Persistent use of HIV prevention methods can be a challenge, particularly for some younger women. The long-acting, discreet, woman-centric dapivirine vaginal ring offers promise as a prevention ...method with less user burden, which could support continued use. We assessed dapivirine vaginal ring use to understand adherence patterns and identify characteristics influencing patterns.
Participants enrolled in South Africa in the MTN-020/ASPIRE randomized placebo-controlled trial.
We used group-based trajectory modeling to identify clusters of participants with similar longitudinal patterns of adherence in the last year of participation and potential predictors of group membership. Women with at least 1 year of follow-up were included (n = 626).
Five adherence patterns were identified: (1) consistently high, 34%, (2) consistently moderate, 34%, (3) consistently low, 16%, (4) decreasing, 9%, and (5) increasing, 7%. Women younger than 22 years adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI): 1.0 to 3.0, using an intrauterine device (AOR 3.3, 95% CI: 1.4 to 7.8) or oral contraceptives (AOR 3.9, 95% CI: 1.7 to 8.9), experiencing menses (AOR 1.8, 95% CI: 1.1 to 3.0), and who reported inconsistent condom use (AOR 1.8, 95% CI: 1.0 to 3.3) were more likely to be classified as consistently low compared to consistently high (referent).
Most South African women successfully persisted with a moderate or high level of use. Encouraging ring replacement with completion of menses may help to decrease concerns about hygiene and improve persistence. Associations between contraception and persistent low adherence suggest efforts may be needed to ensure contraceptive method choice does not interfere with ring use.
Given challenges with adherence to existing HIV prevention products, the development of an extended duration vaginal ring could improve adherence while reducing patient and provider burden. ...Additionally, women have other interlinked sexual health concerns such as unintended pregnancy. We evaluated acceptability of a 90-day ring to prevent HIV and hypothetical preferences for a dual (HIV and contraceptive) indication. This was a secondary analysis of a Phase 1, two-arm, multi-site, placebo-controlled randomized trial evaluating safety and pharmacokinetics of a 90-day vaginal ring containing tenofovir for HIV prevention (N = 49). We used a mixed methods approach to assess quantitative data on acceptability (n = 49) and used qualitative data from a random subset to explain the quantitative findings (N = 25). The 3-month extended duration tenofovir ring was highly acceptable. Participants perceived the ring to be easy to use, comfortable and reported liking it more over time. About half felt the ring during sex but most of those participants said it bothered them only a little. Concerns about hygiene increased over the study period but were often outweighed by the benefits of an extended duration ring. Interest in a multi-purpose ring was high (77%) and even higher among those who were sexually active and had male partners. The 3-month extended duration tenofovir ring for HIV prevention was highly acceptable among women and interest in an MPT was high.
The monthly dapivirine vaginal ring has proven efficacious in reducing HIV incidence in two Phase 3 clinical trials. When considering the potential future availability of the ring to the public, key ...questions remain about the feasibility of integrating the ring as an HIV prevention intervention into women’s lives. We conducted qualitative mapping interviews (
n
= 66) among women enrolled in MTN-025/HOPE, an open-label trial conducted in Malawi, South Africa, Uganda and Zimbabwe, to examine how home environments influenced use of the dapivirine vaginal ring. Most women had secure places to store their rings including wardrobes, suitcases, and bags. The primary concerns for ring storage were potential tampering from children or rodents. Household overcrowding limited the privacy some women had which made removal and insertion of vaginal rings challenging. Despite these challenges, ring storage, insertion, and removal was feasible across social and living contexts.
Low adherence to investigational products can negatively impact study outcomes, limiting the ability to demonstrate efficacy. To continue advancing potential new HIV prevention technologies, efforts ...are needed to improve adherence among study participants. In MTN-020/ASPIRE, a phase III randomized, double-blind, placebo-controlled study of the dapivirine vaginal ring carried out across 15 sites in sub-Saharan Africa, a multifaceted approach to adherence support was implemented, including a strong focus on participant engagement activities (PEAs). In this manuscript, we describe PEAs and participant attendance, and analyze the potential impact of PEAs on ring use.
All sites implemented PEAs and submitted activity and attendance reports to the study management team throughout the study. Participant demographics were collected via case report forms. Residual dapivirine remaining in the last ring returned by each participant was used to estimate drug released from the ring, which was then adjusted for time participants had the ring to calculate probable use categorized into three levels (low/intermittent/high). Product use was connected to PEA attendance using participant identification numbers. We used multivariate Poisson regression with robust standard errors to explore differences in ring use between PEA attendance groups and reviewed qualitative reports for illustrative quotes highlighting participant experiences with PEAs.
2312 of 2629 study participants attended at least one of 389 PEAs conducted across sites. Participant country and partner knowledge of study participation were most strongly associated with PEA attendance (p < 0.005) with age, education, and income status also associated with event attendance (p < 0.05). When controlling for these variables, participants who attended at least one event were more likely to return a last ring showing at least some use (RR = 1.40) than those who never attended an event. There was a stronger correlation between a last returned ring showing use and participant attendance at multiple events (RR = 1.52).
Our analysis supports the growing body of work illustrating the importance of meaningfully engaging research participants to achieve study success and aligns with other analyses of adherence support efforts during ASPIRE. While causation between PEA attendance and product use cannot be established, residual drug levels in returned rings strongly correlated with participant attendance at PEAs, and the benefits of incorporating PEAs should be considered when designing future studies of investigational products.
Introduction
Tenofovir‐based oral pre‐exposure prophylaxis is currently approved for HIV prevention; however, adherence in women has been low. A vaginal gel containing tenofovir (TFV) demonstrated ...partial protection to HIV but protection was not confirmed in additional studies. Vaginal rings offer user‐controlled long‐acting HIV prevention that could overcome adherence and protection challenges. TFV may also help prevent herpes simplex virus type 2 acquisition when delivered intravaginally. We evaluated the pharmacokinetics, safety, adherence and acceptability of a 90‐day TFV ring.
Methods
Between January and June 2019, Microbicide Trials Network (MTN)‐038 enrolled 49 HIV‐negative participants into a phase 1, randomized (2:1) trial comparing a 90‐day ring containing 1.4 grams (g) TFV to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid and cervical tissue, and TFV‐diphosphate (TFV‐DP) in cervical tissue. Used rings were analysed for residual TFV. Safety was assessed by adverse events (AEs); acceptability and adherence by self‐report.
Results
Mean age was 29.5; 46 identified as cisgender‐female and three gender non‐conforming. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs in the TFV versus placebo arms (p = 0.41); no grade ≥3 AEs were reported. Geometric mean TFV concentrations increased through day 34 in CVF/rectal fluid and day 59 in plasma, but declined across compartments by day 91. Geometric mean TFV‐DP tissue concentrations exceeded the 1000 fmol/mg target through day 56, but fell to 456 fmol/mg at day 91. Among 32 rings returned at the end of the study, 13 had no or low (<0.1 g) residual TFV. Residual TFV did not differ by socio‐demographics, sexual activity, Nugent Score or vaginal microbiota. Most participants reported being fully adherent to ring use: 85% and 81% in the TFV and placebo arms, respectively (p = 1.00). A majority of participants reported liking the ring (median 8 on a 10‐point Likert scale) and reported a high likelihood of using the ring in the future, if effective (median 9).
Conclusions
The 90‐day TFV ring was well‐tolerated, acceptable and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use.
Vaginal rings address a critical need for an independently initiated, long-acting HIV prevention method, but their design must be acceptable to promote uptake and adherence. Human-centered design ...(HCD) may help address design preference questions. In two Phase I studies of vaginal rings for HIV prevention conducted in the United States, we used qualitative interviews to assess participants' perceptions and opinions of the physical characteristics of the ring they used and of a ring's physical characteristics after comparing four ring designs presented via a visual tool. Users were found to prefer ring designs that appear easy to use, are physically comfortable, that function well, and are aesthetically pleasing. The parameters for these features varied widely. Product developers and marketers should consider marketing messages in which the target users feel this product is made to meet their needs and desires. Product developers are encouraged to design using HCD early in ring development (Clinical Trial Registration number: NCT03234400 and NCT03670355).
This study examines qualitative acceptability of the dapivirine vaginal ring (DVR) and oral daily pre-exposure prophylaxis (PrEP) among breastfeeding persons participating in Microbicide Trials ...Network 043/B-PROTECTED, a phase 3B safety and drug detectability study of DVR and oral PrEP in breastfeeding. A subsample of 52 participants were purposively sampled to participate in an in-depth interview (IDI). Breastfeeding participants found both study products to be acceptable, and easy to use. A common motivation for product use was to protect the baby from HIV, although participants’ understanding of how the study drug would work to protect their babies was often unclear. While most participants did not report experiencing side effects, fears about side effects were common as both initial worries about how the study products would affect their health and the health of their baby, and increased anxiety that health issues experienced by them, or their baby were from the products.
Depression is associated with lower adherence to oral pre-exposure prophylaxis (PrEP) to prevent HIV, but data are not currently available on how depression may affect use of other HIV prevention ...methods including the dapivirine vaginal ring (DVR). We conducted a mixed methods study using data from the Microbicide Trials Network (MTN) 042/DELIVER (
n
= 558) and MTN-043/B-PROTECTED (
n
= 197) studies to describe the prevalence of depressive symptoms and explore how depressive symptoms may have influenced attitudes about use of the monthly DVR and once-daily oral PrEP tablet among pregnant and breastfeeding persons, respectively, in Malawi, South Africa, Uganda, and Zimbabwe. Eleven participants had high Edinburgh Postnatal Depression scores ≥ 10 in MTN-042/DELIVER (2%) and four participants (2%) in MTN-043/B-PROTECTED. In interviews with 9 participants who had high scores (6 DVR, 3 oral PrEP), those with depressive symptoms described overlapping stressors which were magnified by job loss and economic instability during the COVID-19 pandemic, and by experiences of pregnancy/postpartum. These participants experienced a lack of support from partners or family members, and conflict with partners related to trust, and infidelity. While we did not find evidence of a change in product adherence, there was a strong sense of commitment and motivation to use the study products for protection from HIV for participants themselves and their baby. Although lack of social support is usually an obstacle to adherence, in this study, the participants’ lives and relationships seemed to have reinforced the need for HIV prevention and motivated women to protect themselves and their babies from HIV.
BACKGROUND:Monthly use of the dapivirine vaginal ring has been shown to be safe and effective for HIV-1 prevention in nonpregnant reproductive-aged women. The impact of dapivirine on pregnancy ...outcomes and infant is not known. We compared pregnancy incidence and outcomes by study arm among HIV-1–uninfected women who became pregnant while participating in MTN-020/ASPIRE.
METHODS:ASPIRE was a randomized, double-blind, placebo-controlled phase III safety and effectiveness study of the dapivirine ring for HIV-1 prevention. Sexually active women aged 18–45 years from Malawi, South Africa, Uganda, and Zimbabwe were enrolled. Urine pregnancy tests were performed monthly, and, if positive, study product was withheld during pregnancy and breastfeeding. Pregnancy-related outcomes included the followingpregnancy incidence, pregnancy outcomes (live birth, preterm birth, pregnancy loss, and congenital anomalies), and infant growth.
RESULTS:Of 2629 women enrolled in ASPIRE, 169 became pregnant during follow-up, resulting in 179 incident pregnancies and 181 pregnancy outcomes. No difference in pregnancy incidence by study arm was observed (hazard ratio = 0.93; 95% confidence interval0.68 to 1.26). The distribution of pregnancy outcomes was similar by study arm, and no difference was noted in the frequency or pattern of congenital anomalies or infant growth parameters by study arm.
CONCLUSIONS:Dapivirine use in the periconception period does not seem to be associated with adverse effects on pregnancy or infant outcomes. Our findings provide support for additional safety studies of the dapivirine ring throughout pregnancy.
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.).
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