT (29% and 94%) and ILI case definition (70% and 48%) for pH1N1 were calculated using MassTag PCR as the standard. Results of RIDT took a median of 6 days. CONCLUSIONS: Despite low RIDT sensitivity for pH1N1 and limited timeliness, integration of EHR and diagnostic data has potential to provide valuable epidemiologic information, guide public health response, and represents a new model for community surveillance for influenza and respiratory viruses.

Ex Vivo Colonic Tissue Susceptibility to HIV-1 in Cisgender Men and Women.

The biology of HIV-1 acquisition through unprotected receptive anal intercourse is understudied. Considering that sex hormones are implicated in intestinal physiology, pathology, and HIV acquisition and pathogenesis, we explored links between sex hormones, ex vivo HIV-1BaL infection of colonic mucosa, and candidate biomarkers of susceptibility to HIV-1 (CD4+ T cell frequencies and immune mediators) in cisgender women and men. No consistent significant associations between sex hormone concentrations and ex vivo tissue infection with HIV-1BaL were detected. In men, serum estradiol (E2) concentrations were positively associated with tissue proinflammatory mediators (IL17A, GM-CSF, IFNγ, TNFα, and MIG/CXCL9) and serum testosterone concentrations were negatively associated with frequencies of activated CD4+ T cells (CD4+CCR5+, CD4+HLA-DR+, and CD4+CD38+HLA-DR+). In women, the only significant interactions were positive associations between progesterone (P4)/E2 ratios and tissue ILRA concentrations and between P4/E2 ratios and frequencies of tissue CD4+α4ß7high+ T cells. The study did not reveal relationships between biological sex or phase of the menstrual cycle and ex vivo tissue HIV-1BaL infection and tissue immune mediators. A comparison of CD4+ T cell frequencies between study groups revealed a higher frequency of tissue CD4+α4ß7high+ T cells in women versus men. In contrast, higher frequencies of tissue CD4+CD103+ T cells were detected in men versus women in the follicular phase of the menstrual cycle. Overall, the study identified associations between systemic sex hormone concentrations, biological sex, and tissue candidate biomarkers of susceptibility to HIV-1. The significance of these results for tissue susceptibility to HIV-1 and early HIV-1 pathogenesis warrants further investigation.

Herpes Simplex Virus Type 2 Prevalence and Association with Inflammatory Cytokines Among Sexual and Gender Minorities Living With and Without HIV-1 from Lagos, Nigeria.

Herpes simplex virus type 2 (HSV-2) is common globally and contributes significantly to the risk of acquiring HIV-1, yet these two sexually transmitted infections have not been sufficiently characterized for sexual and gender minorities (SGM) across Sub-Saharan Africa. To help fill this gap, we performed a retrospective study using plasma and serum samples from 183 SGM enrolled at the Lagos site of the TRUST/RV368 cohort in Nigeria, assayed them for HSV-2 antibodies with the Kalon ELISA and plasma cytokines and chemokines with Luminex, and correlated the findings with HIV-1 viral loads (VLs) and CD4 counts. We found an overall HSV-2 prevalence of 36.6% (49.5% and 23.9% among SGM with and without HIV-1, respectively, p < .001). Moreover, HSV-2-positive status was associated with high circulating concentrations of CCL11 among antiretroviral therapy-treated (p = .031) and untreated (p = .015) participants, and with high concentrations of CCL2 in the untreated group (p = .004), independent of VL. Principal component analysis revealed a strong association of cytokines with HIV-1 VL independent of HSV-2 status. In conclusion, our study finds that HSV-2 prevalence among SGM with HIV-1 is twice as high than HSV-2 prevalence among SGM without HIV-1 in Lagos and suggests that this is associated with higher levels of certain systemic cytokines. Additional work is needed to further characterize the relationship between HSV-2 and HIV-1 in SGM and help develop targeted therapies for coinfected individuals.

New approaches for developing biomarkers of hormonal contraceptive use.

To identify biomarkers of hormonal contraceptive (HC) use in urine and saliva, we conducted a pilot study with 30 women initiating levonorgestrel (LNG) containing combined oral contraceptives (COCs) or depot medroxyprogesterone acetate (DMPA) (15/group). Based on established COC pharmacokinetics, we collected serum and urine samples before COC ingestion and during Days one and three of use, or before DMPA injection and on Days 21 and 60 post-injection. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure serum/urine LNG and MPA. LNG was undetectable at baseline (specificity 100%); post ingestion, most urine samples had detectable LNG levels (sensitivity: 80% 6 h post Dose one, 93% 6 h post Dose three). We used a DetectX LNG immunoassay kit and showed 100% sensitivity measuring urine LNG. Urine MPA levels were undetectable in 14/15 women at baseline (specificity 91%); post-injection all urine samples had detectable MPA levels (sensitivity: 100% days 21 and 60). Results suggest urine sampling can be used to identify a biomarker of LNG and MPA use. Based on evidence from other steroidal hormonal studies showing changes affecting the transcriptome profile of saliva at 24 h, we used the same (COC, DMPA) timepoints to collect saliva. We performed transcriptome analysis and detected several differentially expressed genes in DMPA users' saliva on Days 21 and 60 compared to baseline; none among COC users. We plan further research of differential gene expression in saliva as a HC biomarker of DMPA use, and will explore longer periods of COC use and saliva collection times, and application of microRNA sequencing to support using saliva as a COC biomarker.

Antimicrobial and Antioxidant Properties of Theobroma cacao, Bourreria huanita, Eriobotrya japonica, and Elettaria cardamomum - Traditional Plants Used in Central America.

The search for alternative naturally occurring antimicrobial agents will always continue, especially when emerging diseases like COVID-19 provide an urgency to identify and develop safe and effective ways to prevent or treat these infections. The purpose of this study was to evaluate the potential antimicrobial activity as well as antioxidant properties of commercial samples from four traditional medicinal plants used in Central America: Theobroma cacao, Bourreria huanita, Eriobotrya japonica, and Elettaria cardamomum. Ethanolic extracts were prepared from commercial products derived from the seeds or flowers of these plants. Total phenolics and antioxidant activity were assessed using commercial kits. The cytotoxicity and antiviral activity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) were evaluated using the XTT colorimetric assay and a SARS-CoV-2 delta pseudoviral model. The half-maximal cytotoxic concentration (CC50) and half-maximal effective concentration (EC50) were used to calculate the therapeutic index (TI). Additionally, the antibacterial activity against Escherichia coli and Staphylococcus epidermidis was tested using a spectrophotometric method. The extracts showed total phenolics in the range of 0.06 to 1.85 nM/µL catechin equivalents, with T. cacao bean extract showing the highest content. The antioxidant activity showed values between 0.02 and 0.44 mM Trolox equivalents. T. cacao bean extract showed the highest antioxidant activity. Most plant extracts showed zero to moderate selective antiviral activity; however, one T. cacao beans sample showed excellent antiviral activity against SARS-CoV-2 with a TI value of 30.3, and one sample of E. japonica showed selective antiviral activity with a TI value of 18.7. Significant inhibition of E. coli and S. epidermidis by an E. japonica ethanolic extract (p<0.001) was observed using a spectrophotometric method that monitors bacterial growth over time. Additionally, ethanolic extracts of E. cardamomum showed significant inhibition of S. epidermidis growth (p<0.001). The results warrant further investigation of the antimicrobial and antioxidant properties of these plant extracts.

Incidence and characteristics of stillbirths before and during the Coronavirus 2019 pandemic.

OBJECTIVE: The aim of this study was to determine the incidence and characteristics of stillbirths during the initial wave of the Coronavirus 2019 (COVID-19) pandemic and whether or not this differed from the incidence and characteristics of stillbirths that occurred in the pre-pandemic period. STUDY DESIGN: This was a single-center retrospective cohort study of pregnant individuals who delivered stillbirths during two different time periods: March-September in 2017, 2018, and 2019 (pre-COVID-19 pandemic period) and March-September 2020 (COVID-19 pandemic period). RESULTS: No difference in the rate of stillbirths was found between the two time periods. The women who experienced a stillbirth during the pre-pandemic period attended on average more prenatal visits than women who experienced a stillbirth during the pandemic period (p < .05). During the pandemic period, a higher proportion of stillbirths were suspected to be due to poorly controlled hypertension (p = .04). CONCLUSIONS: The incidence of stillbirth during the pandemic period was similar to that during the pre-pandemic period; however, there were more stillbirths that occurred due to poorly controlled hypertension, a potentially preventable cause of stillbirth, during the pandemic period when compared to those of the pre-pandemic period. While the impact of the disease process of COVID-19 on stillbirth remains uncertain, the change in the provision of prenatal care during the pandemic period may have had unintended consequences with respect to the prevention and management of hypertension and the risk of potentially preventable stillbirths.

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.

Syndromic surveillance during pandemic (H1N1) 2009 outbreak, New York, New York, USA.

We compared emergency department and ambulatory care syndromic surveillance systems during the pandemic (H1N1) 2009 outbreak in New York City. Emergency departments likely experienced increases in influenza-like-illness significantly earlier than ambulatory care facilities because more patients sought care at emergency departments, differences in case definitions existed, or a combination thereof.

Study of electronic prescribing rates and barriers identified among providers using electronic health records in New York City.

BACKGROUND: Increased electronic prescribing (eRx) rates have the potential to prevent errors, increase patient safety, and curtail fraud. US Federal meaningful use guidelines require at least a 40% electronic prescribing rate. OBJECTIVE: We evaluated eRx rates among primary care providers in New York City in order to determine trends as well as identify any obstacles to increased eRx rates required by meaningful use guidelines. METHODS: The data we analysed included automatic electronic data transmissions from providers enrolled in the Primary Care Information Project (PCIP) from 1 January 2009 to 1 July 2010 and follow-up telephone calls to a subset of these providers to identify potential barriers to increased eRx usage. RESULTS: Over the course of the study, these providers increased the eRx rate from 12.9 to 27.5%, with an average rate of 24.1%. Conversations with providers identified their perceived barriers to increased eRx use as primarily patient preference for paper prescriptions and a belief that many pharmacies do not accept eRx. CONCLUSIONS: The data gathered from our providers indicate that there is an increasing trend in the eRx rate to 27.5% by July 2010, but still short of the 40% meaningful use level. However, obstacles to increased rates remain primarily providers' belief that many patients prefer paper prescriptions and many pharmacies are not yet prepared to accept electronic prescriptions.

Segesterone acetate serum levels with a regression model of continuous use of the segesterone acetate/ethinyl estradiol contraceptive vaginal system.

OBJECTIVE: To predict serum segesterone (SA) and ethinyl estradiol (EE) levels after 364 days of hypothetical continuous use (without removal) of a cyclic contraceptive vaginal system (CVS) containing 0.15 mg SA and 0.013 mg EE. STUDY DESIGN: We used pharmacokinetic (PK) data (n = 37) from a multicenter, open-label, nonrandomized study of healthy women (18-38 years) that used the CVS for 13 cycles in a 21 days-in/7 days-out regimen to develop a linear regression model to predict daily serum SA and EE levels for 364 days of continuous CVS use. We then determined residual SA/EE levels in vitro from 18 randomly chosen CVS used by women who completed 13 cycles. Serum SA and EE levels were also predicted for 364 days of continuous CVS use in another in vitro study. RESULTS: After a hypothetical 364 days of continuous CVS use, we predicted daily mean serum levels to be 184 pmol/L (95% confidence interval [CI], 102‒332 pmol/L) for SA and 43 pmol/L (95% CI, 19‒95 pmol/L) for EE. We did predict that serum EE levels would not accumulate over time. Residual SA and EE in the CVS were 60% and 80% of the original load after 13 cycles, respectively. CONCLUSION: The predicted serum SA level after 364 days of hypothetical continuous CVS use was comparable to reported levels at which no pregnancy occurred (>100 pmol/L), showing the potential of the CVS for one year of continuous use. Clinical trials on continuous CVS use are planned. IMPLICATIONS: Based on statistical modeling, the long-term, user-controlled contraceptive vaginal system containing segesterone acetate and ethinyl estradiol may have the potential to provide effective pregnancy prevention if used continuously (without removal) for one year. Further investigation is warranted.

Pharmacodynamics and pharmacokinetics of a copper intrauterine contraceptive system releasing ulipristal acetate: A randomized proof-of-concept study.

OBJECTIVES: To assess pharmacodynamic and pharmacokinetic outcomes of a novel copper (Cu) intrauterine system (IUS) releasing ulipristal acetate (UPA) in healthy women. STUDY DESIGN: In this single-blinded, randomized proof-of-concept study, ovulatory women received one of three Cu-IUSs releasing low-dose UPA (5, 20 or 40 µg/d) for 12 weeks. The study included a baseline cycle, three 4-week treatment-cycles and 2 recovery cycles. Primary outcomes included effects of the IUS on bleeding profile, ovarian function, and the occurrence of progesterone receptor modulator associated endometrial changes (PAEC). Pharmacokinetics and safety profile were secondary outcomes. We compared outcomes in treatment-cycle 3 with baseline, using generalized linear mixed models with orthogonal contrasts. RESULTS: We randomized 29 women (5 µg/d = 10, 20 µg/d = 10, 40 µg/d = 9). All had a successful IUS insertion; 27 completed the 12-week treatment period. Compared to baseline, the mean number of bleeding-only days at treatment-cycle 3 declined by 16.7% in the 5 µg/d group (3.6 vs 3.0, p = 0.66), 40.5% in the 20 µg/d group (4.2 vs 2.5, p = 0.14), and 77% in the 40 µg/d group (3.9 vs 0.9, p = 0.002). Most women reported reduction in the amount of bleeding: 4/8, 8/10, and 7/9 for the 5 µg/d, 20 µg/d, and 40 µg/d groups, respectively. During IUS use, ovulation occurred in most cycles [5 µg/d: 23/24 (96%), 20 µg/d: 26/30 (87%), 40 µg/d: 22/27 (81%)]. The frequency of PAEC at IUS removal was 1/10 (10%), 1/10 (10%) and 4/9 (44%) in the 5 µg/d, 20 µg/d, and 4 0 µg/d groups, respectively. No serious adverse events occurred. CONCLUSIONS: Reduction in bleeding, low incidence of PAEC, and no serious adverse events are reassuring findings of the novel Cu-UPA-IUS. The 20 µg/d seems the lowest dose promoting a favorable bleeding profile and limiting PAEC. IMPLICATIONS: The preliminary results of this short-term study of a novel copper intrauterine system (IUS) delivering ulipristal acetate showed reduction of bleeding, low incidence of progesterone receptor modulator associated endometrial changes, and absence of serious adverse events. By preventing copper-induced increase in bleeding, this IUS could provide a noncontraceptive benefit, especially for women with low hemoglobin.

Progesterone vaginal ring as a new contraceptive option for lactating mothers: Evidence from a multicenter non-randomized comparative clinical trial in India.

OBJECTIVES: Evaluate and compare contraceptive efficacy, safety, continuation rates and duration of lactational amenorrhea (LA) in married lactating women (20-35 years) using the progesterone vaginal ring (PVR) or Copper-T380A intrauterine device (IUD) during the first postpartum year. STUDY DESIGN: We conducted a one-year multicenter, non-randomized, non-inferiority, open-label, comparative trial at 20 centers in India and compared efficacy, safety, continuation and LA plus feeding patterns and growth/well-being of participants' infants. Women used four 3-month PVRs consecutively (lost PVRs were not replaced) and were to breastfeed at least four times/day. We used Pearl Index (PI) and Kaplan Meier (K-M) rates to analyze pregnancy and K-M for continuation. RESULTS: We enrolled 789 women (459 PVR, 330 IUD). Neither PI nor K-M one-year pregnancy rates differed significantly between groups (PI: PVR-0.62; IUD-0.35); (K-M: PVR-0.7; IUD-0.4, p = 0.58). Continuation rates at 12 months were 78.5% (IUD) vs. 56.9% (PVR) (p < 0.001). Ring expulsions and menorrhagia were the most common discontinuation among PVR/IUD users respectively. The median duration of LA among PVR vs. IUD users was 405 vs. 120 days (p < 0.001). Both groups reported similar adverse events (PVR: 24.2%; IUD: 23.0%); there were no serious adverse events among PVR users. Infants from both groups fed 12-7 times/day and grew at expected rates. CONCLUSIONS: Efficacy and safety outcomes were comparable among women in both groups. Continuation rates for PVR, a woman-controlled method, were shorter than IUD rates while PVR users maintained LA significantly longer than IUD users. Infant breastfeeding and growth patterns/well-being were favorable in both groups. IMPLICATIONS: PVR, a user-controlled device, offers an additional contraceptive choice for lactating women for one-year postpartum use and can help to address the unmet need for contraception among postpartum women while encouraging breastfeeding to enhance infant growth and well-being.

Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Female-initiated HIV-prevention options, such as microbicides, are urgently needed. We assessed Carraguard, a carrageenan-based compound developed by the Population Council, for its efficacy and long-term safety in prevention of HIV infection in women. METHODS: We undertook a randomised, placebo-controlled, double-blind trial in three South African sites in sexually-active, HIV-negative women, aged 16 years and older. 6202 participants, who were randomly assigned by a block randomisation scheme to Carraguard (n=3103) or placebo (methylcellulose [n=3099]), were instructed to use one applicator of gel plus a condom during each vaginal sex act. Participants were followed up for up to 2 years. Visits every 3 months included testing for HIV presence and pregnancy, pelvic examinations, risk reduction counselling, and treatment for curable sexually transmitted infections and symptomatic vaginal infections. The primary outcome was time to HIV seroconversion. Analysis was in the efficacy population (a subset of the intention-to-treat population, excluding participants for whom efficacy could not be assessed). This study is registered with ClinicalTrials.gov, number NCT00213083. FINDINGS: For the primary outcome (time to HIV seroconversion) we analysed 3011 women in the Carraguard group and 2994 in the placebo group. HIV incidence was 3.3 per 100 woman-years (95% CI 2.8-3.9) in the Carraguard group (134 events) and 3.8 per 100 woman-years (95% CI 3.2-4.4) in the placebo group (151 events), with no significant difference in the distribution of time to seroconversion (p=0.30). The covariate-adjusted hazard ratio was 0.87 (95% CI 0.69-1.09). Rates of self-reported gel use (96.2% Carraguard, 95.9% placebo) and condom use (64.1% in both groups) at last sex acts were similar in both groups. On the basis of applicator testing, however, gel was estimated to have been used in only 42.1% of sex acts, on average (41.1% Carraguard, 43.1% placebo). 1420 (23%) women in the intention-to-treat population had adverse events (713 Carraguard, 707 placebo), and 95 (2%) women had adverse events that were related to gel use (48 Carraguard, 47 placebo). Serious adverse events occurred in 72 (2%) women in the Carraguard group and 78 (3%) in the placebo group, only one of which was considered possibly related to gel use (placebo group). INTERPRETATION: This study did not show Carraguard's efficacy in prevention of vaginal transmission of HIV. No safety concerns were recorded.

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 [

Post-use ring weight and residual drug content as potential objective measures of user adherence to a contraceptive progesterone vaginal ring.

OBJECTIVES: The primary aim was to investigate post-use ring weight as a potential measure of cumulative adherence to a progesterone-releasing vaginal ring. STUDY DESIGN: We weighed and quantified residual progesterone in 115 vaginal rings following 90-day use by participants in an acceptability trial conducted in Nigeria, Senegal and Kenya. The primary objective was to correlate residual progesterone content with post-use ring weight. Secondary objectives included correlating ring weight with putative duration of ring use, and, where participants used two rings consecutively in the study, correlating residual content between these paired rings. RESULTS: Mean ring weight and progesterone content of used rings was 8.62±0.24 g and 1245±245 mg respectively, versus 9.37±0.02 and 2058±21 mg for control rings. Most used rings (90.4%) had residual progesterone levels less than 85% of the nominal loading. Linear regression showed a strong positive linear trend between residual progesterone content and post-use ring weight for all rings (r2=0.82). Duration of ring use was inversely associated (p=.00020) with ring weight. CONCLUSIONS: Post-use ring weight is highly correlated with residual progesterone content, a benchmark objective cumulative measure of adherence, and thus potentially useful as a surrogate objective measure of cumulative adherence to a progesterone-releasing vaginal ring. IMPLICATION STATEMENT: For vaginal rings containing a high initial drug loading and releasing a relatively large fraction of the initial loading during clinical use, post-use ring weight may offer a simple and inexpensive alternative to residual content testing for accurate monitoring of user adherence.

Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation.

OBJECTIVES: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. STUDY DESIGN: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive days and removed it for 7 days of each 28-day cycle. Four studies used the final manufactured CVS, including a 1-year pharmacokinetic study, two 1-year phase 3 trials and a second-year treatment extension study. We assessed safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. RESULTS: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m2] received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of use. Women using the final CVS most commonly reported adverse events of headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%) and abdominal pain (n=225, 10%). Few (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29 kg/m2 (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions in 4259 (19.5%) cycles and complete expulsions in 1509 (7%) cycles, most frequently in the initial cycle [499/2050 (24.3%) and 190/2050 (9.3%), respectively]. Safety-focused studies revealed no safety concerns. CONCLUSION: The 1-year SA/EE CVS has an acceptable safety profile. Additional studies are warranted in obese women at higher risk of VTE. IMPLICATIONS: This 1-year contraceptive vaginal system represents a new long-term, user-controlled and procedure-free option with a safety profile similar to other combination hormonal contraceptives. The same precautions currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.