Learning from women about HIV risk, HIV testing behaviors, and prevention practices in Mpumalanga, South Africa: A descriptive study to inform microbicides introduction

The provision of any new prevention product in clinical trial settings is often vastly different from implementation in “real life” public sector settings. In addition, use of antiretrovirals (ARV), such as tenofovir gel, for pre-exposure prophylaxis requires regular HIV testing to ensure users are uninfected before initiating and continuing product use. Therefore, before any ARV-based prevention product can be introduced to women, information is needed on HIV testing practices, how best to integrate products into existing primary health care systems, and women’s risk perception and health-seeking behaviors. The Population Council, in partnership with Solutions IPPT, conducted a study to learn more about women’s experiences in routine primary health care centers in Mpumalanga, South Africa to inform microbicides introduction. This report discusses the issues explored in the study: service seeking, constellation of services, HIV testing behavior, self-assessment of risk, and interest in tenofovir gel

Does size matter? A randomized controlled trial to assess the impact of external diameter on adherence to 3 different intravaginal rings among 24 US couples

Background: Intravaginal rings (IVRs) are being developed as multipurpose prevention technologies (MPTs) for simultaneous HIV and pregnancy prevention. However, no empirical data exists to support the current 54-58mm size as ideal. Understanding the impact of IVR size on adherence is critical for developing a product that can be used correctly and consistently. Methods: We conducted a randomized, open-label, 3-way crossover trial comparing adherence, preference, and acceptability of 3 non-medicated silicone IVRs of differing external diameters: 46mm, 56mm and 66mm. 24 couples in Atlanta, GA and Bronx, NY were randomized to the sequence of IVR use, used each continuously for ~30 days. The primary objective was to compare ring adherence, defined as never having the IVR out of the vagina for \u3e 30 minutes in 24h. Women reported occurrence and duration of expulsions and removals via daily text. We summarized the proportion of days the IVR was removed, expelled, or out all day, and the proportion of women adherent to each IVR. We used mixed methods logistic regression models with random intercepts (per participant) to compare the probability of each event happening per day of IVR use, per IVR. Results: 23/24 couples completed the study. 78%, 75% and 59% of participants were adherent to the IVRs of diameter 46mm, 56mm and 66mm respectively (Table 1). The 46mm and 66mm IVR performed similarly, with more expulsions and 24h outages for the 66mm IVR. When adjusting for size and sequence, women had \u3e 15 times the odds of the 66mm IVR being out all day versus the 56mm IVR (15.7, 95% CI: 3.4, 72.6). Conclusions: External diameter of these non-medicated IVRs had a significant impact on frequency of removal and expulsion. Product developers should prioritize IVRs in the range of 46mm-56mm

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 aeyen85 % of sex acts). Women who reported aeyen1 vaginal sex act, returned aeyen1 opened applicator, and had aeyen1 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 aecurrency sign2 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.Peer reviewe

Results of a phase 1, randomized, placebocontrolled 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

Factors associated with non-adherence to instructions for using the Nestorone®/ethinyl estradiol contraceptive vaginal ring

Objectives: We sought to identify factors associated with non-adherence to instructions for using a novel contraceptive providing 1-year of protection. Study design: Data from a multi-country Phase 3 trial of the Nestorone® (segesterone acetate)/ethinyl estradiol (NES/EE) CVR were analyzed. Participants were instructed to use the CVR over 13 cycles and follow a 21/7 regimen. Their reports of CVR removals\u3e2 h outside scheduled removal periods served as a proxy for non-adherence. We used multivariate logistic regression to determine factors associated with such use. Results: Of 905 participants, 120 (13%) reported CVR removals\u3e2 h. Removals for washing (OR 3.96, 95%CI 2.50–6.27) or sexual intercourse (OR 3.19, 95%CI 2.03–4.99), and finding CVR insertion difficult (OR 2.80, 95%CI 1.36–5.80) were factors associated with removals\u3e2 h. Lower educational attainment also predicted ring removal \u3e 2 h (OR 3.23, 95%CI 1.55–6.75). Women residing in Europe or Australia were less likely to remove the ring for \u3e 2 h compared with women in the US (OR 0.44, 95%CI 0.24–0.83 and OR 0.13, 95%CI 0.02–0.98, respectively). Participants who reported removals \u3e 2 h were more likely to discontinue CVR use (OR 1.93, 95%CI 1.24–2.95), report dissatisfaction (OR 2.20, 95%CI 1.32–3.69), and become pregnant during the study (OR 4.07, 95%CI 1.58–10.50). Conclusions: Removing the CVR for washing and before intercourse are factors associated with non-adherence to ring use. These are important topics for counseling women who are considering or using vaginal rings, including the NES/EE CVR. Implications: Findings from this study may be useful in guiding counseling for current and prospective vaginal ring users. Anticipatory guidance should focus on how the ring feels in the vagina and during sex. Asking about ring removals may help identify women who are at increased risk for having an unplanned pregnancy

Estradiol inhibits HIV-1BaL infection and induces CFL1 expression in peripheral blood mononuclear cells and endocervical mucosa

An inhibitory effect of estradiol (E2) on HIV-1 infection was suggested by several reports. We previously identified increased gene expression of actin-binding protein cofilin 1 (CFL1) in endocervix in the E2-dominated proliferative phase of the menstrual cycle. Actin cytoskeleton has an integral role in establishing and spreading HIV-1 infection. Herein, we studied in vitro effects of E2 on HIV-1 infection and on CFL1 expression to gain insight into the mechanism of HIV-1 inhibition by E2. E2 dose-dependently inhibited HIV-1BaL infection in peripheral blood mononuclear cells (PBMCs) and endocervix. In PBMCs and endocervix, E2 increased protein expression of total CFL1 and phosphorylated CFL1 (pCFL1) and pCFL1/CFL1 ratios. LIMKi3, a LIM kinase 1 and 2 inhibitor, abrogated the phenotype and restored infection in both PBMCs and endocervix; inhibited E2-induced expression of total CFL1, pCFL1; and decreased pCFL1/CFL1 ratios. Knockdown of CFL1 in PBMCs also abrogated the phenotype and partially restored infection. Additional analysis of soluble mediators revealed decreased concentrations of pro-inflammatory chemokines CXCL10 and CCL5 in infected tissues incubated with E2. Our results suggest a link between E2-mediated anti-HIV-1 activity and expression of CFL1 in PBMCs and endocervical mucosa. The data support exploration of cytoskeletal signaling pathway targets for the development of prevention strategies against HIV-1

Factors predicting improper use of a woman-controlled long-acting reversible contraceptive: Results from the acceptability study of a novel contraceptive vaginal ring

Objectives: Improper contraceptive use accounts for a large proportion of unintended pregnancies. We sought predictors of improper use of an investigational 1-year, reusable contraceptive vaginal ring that is woman controlled

Risk factors for and outcomes of ring expulsions with a one year contraceptive vaginal system

Background: The FDA-approved, segesterone acetate/ethinyl estradiol, ring-shaped contraceptive vaginal system, known was Annovera (Sever Pharma Solutions/QPharma, Malmö, Sweden inserted and removed under a woman’s control for a 21 day in/7 day out regimen for up to 13 cycles of use. Objectives: We aimed to describe patterns of ring expulsion over time, identify potential predictors of expulsion and evaluate the impact of expulsions on method discontinuation and pregnancy risk. Study Design: Using data from 2064 participants in two multinational Phase 3 clinical trials 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, adjusting for background and demographic characteristics, using mixed-effects logistic regression models with random intercepts. We compared probability of continuation between those who did and 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 risk of pregnancy, we calculated Pearl Indices. Results: Most participants (75%) never experienced any expulsions during any cycle of use, with 91-97% not experiencing an expulsion during any one cycle. The incidence of expulsion was highest in Cycle 1 (9%). The odds of experiencing expulsions decreased by half in cycles 2-8 3 vs cycle 1 (0.48 95% CI 0.40-0.58) and in in cycles 9-13 expulsions were about a third that in cycle 1 (0.32 95% CI 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 U.S. had higher odds of not experiencing an expulsion (OR 1.95, 95% CI 1.45-2.63). Women with more education had higher odds of experiencing an expulsion. Notably, parity, age and BMI were not associated with expulsion. Participants who did experience any expulsions in Cycle 1 were more likely to discontinue early hazards ratio 1.28, 95% CI (1.14, 1.43) compared to participants who had an expulsion. The Pearl Index for participants who had expulsions during Cycle 1 was 3.99 (95% CI: 1.29-9.31), higher than among participants who reported no expulsions (PI 2.39, 95% CI: 1.61-3.41) but the overlapping confidence intervals indicate there is not sufficient evidence to demonstrate an association between expulsions and pregnancy risk. Conclusions: Expulsions were infrequent overall, decreased with subsequent cycles of use and were not associated with BMI or parity. Early discontinuation of product use was higher among participants who experienced an expulsion during Cycle 1. While it is unclear whether pregnancy risk is associated with expulsions, early recognition of expulsions among users may identify those at higher risk for discontinuation and may highlight, where enhanced anticipatory counselling and guidance may be advantageous