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.

Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women.

BACKGROUND: Postmenopausal women have unique sociobiological human immunodeficiency virus (HIV) risks. We evaluated the safety, pharmacokinetics, and acceptability of a microbicide dapivirine (DPV) vaginal ring (VR) versus placebo in postmenopausal women. METHODS: We enrolled 96 HIV-negative postmenopausal US women in a phase 2a double-blind, randomized (3:1) trial of monthly VRs containing 25 mg DPV or placebo used continuously for 12 weeks. We assessed safety by adverse events (AEs). DPV concentrations were quantified in plasma and vaginal fluid. Steady-state concentrations were analyzed at 4, 8, and 12 weeks using repeated measures ANOVA. We assessed acceptability by self-report. RESULTS: We found no differences in the proportion of women with related grade 2 or higher reproductive system AEs (DPV: 6/72 (8%), placebo: 3/24 (13%), P = .68) or grade 3 or higher AEs (DPV: 4/72 (6%), placebo: 0/24 (0%), P = .57). In the DPV arm, 2/72 (3%) declined to resume product use due to AEs. Median DPV concentrations in plasma (262.0 pg/mL at week 12) and vaginal fluid (40.6 ng/mg at week 12) were constant over 12 weeks and exceeded the in vitro 50% effective concentration by 5000-fold in vaginal fluid by week 4. VR acceptability was high; 84/93 (90%) "very much liked or liked" the VR. CONCLUSIONS: DPV VRs were safe, well tolerated, and acceptable in postmenopausal women. Plasma concentrations were comparable to published data on DPV use in reproductive-age women (median plasma concentration: 264 pg/mL). Given the reassuring safety and pharmacokinetic data, the DPV VR is promising for preexposure prophylaxis in postmenopausal women. CLINICAL TRIALS REGISTRATION: NCT02010593.

Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women Using the Dapivirine Vaginal Ring.

Breastfeeding (BF) women are an important population for biomedical HIV prevention strategies, but they are rarely included in trials. The 25-mg dapivirine vaginal ring (VR) reduced women's risk of sexually transmitted HIV infection in two phase 3 trials conducted in Africa. We conducted a phase 1, open-label study (MTN-029/IPM 039) of dapivirine VR use among lactating women in Pittsburgh, PA, and Birmingham, AL, USA. MTN-029/IPM 039 enrolled 16 healthy adult women who had already weaned their infants but were still able to express breast milk. Women were instructed to use the VR continuously for 14 days and provided milk, plasma, and cervicovaginal fluid (CVF) samples for pharmacological analysis. No infants were exposed to the drug, but infant dosage was estimated according to FDA guidance. Adverse events (AEs) were collected at all contacts. The study was completed with 100% participant retention. Median dapivirine concentrations were 676 pg/ml in breast milk, 327 pg/ml in plasma (milk/plasma ratio ∼2.0), and 36.25 ng/mg in CVF. Six participants experienced 10 total AEs, none of which required VR discontinuation. The estimated mean daily infant dosage was 74.3 ng/kg/day. In this first study of dapivirine exposure during lactation, dapivirine VR use was associated with lower concentrations of detectable dapivirine in milk and plasma than in CVF samples and a favorable safety profile. Estimated daily levels of infant dapivirine exposure were also low. Additional studies are needed to evaluate longer periods of dapivirine VR use among BF mother-infant pairs living in regions with higher incidence of sexually transmitted HIV infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02808949.).

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 .).

Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women.

BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).

Contraceptive Preference Among Women at Risk of HIV Acquisition in a Preparatory Screening Study for a Phase III Microbicide Trial in South Western Uganda.

Contraceptive preferences of women at risk for HIV acquisition are not well documented. We report on contraceptive choices among women residing in small townships in southwestern Uganda. This was part of preparatory efforts for recruitment into the Ring Study, a phase 3 microbicide trial, between July 2013 and October 2014. Clinicians provided contraceptives per a woman's choice. HIV testing and screening for other sexually transmitted infections were done at first contact and at screening for the trial. Contraceptive choice was summarized by demographics and regression analysis to show factors associated with use of the injectable method. Of 6725 women contacted, 489 were prescreened. Of these 489 women, most (306, 63%) were already using contraception. Injectables were most preferred (58.7%), followed by implants (23.9%). Women living with a regular sexual partner preferred the injectable method (61.0%, P = 0.06), compared with other methods. Women at risk for HIV infection are willing to initiate use of modern contraceptives, which may reduce study dropout during intervention trials due to unintended pregnancy. Registration no: NCT01539226.

Adherence and Acceptability of a Multidrug Vaginal Ring for HIV Prevention in a Phase I Study in the United States.

We evaluated the adherence and acceptability of a vaginal ring containing dapivirine, maraviroc, or both drugs for 28 days during a Phase I placebo-controlled trial in 48 HIV-negative sexually abstinent U.S. women aged 18-40. Adherence was assessed weekly by clinical interview and computer-assisted self-interviewing; acceptability assessment occurred at the last product-use visit. Study retention was 98 % (47/48); 94 % (45/48) reported being fully adherent with ring use during the 28-day period. Two participants experienced the ring partially coming out. Analysis was blinded and behavioral data were combined across study groups. Most women reported being very comfortable having the ring in their vagina; 44 % preferred continuous use, whereas 51 % had no preference compared to episodic use. Although a range of minor ring concerns were expressed, few were actually experienced. High adherence to and acceptability of this vaginal ring in this Phase I trial contributes to its promise as a sustained mechanism for multidrug vaginal microbicide delivery.

Acceptability of the Dapivirine Vaginal Ring in Postmenopausal US Women.

For women in the United States who remain sexually active beyond child-bearing years, susceptibility to HIV infection remains, yet condom use is low. We assessed acceptability of the dapivirine vaginal ring (ring) among 96 postmenopausal US women enrolled in a placebo-controlled multisite phase II trial of the ring, using questionnaires and in-depth interviews. Three quarters of women reported "perfect" adherence (ring never out) over the 3-month trial period. At study exit, the ring was found to be very easy to use by 72%, very comfortable to wear by 65%, and 4% reported it ever interfered with their daily activities. The most common worries among participants at preinitiation had decreased significantly at study exit (e.g., worries about inserting the ring declined from 46% to 6%, discomfort during daily activities from 53% to 3%, ring not staying in place from 48% to 14%, all p < 0.0001). Despite some couples feeling the ring during sex, the ring was perceived as more suitable than condoms for prevention because it was not burdensome to use, did not interfere with erection, and provided (for some) additional vaginal lubrication. The ring is a promising, highly acceptable HIV prevention method that is suitable to the lives of postmenopausal women and their male partners and can provide them with an additional prevention choice. Clinical Trials Registration: NCT02010593.

High human immunodeficiency virus incidence in a cohort of Rwandan female sex workers.

BACKGROUND: Measurement of human immunodeficiency virus(HIV) incidence among female sex workers in Rwanda is a key part of preparing for HIV prevention trials. METHODS: HIV-negative, nonpregnant female sex workers (N =397) were tested for HIV-1, sexually transmitted infections, and pregnancy quarterly for 12 months, and again at a 1-time year 2 visit. Additional women (N=156) were tested for HIV at baseline and 6 to 12 months thereafter in a parallel study. RESULTS: A total of 19 participants seroconverted during follow-up,with 13 in the first 12 months. The 12-month HIV incidence rate (IR)was 3.5 (95% confidence interval: 1.6, 5.4) per 100 person-years (PY).There was a nonsignificant downward trend from 4.6/100 PY (1.6, 7.7)in the first 6 months to 2.2 (0.1, 4.4) in the second 6 months (IR ratio:2.1 [95% confidence interval: 0.7, 7.8]). The year 2 IR was 2.1 (0.4,3.7), and the HIV IR in the parallel study (in the absence of frequent study visits) was 3.3/100 PY (0, 7.0). HIV testing history, lifetime pregnancies, recent initiation of sex work, gonorrhea, syphilis, and change in reproductive intentions were associated with incident HIV infection. Incidence of pregnancy, herpes simplex virus-type 2,trichomoniasis, gonorrhea, chlamydia, and syphilis per 100 PY were as follows: 26.3 (21.9, 30.7), 8.7 (4.0, 13.4), 16.9 (12.7, 21.1), 12.1 (8.2,15.9), 8.1 (5.1, 11.2), and 6.2 (3.7, 8.7). CONCLUSIONS: The HIV/sexually transmitted infections burden int his group was high. HIV IR was highest in the first 6 months of the cohort, and in the parallel study in which there were no risk-reduction procedures. HIV prevention and family planning interventions are needed.

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.

Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study.

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

Association of HIV infection with distribution and viral load of HPV types in Kenya: a survey with 820 female sex workers.

BACKGROUND: Human papillomavirus (HPV) and HIV are each responsible for a considerable burden of disease. Interactions between these infections pose substantial public health challenges, especially where HIV prevalence is high and HPV vaccine coverage low. METHODS: Between July 2005 and January 2006, a cross-sectional community-based survey in Mombasa, Kenya, enrolled female sex workers using snowball sampling. After interview and a gynaecological examination, blood and cervical cytology samples were taken. Quantitative real-time PCR detected HPV types and viral load measures. Prevalence of high-risk HPV was compared between HIV-infected and -uninfected women, and in women with abnormal cervical cytology, measured using conventional Pap smears. RESULTS: Median age of the 820 participants was 28 years (inter-quartile range [IQR] = 24-36 years). One third of women were HIV infected (283/803; 35.2%) and these women were y more likely to have abnormal cervical cytology than HIV-negative women (27%, 73/269, versus 8%, 42/503; P < 0.001). Of HIV-infected women, 73.3% had high-risk HPV (200/273) and 35.5% had HPV 16 and/or 18 (97/273). Corresponding figures for HIV-negative women were 45.5% (229/503) and 15.7% (79/503). After adjusting for age, number of children and condom use, high-risk HPV was 3.6 fold more common in HIV-infected women (95%CI = 2.6-5.1). Prevalence of all 15 of the high-risk HPV types measured was higher among HIV-infected women, between 1.4 and 5.5 fold. Median total HPV viral load was 881 copies/cell in HIV-infected women (IQR = 33-12,110 copies/cell) and 48 copies/cell in HIV-uninfected women (IQR = 6-756 copies/cell; P < 0.001). HPV 16 and/or HPV 18 were identified in 42.7% of LSIL (32/75) and 42.3% of HSIL (11/26) lesions (P = 0.98). High-risk HPV types other than 16 and 18 were common in LSIL (74.7%; 56/75) and HSIL (84.6%; 22/26); even higher among HIV-infected women. CONCLUSIONS: HIV-infected sex workers had almost four-fold higher prevalence of high-risk HPV, raised viral load and more precancerous lesions. HPV 16 and HPV 18, preventable with current vaccines, were associated with cervical disease, though other high-risk types were commoner. HIV-infected sex workers likely contribute disproportionately to HPV transmission dynamics in the general population. Current efforts to prevent HIV and HPV are inadequate. New interventions are required and improved implementation of existing strategies.

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.

Brief Report: Phase IIa Safety Study of a Vaginal Ring Containing Dapivirine in Adolescent Young Women.

BACKGROUND: Young women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence. METHODS: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews. RESULTS: Ninety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits. CONCLUSION: The dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents.

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 of a silicone elastomer vaginal ring as potential microbicide delivery method in African women: A Phase 1 randomized trial.

BACKGROUND: Women in sub-Saharan Africa are in urgent need of female-initiated human immunodeficiency virus (HIV) preventative methods. Vaginal rings are one dosage form in development for delivery of HIV microbicides. However, African women have limited experience with vaginal rings. OBJECTIVES: This Phase I, randomized, crossover trial assessed and compared the safety, acceptability and adherence of a silicone elastomer placebo vaginal ring, intended as a microbicide delivery method, inserted for a 12-week period in healthy, HIV-negative, sexually active women in South Africa and Tanzania. METHODS: 170 women, aged 18 to 35 years were enrolled with 88 women randomized to Group A, using a placebo vaginal ring for 12 weeks followed by a 12-week safety observation period. 82 women were randomized to Group B and observed for safety first, followed by a placebo vaginal ring for 12 weeks. Safety was assessed by clinical laboratory assessments, pelvic/colposcopy examinations and adverse events. Possible carry-over effect was addressed by ensuring no signs or symptoms of genital irritation at crossover. RESULTS: No safety concerns were identified for any safety variables assessed during the trial. No serious adverse events were reported considered related to the placebo vaginal ring. Vaginal candidiasis was the most common adverse event occurring in 11% of participants during each trial period. Vaginal discharge (2%), vaginal odour (2%), and bacterial vaginitis (2%) were assessed as possibly or probably related to the vaginal ring. Thirty-four percent of participants had sexually transmitted infections (STIs) at screening, compared to 12% of participants who tested positive for STIs at crossover and the final trial visit. Three participants (2%) tested HIV positive during the trial. CONCLUSIONS: The silicone elastomer vaginal ring had no safety concerns, demonstrating a profile favorable for further development for topical release of antiretroviral-based microbicides.

The future of HIV prevention: prospects for an effective anti-HIV microbicide.

Topical microbicides are self-administered products for prevention of HIV transmission, and they present one of the most promising strategies for combating the HIV-AIDS epidemic. The development of microbicides is a long and complicated process, with many hurdles that are unique to this class of product, including challenges in product design, in the conduct and design of clinical trials, and in obtaining licensure of a new class of products intended for use almost exclusively in developing countries. Once they have been registered, there are additional challenges to the marketing and distribution of microbicides. An overview of the types of microbicide currently in development, and a summary of the issues and the approaches being taken to address them, are provided.

Post-use assay of vaginal rings (VRs) as a potential measure of clinical trial adherence.

Adherence measurement for microbicide use within the clinical trial setting remains a challenge for the HIV prevention field. This paper describes an assay method used for determining residual dapivirine levels in post-use vaginal rings from clinical trials conducted with the Dapivirine Vaginal Matrix Ring-004 developed by the International Partnership for Microbicides to prevent male to female HIV transmission. Post-use assay results from three Ring-004 clinical trials showed that of the 25mg drug load, approximately 4mg of dapivirine is released from the matrix ring over a 28-day use period. Data obtained by both in vitro and in vivo studies indicate that dapivirine is released according to a diffusion mechanism, as determined by conformance of both data sets to the Higuchi equation. This, coupled with the low variability associated with batch production over two manufacturing sites and 20 batches of material, provides evidence that post-use ring analysis can contribute to the assessment of adherence to ring use. Limitations of this method include the potential of intra-participant and inter-participant variability and uncertainty associated with measuring the low amount of dapivirine actually released relative to the drug load. Therefore, residual drug levels should not serve as the only direct measurement for microbicide adherence in vaginal ring clinical trials but should preferably be used as part of a multi-pronged approach towards understanding and assessing adherence to vaginal ring use.

Pharmacodynamic correlations using fresh and cryopreserved tissue following use of vaginal rings containing dapivirine and/or maraviroc in a randomized, placebo controlled trial.

BACKGROUND: The ex vivo challenge assay is a bio-indicator of drug efficacy and was utilized in this randomized, placebo controlled trial as one of the exploratory endpoints. Fresh and cryopreserved tissues were evaluated for human immunodeficiency virus (HIV) infection and pharmacokinetic (PK)/pharmacodynamic (PD) relationships. METHODS: HIV-negative women used vaginal rings containing 25 mg dapivirine (DPV)/100 mg maraviroc (MVC) (n = 12), DPV only (n = 12), MVC only (n = 12), or placebo (n = 12) for 28 days. Blood plasma, cervicovaginal fluid (CVF), and cervical biopsies were collected for drug quantification and the ex vivo challenge assay; half (fresh) were exposed immediately to HIV while the other half were cryopreserved, thawed, then exposed to HIV. HIV replication was monitored by p24 enzyme-linked immunosorbent assay from culture supernatant. Data were log-transformed and analyzed by linear least squared regression, nonlinear Emax dose-response model and Satterthwaite t test. RESULTS: HIV replication was greater in fresh compared to cryopreserved tissue (P = 0.04). DPV was detected in all compartments, while MVC was consistently detected only in CVF. Significant negative correlations between p24 and DPV levels were observed in fresh cervical tissue (P = 0.01) and CVF (P = 0.03), but not plasma. CVF MVC levels showed a significant negative correlation with p24 levels (P = 0.03); drug levels in plasma and tissue were not correlated with HIV suppression. p24 levels from cryopreserved tissue did not correlate to either drug from any compartment. CONCLUSION: Fresh tissue replicated HIV to greater levels and defined PK/PD relationships while cryopreserved tissue did not. The ex vivo challenge assay using fresh tissue could prioritize drugs being considered for HIV prevention.