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.

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.