Self-reported removal and expulsion of the dapivirine vaginal ring: qualitative reports from female ring users and their male partners in the Ring Study (IPM 027).

BACKGROUND/AIMS: The dapivirine vaginal ring is a self-administered, women-initiated, discreet, long-acting HIV-1 prevention option for women. It was found to be safe and effective in healthy HIV-negative women who adhered to product use instructions, and has been approved for use in women aged 18 and older in some African countries. A qualitative study was conducted to explore participants' and their male partners' discussions on accidental/purposeful vaginal ring removals during The Ring Study (IPM 027 clinical trial). METHODS: Data were collected via in-depth interviews and focus group discussions with female trial participants and their male partners, from seven research centres in South Africa and Uganda. Data were thematically analysed using NVivo. RESULTS: More participants reported purposeful ring removals than accidental expulsions. Various factors influenced purposeful ring removal - including individual (discomfort during use/sex and to clean it), partner (to show them, because of discomfort during sex, to test if partners could feel it, and concerns of harm), organisational (doctor's request), and socio-cultural (rumours about sickness and infertility). Some described their own ring use removal, others discussed why other participants removed their rings. CONCLUSIONS: Vaginal ring adherence is critical to improve and support product efficacy. Counselling on vaginal anatomy, vaginal ring insertion and importance of adherence is important to minimise vaginal ring removal. Couples counselling is also important to facilitate support and long-term vaginal ring adherence behaviour. Understanding factors influencing vaginal ring adherence is important for tailoring and targeting messages to support correct and consistent vaginal ring use as it is made available to the public.

Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study.

BACKGROUND: The Ring Study, a phase 3 trial in 1959 sexually active women (randomised 2:1), showed a favourable safety profile and a 31% HIV-1 infection risk reduction for a vaginal ring containing 25 mg of dapivirine, compared with a placebo ring. We report here the DREAM study, which aimed to evaluate safety, adherence, and HIV-1 incidence in those using the dapivirine vaginal ring (DVR) in open-label use. METHODS: The DREAM study is an open-label extension of The Ring Study, done at five research centres in South Africa and one research centre in Uganda. Former participants from The Ring Study, who remained HIV-negative and who did not discontinue the study due to an adverse event or safety concern that was considered to be related to the investigational product, were eligible. Women who were pregnant, planning to become pregnant, or breastfeeding at screening for DREAM were excluded. All participants received the DVR for insertion at the enrolment visit. Participants attended a 1-month follow-up visit and could either proceed with visits once every 3 months or attend monthly visits up to month 3 and then continue with visits once every 3 months. At each visit, HIV testing and safety evaluations were done, and residual dapivirine measured in used rings (approximately 4 mg is released from the DVR over 28 days of consistent use). HIV-1 incidence was compared descriptively with the simulated incidence rate obtained from bootstrap sampling of participants in the placebo group of The Ring Study, matched for research centre, age, and presence of sexually transmitted infections at enrolment. This study is registered with ClinicalTrials.gov, NCT02862171. FINDINGS: Between July 12, 2016, and Jan 11, 2019, 1034 former participants from The Ring Study were screened, 941 were enrolled and 848 completed the trial. 616 (65·5%) of 941 participants reported treatment-emergent adverse events. Of these, six (0·6%) had events considered to be treatment-related. No treatment-related serious adverse events were reported. Measurements of monthly ring residual amounts in participants enrolled in both trials showed consistently lower mean values in DREAM than in The Ring Study. Arithmetic mean ring residual amounts of participants in The Ring Study DVR group who enrolled in DREAM were 0·25 mg lower (95% CI 0·03-0·47; p=0·027) than the mean ring residual amounts of these participants in The Ring Study. 18 (1·9%) HIV-1 infections were confirmed during DVR use, resulting in an incidence of 1·8 (95% CI 1·1-2·6) per 100 person-years, 62% lower than the simulated placebo rate. INTERPRETATION: Although efficacy estimation is limited by the absence of a placebo group, the observed low HIV-1 incidence and improved adherence observed in DREAM support the hypothesis that increased efficacy due to improved adherence occurs when women know the demonstrated safety and efficacy of the DVR. The feasibility of a visit schedule of once every 3 months was shown, indicating that the DVR can be used in a real-world situation in usual clinical practice. FUNDING: The Ministry of Foreign Affairs (MFA) Denmark, Flanders MFA, Irish Aid, Dutch MFA, UK Aid from the UK Government's Foreign, Commonwealth and Development Office, and the US President's Emergency Plan for AIDS Relief through the US Agency for International Development.

Performance of Male Condoms When Used With and Without a Silicone Placebo Vaginal Ring-A Randomized, Crossover Trial.

BACKGROUND: The dapivirine vaginal ring reduced the risk of HIV infection by approximately 30% in Phase III trials. To ensure higher levels of protection against HIV and sexually transmitted infections, women should be counseled to use condoms when using the vaginal ring. This article evaluates the compatibility of male condoms with a placebo vaginal ring. METHODS: This was a 2-period crossover, randomized, noninferiority trial. Couples in 2 sites in the United States were randomized to male condom use, with and without a placebo silicone vaginal ring, and asked to use 4 male condoms in each period. The primary noninferiority end points were total clinical failure and their component failure events (clinical breakage or slippage). Frequencies and percentages were calculated for each failure mode and differences in performance of the 2 periods using the male condom without the ring as reference. Noninferiority was defined using a 3% margin at the 5% significance level. Safety and acceptability were also assessed. RESULTS: Seventy couples were enrolled, and 68 completed the trial with a total of 275 male condoms used in each period. Total condom clinical failure rates were 2.2% and 4.0% in the presence and absence of the vaginal ring, respectively, with a difference of -1.9% (95% confidence interval: -5.3% to 1.5%), thereby demonstrating noninferiority when used with the ring. There was no difference in safety between the 2 periods. DISCUSSION: Concurrent use of the placebo silicone vaginal ring had no significant effect on male condom functionality or safety outcomes.

Performance and Acceptability of the FC2 Female Condom When Used With and Without a Silicone Placebo Vaginal Ring-A Randomized, Crossover Trial.

BACKGROUND: The silicone Dapivirine Vaginal Ring 25 mg, has been developed to provide an additional HIV prevention option for women. If approved for use, women will always be counselled to use condoms when using the vaginal ring for maximum protection. This paper evaluates the compatibility of female condoms with the ring. METHODS: This was a 2-period crossover, randomized noninferiority trial. Couples in 2 sites in the United States of America were randomized to FC2 Female Condom (FC2) with and without a placebo silicone ring and asked to use 4 female condoms in each period. The primary noninferiority endpoint was the clinical failure rate during intercourse or withdrawal (self-reported clinical breakage, slippage, misdirection, and invagination). Frequencies and percentages were calculated for each failure mode and differences in performance of the 2 periods, using the female condom without the ring as reference. Noninferiority was defined using an 8% margin at the 5% significance level. Safety and tolerability were also assessed. RESULTS: Eighty-one couples were enrolled and 79 completed the trial using a total of 596 female condoms (297 and 299 with/without a ring inserted, respectively). Total female condom clinical failure was 14.1% and 15.7% in the presence and absence of a ring, respectively, with a difference of -2.1% (95% confidence interval: -7.8% to 3.6%), thereby demonstrating noninferiority when used with the ring. There were no differences in safety and tolerability between the 2 periods. DISCUSSION: Concurrent use of the placebo silicone vaginal ring had no significant effect on female condom functionality or safety outcomes.

Social harms in female-initiated HIV prevention method research: state of the evidence.

OBJECTIVES: Assessment of safety is an integral part of real-time monitoring in clinical trials. In HIV prevention research, safety of investigational products and trial participation has been expanded to include monitoring for 'social harms', generally defined as negative consequences of trial participation that may manifest in social, psychological, or physical ways. Further research on social harms within HIV prevention research is needed to understand the potential safety risks for women and advance the implementation of prevention methods in real-world contexts. METHODS: Secondary analysis of quantitative data from three randomized, double-blind, placebo-controlled trials of microbicide candidates in sub-Saharan Africa was conducted. Additionally, we assessed data from two prospective cohort studies that included participants who became HIV-positive or pregnant during parent trials. RESULTS: Social harms reporting was low across the largest and most recent microbicide studies. Social harm incidence per 100 person-years ranged from 1.10 (95% CI 0.78-1.52) to 3.25 (95% CI 2.83-3.74) in the phased trials. Reporting differed by dosing mechanism (e.g. vaginal gel, oral tablet, ring) and study, most likely as a function of measurement differences. Social harms were most frequently associated with male partners, rather than, for example, experiences of stigma in the community. CONCLUSION: Measurement and screening for social harms is an important component of conducting ethical research of novel HIV prevention methods. To date, social harm incidence reported in microbicide trials has been relatively low (<4% per 100 person-years), and the majority have been partner-related events. However, any incidence of social harm within the context of HIV prevention is important to capture and understand for the safety of individuals, and for the successful impact of prevention methods in a real-world context.

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .).